Exhibit (complaint, Ex. 11) — Apter v. HHS

Record facts

U.S. District Court for the Southern District of Texas (Galveston Division) · No. 3:22-cv-00184 · Doc. 1-11 · 2022-06-02 · Docket on CourtListener

Full text

Exhibit 11
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 1 of 382

CENTER FOR DRUG EVALUATION AND RESEARCH
APPROVAL PACKAGE for:
APPLICATION NUMBER:    050742         
TRADE NAME:   Mectizan     
GENERIC NAME:        Ivermectin  
SPONSOR: Merck Research Laboratories          
APPROVAL DATE: 11/22/96 
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 2 of 382

*SI..8L,,
~.
*4
%,
.~=
~
DEPARTMENT
OF HEALTH
& HUMAN
SERVICES
:
Public
Heaw
Sewice
,%*+‘* >%,,.
Food and Drug Administration
Rockville
MD
20W7
.
NDA 50-742
Kenneth R. Brown, M.D.
Exetxtive
Director
Worldwide Regulatory
Liaison
Biologics/Vaccines
Merck & Co., Inc
West Poin~ PA 19486-0004
NOV22
19%
Dear Dr. Brown:
Reference is made to your March
29, 1996 new drug application
(NDA) and your resubmission
dated October 15, 1996, submitted under section 507 of the Federal Food, Drug, and Cosmetic
Act
for Tablet STROMECTOL@
(ivexmectin) 6-mg.
We acknowledge receipt of your amendments
dated April 16, June 28, July 9,
16, 22,
and 31,
August 23, and 28, and October 4, 1996.
This new drug application
provides
for the treatment
of strongyloidiasis
and onchocerciasis.
We have completed the review of this application,
including the submitted draft labeling, and have
concluded
that adequate
information
has been presented
to demonstrate
that the drug product
is
safe and effective
for use as recommended
in the enclosed
draft
labeling.
Accordingly,
the
application
is approved
effective
on the date of this letter.
The fml
printed labeling (FPL) must be identical to the enclosed draft labeling.
Marketing
the
product with FPL that is not identical to this draft labeling may render the product misbranded
and
an unapproved
new drug.
Please submit sixteen copies of the FPL as soon as it is available,
in no case more than 30 days
after it is printed.
Please individually
mount ten of the copies on heavy weight paper or similar
material.
For administrative
purposes
this submission
should be desigmted
“FINAL
P~TED
LABELING”
for approved
NDA 50-742.
Approval
of this submission
by FDA is not required
before the labeling is used.
..
Should additional information
relating to the safety and effectiveness of the drug become available,
revision of that labeling may be required.
In addition, please submit three copies of the introductory
promotional
material
that you propose
to use for this product.
All proposed
materials should be submitted in draft or mock-up form, not
final print.
Please submit one copy to the Division of Anti-Infective
Drug Products and two copies
of both the promotioml
material
and the package insert directly to:
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 3 of 382

Page
2
.
Food and Drug Administration
Division
of Drug
Marketing,
Advertising
and Communications,
HFD-40
5600 Fishers
Lane
Rockville,
Maryland
20857
Validation of the regulatory
methods has not been completed.
At the present time, it is the policy
of the Center not to withhold
approval
because the methods are being validated.
Nevertheless,
we expect your continued
cooperation
to resolve any problems
that may be identified.
Please submit one market package of the drug when it is available.
We remind you that you must comply with the requirements
for an approved NDA set forth under
21 CFR 314.80 and 314.81.
If you have any questions,
please
contact:
Ms. Pauline
Fogarty
Regulatory
Health
Project
Manager
(301)
827-2125
Sincerely
yours,
-.
.-
w~fq—?
David
W. Feigal,
Jr.,
.D., M.P.H.
Acting
Director
OffIce of Drug Evaluation
IV
Center
for Drug Evaluation
and Research
ENCLOSURE
,“
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.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 5 of 382

Applicant:
Date of submission:
CDER stamp date:
MEDICAL
OFFICER REVIEW OF NDA
NDA 50-742
Merck Research Laboratories
Sumneytown
Pike
West PoinL PA 19486
Contact:
Kenneth Brow
MD
Executive Director, Regulatory
Affh.irs
(610) 397-2552
29 March 1996
1 April 1996
Date review completed:
23 September
1996
Drug identification:
Generic name:
Ivermectin
Proposed trade name:
Stromectol@
Molecular formulae:
Cq8H7d01g(component
HzB1~
C,THnO1d (component
HzB,~)
Molecular weights:
875.10 (component
H2B1J
861.07 (component
HzB1~)
Chemical name:
5-O-demethyl-22,23
dihydroavennectin
A1,;22,23-dihydroavennectin
B1,/5-Odemetiyl-25de(metiylpropyl)-22,23dfiy&o-25-(l
-methylethyl)
avermectin
A1~;22,23-dihydroavennectin
B1~
structural
formula
H,
H
H,
Ii
canjmentE&R - C%
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 6 of 382

Iverrnectin
in the treatment
of Strongyloidiasis
1
2.
3.
4.
The disease
a. Life cycle
b. Clinical manifestations
c. Therapy
OVerviewof studies submitted in support of indication
study
004 (Gentiiini)
a
Study ~
b. Deviations from protocol
c. AppIicant’sfindings
d MO findings
e. Conclusions
Study020 (Dreyer)
a. Study summary
b. Deviations from protocol
c. Applicant’s fidings
d. MO findings
e. Conclusions
5. Studies O14(Berk) and O16(GamI)
a. Study summary
b. Deviations from protowl
c. AppIieant’s findings
d MO iiidings
e. COnchsions
. .
6. WI-10 Study” (Mar@
a. Study summary
b. Applicaut’s tidings
c. MO findings
d. Conehu$ions
7. Submitted literaturcj including Naquira study
a Study summq
c- Applicant’s findings
d MO fhdings
e. COxleluskma
8. Statistical considerations
9. overall conclusions
10. Recommendations
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 7 of 382

NDA 50-742
Page 2
Me&an”
(Ivennectin)
Introduction
Pharmacologic
category:
averrnectin antiparasitic
Dosage form:
6-mg scored tablets
Route of administration
oral
Proposed INDICATIONS
AND USAGE section
Proposed DOSAGE AND ADMINISTRATION
section:
/
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 8 of 382

NDA 50-742
Page 3
Mcctizm* (Ivernwlin)
lntrodudion
Materials reviewed:
1. NDA 50-742, volume
1.1 and volumes
1.15-1.27
2. Additional
information
submitted
9 JuIy 1996. 34 volumes. (included all information
previously
submitted
as a Marketing
Authorisation
Application
w]
to the French
regulatory authority)
3. Safety Update report submitted31
July 1996.
1 volume.
.,,”
.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 9 of 382

NDA SO-742
l’agc1
Mcclti”
(lvmncdin)
Stiongyioid&iS
1. The disease
A. Life eyclc:
Srvngyfoidcs
stemoralis
(heretofm refh
to as SS) is a nematodeparatite of UKclam Phasmidia,
which also inchxles such humsn parasites as the hookworms (Aneylostoma
and Neeator), Tn”choM-ong@s,
and
Angiosmmg.vlus.
These psrasites aIl develop from the egg stagq through f-
awecssive Iamal stages, tbcn finally
mature to the adultstwe. SS has a lifeeyelewhichis uniqueamongall humanhelminthparasitesin that it has a free-
living phase of the Iife-qcle and ean al~ continually reinfd
the s&e W
The eornplete SS life cycle is demonstrated in the followingdiagrsm:
..
----
...
.
..-- ...
. —- .. .
LIFE
CYCLE
OF STRONGYLOIDES
.
!. PARASITIC
$TAGESA~
IN
TRANSIT
THROUGH
AND IN
THE
LUNGS
* I
,
‘[
TRACT
(ESPECIALLY
“n
IINTERNAL{ROUW
m LUNC
@A~hk
Q(WTli
OR
WITHOUT d) ENTERS
MUCOSAAND bEpOSfTS
fwso
WH!CH HATCHAND
ES-
INTO INTESTINE.
11+~ I[)PASS boWN AND
ARk tvAcuAt
ED, OR(2)
TRANSFORM INTO FILAR
lR)Rti LARVAE AND
I
UNbEFl OPTIMUM
cOt4tNtfOt4SINTHE
so IL FREE -LIVN.lG
DEVELOPMENT
t.AAY CONTINUE
[NDEFIN
ITEt_Y
II%I%%M:A
I
I
t
?-
METMODS OF (NWCTION
i. HLAfIttoRM LAtiAE ENTER SKIN IN CONTACT
ww
SOIL
A. FoLLoWING
OIRECT
nH‘F
LARVAL
DEVELOPMENT
6. FoLLoWINGFREE-LIvING
CYCLE
N-4THE
SO(L
2.F{LARtFORM
LARvAE
DEVELOP
t3EFoRE
LEAVING
PATIENT
A. FoLLOwI~JG
DEPosI
moN
ON T HE SOIL,ENTER
EXPOSED sttm
B. ENTER
PER(ANAL
SKtN
AND lNlmATE
AUTOINFECTION
C
ENTER
INTESTIIJAL
MUCOSA,
MIGRATE
TO LUNG
AND
INITIATE
AUTO IWECTION
(.::.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 10 of 382

NDA 50-742
Page 3
M&”
(iwmuxiin)
Slrongyloidiasis
.
The following aspecls of the life cycle are relevant to clinical trial design:
.
Theusualmodeof tnmsmkion iaviapemutaneouspenetrationbyaninfectivethird-stagelarva. Oncethis
occurs,thepre-patent period (i.e., the time h
initial infection to detection of SS larvae in the stool) is
roughly 28 days. Therefbre, ifpaticuts are treated for this inf’on
but then return to a potentiall@fkclious
environment follow-up stool examinations beyond that time point will not be able to distinguish relapse of the
original inkction (i.e., drug fdure) fi-omm-infection.
.
lk
adult fde
is not nearly as prodigious as most of her nematode relatives. It is estimated that the daily egg
output of a mature female SS is approximately 30 eggs per day. (Comparatively, an aduh Asearis
Iumbricoides fernalelaysapproximately 200,000 eggs per day.) As a resuk detection of SS larvae in the stool
of an infected patient requkes concentration methods. The most sensitive method for direct parasite dekcl.ion
is the Baermann technique, m which a relatively large stool qxcimen can be processedsuchthatthe larvaeof
SS. if press% will migrate out of the specimen This technique was reportedly udlized for all parasitologic
specimens processed in the trials submittcxiby the applicant fbr this indication.
.
%c.ause of this low-level shedding of larvae in the stool of the ho% the definition of ‘cure’ should be based on
more than a single negative stool examination. There does no+ however, appear to be a umensus
in the
literature as to how many consecutive negative stools shotdd be requira
and over what period of time post-
therapy they should be checked.
.
Infection may persist for years, due to the internal autoreirdkction aspect of the life cycle. Larvae hatched in the
host intestine may undergo accelerated development into infective third-singe lame while still in the intestinal
lumen. These infective larvae then penetrate the gut epitheliumsor @anal
skim enter the host circulati~
and
repeat the pulmonary + trachea+ gastrointestinal migration which results in the continued presence of
sexuaIlymature, parthenogenic finale worms. Elderly adult veterans of the Second World War, particularly
those who were prisoners of war in the Pacific theatre of operations, have been diagnosed with strongyloidiasis
30+ years after their initial exposure.
.
Strongyloidiasis can become disseminated if the host becomes immunocompromised. The medical literature
documents cases in which quiesent infectionsdkerninate when the host is given immunosuppressive
chemotherapy. The advent of the HIV epidemic has brought about an increased number of cases of
disseminated Strongyloidiasisin those geographic areas in which the two&eases
are both p-t.
Disseminated disease is notoriously difficult to indicate via anthelminthic therapy alone.
B. Clinical mmifkstations
In general the severity of clinical symptoms is related to the intensity of the infection Law-level infections can
be rehtivdy asymptomadc. Heavy i.nfkdona, pSrtiClddy when di
“ qcanbefatal-
The tiected patientcanmmifeatsymptomswhichcomqond tothemigrationoftheparasite. Initial
_m&ti~wtixrntiti
*-_kem@-@Wti&Wldti~b-
h&@ion.b*lm=amti~M-tim
*a~@~P-*fi=**
migrate intotheahecdi.
‘fhiapmeeaamayrestdt
ineagk~~b~
onia-like puhmnmy
symptoms.
FolIowinganival intheqpta ofthesmallma
f-e
worms rapidly ~
and invade the tissues ofthewfi
.
~fd=mvetiat~f-at
hb=oftietimhtidq~
~-e~=tiqp-
Theseeggspromptly hatch and the first-stage (rhabditiform) lamae burrow towards the intestinal lumen In light
infections,intestinal symptoms may be mild. In heavy infections, the mucosa may be honeycombed by the adult worms
““
and lamae, and sloughing of extensive patches may occur. Watery, mucous and blood-laden diarrhea can result- The
patient may experience various de~ees of abdominal pain with alternating bouts of diarrhea and constipation
Secondaq bacterial infectio~ including bacteriid sepsis, may result from such massive compromise of the intestinal
epitheliums.Leukocytosisand msinophilia are.common features of this illness. Cutaneous mani$sstations,particularly
urticaria and Iama currens (similar to larva migrans but more rapid in evolution) may also be seen.
In disseminated disease, a variety of clincial manifestationsmay result from the migration of the SS larvae.
Pulrnomuyinfikatcs and progressive respiratory compromise can result, ~~lhichwill progress despi[e the initiation of
empiric antibac(e~ialtherapy. Central nervous syslem involvement has also been described
(FIB:in this NDA,
the
appllcmf is not swking a disseminated strongyloidiasis indics[ion.)
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 11 of 382

NDASO-742
Page 4
Medizan” (Ivcrmxtin)
Swcmgyloidimis
C. Therapy
CurrcntJy,there is one FDA-approved agent for the treatment of strorgyloidiasis: thiabendazole (Minte.@
Merck). This agent was approved for this indication in 1966 and remains the maimtay of therapy for this disease in the
US. The approval of this indication was based on a total of i03 patients with strongyioidiasis treated by investigators in
the United States, with a reported 89?? cure rate, and an additional 2% -of
stron~loidiasis submitted-liom
internationalclinical studies, with a reported cure rate of 99% (M. Albueme, Medical Officer review of NDAs 16~%
and 16-097, dated 26 January 1%7). These studies were presumably open-label and noncomparative, as there was no
accepted,reasonably efficacioustherapy for strongyloidiasis at that time. (Unfortunately, the nature of the trial desigo of
the various studies submitted in support of this application is not discussed inDr. Albuerne’s review.)
Although thiabendazole is the only currently-approved drug for this indication the precise mechanism of its
anti-strongyloidcsactivity is unclear. According to Grove in his reference textbook Sronmdoidiasis: A maior
roundwoxminfection of man (Londom TayIor& Francis, 1989):
When the actions of thiabendazole on the various phases of infkctionwith S. ruffi in mice were investigate@the
drug was found to have little effect on migrating larvae, nor did it eradicate adult worms from the intestinal
tract. Excretion of eggs in the fames was markedly reduced, howevw, this was shown to be due to impaimncnt
by thiabendazole of the fkcundityof parasitic females in the gut. Thiabendazole had no efkct on S. stercorak
filariform larvae in the muscles of mice...
These findings suggest that thiabendazole cannot be relied upon in treatment. It appears to be inactive against
both migrating larvae and intest.imdadult worms. its apparent effkacy being due to a marked reduction in the
fecundityof parasitic finale adult worms. It is possible, however, that this action reduees considerably the
intensity of infection. (Page 205-6)
On the other hand, there is evidence from animal studies that ivermectin has better Iamicidal activity. In the chapter
discussing the rat model of strongyloidiasis (which involves a difkrent species, Sfrongyloides
rutt~~,the above-
ref~eneed text discusses the anthehninthic activity of the avcrmedns:
Avcnnectin BI act$by p*aIyzing worms and permitting host responses to remove the parasite. Paralysis of the
worms occurs when avermectin B, stimulates the pre-synaptic release of gamma aminobutyric acid which
blocks the postqnaptic
transmission of nerve impulses. Averrnectin was found to be efYkctNeagainst S. rutti
and totally suppressed the fecal larval excretion. Avermectk acted on tissue migrating huwaeand completely
prevented the appearance of S. ratti in the d
intestine. (Grove, op. cit. atpage 325)
At presentj thiabadazole appears to retain its activity against this parasitq drug resistance does not appear to
be a aiginificantproblem- Tolerability, on the other Ix@ does appear to be au issuq epigastric &tress, diarrh%
nausea,vomiting, dizziness and Weakss
am common thiatnmdazole-related adveme drug efkcts.
The Minted
producl label calls fix a dose of approximately22m@&givm
BID fortwocxmseah .ve days. (Note that the
thiabdazole
regimens in the atudieadetailed below are threeday reginms.
IvfaqIparasitic disease exper@ including
the WHO,recommend a threeday thiabendazole reginxm fm the treatment ofintestinal strongyloidiasis.)
Gastroiitcstinal side-effects are sometimes severe eaough to interfere with patient cxxnpliancewith this regimen.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 12 of 382

~DA 50.742
Page 5
Mcclizmm(IvamcUin)
St ongyloidiasis
2. Overview of studies submitted in support of this indication.
The applimnt has submitted five clinical studies in support of this indication.
T
t
T
D20/Brazil
Dreyer
Ivermecin
arms
single dose
single dose
QDX2
single dose
QDX2
singledose
QDX2
Comparator
albendazole
BIDX3
days
thiabendazolc
BIDX3
days
thiabendazolc
BIDX3
days
thiabendazolc
BIDX3
days
albendazole
BIDX3
days
Study I
Patknt-
design
kvd data
submitted?
I
open label
Yes
random
I
open label
yes
random
open label
yes
random
-h
open label
yes
random
open label
no
random
I
Cmsiderd I
iiunber
‘@VOtd’ by
randomized
applicmt?
Yes
ABz
27
IwX1
29
no.
I
Ivcrxl
4
IverX2
6
Thiabas 6
no
Iverxl
17
IwX2
17
-rhiabal 15
yes
m
209
k? x I 208
-.
As can be seen above. of the two studies considered ‘pivotal’ by the applicanL
only one has patient-level data submitted
with the NDA This was&cussed
with the applican~at the ~e
of ~eFileability-dctermina‘tioI.Land the applicant
agreed to attempt to recover some of these data.
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NDA 50-742
Page 6
Mcclizan*~VCMS@iIS)
Stmngyloidi=is
.
3. Study004 (Gentilini): An open, randomized studyof dkq,
safety,and tolerability of ivermectin single dose vs.
albendazde (threeday course) in the &eatmentof patients infected with S&ongyloides sfexoralis.
A Study ~:
lle foI1owingmmmmrkm
this study (t.akmibmpages
D-2148-57, volume 1.21 of NDA):
—
-.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 14 of 382

MK-0933
Prot. No. 004
Prof Gentilini
(f’.7-
-3-
.
11.
SUMMARY
OF PROTOCOL
AND
STUDY
PROCEDURES
B.
c.
D.
Protection of Human Suhiects
This study was conducted
in conformance
with applicable country
or local
requirements regarding ethical committee review, informed consen~ and other
statutes or regulations regarding the protection
of the rights and welfare of
human subjects participating in biomedical research.
Investi~atm-s
Prof Marc Gentilini, M.D./Annick Datry, M.D.
Deparment De Medecine Tropical*Parasitologie
Hopital De La Salpetriere
43 BD de 1’Hopital
75013 Paris, France
Ohiective
To study the efficacy, safety, and tolerability of ivermectin vs.
treatment of patients infected with Strongyloides stercora!is.
Patient
SeIection
Approximately 50 patients were entered into this study.
Patient Inclusions
1.
2.
3.
Patients infk.ctedwith Strongyloides stercoralis.
Patients were between 5 and 70 years of age.
albendazole in the
An examination of the stool done 6 days or less before entry into the study
was positive for Strongyloides stercoraIis latvae or duodenal aspirates or
jejunal biopsies were positive for the larvae.
.,
MK-0933U3C869
DOC
07FE1396
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MK-0933
Prot. No. 004
Prof. Gentilini
D.,
-4-
Patient Selection (Cont.)
Patient Exclusions
1,
2.
3.
4.
5.
6.
7.
Age under 5 or over 70 years.
Women of childbearing potential.
Medical histo~ of mental illness, seizure, or other serious illnesses.
D–
2149
@-a
SGOT or SGPT greater than twice the upper normal limit, creatinine greater
than 2.0 mgll 00 rnL or grossly abnormal BUN or urine analysis.
An abnormal ECG or history of an abnormal EEG.
Moderate or severe anemia, i.e., hemoglobin less than 10 g or hematocrit less
than 30%; any abnormality of white blood cell count and/or differential
(except eosinophilia).
Any past or concurrent
medical illness which the investigator
felt might
influence either the outcome
of the study or interpretation
of the data
accrued.
E. Study Design
General Description
This study was an opeq randomized study of the efficacy, safkty, and tolerabiliq
of a single ivermectin dose vs. albendazole
for 3 days in the treatment
of
ambulatory patients who have an infection with Szron@oides stercorah.
Although the study was open in design, stool specimens were examined by one
single expat
who was to remain blinded as to the treatment allocations.
MK41933LBC869.DOC
07FEB96
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lJ–
215U
MK-0933
Prot. No. 004
Prof. Gentilini
6’
.5
E
-5-
Study Design (Con&)
Patients who satisfied all inclusion
titeria
(except as noted in section LI.LB.2)
and none of the exclusion criteria specified above were randomly allocated to
receive either a single dose of ivermectin
(target
dose of 200 mcg/kg)
or
albendazole (200 mg b.i.d. for 3 days). It should be noted that the actual dose of
ivermectin administered to patients in this study was approximately
170 mcg/kg
(medkn
169 mcgilcg).
The reason for this was that the dosage schedule (i.e.,
combinations
of ivermectin
6-mg tablets
by body weight)
included
in the
protocol for the study was in error.
The difference between the administered
dose and the target dose is not considered meaningful [8].
The efficacy and stiety
of iverrnectin was evaluated on the basis of physical
examinations and laboratory tests prior to treatment and on Days 7 (5 to 9), 30
(26 to 34), and 90 (85 to 95) posttreatment.
In the event that mild or moderate reactions to drug treatment
occwed,
they
could be treated with aspirin and antihistamines; other medications were not to
be administered during the first week of drug administration except for necessary
treatment of patients with severe aIlergic reactions.
Although not required by the protocol, patients remained in France throughout
the study period, thus eliminating the confounding variable of reinfection.
Patient Allocation
After completion
of the infoxmed consent
procedures
and documentation
of
strongyloidiasis
evidenced by stool examinatio~
patients were randomized to
receive either ivermectin or albendazole according to an allocation
schedule.
The patients were dosed at least 2 hours before breakt%st.
During the week prior to the study, the patient was screened to assure that
hehhe was in good physical condition.
The patient had a physical examination
and a laboratory screen.
Vital signs were recorded on Day -1 (the day before
drug administration).
MK-0933U3C869
MC
07FEB96
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MK-0933
Prot. No.
004
Prof Gentilini
E
-6-
Studv Design (Cent+)
Treatment
Ivermectin wasprovided
as6-mgcommercial
tabIets.
Thedose
closest to that
calculated on the basis of body weight was utilized. A schedule of recommended
combinations of these tablets for patients who weigh between 15 and 84 kg is
shown in the following tab!e (Table 1).
Table 1
Ivennectin Dosage Recommended Tablet Combimtions
Based on Patient Body Weight
Patient Body
Weight (kg)
Tablets (6 mg)
15t025
‘/2
26 to 44
1
45 to 64
1%
65 to 84
2
Albendazole
was” provided
as 200-mg tablets.
Each
patient
in this group
received two tablets each day for 3 days for a total of 6 tablets.
Failure to respond to therapy could be determined in 5 to 9 days, and although
there were no provisions in the protocol for the retreatment of treatment fidlures,
the investigator did retreat all treatment failures as follows:
.
Ivermectin-treated
patients who t%.iledwere treated with two doses of the
same ivermectin dose as previously administered 24 hours apaxt.
.
Albendazole-treated
patients who failed were treated with a single dose of
iverrnectin in accordance with their body weight (Table 1).
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D–
2152
MK-0933
Prot. No. 004
Prof Gentilini
-7-
F. ~inical
Observations
and Laboratow
Measurement
The patient was evaluated medkally for suitability for the study.
Based on =WS
and symptoms of disease, the investigator categorized the patient’s clinical illness
as mild, moderate, or severe.
Categorizing the patient’s severity of illness was
not formally required by the protoml; however, such art evaluation is in keeping
with the exercise of good clinical judgment in comparing patients in this clinical
setting.
Table 2 shows the schedule of clinical observations and laborato~
measurements
during the study.
Table 2
Schedule of Clinical Observations and Laboratory Measurements
Day 7
Day 30
Day 90
Prcstudy
J
2
3
(5 to 9)
(26 to 34)
(85 to 95)
Drug Administration
x
or
x
x
x
Physical Examination
x
x
x
x
x
Vital Signs
-
x
x
x
LabolatoIy Saf@y
x
x
StoolExamination
x
x
x
x
HOphili.a+
x
x
x
x
+This t~
@,
hypcmsinophilia)
was not a specificprotml
r~~ent
nor ~
the ~o~tion
made part of a MFtL analysis.
However, the information was part of a sub-protocol at the
~
“
site and
Itcdbyt.hc investigative tcm[ll].
6’-11
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D–
2153
MK-0933 Prot. No. 004
Prof Gentilini
F.
.
-8-
Clinical Obsemations
and Laboratory Measurements (Cont.)
Obsewations” and measurements
relating to efficacy and safety are desc~ed
below:
Eflicacv Measurements
Baseline evaluation of Strongyloides stercoralis was to be established in each
patient prior to study drug administration.
Although
the
protocol
allowed
duodenal
or jejunal
biopsies
for the determination
of S. stercoralis,
only
examination of stool samples by the Baermann technique [10] was used in the
study.
All stool specimens were examined by one single expert who was to
remain blinded as to the treatment allocations.
Although the protocol allowed for severrd diagnostic examinations for detection
and quantification of S. stercoralis in stools, parasitological
cure, the primary
measure
of
efficacy,
was
assessed
using
three
repeated
Baerrnann
stool
examinations during each of the three follow-up periods on (Days 5 to 9, 26 to
34, and 85 to 95).
The Baermann technique [1O] is a method examining a stool specimen suspected
of having small numbers of Strongyloides larvae and uses the modified Baermann
apparatus.
The technique is dependent on the migration of active larvae out of
the fecal material, through a wire gauze covered with gauze padding and into
water, where they settle out. The procedure is as follows:
a. Fti a fimneI (6-inch) with water (attach rubber tubing with a pinch clamp to
the bottom of the finnel) and place the wire gauze, one or two layers of gauze
padding on it, on the finnel.
b. Place 100 g (or other weighed amount) of fecal material on the gauze padding
so that it is covered with water.
C. Mow
the apparatus to stand for 2 or more hours, draw OR 10 fi
Offluid bY
.
releasing the pinch clamp, spin it down in a centrifuge and examine the
sediment with a magnifier or low power microscope to count and confirm the
.
species of the larvae.
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D–
2154
MK-0933
Prot. No. 004
,Y-
Prof Gentilini
-----
F.
-9-
Clinical Observations
and Labomtow
Measurements (Cont.)
Because the investigator gave actual counts (number of laxvae per grn stodj
for
some of the patients and plus (+) or word designations for others, it was decided
to use the following scheme to have consistency for all patients (Table 3).
Table 3
Scheme to Translate Between Lamae Counts, Word Designations and
“PIus” Designations
Word
Larvae Counts Per
Designations
grn stool
‘Plus’ Designations
Few
1to 15
+
16t030
-H-
Many
31 to 100
+ii-
>100
The above scheme is presented only for purposes of quanti&ing the level of
itiestation
(intensity of infection) per patient and important ordy to determine
comparability of treatment groups and to examine whether there is an interaction
between
rntensity of infection and clinical outcome.
This scheme was not
specifically stated in the protocol; however, MRL believes that such an analysis
between intensity of inkction and outcome is vahd.
Since intensity of infixtion
(in addition to age, s%
race, and severity of infkction) was found to be not
related to are
rate at the CY=O.10 level of significance (see H Statistical Planning
and Analvsis) it was dropped from the statistical model, leaving only treatment
group.
....’
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t)–
2155
MK-0933 Prot. No. 004
Prof. Gentilini
F.
.
-1o-
~inical
Observations and Laboratory Measurements (Cont.)
Safetv Measurements
A complete physical examination was done during the week preceding
study
drug administration
and repeated at follow-up visit.
Prestudy and follow-up
samples for the laboratory safety studies on blood and urine included:
a.
Hematology:
Hematocrit
Hemoglobin
White blood cell count, total
Differential
counts
will be made
if WBC
is
abnormally low or high
Blood smear for malaria parasites (saved until the
foIlow-up examination is completed)
b.
Blood Chemistries:
Blood urea nitrogen
Serum creatinine
SGOT
SGPT
Total bilirubin
Alkaline phosphatase
c.
Urinalysis:
Urinalysis
was
performed
abnormal
serum
creatinine
signdsymptoms
or urinary tract infection.
,
in
patients
with
values
or
with
The investigator could carry out addtiional analyses as required by the hospital
or as indicated for optimum patient care.
Vital signs (blood pressure and pulse rate, both supine and ere@ respiration rate
and temperature) were recorded on Day-1
and therea.fier according to hospital
routine for patients who remained in the hospital.
f
1+
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D–
2156
MK-0933 Prot. No. 004
Prof Gentiliti
-11-
6’-
15
----
G. Evaluation Criteria
1. Evaluability
All patients whose data was reeeived by August 30, 1991-were classified by
the MRL clinicxd monitor
as evaluable
or unevaluable
with respect
to
efiicaq.
These evaluations by the MRL monitor, although not specified in
the protoco!, were in keeping with the dictates of the protocol (i.e., inclusion
and exclusion criteria) and the exercise of good clinical judgment.
Thus,
patients were considered evaluable for efficacy if
a.
Strongyloidiasis was documented on stool examination
b.
The patient did not receive other
effective therapy
period.
c.
The patient was compliant with therapy.
d.
Adequate
follow-up
stool
examinations
were
deterrnimtion of effie.acy.
during
the
study
performed
for
e.
There was no violation of inclusion and/or exclusion criteria that would
compromise efhcacy evaluation.
2.
E~cacY
As described earher, baseliie evaluation of Strongyloidks stercoralis was to
be established in each patient prior to study drug administration.
Although
the protocol allowed duodend
or jejunal biopsies for the determination of S.
sfercoralis, only examination of stool samples by the Baermann technique
[10] was used in the study.
AU stool speeimens were examined by one single
expert who was to remain blinded as to the treatment allocations.
...’
The primary measure of efficacy in this study was the absence of Luvae in
posttherapy Baemmn
fecal examinations.
The detection of Iawae on any
-
posttreatment
stool
examination
meant
ftilure.
patients
with ad~uate
.,.
follow-up examinations which were all negative for larvae were considered
cured.
It should be noted that
although
not specified in the protocol,
parasitological cure (i.e,, stool exams negative for larvae) without resolution
of symptoms was counted as a clinical failure.
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D–
2157
MK-0933
Prot. No
004
Prof Gentilini
G. Evaluation Criteria (Cont.)
-12-
(i’-
IL
H.
L
3.
Safety
All patients were
evaluated
for safkty by physical examination
and laboratory
studies.
In additio~
the patient was questioned daily (by phone) regarding
adverse experiences with particular attention to evidence of allergic reactions
(rasi
itching
and anaphylaxis).
Adverse experiences were described and
recorded
by the investigator
who determined
the durations,
seriousness,
seventy, and drug relationship as well as the eventual outcome
of each
adverse experience.
Statistical Planninz and Analvsis
Methods of Analvsis
The primag measurement of efficacy was the cure rate. Logistic regression was
used to
determine if any concomitant
factors, i.e., age, sex, race, severity of
infectio~ intensity of infkction, affected the cure rate. None of these factors was
related to cure rate at the a=o. 10 level of significance.
Thus, aJl were dropped
from the statistical model, leaving only treatment group.
The treatment groups
were compared using Fisher’s exact test for the proportion of patients who were
cured.
.
Baseline characteristics were analyzed using either Fisher’s exact test or the
Chi-square test of the Wdcoxon
Rank Sum test, as appropriate.
Confidence
intends
were cakx.dated using the method of Blyth and Still.
All statistical tests for treatment-group
differences were two-tailed (a=O.05).
Clinical Sumdies
Ivermectin
in the form of commerchd
tablets
(Lot 9H9476)
were
obtained
through MSD-Chiiret.
Albendazole (200 mg ZENTEL)
tablets were obtained
-
through a Iocal pharmacy in Paris.
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NDA50-742
pa~~17
Mectizan*{Ivemsectin)
Strongyioidiasis
200 mg BID X 3 a@s.
It shares similariti~
with theother submitted
studies in the NDA for this indication,
particularly in that patients
were required to have stools positive for SS by Baermann technique.
This method OJ
stool processing
was &o
usedfor
allfollowup
examinations.
The dosing ofalberuizzole
k generally
consistent
with product
labeling in those countries
w=e
ii is
approved for the treatment
of stron~loidiasis
(namely: Australia,
France, Germany, India. South Africa, and
Switzerlar@.
Those labels do, however, spec:~
that the dosing should be 400 mg daily as a single dose for three
&ys; the Gentilini stub
uti1tied200
mg BID for three abys.
It is also of note that the product
label in Germany
indicates thatin ‘severe’ infections (not otherwtie dq$ned in the labe~ the dose of albedzzole
should be 800 mg qd
for 3 days.
Labelsfiom
both Germany and India cailfor
a second corse of aibenalzrole
ifthe stools are stilipositive
~ter
14-21 alzys.
The Swtis Iabeispeciflcally
states that albendzsole
at 400 mg QDX3
@Ys is “not suitable
dosage for the therapy of immunocompromisedpatients”.
It must aLro be noted that the dosing schedule for ivermectin
used in this study deviates from that used in
all the other submitted studies in support of thti indication:
Protocoi-specified
Ivermectin
Dosing Schedules
Genti[ini stuc$
Ber~ Gann, Dreyer,
patient
wei~ht (k~l
#J?&l@
Patient wei~ht (k~l
15 to 25
E
15 to 24
26 to 44
1
25 to 35
45 to 64
1%
36 to 50
65 to 84
2
51 to 65
66 to 79
80 and over
and Marti studies
&@&Is
Z*
1
1%
2
2%
3
The net result of this discrepant
is that the patients in the Gentilini stu& were relatively
underdosed
compared
to
the other submitted
studies.
For example, a 55 kg subject enrolled in Gentilini would receive
1% tablets,
whereas
the same subject in any other s@Y
would have received 2 tablets.
This resulted in a median ivermectin
dose of 169
pg/kg in this stuc&. Sim
this discrepancy
results in relative
&dosing
rather than overdosing,
it is reasonable
to
combine r~uhs.
If the opposite
were true (i.e., subjects in the ivermectin arm of this study were relatively
&rdos&),
then combining
these results with those of the remaining submitted studies would be more problematic.
B. Deviations from protocol:
In reviewing the study summary and the original protocol, the following deviations were noted:
G
the protocol calls for the entry stoolto documentStrongyloides
infection to have been collected “six days or
less before entry into the study”; however, the majority of enrollees in both arms of the study had their
infection documented well before day -6. (One subject’s entry stool was collected 100 days prior to
enrollment.)
Medicai oficer
comment:
in genera[, stools collected
earlier than 6 ahys prior to enrollment
will be considered
acceptable.
However,
a single stool over three months prior to entry seems to stretch this a bit. It is unclear why a
repeat stool could not have been collected
at the time the subject was enrolled and treated with study medication.
.
the protocol calls for followup stools to be collected at days 7,30, and 90 post-therapy; cure is defined as
(Page D-2228 of VOI1.21) “the absence of detectable larvae in the follow-up stool examinations.”
However, many of the subjects only have stools recorded at/around the day 7 timepoint, then variably at the
30 and 90-day timepoints. No mention is made of how these subjects will be dealt with in evaluating
efficacy.
Medical officer comment: because
this study was conducted
in France, where s(ronwloidiasis
is not present,
these
subjee!s (all of whom remained
in France for the duration ofdw
slud>j, according
[o [he appiicun[ [page
D-2162])
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NDA 50-742
Page 18
Meckan=’ (Iverrmxtin)
Swon:yloidiasis
.
are not subjecl to the confounding
variable
of reinr~tion
post-therapy.
Therefore, ANY positive
S!OO[posi-therapy,
no matter how many ahys outfiom
therapy that may be, should be considered
afailure.
The applicant
(Page D-
2162) concurs with this assessment.
It ik unclear whether the apphkant
required
‘cured’ subjects to have negative stools documented
at &
of
these post-thera~
time points.
In other worak, l~the 30-&y
stool collection
was missed, but the sub~ct
was shown
to have a negative stool at ahy 90, was this subject caiied a ‘cure’?
.
the protocol makes no mention of a requirement forretreatment but the investigator apparently
re-treated
several patients with positive stools on follow-up.
Medical oflcer
comment: some of these retreatedpatients
were given a dose of ivermectin
(either a repeat dose, or
an initial dose l~the subject hadprevioudy
been given albendazole)
as recently as seven days after their initial
dosing regimen had been completed
In other studies submitted
in support of this indication,
this practice
was LKZ
done and it h clear that some patients
ciear their parasites from the stool more slowly than others.
In these
prompdy
retreated
subjects,
it is dlficult
to definitively
state that they failed
their initial course of therapy.
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NDA 50-742
Page 19
Meclizan- (Iverrncctin)
Strongyloidiasis
.
C. Applicant’s tindings:
The applicant’s interpretation of the results of this study are found on the following pages, which are taken
from pages D-2158 to 2171 of volume 1.21 of the NDA:
..
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D–
2158
MK-0933
Prot. No. 004
----
Prof Gentilini
-13-
111. RESULTS
L
Patient Characteristics
A sumrmuy of demographic
Mormation
for both evaluable patients and all
enrolled patients is provided in Table 4.
There were no statistically significant
differences in the characteristics
of the two treatment
groups.
A detailed
summay of each patient’s treatment therapy maybe found in Appendix 1.
Eleven of 29 patients in the ivermectin group (37.9%) and 11 of 27 patients in
the albendazole group (40.7Yo) had secondary diagnoses.
A detailed sumnuuy of
each patient’s secondmy diagnoses maybe found in Appendix 2.
Twelve patients (41 .38Yo) in the ivermectin and 7 patients in the albendazole
group
(25.93%)
received
concomitant
therapy
during
the
study.
No
concomitant therapy had activity against S. s~ercoralis or might have modified
symptoms
related to S. stercorafis infkction.
A detailed summary of each
patient’s concomitant therapy may be found in Appendix 3.
As stated earlier in this report, the actual dose of ivermectin administered
to
patients in this study was approximately
170 mcgkg
(median 169 mcgkg
- see
Table 5) instead of a targeted dose of 200 mcg/kg.
The reason for this was that
the dosage
schedule (i.e., combinations
of ivermectin 6-mg tablets by body
weight)
included in the protocol
for the study was actually targeted
at an
approximate dose range of 150 to 171 mcgkg
ivermectin and not 200 mcgkg.
However, the difference between the administered dose of ivermectin and the
target dose (200 mcgkg)
is not considered meaningful [8].
IWK4933U3C869.DOC
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MK-0933
Prof. No. 004
.....
Prof. Gentilini
-14-
A. Patient Characteristics (ConC)
......
,
Number ofPatients
MeanAge(AgeRangeinYears)
MaIe(AgeWngein Years)
Female(AgeRangeinYears)
Sex
Male
Female
Race
Caucasian
Asian
Negro
Indian
Mulatto
jeverityof Infection
Mild
Moderate
severe
No data
ntensity of Infection
1+
2+
3+
4+
Table 4
Baseline Characteristics
All
W*
29
36 (21+57)
(23-67)
16 (55%)
13 (gs~o)
6(2 1~0)
6 (21%)
14 (48%)
I ( 3’%)
2 ( 7%)
18 (64’%0)
9 (32%)
1 ( 4%)
1 ( 4%)
12 (41%)
7 (24%)
8 (28%)
2 ( Wo)
hems
-*
27
36 (16-74)
(16-74)
15 (56%)
12 (44%)
8 (30??)
3 (11%)
16 (59%)
o
0
19 (xl’%)
5 (19%)
3 (11%)
o
9 (33%)
6 (22%)
11 (41YO)
1 ( 4%)
—
Evaluat
W*
28
36 (2147)
(2347)
16 (57??)
12 (43%)
6 (21%)
6 (21%)
13 (46%)
1 ( 4%)
2 ( 7%)
18 (67%)
8 (30%)
1 ( 4%)
1 ( 4%)
12 (43%) - “-
6 (21%)
8 (29%)
2 ( 790)
==1
23
36 (19+5)
(20+7)
11 (48Yo)
12 (sz~o)
7 (30YO)
3 (13%)
13 (57’%0)
o
0
15 (65%)
5 (22%)
3 (13%)
o
9 (39VO)
6 (26’%)
7 (m%)
1 ( 4%)
‘herewere no significant
differencesbetweentreatmentgroups.
!Wivermectin
ALB=albendamle
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MK-0933
Prot. No. 004
Prof Gentilini
-15-
A
Patient Characteristics
(Cent-)
Table 5
Ivermectin Dosage
.
PatientBOdy
AN
Ivcrmcctin (mg)
Weight(kg)
mcglkg
9
49
184
9
59
152
12
70
171
12
67
179
9
60
150
9
64
141
12
75
160
9
59
152
9
57
158
9
51
176
9
53
170
12
78
154
12
80
150
12
73
164
12
70
171
12
65
185
12
76
158
9
61
147
12
65
185
9
60
150
9
63
143
12
67
179 -
9
52
173
12
81
148
12
68
176
12
65
185
9
52
173
12
71
169
12
71
169
Maiian
169
Mean
164.6
—
,/
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D–
2161
MK-0933
Prot. No. 004
Prof. Gentilini
-16-
B. Patient Accounting
1. Accounting for Patients in the Study
Table 6 presents
a summary
of patients
discontinued the study by treatment group.
who enter~
completed,
and
Table 6
Accounting for Patients in the Study by Treatment Group
~
Iwrmcctin
Albcndazole
patients
Treatment
Treatment
Total Patients Entered
29
27
Told Patients Completed
22
11
Total Patients Discontinued
7
16 “
Adverse Clinical Experience
o
0
Mverse
Laboratory Experience
o
0
Lost to Fo11ow-UP
o
0
PatientDeath
o
0
PatientUncuopemtie
1
2
NoTherapeuticWgimen/Retxwt
4
0
ProtocolD&iation
1
0
No ThCGi~tiC
RcqJonse
1
0
No ThCEijEUtiC~ni$dhatm.nt
bge
o
14
. .-
*
2. Accountin? for Patients in the Analvsis
Table 7 presents a sumrntuy of patients who were evaluable and nonevaluable
in the efiicacy and safety analysis.
ir23
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MK-0933
Prot. No. 004
Prof Gentilini
-17-
B., Patient Accounting
(Cont.)
Table 7
Accounting for Patients in the Analysis of Efficacy and Safety by Treatment Group
Patients
Evaluable for Efficacy Analysis
Nonevaluablcfor Efficaq Analysis
Rzason for Nonevaluablefor 133icacyAnalysis:
Diagnosis 10Treatment >30 days
Inadequate Follow-UpParasitology
No Follow-UpV&its
Evaluable for Safety
Ivermectin
Treatment
28
1
I (AN 24)
o
0
29
A&ndazole
Treatment
23
4
2 (AN7, 19)
1 (AN 16)
1 (AN 28)
27
Patients who did not fidfill the criteria for efficacy evaluation
outlined in
Section 11.G. were considered nonevaluable for efficacy. However, failure to
satis~
the entrance criteria
in Section 11.D. did not necessarily
exclude
patients from the analyses of efficacy if the criteria for efficacy evaluation
were titisfied.
The inclusion criteria in Section 11.D. required that the time
period from diagnosis of strongyloidiasis
(i.e., detection of lamae on stool
examimtion) to initiation of therapy not exceed 6 days. In practice, this was
often not possible.
Because the mtural histoty of Strongyloidiasis is one of persistence
over
time, patients who received study drug therapy within 30 days of a diagnostic
stool examination were considered evaluable.
In additio~ if the pefiod from
diagnosis to therapy was greater
than 30 days but a postthempy
stool
examination was positive for S. sfercorzdis kuvae, thus confirming that the
patient was infkzted at the time of therapy sirIce reinfkcdon would not occur
in France, the patient was considered evaluable.
It is recognized that these changes in entry and evaluation criteria differ from
the requirements of the protocol; however, they are considered by MRL as
consistent with the treatment
of patients
in nonendemic
are+m
A
such
MRL believes that the alterations from the protowl
as specified above do
not impact on the validity of the results of this study.
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D–
2163
MK-0933
Prot. No. 004
Prof. Gerltilini
-18-
B. Patient Accounting (Cont.)
~
patienti @ermAn-15,
albendazole-15)
with diagnosis to tr~tment
periods of 7 to 30 days were considered evaluable.
One patient (AN 57) had
a diagnosis to treatment
period of 39 days but was cihsidered
evaluable
(faiIure) based on positive follow-up
stool examination
on Posttreatment
Days 7 and 8.
One patient
(AN 21)
had negative
stool
examinations
following ivermectin therapy but symptoms recurred during follow-up.
The
patient was treated with other
antistrongy[oidiasis
therapy. based
on the
clinical picture.
This patient was considered
evaluable as a therapeutic
ftilure.
Results of alI parasitological examinations appear in Appendix 4.
OveraI1,96% (28/29) of patients in the ivermectin treatment group and 85%
(23/27)
of the
albendazole-treated
patients
were
considered
evaluable.
Table 7 above identifies the reason for each patient being excluded from the
efficacy evaluation.
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D–
2164
MK-0933 Prot. No.
004
Prof Gentilini
.
-19-
,
c. Efmacv
There were a total of51
evaluable patients in the study (Table 8), 28 in the
ivermectin treatment group and 23 in the albendazole treatment group.
A total
of 7!Y/o(2228)
of patients were cured following ivermectin therapy compared to
43% (10/23) of those receiving albendazole.
This difference in cure rates is
statistically significant (p=O.02). Logistic regression analysis demonstrated
that
no other factor (age, s%
race, clinical severity of infkctio~
and intensity of
inkction)
was significantly related to treatment fkilure.
Table 8
Study Outcome -- Evaluable Patients
Ivermectin (N=28)
Albendazole (N=23)
Cure
Percent
95% C.I.
cure
Percent
95% C.I.
oval
22f28*
79
(59, 91)
10/23
43
(24, 65)
sex
Male
13/16
81
(54, 95)
2/11
18
(3, 52)
FemaIe
9/12
75
(43, 93)
8112
67
(35, 89)
Raa
Caucasian
4;6
67
(24, 94)
4r7
57
(20, 88)
Asian
6/6
100
(52, 100)
213
67
(13, 98)
Negro
9/13
69
(39, 90)
4/13
31
(10, 61)
Indian
1/1
100
(5, 100)
010
Mulatto
2/2
100
(20, 100)
0/0
Sevexityof Infection
Mikl
14/18
78
(52, 93)
6/15
40
(17, 67)
Moderate
718
88
(47, 99)
2/5
40
(7* 83)
-Severe
0/1
o
(o, 95)
2/3
67
(13, 98)
No daIS
1/1
100
(5, 100)
0/0
Intensityof Infection
1+
10/12
83
(51, 97)
5/9
56
(23, 85)
2+
516
83
(36, 99)
3/6
50
(14, 86)
3+
5/8
62
(26, 90)
m
29
(5, 70)
4+
Z2
100
(20, 100)
0/1
o
(o, 95)
‘Significant difference between treatment groups @cO.05)
N4K-0933U3C869.DOC
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D–
2165
MK-0933
Prot. No. 004
Prof Gentilini
-20-
C., Eflicacy (Cent)
If only those
patients
who
met the
entrance
criteria of Section
11.B. are
considered
for efficacy evaluation
(i.e., if those patients
with diagnosis
to
treatment
periods of greater
than 6 days are removed), qO of
13 (76.9%)
ivermectin-treated
patients and 2 of 6 (33.30A)patients treated with albendazole
were cured.
These cure rates are not statistically different from those calculated
when
patients
with
a prolonged
diagnosis
to
treatment
intend
are
also
considered evaluable (see above).
The similarities in efficacy seen with these
comparisons emphasizes the clinical equivalence of the two groups.
Similar results are seen if all patients, regardless of their efficacy evaluation
status, are considered for analysis.
Twenty-three
of 29 (79%) patients were
cured
following
ivermectin
treatment
versus
13 of 27 (48°/0) cured
after
albendazde
(p=.03).
A single patient
(AN21
in the ivennectin
group)
deveIoped
recmdescent
symptoms and was considered a failure despite negative stool examinations.
Table 9 presents a summaxy of the 17 patients who failed their initial course of
therapy (4 ivermectin-treated;
13 albendazole-treated)
and rcxxived a follow-up
course of ivermectin.
This information is offered for purposes of fill disclosure
only and is not brought to bear on the interpretation of this study.
.2.-
(7
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MK-0933 Prot. No. 004
Prof Gentiliti
-21-
C
Efficacv (Cent)
AN
Table 9
Summaty of Patients Who Failed Initial Course of-Therapy
and Received a Follow-Up Course of Ivermectin
Initial
Treatment*
Iv
Iv
Iv
Iv
ALB
ALB
A.LB
ALB
A.LB
ALB
Second
Treatment*
Iv
Iv
Iv
IV
Iv
Iv
Iv
Iv
Iv
Iv
IV
IV
Iv
Iv
Iv
Iv
Iv
Days Between
First and
Second Treatment
36
181
25
111
184
20
11
9
42
10
11
41
24
39
11
10
40
Outcomet
I
Cure
In.sufkient Parasilolofl data to evaluate
Cure
Insufficient parasitology data to evaluate
Insufficient parasitology data to evaluate
Cure
Cure
Cure
cure
Cure
Cure
Cure
-.
Insufficientparasitologydatato evaluate
Insufficientpararn“tologydatato evaluate
rv=xvennectin
ALB=AIkdazole
Outcomeis basedon an evaluationof the pmsitologic resultsavailablefor the patient indicated
Cure
implies
examinations after the second course of trcatmert
A quality assurance
audit was pdormed
on this study 3.5 years after the
completion of the trial (reference Audit Information Sheet - Appendix 5).
The
~
representative
who cmducted
the audit found certain ~P
compliance
issues relating to insufficient documentation
of informed consent, incomplete
--
case report form documentation
at the site, protocol
compliance, incomplete
,
regulatory documentation
at the site and lack of study monitoring.
Examples of
the audit findings included
MK4)933U3CS69
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D–
2167
MK-0933
Prot. No. 004
Prof Gentilini
-22-
C.. Eficacy
(Cont.)
G
G
G
G
G
There was no record of drug supplied to the patients and no rti~d
of
unused drug having been returned to MRL.
There was no routine field monitoring conducted at this site.
Lack of availability of patient consent forms for some patients (6) while
others had consent forms which were not signed by the patients (3) and of
those with signed forms some (4) were dated by the investigator and not the
patient.
Insufficient case report form documentation
in MRL’s Official Regulatory
File and at the site (missing for 4 patients and incomplete for 38 patients).
The 4 patients whose case reports were not submitted were entered in the
study but were not reported to MRL. It is not clear at this time why data for
4 patients were not submitted to ~,
however, it may have resulted from
MRL data cut-off dates imposed for the assembly of the French M.AA. Data
for these 4 patients are not included in this sumrnay
(60 patients were
entered into the trial by the investigator rather than the 56 included in this
write up).
However, comparing the results of the trial for-all 69 patients
(which were
published [10] in 1994) with the results summarized
here
indicate
no
substantive
difference.
In additio~
as stated
earlier,
the
investigator
included an analysis of hypereminophilia
which was
not a
requirement
of the protocol
nor made part of MRL’s analysis.
Table 10
summarizes the dtierences
in the two reports.
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MK-0933
Prot. No. 004
D–
2168
(
- 30
—
Prof Gentilini
-23-
. C. E~lcacy (Cont.)
Table 10
ComparisonBetween MRL Data Reeeived From Investigative Site and Data Published
by the Investigative Team [10]
I
i
I
tM
Patient Accounting:
iv* -
Patients Entered
29
Evaluable Patients
28
(Efficacy)
Nonevaluable Patients
1
(-Efiicacy)
Cure Rate (%)
22/28
(79)
*
IV= Ivermeetin;
ALB = AIbendazol~
J Summaly
Publieati
ALB*
ALL*
N*
MB*
27
56
32
28
23
51
29
24
4
5
3
4
10/23
N!A
24/29
9/24
(43)
(83)
(38)
(
) = Pereent cured
ALL*
60
53
7
WA
,.”
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D–
2169
0
-3\
-24-
MK-0933 Prot. No. 004
Prof. Gentilini
C
E-ficacy (Cont.)
In the opinion of MRL, the lack of a complete file of case report forms~t
the
investigative
site does not aff’
the integrity
of the itiormation
originally
received from the investigator and used to produce this MRL ~ary.
AIthough not specified in the protocol, patients who ftiled initial therapy with
either agent were retreated with ivermectin in an open, nonrandom
manner
(Reference Section 11.E. Study Design).
In additioq
the investigator
did not
always follow the complete dictates of the protocol requirements dealing with
examinations, vital signs, and laborato~
tests and in some cases recordings of
same were made to workbooks but never transfemd
to case report forms that
were fonvarded to MRL. The investigator did not maintain adequate regulatory
documentation (e.g., no signed copy of the final approved protocol, no signed
Normal Ranges for Laboratory Tests, no drug supply records, etc.).
Despite these regulatory compliance issues, MU
believes that the results of this
study, that are reported
in this summary,
suppoxt the use of ivermectin in
strongyioidiasis of the gastrointestinal tract and that the integrity of the data and
conclusions drawn are generally consistent
with the findings reported
by the
investigative group [I 1].
D. Safety
-
1. Adverse Experienc-inical
& OveraI1Assessment of Clinical Adverse Experiences
All 56 patients, regardless of evaluability for efficacy, were included in
this saf~
analysis. Three patients, one in the ivermectin group and two
in the albendazole group, had clinical adverse experiences.
There were
no
statistically
significantdifferences
in the
fkquency
of
adverse
experiences between the two groups.
AN 3 in the ivermectin group experienced mild nausm
fatigue, dizziness,
sleepiness, tremors, and mild vefiigo study day one to two days afier
treatment each lasting 18 hours.
The investigator considered them to be
probably drug related.
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MK-0933
Prot. No. 004
.
Prof Gentilini
-25-
D. Safety (Cork)
b.
c.
in the albendazole group on the firstday of treatment
expen%aid
mild vertigo lasting 24 hours and epigastric pain 72 hours duration which
was also mild in intensity.
Both events were considered possibly drug
related. On the first day of albendazole treatmen~
experienced an
increase in nausea and abdominal discotiort
of moderate intensity lasting
for 12 hours which the investigator considered possibly related to drug
treatment.
SCrious Clinical
Adverse Emergences
There were no clinical adverse experiences that were considered serious
by either the investigator or the clinical monitor.
Patients Discontinued
Due to Clinics! Adverse Exr)eriences
No patient in this study was discontinued because of a clinical adverse
experience.
2. Adverse Exnenences--Laborator-y
a.
..
Overall Assessment of Laboratory Adverse Experiences
Three patients, 2 in the ivermectin and 1 in the albendazole group, had
laborato~
adverse experiences.
in the ivermectin group had an increase in SGPT and alkaline
phosphatase
6 days posttreatment
that was considered
probably
not
related to ivermectin but more likely concomitant halofiintrine treatment
for mahri~ which has been associated with such elfkots [12].
m the
ivermectin
group
had
anemia
(hemoglobin
11.2°/0,
hematocrit 33.5%)
and Ieukopenia white count 2.74 ths/mm3 31 days
posttreatment considered probably related to ivermectin.
MK-0933U3C869.DOC
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D–
2171
MK-0933
Prot. No. 004
Prof Gentilini
-26-
D. Safetv(ConL)
b.
c.
in the albendazole group had a very slight increase in SGPT (21
to 59 U/L, normal range 5 to 45).
Since the patient had a Iaparotomy
petionned
within the past month
drug relationship
was
difficult to
establish and considered unknown by the investigator.
Since no fbrther
follow-up tests were performed the outcome was also unkno~
but the
patient was clinically well at last visit.
Serious Laboratory
Adverse Experiences
None of these laboratory adverse experiences was considered serious.
Patients
Discontinued
Due to Laboratory
Adverse Experiences
No patients discontinued due to a laboratory adverse experience.
3.
Adverse Experiences-Other
(Special Examinations)
There were no other adverse experiences.
4.
Clinical Safety Measurements
No clinically significant changes in clinical measures of safety were noted.
5.
Laboratory Safetv Measurements
No consistent or significant changes
noted.
in laboratory measures of dety
were
(f”
33
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....
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NDA 50-742
Page 34
Meu”m-
(Ivcrrnectin)
.
SWongyloidiasis
D. Medical Ofllcer findings: effkacy
Since this study took place in Fmnce, it is assumed that there is no possibility of re-infection and that any
follow-up stool exam that is positive represents a treatment failure.
The following
criteria were utilized to determine evaluability and eflicacy:
A positivestool no morethan60 days prior to entry into study
Present for follow-up for the day 30 and day 90 (or later) timepoints
Have three consecutive negative stools to be called a cure.
Medical officer evaluation
of enrolled
patients
by treatment
group and patient number
Gentilini
study 004
Patient #
Evaiuable?
Reason
Cure?
Reason
Treatment arm: Ivermectin X 1
yes
Yes
= stool up to day 95
yes
Yes
m stool up to day 93
yes
Yes
= stool up to day 85
yes
No
+ day 29; retreated
yes
Yes
_ stool up to day 102
yes
Yes
_ stool up to day 87
yes
No
_ day 28; + day 93,94,95
yes
Yes
_ stool up to day 102
no
lost to flu
yes
Yes
_ stool up to day 99
no
lost to flu
yes
Yes
_ stool up to day 92
yes
Yes
_ stool up to day 155
no
entry stool day -100
yes
Yes
_ stool up to day 138
yes
Yes
_ stool up to day 103
yes
Yes
_ stool up to day 90
yes
Yes
_stool
up today 124
yes
Yes
_ stool up to day 123
yes
No
* day 25; retreated .
yes
Yes
_ stool up to day 85
yes
No
-day
105; G day 106
yes
Yes
_ stool up to day 91
yes
Yes
_ stool up to day 92
yes
No
-day
Il; +day
100, 101
yes
Yes
_ stool up to day 101
yes
Yes
= stool up to day 87
yes
Yes
_ stool up to day 91
yes
Yes
_ stool up to day 90
Totals
Evaluable
26
Cure 21 (810A)
Unevaluable 3
Fail 5 (19”A)
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NDA 50-742
Page 35
Mectizan=’(Ivermectin)
.
Stron:yloidiasis
Medical officer evaluation
of enrolled
patients
by treatment
group and patient number
Gentilini
study 004
(Continued)
Patient #
Evaluable?
Reason
Cure?
Reason
Treatment arm: Albendazole 200 mg BID X 3 days
yes
No
+ day 33; retreated
yes
Yes
= stool up to day 89
yes
Yes
= stool up to day 100
yes
Yes
a stool up to day 197
yes
No
~ day 8; retreated
no
lost to flu
yes
Yes
= stool up to day 166
no
no pre-therapy stool recorded
yes
No
+ day 8; retreated
yes
No
+ day 39, 40; retreated
yes
No
* day 9; retreated
yes
Yes
_ stool up to day 96
no
lost to flu
yes
Yes
- stool up to day 220
yes
Yes
_ stool up to day 131
yes
No
+ day 7,8; retreated
yes
No
+ day 29,30,31
yes
Yes
_ stool up to day 92
yes
No
41day 10; retreated
yes
Yes
= stool up to day 58
yes
No
+ day 29,30,31
yes
Yes
_ stool up to day 97
no
retreated day 1I after_
stool day 8
yes
No
+ day 5,6,7; retreated
yes
Yes
= stool up to day 87
no
lost to flu
yes
No
+ day31, 32; retreated
Totals
Evaluable
22
Cure 12 (550A)
Unevaluable
5
Fail 10 (45%)
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NDA 50-742
Page 36
Mectizarr””{Ivetmectin)
.
Strongyloidiisis
Results per medical
officer
Gentilini
study 004
1
I
.
1
Ivermeetin
X 1
Albendaz.oje
Enrolled, Total
29
27
Evaluable
per Medieal Officer
~
26
~
22
Cure at 30 days
I
24
I
12
Fail at 30 days
!
2
!
10
I
Cure at 90 days
I
21
1
10
I
Fail at 90 days
I
3
I
I
I
Last to f/u from days 30 to 90
~
o
~
I
Cure day 90(%
of evaluable)
I
21/26 (81”A)
I
10/22(45”/’0)
Medieal Officer findings: Safety
The patient-level clinical and iaborato~ data was reviewed and the applicant’s summaty (see SectionC
above) was corroborated.
The applicant mentions two subjeets in the ivermectin arm who had adverse iaborato~ events that the
investigator thought to ~ worthy of mention. One of these subjects (~
was found to have anemia and Ieucopenia
‘probably related to ivermectin”. Upon closer examination of the laboratory values reported in the ivermectin-
treated subjects, the following was found:
Subjeet #
lab finding (day of study)
Comments
AST 32+86
(d6); ALT 57-0167 (d6)
repofied by applicanc ? Seeondary to Halfan
Hgb 16.0+ 11.2; Hct 47+ 33(cI31)
reported by applicant
WBC 6.7-2.7(d31)
ALT24+
61 (d31)
WBC 3.2+ 2.5 (d29)
Not commented on by investigator
WBC 5.3+ 3.7 (d6h
3.4 (d100)
U*1
WBC 8.9+ 6.9 (d26~
5.6 (d98)
,’*,
WBC 6.5-
4.3 (d7)
“v,
WBC 5.944.3
(d8)+ 3.9 (d104)
6’n
WBC 7.9+ 3.2 (dl 1)-o 4.2 (d41)-+ 4.4 (d103)
.’,,
WBC 5.5+ 5.8 (d8~
4.5 (d37)+ 3.6 (d84)
“,7
Thus there were a total of 8 of the 29 iverm+tin-treated
subjects who had a drop in WBC count. Additional cases
were found but these appeared to be related to resolution of elevated eosinophil counts following ivermectin
treatment; these are not included in the above table. A similar pattern was not readily evident in the albendazole
arm.
From this it would seem appropriate to mention ‘decline in WBC count’ as a laboratory adverse event that maybe
associated with ivemlectin therapy.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 44 of 382

NDA 50-742
Page 37
Mcctizan-’ (Ivermectin)
.
Strongyloidiasis
4. Study 020 (Dreyer): An open, randomized study of effkacy, safety, and tolerability of ivermectin single dose (one
or two day course) vs. thiabendazole (threeday
course) in the treatment of patients infected with S[ron~loides
slercoraiis.
A. Study summary: The applicant’s synopsis of this study is presented below (taken fiom~ge
D-2592-3,
volume 1.22 of NDA)
..
/“
——.
.. -.
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D –2592
(Y-3’%
MERCK RESEARCH LABORATORIES
.
PRODUCT:
MK-0933, Ivermectin Tablets
PROTOCOL TiTLWNO.: h
om
W-
smd~ Of Effi~w.
sti~.
ad
#020
Tolerability
of 1vermech
SingIe ‘Dose (One or Two
Day Course) vs~ “~abe&azole
(Three-Day
Course)
in
the
Treatmnt
of
Patients
In&ted
With
Strongyloides
Stercoralis
INVESTIGATORS: Dr.GerusaDreyerflrof. Anaatuy tiutinho,
Reciik, Brazil
PRIMARYTHE~y
PERIOD: hhy 91to k
91
CLINICAL’PHASE: I-
II-
IIr-x
DURATION:Study dumtion - ~PKIXiIWltdy1 year (6-monthmrolhnc@ 6-monthfollow-up). Treatment
period lto3&ysdepcding
ontm@mwntgroup.
PRIMARYOBJECTIVES: To studythecfficaey,sakty, andtokmbilityof iwnnectm. vs.thiabendazolein the
treatment of patients infixted with Strongyloides_sterw~aIis.
STUDYDESIGN. C&q randomizedtrial m ambulatmy patiemts with strongyldiask
of the gastrointestinal
ttaet. Following diagnostic studies and Iabomtory tests, patients received either a single dose of ive-
two
single doses of iverrneztin I &y apart or thiabendazde twice a day for 3 days.
Follow-up visits were held
weekly for 4 weeks.
DIAGNOSIWINCLUSION
CRITERIA:
Males and females between the ages of 5 and 70 years weighing at
least 15kg who have strongyloidiasis ecdrmed
by stool examination.
PATIENT ACCOUNTING:
H
Ivermeetin 1x
Iverrneetin 2x
Thiabendazole
ENTERED: Totzd
49
[7
17
15
Male (age range years)
42(4
to 64)
14 (18-37)
16 (4-63)
12 (18-64)
Female (age range years)
7(7t051)
3 (17-27)
1 (44)
3 (7-51)
COMPLETED:
47
15
16
15
DISCONTINUED:
Tots!
2
2
1
0
Adverse clinical experience
o
0
0
0
AdversekibOIZitOly
experience o
0
0
0
other
2
2
1
0
DOSAGWFORKULATION
NOS.:
Single 200+neg/kg
ivcrmectin oral dose, two 200+neg/kg
oral doses of
ivermcetin 1 day apart or 3 days of 25 mg/kg b.i.d. oral treatment with thiabendamle.
Gnnmereial ivermwtin
obtaindtbrough
MSD-Chibrq
(Lot H7502) and commmid
.
d@en&zole
obtained Ioealiy.
EVALUATIONCRITERIk
Pamsitologid
Minimum of three rqeated
stool examhhm
on Days 5 to 9,
Iatmtory Studies.
STATISTICALPLANNINGANDMETHODS: The prisnaty measurcanemt of cfficaey
was the cure rate.
mm----
fw*wtitit*ti
lddtipmtimof@af@a
qerknc@adverseexperieace
using Fisbedsexaet
test. Baseiinec&mter@ - “a wem analynd
using Fisher’s
exact ~thedliqlam
test or the wlleoxon Rauksum wasappropfiate.
Coofidcneeintcrvakwem
calculatedusingthe methodof Blythand StiU. Allatatistiealtests for tmatmmt groupd&wllees weretwo-
tailed(a=O.05).
MK4933U3C850DOC
,
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D –2593
if
-35
-2-
f>..
.
~.~
RESULTS:
Efiicaqc
-
There mre
no statistically significant differences in cam rates among the trcatmeat
groups (singledose
kmeetin-67°/q
twodose iverme&n- 82%, thiabendazole-87%).
Safety:
A summary of Adverse Experkm
(A&) follows:
IVerm@in
Ivermectin
Srngk-lkae
Two-Dose
Thiabendazole
Treatment Group
(N=17)
(?4=17)
(N=15)
Patientswith Clinical AEs
o
2(11.8)
9 (60%)
SeriousClinical AEs
o
0
0
Dismntinuationsdue to CIinical AEs
o
0
0
L)mg-Rela@dClinicalAEs
o
0
9 (60Y.)
W
difference in the inciderm of clinical adverse experiences (A&) between the singledose iverrnectin group
and the thiabendazole group was significant (p<O.001) as was the difIercnce Mxveen the two-dose ivermectin and
thiabcndazole groups (p=O.008).
There was no statistically significant differcmce in the incidence of clinical AE
betwen
the two ivermectin treatment groups (p=O.48).
There was no laboratory AEs.
There were no serious
clinicalAE5 or serious laboratory AEs.
CONCLUSIONS:
(1) Iwmmctin (200 mcglcg) as a single dose and as two doses on consecutive
&ys
and
FIn -
thiabendade
(25 mg/kg b.i.d x 3 days) are effkctive thempies fir strongyloidiasis of the gastrointestinal tract.
(2) Immectin
is geue@ly
well tolerated and is associated with t%werclinical adverse experiences
than
thbdazole.
REGULATORYCOMPLIANCEISSUES:
Regulatory compliance issues were fbund during an MRL
audit conducledat thisinvest@*site
3yearsafter
theeompletion ofktriaI
andthese
fidings
m-reportedin
this summary.
Despite these findings,MRL believesthe results presmted in this report su&ort A
use of
ivermectiniuthetmatmmt of strongyloidiasis.
In additiom the results remrted herein enable one to evaluate
.
.
P
prdoutcmeswithregar
dto~efficacyand
aafkty.
A~HORS:
F. M. Ricci
T. ~
M.S.
G. B. ~
M.D.. Ph.D.
Director
Aso&ate
Director
Senior Director
CBARDS
clinical Research
.,.
h4K4933u3cf350.Doc
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NDA 50-742
Page 40
Mectizan” (lvermcctin)
.
Ssrongyloidiasis
B. Deviations from protocol.
in reviewing the documentation of the conduct of this study, the following deviations from the stated
protocol were detected:
.
Inclusion criteria call for an examination of stool samples done 2 weeks or Iess before entry into study to be
positive for S.srercorufis larvae. Of the 49 patients enrolled, 34 had their entry stool listed as being
collected >2 weeks prior to drug dosing. Many enrollees (10) had the only positive stool recorded pre-
therapy over one month prior to enrollment. One subject was listed as having one positive stool pre-
therapy, taken 102 days prior to study entry.
Medical oficer
comment: the issue of whether some patients
can self+ure from intestinal strongvloidiasis
is
controversial.
It is reasonable
to assume that, l~no intervening
thera~
was given during the 102 &ys
that this
patient had known strongyloidiasis
prior to study entty, he still had the disease at the time of enrollment.
However,
it woould not seem unreasonable
to expect a repeat stool collection
at the time the patient
was actually enrolled in
the stu~
(i.e., at d~
O). Even t~such a specimen
had been coilected
and were negative,
il would nof necessarily
indicate spontaneous
cure, &u!rather indicate thai light infections are sometimes
d@cult
to diagnose,
even with the
Baermann technique.
.
Sera were to be collected for specific lgG antibody studies, but these data were not presented because the
collection of such specimens was not consistently adhered to during the conduct of the study.
.
The protocol defined parasitological cure as the primary study endpoinl and called for stool specimens to
be collected for analysis at the following time points [acceptable range] post-therapy: day 7 [5-9], day 18
[16-19], day 28 [26-34], and at months 3 and 6. However, (page D-2601) “several changes to the protocol
were agreed to by MRL [applicant] and the investigato~ however, the changes were not made into a formal
protocol amendment.” Two specific changes were agreed to: 1) patients who had “highly reproducible
positive stool examinations (at least two of four pretreatment stool examinations positive) were selected for
entry”, and 2) “the follow-up period was restructured...conducting these [Baermann] studies approximately
weekly with the final follow-up at approximately day 30.”
Medical oflcer
comment: as discussed
earlier in this review, it k unreasonable
to require continued
negalive stools
when the treatedpatient
returns to his home environment,
where he ti likely to be re-infected
Therefore, since the
pre-patent
period
is approximately
28 ahys, it b reasonable
to have the 30-day follo+up
be the test-of<ure.
However, given that light infections may show intermittently
negative
on stool examination
it k necessary
to have
three negative stools documented post-therapy
in order to be called a cure. If repeated
negative stools are obtained
after the one-month timepoint in order to document three consecutive
negative stools, then that patient
will sti[l be
consi&red
a cure.
?%eflrst change referred to by the applicant
is do
reasonable.
The d@ul~
is that, of ail the 34 enrolled
patients
mentioned above who have positive
stacz% dacumentd
more than 14 C@
pre-enrollment,
NONE have w
dacumentedposittie
pretreatment
stools.
Therefore, l~the applicant
were to be strictly held to these amended entry
criteria, 34 of the 49 enrolledpatients
would be acluddfiom
analysis.
In theopinion of thti medictd oflcer,
this is
unreasonable.
.
Criteria for evaIuability were not defined in the original protocol, but the study summary (page D-2603 of
volume 1.22) defines an evaluable patient as one who had: a) strongyloidiasis documented on stool
examination; b) not received other anti-helminthic therapy during the study period; c) been compliant with
therapy; and d) had at least four stool samples submitted during the one-month post-therapy follow-up
period.
Medical oficer
comment: !hus it appears that the evaluability
criteria
were altered re[rospectiveiy
such that any
posi[ive stooi, at any time prior to study ent~,
was considered
adequa~e for enrollment
and evaluabili[y,
as long as
dle pa[ien: deilicd intervening aiz!i-helminthic therapy.
Again, it does no[ seem unreasoirable
to expecl tiw[ a siool
sample co~ild hove been collected
at the time the patient presented for raildomizatioil
and drug ini[iaiion,
The applicant
inakes no mei?[ion of how enrolled
szibjecls will be classi~ed
O( the time ojfollow-up
!fthcy
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NDA 50-742
Page 41
Mec[izan” (Ivenncc[in)
.
SIron:yloidixiS
have stoo!s positive for SS AFTER [he 30-day pos[-lherapy
Iitne poin[.
Are lhese subjects all IObe considered
failures?
Are they alI considered
reinJec[ion~, and thus only lhe specimens
up to and inchding
the 30-dql
specimen
are to be considered?
How the applicant has dealt witil this issue, on a patient-bppatienl
basis, is no~cleari’
delineated
in the submitted
information.
C. Applicant’s findings
The applican~’sresults are presented on pages D-2605-2616 of the study summary, volume 1.22 of the
NDA. This study summary appears on the following 28 pages:
,/
—
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u
—.2>9
(f-
42-
MK-0933
Prot. No.
020
Ivermectin
vs. Thiabendazo!e
COMPREHENSIVE
STUDY SUMMARY
.
An Open, Randomized
Study of Eff]cacy, Safety, and~olerability
of
Ivermedin
Single Dose (One or Two Day Coume) vs. Thiabendazole
(Three-Day Course) in the Treatment of Patients Infected With
Strongyloides Stercora!is
I.
BACKGROUND
Tens of millions of people around the globe are cumently infixted with StrongyIoiaks
stercoraiis [1].
It is widespread, not only in moist rainy areas of the tropics and
subtropics, but also in some areas of southern and eastern Europe and Southeastern
United States. StrongXoides sfercorak
is an intestinal nematode that usually causes a
limited intestinal infection. Patients may remain asymptomatic but recument cutaneous
and gastrointestinal symptoms are common.
The intestinal disease is rarely fatal and
usually associatai with eosinophilia.
Strongyloidiasis begins when infective Ia.tvae in contaminated soil penetrate intact skin
and cause an fichy erythematous rash at the point of entry. The larvae are then tied
in the bloodstream to the lungs where they ascend the bronchial tree before being
swallowed.
They then enter the small intestine where they penetrate the mucosa and
mature into adult worms. Eggs shed by f-e
WOMISare tradormed
into huvae that
are excreted in the intestinal lumen. Most kvae
are excreted in the stoo~ but some may
penetrate the mucous membrane of the lower bowel or periarta! skin resulting in
autoinktion
which intensifms and perpetuates the intestinal colonization [2].
This phenomenon of autoinfbction is unique to S. sferwralis and is not found in the
other nematode parasites cxmunotdy infkcting humans. In this forq
the disease can be
perpetuated for an indefinite period of time.
World War II veterans who had beeu
former prisoners of war in Southeast tia
as well as Vktnam veterans have been
diagnosed as having strongyloidiasis without being fixther exposed for periods of over
40 years [1].
MK-0933U3C8S0.DOC
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D –2595
ff’
+3
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
.
-2-
1.
BACKGROUND
(CONT.)
Thiabendazole (TBZ) has been the “chug of choice” for treatment of-strongyloidiasis for
almost 30 years since ithasa wide range of action and is readily absorbed from the G.I.
tract.
However, it sIso is responsible for frequent and sometimes serious side effkcts
[3,4]. Ahendazole, a more broad spectrum anthehnintic, has efficacy in strongyloidiasis
similar or dightly less than that of thiabendazole.
Albendazole is, however, better
tolerated than thiabendazde.
Both drugs rquire
administration of multiple doses [3].
Treatment ftilures occur with both albendazole and thiabendazole and a few patients are
not cured even when treated with increased amounts of drug for a long time. A single-
dose drug with fewer side effkcts and increased efficacy would be usefid in the treatment
of strongyloidiasis.
Ivermectin, a derivative of avermectin J3,is an orally effective nicrofilaricidal agent, It is
now
the current drug of choice for treating patients infiimd
with the nematode
Onchocerca wbuhs, which is a major cause of blindness in inhabitants of tropical areas
[3].
More than 5.2 million peopIe worldwide have received at least one single oral dose of
ivermectin at kvels up to 200 tncglkg for onchocerciasis [5].
Ivermectin given as a
single oral dose of 100, 150, or 200 mcgkg has been found to be a relatively safe and
effective microfila.ricidereducing 0. VIAJUIUSskin microfilariae counts to near zero for
up to 12 months [6]. Based on the tiety
and tolerabtity evaluations born these studies,
150 mcg/kg was judged to be the optimal oral dosage [6]. Ivermectin was approved by
the French Regulato~ Agency for the treatment of onchocerciasis in October 1987.
There is substantial evidence to suggest that Nermectin may be a usefhl therapeutic
alternative for treatment of strongyloidissis.
Ivermectin has demmstmt Cd activity in
animal models of infkction [7J.
More importantly, ivermectin has been shown to be
effective against human strongyloidiasis in rtoncomparative studies [8,9].
Ivwmectin
was well tolemted and a single dose demonstrated
good activhy.. ““Based on this
experience, we have undertaken a randomized, comparative trial of ivermectin versus
thiabenda.zolein the treatment of strongyloidiasis.
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D –2596
MK-0933 Prot. No. 020
Iverrnectin vs. Thiabendazole
-3-
11.
SUMMARY OF PROTOCOL AND STUDY PROCEDURES–
A. Protection of Human Subiects
B<
c.
D.
This study was conducted
in cofiormance
with applicable
count~
or
local
requirements regarding ethical committee review, informed consent, and other
statutes or regulations regarding the protection of the rights and welfare of human
subjects participating in biomedical research.
Investi2ator(s\
Dr. Gerusa Dreyer/Prof Amaury Coutinho
Fundacao Oswaldo Cruz
Centro de Pesquisas Aggeu Magalhaes (CPqAM)
Campus de Universidade Federal de Pemambuco
Av. Moraes Rego S/n Cidade
CEP 60030
Universitaria, 50730
Recife, Pemambuco, Brazil
Obiectks
To study the efficacy, safety, and tolerability of one or two oral doses (200 mcgkg)
of ivermectin compared to a 3day regimen of 25 mgkg b.i.d. thiabendazole in the
treatment of patients infected with StrongyIoidess!ercorc.dis.
Patient selection
Inclusion Criteria
1. Patients infixted with StrongyIoidesstercoralis.
..
2. Patients were between 5 and 70 years of age.
3. Anexamin@ .on of the stoo! samples done 2 weeks or less before cn~
into the
study was positive for SZrongyioidesWwwrafis larvae.
4. No treatmentfor strongyloidiasis within the previous 3 months.
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D –2597
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
-4-
D. Patient Selection (Cont.)
Exclusion Criteria
1. Age under5 or over 70 yearsor weight under 15 kg.
-
2. Women ofchildbm”ng
potential (unless they have a negative HCG).
3. Medical history of mental illness, seizure, or other serious illnesses.
4. Abnormal levels of SGGT or SGPT, creatinine greater than 2.0 mg/100 mL or
grossly abnormal BUN or urine analysis.
5. A history of an abnormal ECG,
6. Moderate or severe anemi~ i.e., hemoglobin less than 10 g or hematocd
less than
30%; any abnormality of white blood cell count and/or differential (except
eosinophilia).
7. AIIypastor concurrent medical illness which the investigator fds
might influence
either the outcome of the study or interpretation of the data accmed.
E. Studv Desipn
This was an open, randomized study in ambulato~ patients who had strongyloidiasis
evidenced by microscopic stool examimtion or positive stool culture.
Using a local
allocation-schedule patients were randomized into three groups of patients each to
receive either ivermectin (single dose or wo
single doses
1 day
apart)
or
thiabendazoie (3 days of b.i.d. dosrng).
During the 2 weeks prior to the study, the patient was screened to &mre that hdshe
was in good physicid condition.
The patient had a physical emmhation
and a
laborato~
screen.
V:taf signs were recorded on Day-1
(the same day as drug
administration but before drug was administered), Day 1 (the first day of chug
administration), and 7 days later.
Generally prestudy vital signs were recorded on
Day 1 prior to admkktration
of study drug, howmq
there may have been occasion
for vital signs to be recorded the day prior to the administration of study drug. Since
all patients had no cammnt
illness which the investigator fdt might influence the
interpretation of data collected, this deviation from protocol was viewed by MRL as
inconsequential.
MK4933V3C850.DCK
.--
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MK-0933 Pro~. No. 020
lverrnectin vs. Thiabendazole
-6-
E. Study Desire (Cont.)
Table 1
ReecmunendedDosage Schedules
v
IverrnwtinDosageRecommended
Tablet Combinations for
200-mcg/kg Dose
Numberof Tablets(6 mg)
PatientWeigh (kg)
15to 24
‘Y’
25 to 35
1
36t050
1!4
51 to65
2
66 to 79
2!4
80 and over
3
Tbiabendazole(MINTIZOL@)Dosage
Tablet Combinations for
50-mgA<gDose
Number of Tablets
PatientWeight(kg)
(500 mg)
15.0-22.2
0.25 (%tablet)
22.3 -33.4
0.5 (1 tablet)
33.5 -44.5
0.75 (1%tablets)
44.6 -55.7
1.0(2 tabks)
55.8 -66.8
1.25(2%tablets)
669 and mm
15 C tablets}
,,
MK-0933WC850.DOC
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u
—J_uuu
MK-0933 Prot. No. 020
Iverrnectin vs. Thiabendazole
-7-
F. Clinical Observations and Laboratom Measurements
Table 2 shows the schedule of clinical observations and laboratory mfirements
during the study. In additio~ the patient was questioned daily.(%yphone) regarding
the adverse experiences with pmicular
attention to evidence of allergic reactions
(rash itching and anaphylaxis).
Ilb!$Q
Schedule of Clinical Obsewations and Laborato~ Measurements
DrugAdministration
PhysicalExamination
VitaISigns
Labolatmy safety*
StoolExamination
I&
EosinopMia++
Es?w
or
or
x
x
x
x
x
1
x
x
x
x
x
2
x
x
3
x
s
5-9
x
x
x
x
16-19
..
x
x
x
+
Prcstudy=During2 weeks(14 d ys) pr=g
the i at day of studydmg
notII& with anydegreeof &istemy
to allowfir appropriateanalysis.
r
Bloodeknktries
wereperformedonlyif indicatedafter prestudy evaluations.
Observations and measurements related to effioacy and safkty are desoriied below.
—
28-36
x
x
x
h4K4933u3c850.m
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u –LL)U I
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
-8-
F.
CIinieal
Observations and Laboraton
Measurements (Cont.)
EfYicacvMeasures
Baseline evacuation of Srrongyloities stercora!is asdetermined by larval munts using
a modification of the Baermantt’stechnique [10] was to be established in each patient
prior to drug administration.
All stool specimens were examined by one single
expert who was to remain blinded as to the treatment allocations.
Parasitological cure was the primary measure of efficacy.
A!though the protocol
required follow-up stool examinations at Days 5 to 9, 16 to 19, 26 to 34, and at
Months 3 and 6, both the investigator and MRL realized after fidzation
of the
protocol that this design was not appropriate for an area of high endemicity because
the risk of reinfection was considered to be high over this extended period (i.e.,
greater than 1 month). Therefore, several changes to the protocol were agreed to by
MRL and the investigator
however, the changes were not made into a formal
protocol amendment.
The foIlowing changes were instituted:
G
Patients with highly reproducible positive stool examinations for Sfrongyloides
szercoralislarvae(at least tsvo of four pretreatment stool examinations positive)
were selected for entry into the trial.
G
The follow-up period was restructured, maintaining a high number of Baermann
stool examinations but conducting these studies approximately weeldy with the
final follow-up at approximately Day 30 (range: Days 28 to 36).
MRL betieves that these changes do not impact on the overall VaIidityof this study
rather, it allows for appropriate clinical outcomes to be assessed in an area of high
endemicity for Strongyfoidesstercora!is.
The Baermann technique [10] is a method of examining a stool specimen suspected
of having small numbers of Strongyloides lanme and uses the modified Baermann
apparatus.
The technique is dependent on the migration of active lmae
out of the
fecal mat~
through a wire gauze covered with gauze padding and into water,
where they settle out. The procedure is as follows:
1. Fill a finnel (6-inch) with water (attach rubber tubing with a pinch clamp to the
bottom of the funnel) and place the wire gauze, one or two layers of gauze
padding on it, on the funnel.
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u
—&u L/.
MK-0933 Prot. No.
020
lvermectin vs. Thiabendazole
. .
-9-
F. Clinical Observations
and Laboratory Measurements (Cont..)
2. Place between 50 and 100 g of fecal material on the gauze padding snhat
it is
covered with water. If the fd
material is too finr+ break i~up slightly.
3. AIJow the apparatus to stand for 2 or more hours, draw off 10 mL of fluid by
releasing the pinch clamp, spin it down in a centfige
and examinethe sdment
with a magnifier or low power microscope to count and confirm the species of the
lwae.
Although not outlined in the protocol, Ritchie’s concentration Kato or fresh stool
counts were done for many patients; however, the lawal counts obtained from the
Baermann technique are the basis for evaluation of efficacy.
In addition, although not specified in the protocol, the intensity of infection at
baseline was also assessed.
Quanti&ing the level of infestation (intensity of
infection) per patient was important only to determine comparability of treatment
groups and to examine whether there was an interaction between intensity of
inkction and clinical outcome. Because the investigator gave actual counts (number
of kwae per gm stool) for some of the patients and pIus (+) or word designations
for others, it was decided to use the following scheme to have consistency for all
patients (Table 3).
Table 3
Scheme to Translate Between Lawae Counts, Word Designations and “Plus”
Designations
7
Word
Lame
counts
‘Plus”
Designations
VW
stool
Designations
Few
1to15
+
16to 30
++
31toloo
+H-
>100
This scheme was not specifically stated in the protocm~ however, MRL believes that
such an analysis between intensity of infection and outcome is valid.
.,,
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0-
5-I
-.
hfK-0933 Prot. No. 020
Iverrnectin vs. Thiabendazole
-1o-
F. Clinical Obsewations
and Laboratow
Measurements
(Cent)
Safetv Measures
.-
A complete physical examination was done during the 2 weeks preceding study drug
administration and repeated at follow-up visits. Prestudy and follow-up samples for
the laboratory safety studies on blood and urine included:
a. Hematology:
b. Blood Chemistries:
c. Urinalysis:
Hematocrit
Hemoglobin
White blood cell count total
Differential counts were made if WBC was abnormally low
or high
Blood urea nitrogen
Serum creatinine
SGQT
SGPT
Total bilirubin
AJkalinephosphatase
Urinalysis was petformed in patients with abnormal semm
creatinine values or with signskymptoms of urinary tract
infection
‘
The investigator could cany out additional analyses as required by the hospital or as
indicated for optimum patient care.
Vial signs (blood pressure and pulse rate, both supine and erect, respiration rate and
temperature) were recorded on Day 1.
G. Evaluation Criteria
1. Evnluabilitv
AU patients whose data was received by May 28, 1992 were classified by the
MRL clinical monitor as evaluable or unevaluable with respect to eflkacy.
These evaluations by the MU
monitor, although not apec%edin the protocol,
were in keeping with the dictates of the protocol (i.e., inclusion and exclusion
criteria) and the exercise of good clinical judgment.
Thus, patients were
considered evaluable for eflicq
if
a.
Strongyloidiasis was documented on stool examination.
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D –2604
MK-0933 Prot. No, 020
Ivennectin vs. Thiabenda.zole
-11-
G. Evaluation Criteria (Con~)
b. The patient did not receive other anti-helminthictherapy during the study
period.
.
c.
The patient was compliant whh therapy.
d.
Adquate
follow-up stool examinations were peflorrned for determination of
effica~.
At least four samples during the follow-up period (1 month) were
rquired.
2. Efiicacy
The primary measure of efficacy in this study was the absence of larvae in
posttherapy Baennann fml
examinations.
Cure was defined as the absence of
larvae in the follow-up stool examinations. The detection of larvae on any stool
examination past Day 6 up to 36 days posttreatment
met the definition of
treatment ftilure.
3.
Safety
All patients were evaluated for safety by physical examination and laboratory
studies. In addition, the patient was questioned daily (by phone) regarding
adverse experiences with particular attention to evidence of allergic reactions
(ras~
itching, and anaphylaxis).
Adverse experience
were described
and
recorded by the investigator who determined the duratio~ seriousness, seventy,
and chug relationship
as well as the
eventual outcome
of each
adverse
experience.
H. Statistical Planninr and Analvsis
The primq
measurement of e5cacy was the cure rate. Logistic regression was
used to determine if any concomitant factors, i.e., age, sw
race, seventy of
infbctiotqintensity of ir&tioz
aflkctedthe cure rate. None of these factors was
related to cure rate at the a=(). 10 level of significant.
Thus all were dropped
from the statistical mode~ leaving only treatment group. The treatment groups were
compared for the proportion
of patients who were cured as well as for the
proportion of patient’s experiencing adverse experiences using F&er’s exact test.
-
Baseline characteristics were analyzed using either Fisher’s exact test or the chi-
.
square test of the Wkoxon
Rank Sum test, as appropriate.
Confidence intewals
were calculated using the method of Blyth and Still. All statistical tests for treatment
group differences were two-taikd (a=O.05).
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MK-0933 Prot No
020
Ivermectin vs Thiabendazole
-12-
1. Clinical Supplies
Ivemwctin in the form of commercial MECTIZAN
tablets (Lot H7~02) were
obtained through MSD-Chibret.
Commercial thiabendazole (500 m~ MINTEZOL)
was obtained locally [4].
III.
RESULTS
A. Patient Characteristics
A total of 49 patients were enrolled in the study.
A summary of demographic
information for all patients is provided in Table 4.
There were no statistically
significant differences in the characteristics of the three treatment groups. A detailed
swnma~ of each patient’s treatment may be found in Appendix 1.
Table 4
Baseline
Characwristic:
- All
Patient~
{o~’s
—--- ..----
-------------------
- --------
, , -,
Ivermecl.in
Ivcrmectin
One Dose
Two Doses
Thiabendazole
Nurnlxr of Patierm
17
17
15
M-
Age
22
28
25
sex
Male (age &nge - yrs)
14(18-37)
(82%)
16 (4+3)
(94%)
12(18+4)
(80%)
Female (age range - YTS)
(18%)
( 6%)
(20??)
mu
Caucasian
3
(18%)
4
(24%)
3
(20??)
Black
3
(18%)
Mulatto
11
(65%)
1;
(76%)
1;
(80%)
Intensity of Infkction*
.
2+
8
(47%)
6
(35%)
10
(67%)
3+
7
(41%)
4
(24%)
2
(13%)
4+
2
(12%)
7
(4lYO)
3
(xl%)
G = Comparisonstmwc.n treatment groups of Imcnsity of infection, although not spcciiicd in the
protocol,were done in order tofurtherensurethedetectionof treatment-groupWknces.
Note: There were no significant diffcrcnecs between treatment groups.
.,.”
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u –Zoub
MK-0933 Prot. No. 020
Ivermectin vs. Ttiabendazole
A.
-13-
Patient Characteristics (ConL)
Most patients had other secondary diagnoses at entry into the study &gle-dose
ivennectin - 82.40A, twodose
ivermectin
- 94. 1%, thiabendazole - 60.0%).
The
majority of these diagnoses were gastrointestinal parasitic inkctions
other than
strongyloidiasis.
Two patients in each ivennectin treatment group were diagnosed
as having AIDS;
1 patient
in the thiabendazole
treatment
group
was
HIV
seropositive but ~ptomatic.
A detailed sumrnmy of each patient’s secondary
diagnoses may be found in Appendix 2.
Two of 17 patients (11.8Yo)receiving ivermectin single dose, 4 of 17 patients treated
with ivermectin two doses (23.5’Yo)~and 2 of 15 patients receiving thiabendazole
(13.3%) received concomitant drug treatment an~or
prior antinematode therapy
(Appendix 2). Of these patients, no patients in the single-dose ivermectin group, 2
patients in the two-dose ivermeztin group and 1 patient in the thiabendazole group
had previously received agents with antinematode
activity.
In the two-dose
ivermectin gToup, AN 82 was treated with albendazole for 10 days ending 37 days
prior to entry and AN 453, who was HIV-infected and also receiving AZT’, was
treated with 102 days of thiabendazole ending 37 days prior to enrollment and 6
days of albendazole ending 25 days prior to entg.
The thiabendazole-treated patient
received 3 days of mebendazole (200 mg/d) ending 71 days prior to entry.
Positive stool examinations were documented in each of these 3 patients prior to
initiation of study drug therapy.
There were
significant differences between
treatment
groups with
respect
to
secondary diagnoses, prior therapy, or concomitant therapy.
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D –2607
MK-0933 Prot. No. 020
Iverrnectin vs. Thiabendazole
,.
-14-
B. Patient Accounting
L Accounting for Patients in the Studv
-.
Table 5 following is a sumnmy
of patients who
entefd,
completed, and
discontinued the study by treatment group.
Table 5
Accounting for Patients in the Study by Treatment Group
Ivcrnwtin
lvcrmcctin
Patients
1-DOSC
2-DOSC
Thiabcndazo!e
Total PatientsEntered
17
17
15
Total Patients Completed
15
16
15
Total PatientsDiscontinued
2
1
0
AdverseClinicalExperiences
o
0
0
AdverseLaboratoryE~rienccs
o
0
0
Last to Follow-Up
2
NoTheIapCUtiC
~qxm.$c
]*
G = Although this patient~was
discontinued from study &cause of “No therapeutic
ICSOOILSC”
she is still consideredcvaluablefor cfkim.
2. Accountin~ for Patients in the Analysis
Table 6 is a summary of patients who were included in the analysis of efficacv.
(evaluable patients) ad
&et-y.
.
Table 6
Accounting for Patients in the Analysis by Treatment Group
Patients
Evaluable for Efbcy
halysis
Noncvahtabkfor Efikaq A.n@sis
&n
for Noncw4uabilityfor Eftlcscy
Analysis:
Inadquate Foknv-up Parasitology
Evaluablcfor SafetyAnalysis
Ivemuuin
1-DOSC
15
2
2
%?--+%-
0
0
17
L
17
I
15
-
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D -2608
MK-0933 Prot. No. 020
Ivermectin
vs. Thiabendazole
-15-
B. Patient Accounting (Cont.)
—
A total of 49 patients were enrolled in the trial (ivemnectin one dose - 17,
ivermectin two dose - 17, thiabendazde
- 15). Of the 42 patients enrolled, 47
cmmpleted the study and 2 (both in the singledose
ivermectin group) were
considered discontinued and nonevaluable for efficacy due to lack of follow-up
Patients who did not filfill the evaluability criteria outlined in Section 11.G.were
considered nonevaluable for efficacy. In certain circumstanc&, ftilure to Satisfi
the entrance criteria in Section 11.D.did not exclude patients from the anaIysesof
evaluable patients if the evaluability cnteti
were satisfied.
The inclusion criteria
required that the time period from diagnosis (i.e., positive stool exam) to
initiation of therapy not exceed 14 days. In practice, this was ofien not possible.
Because the naturaI history of strongyloidiasis is one of persistence over time,
patients who received study drug therapy within 30 days of a diagnostic stool
examination were considered evaluable. Furthermore, 1 patient
, single-
dose ivermectin) had four of four positive stool examinations from Study
Day -102 to Study Day -71.
Because of the highly reproducible mture of this
patient’s itiection
status, this patient was also considered evaluable.
Five
patients
in the trial were
HIV-positive;
some patients
had a histo~
of
opportunistic infections. None of these HIV-positive patients had any evidence
of extra-gastrointestinal disease. Because enrollment of patients with underlying
disease who meet ent~ criteria is at the discretion of the investigators, these
patients were considered evaluable. Lastly, patient
(4 years, IO months
old at randomization) was considered evaluable despite an age of less than 5
years old at entry.
All patients in the two-doseivermectin(17)
and the thiabendazde (15) treatment
groups were considered evaluable.
Two patients (2/17, 11.8%) in the single-
dose
ivermectin
group
were
considered
nonevaluable
for
efficacy.
The
t!iiferences in patient evaluabtity among the three groups were not statisticzdly
si~”ficant.
The 2 patient exclusions in the singledose
ivermectin group
were lost to follow-up prior to any posttreatmentoutcome
evaluation and were excluded from analysis of efficacy.
Three patients
- twodose
ivermecti~
tiiabendazo]e)
received antinematode therapy during the 3-month period prior to entry into the
study.
MK4933WC350.IXX
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c
57
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
-16-
en~
and had muhiple positive stool examinations for StrmgyIoides stercmalis
prior to initiation of study drug.
Therefore, these patieq~s were considered
evaluable.
It is recognized that these changes in enby and evaluation criteria differ from the
requirements
of the protoco~
however, they are considered
by MRL
as
consistent with the treatment of patients w-th strongyloidiasis given the natural
history of the disease. In additioq with the exception of the 2 patients .
in the singledose
ivermectin group who were excluded from the
efficacy analysis (outcome in these patients could not be rendered), no data are
excluded from the analysis of efficacy or safety. & such, MRL believes that the
alterations from the protocol as specified above do not impact on the validity of
the results of this study.
C. E~cacv
Ten of 15 (67%) evaluable patients in the single-dose iverrnectin group were cured
compared to 14/17 (820A) in the two-dose ivermectin group and 13/15 (87Yo) of
patients treated with thiabendazole.
There was no significant difference between
treatment groups in the proportion of patients cured. A patient’s likelihood of cure
was not significantly related to age, se% race, or intensity of infection.
Cure rates
with 95°/0.confidence intewals for treatment groups and vmious subgroups are
contained in Table 7.
..-’
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MK-0933 Prot. No. 020
Ivennmin
vs. Thiabend~ole
-17-
C. E~aq
(ConL)
w
Cure Rate - Evaluable Patients
rvcrmecfj~
oneDose
cn
N
I
Tw Doses
I
mjb~m
14
I
Ovaall
sex
Male
Female
Race
Cmlcas&
Black
Mulatto
kn.sity
of~~”m-
2+
3+
4+
-i
15
(3?87
13
(46794)
2
0
2
100
2
50
11
(32:8)
6
(M:99)
7
(2:88)
2
50
I
17
16
1
4
0
13
6
4
7
(56,?5;
(s4:;5)
100
100
0
(46,74)
(24;;4)
75
100
I
.
.
t3
10
3
3
0
10
8
2
3
12
(s1,$7)
3
(&&l
3
100
(29,100;
o
0
12
(s1:;7)
10
(4A)
2
100
3
100
-.
-—
-.
AS sWd
t?dier (Section II. F. of this r~fi),
par-@to]o@d
~
~
fie pd
measure of efficacy. Although the protocof reqtird
folJow-up stool examinations at
D~
5 to 9, 16 to 19, 26 to 34 nd
at h-fon~
3 ~d
6, fi ~
r-
tier
fhdiz#ion
of the protocol that this design was not appropriate for an area of hi@
endem-ti~
because the risk of reinfdon
was considerd
to be high over this
extendd
period (i.e., greater than 1 month).
.7.
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e“
53
MK-0933 Prot. No. 020
Ivermectin vs. TIiabendazole
-18-
C. Ef@w(Con
t.)
Many patients (72%) had follow-p
stool examinations beyond posttr=tment
Day 31. Among these patients, there was a mean fo[low-up period of 124 days (93
days Postday31)
with a mean of 5.4 stool examinations beyond Day 31. For those
ultimately found to have positive stool examinations for S. sfercoralis Iarvae during
extended follow-up, it is not possl%leto distinguish between relapse and reinfection.
For this reasoq outcome at Days 28 to 36 is considered the primaxy measure of
efilcaey.
In order to estimate a “worst outcome” cure rate, effieaey was also evaluated by
desigmting all patients with any positive stool examination at any posttreatment time
point (beyond Day 5) as treatment ftilures, By this criteri~ 10/15 patients (67%) in
the singledose
ivermeetin group,
10/17 (59%)
of patients
in the
two-dose
ivermectin group and 9/15 (60°/0)of patients in the thiabendazole treatment group
were
cured.
As in the primaxy definition of effieaey, there was no significant
difference between treatment groups in the proportion of patients cured and no other
factor was
significady
predictive of outcome.
Although
Postday
31 stool
examinations were performed, none of the HIV-positive patients enrolled in the
study ftikd therapy using this “worst ease” definition. Agai% this data is presented
“for information purposes” only since in this highly endemic area one could not
distinguish between relapse and reitiection.
A quality-assurance audit was performed by the MRL Clinical Quality Assurance
Resources at the study site 3 years after the completion of the trial (reference - Audit
Information Sheet, Appendix 3). The audit indicated certain regulatory compliance
issues relating to source documentation and monitoring. Exampies of audit findings
included:
1,
2.
3.
4.
Source document Iaboratoxy results for hematology, blood chemishy, urinalysis
and parasitological stool resuks were unavailable.
Numerous workbook to CRF transcription errors were noted in the reporting of
total eosinophil counts for some patients.
There were no records of prestudy pregnancy or ECG results as required in the
protocol imlusionkxclusion
crittia.
I-
assay results for tests which were to be performed by the NH
as pafl of a
,
substudy of this protoml were never repmted.
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u—Lub
L
6
-
66
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
.
c.
D.
-19-
Efficacy (Cont.)
5. The ERC approva! of the study was based on a draft protocol and not me final
version.
6. There was no routine monitoring.
The lack of a complete file of source documentation at the investigative site does not
impinge on the integrity of the itiormation originally received from the investigator
during the conduct and subsequent completion of this study some 3 years before.
Nor does it compromise the information used to produce this’ MRL summary.
Despite these GCP-related
findings, MRL believes that the basic scientific and
medical conclusions drawn from this study and described in this summary are valid.
SafeW
All 49 patients were evaluated for safety and tolerability.
1- Adveme Experiences - Clinical.
a. Overall Assessment of Clinical Adverse Experiences
Table 8 below is a summary of the clinical adverse experiences (AEs).
Table 8
Clinical Adverse Experience Summary
I
Iverrnectin
I
Ivennectin
I
Serious Cliical AEs
I
o
Dismntinuations Due to
I
o
Clinic.al
AEs
Drug-Related Clinieal AEs
o
Two-Dose
JHZl-
2(1 1.8%)
o
0
0
Thiabendazole
(’N=15)
9 (60.0%)
o
0
9 (60.0??)
.,,
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D–2613
—
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
D. Safety (ConL)
The difference in the incidence of clinical adverse experiences (AEs) between
he singledose ivermectin group and the thiabendazole group was significant
@KO.001) as was the difference between the twodose
ivermectin and
t.hiabendazole groups
(p=O.008).
There was no statistically signiikant
difference in the incidence of clinical AEs between the two ivermectin
treatment groups Q+I.48).
There were no serious clinical AEs and no
discontinuations due to clinical AEs.
Table 9 lists clinical AEs by body system.
The difference in the incidence of clinical adverse experiences considered by
the investigator to be possibly, probably, or definitely drug related between
the thiabendazole treatment group and each of the ivennectin groups was
statistically significant (pzO.001 for each comparison).
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D -2614
-..
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
D. Safety (Cont.)
-21-
—
Table 9
Cliical Adverse Experiences by Body System
-
.
Ivermectin
Iverrnectin
Thiabendazole
Body System/
Single-Dose
Two-Dose
Diagnosis
(N=17)
(N= 17)
(N= 15)
Patients with AE
o
2(1 1.8%)
9 (60.0??)
Body m a whole:
1 (5.9%)
5 (33.3%)
Malaise
5 (33.3%) [5]
Abdominal Pain
1 (5.9%) [0]
Digestive system:
2(11.8%)
2 (13.3’%0)
Nausea
2 (13.3%) [2]
horexia
1 (5.9%) [0]
Diarrhea
1 (5.9%) [0]
Nervous system
I
8 (53.3%)
psychiatric system
Dizziness
6 (40.0?!) [6]
!kadache
2 (13.3%) [2]
kritability
1 (6.7%) [1]
Wentalacuity decrease
2 (13.3%) [2]
%resthesia
I (6.7%) [1]
feltigo
2 (13.3%) [2]
;pecial senses:
1 (6.7Yo)
ris
1 (6.7%) [1]
Q.B.: Patient counts and event cmunts may not be the same since some patients may have
nore than one clinical AE event.
J Numbers in brackets are those patients who had clinical AEs which were considered
~ossibly,probably, or definitely related to study drug.
..
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D-2615
—.
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
D. Safety (ConL)
-22-
The clinical AEs reported for 2 patients in the twodose
ivemectin
group
were considered
not related to study drug.
One patient ~perienced anorexia
on Study Days 1 and 2 that was considered by the investigator to be probably
not related to study drug.
The second patient repofled abdominal pain on
Study Days 2 and 3 that was considered by the investigator to probably not
be drug related and diarrhea on Study Day 14 considered to be definitelynot
related to ivermectin.
All clinical AEs in the
thiabendazole
group
were
considered
by the
investigator to be drug related (i.e., possibly, probably,
or definitely).
Psychiatric/nervous system complaints accounted for the most commonly
affected body system with 8 patients (53.3% of patients in the group)
reporting adverse events in this category. Six of the 8 patients (40.0°Aof the
patients in the group) reported dizziness, making this the most frequently
repofied clinical AE among patients treated with thiabendszole.
Each patient who entered the trial was asked to give an overall tolerance
assessment of their treatment.
Seventeen of 17 (100°/0)patients in the single-
dose ivermectin group found the treatment to be “well tolerattxl,” compared
to 17 of 17 patients (100%) in the two-dose ivermectin and 6 of 15 patients
(40??) treated with thiabendazole.
The difference between each ivermectin
group and thiabendazole was statistically significant (pEO.001).
Serious Clinical Adverse Experiences
Therewere no adverse experiences thatwere consideredserious by eitherthe
investigatoror the clinical monitor.
Patients Discontinued Due to ClinicaI Adverse Exmxiences
No patient in this study was discontinued from study drug because of an
adverse experience.
2. &dverse Emergences- Laboratoq
a.
Overall Assessment of Laboratow Adveme Experiences
No laboratory adverse experiences were noted during the course of this
study.
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D–2616
MK-0933 Prot. No. 020
Iverrnectin vs. Thiabendazole
-23-
.
D. Safety (Cent)
3.
4.
5.
b. Serious Laborator-vAdverse Experiences
There were no serious laboratory adverse experiences during the course of
tbk study.
c
Patients Discontinued
Due to Laboratom
Adverse Experiences
No patients required discontinuation of study drug due to a laboratory
adverse experience.
Adverse Experiences - Other
There were no other adverse experiences.
ClinicaI Safetv Measurements
No clinically significant changes in clinical measures of safety were noted.
Laboratory
Safety Measurements
No consistent or significant changes in laborato~ measures of safety were noted.
IV.
IIISCUSS1ON
Ivermectin @ an 80:20 mixture of avermectin f31a and avermectin D]b, monocyclic
Iactones produced by the actinomycete Streptomycesavermitilis. While its mechanism
of action is not fi.dlyunderstood, ivermectin appears to exert its activity by inducing a
chloride current via a glutamate-gated
channel in the parasite resuhing in apparent
paralysis and death [11]. It is an orally effkctive antiparasitic agent that has been used in
veterinary medkine since 1981.
Based on its efficacy and excellent aafkty profile,
ivennectin
has achieved widespread
acceptance
as the
treatment
of
choice for
onchocerciasis (river blindness) [3].
During trials aimed primarily at establishing ivermectin’s efik.acy in onchocerciasis, a
number of uncontrolled obsewationa suggested that iverrnectin had significant act-hity
against a number of gastrointestinal
nematodes
[12].
These cliical
notes were -
consistent
with
the drug’s activity
in an
animal model
of atrongyloidiasis
[7J.
,
Subsequently, nonamparative
studies demonstrated that iverrnectin was an effective
,
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MK-0933 Prot. No. 020
Ivermectin vs. Thialxmdazole
-24-
(?”
65
IV.
DISCUSSION(CONT.)
agent against strongyloidiasis [8,9]. Based on these obsewat.ions asawell as the need for
a more effixtive, less toxic therapy in strongyloidiasis, several studies, including this
trial, were undertaken.
This comparative randomized trial evaluated ivermectin’s efficacy.
Inclusion criteria
selected for patients with heavy larval burde~ and a very sensitive techrique for parasite
detection was utilized. The primary measure of efficacy in this trial was the absence of
S. sfercoralis larvae on four posttherapy stool exams, the Iast examination being on
Days 28 to 36.
Although additional follow-up stool examinations were performed for
many patients, later time points were not used because of the increasing ambiguity
between reJapse and reinfection. In fact, reinfection could occur even before the Day31
time point, making this definition somewhat arbitrary. One month follow-up was chosen
as a compromise between minimizing the risk of reinfection and the need for a follow-
up period of reasonable length that
incorporated
an adequate
number
of stool
examinations. It is also uncertain how quickly a patient’s stool should be clear of laxvae.
A positive stool examination pefiormed prior to the first time point (Day 7) was not
considered sufficient to define a patient as having failed as long as at least four
subsequent examinations were negative.
Cure rates of 67V0 (singledose
ivermectin), 82’% (two-dose
ivermectin), and 87??
(thiabendazole) were observed, confirming ivemw%n’s activity in this infkction. While
the single-dose ivermectin group had a somewhat lower cure rate than the other
therapeutic groups, none of the difkences
in cure rates among the treatment groups
were statistically significant. The cure rates for both ivermectin treatment groups were
lower than those reported in one nommmparative study [8].
These difkrences
may
reflect the fotlow-up that patients in this study underwent or the possiile preelection
of
a patient population with a high intensity of infection based on the trial’s entry criteria.
Although efficacy did not differ among treatment groups, the incidence of clinical
adverse experiences was substantially lower among patients tiving
ivermectin.
NO
.
patient in the singledose
ivemwctin group had a clinical adverse experience compared
to 11.89’0of patients treated with two doses of ivermectii and 60?! of patients receiving
thiabendazole.
This higher incidence of adverse
events
among
patients
in the
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D–2618
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MK-0933 Prot. No. 020
Iverrnectin vs. Thiabendazole
-25-
IV.
DISCUSSION
(CONT.)
This difference was magnified when only those adverse experien~s
considered by the
investigator to be drug-related (possibly, probably, or definitely related to study drug)
were considered.
None of the adverse clinical events in the ivermectin groups were
considered
drug-related
compared
to
all
the
events
in
patients
treated
with
thiabendazole.
It is not possible to exclude some bias in the interpretation
of the
relationship between reported symptoms and drug therapy. It is important to note that a
statistically higher incidence of adverse experiences was present when all events were
considered regardless of relationship. The safety profile for thiabendazole seen in this
study is also consistent with other published reports [3,4].
In onchocerciasis, many of the adverse effkcts that occur atler ivermectin treatment are a
result of the patient’s immune response (Mazzotti reaction) to dead microfilariae and
usually appear wittin three days of the dose [13].
The severi~ of the response is
directly related to the initial intensity of 0. vofvuhs infestation. The lack of Mazzotti-
type reactions in this trial following treatment of strongyloidiasis is consistent with
previous experience and would be predicted based on disease pathogenesis.
A criterion for entry into this trial was that patients have strongyloidiasis limited to the
gastrointestinal
tract.
It is
not
possible to
extrapolate
ivermectin’s efficacy in
disseminated disease.
Several patients were HIV-infected, including patients with a
histo~ of opportunistic inf~ons.
While these patients responded well to ivermectin
therapy, the numbersof patients were small, and no conclusions regarding ivermectin
efficacy in immunocompromised patients can be drawn from this study.-
(
CL
This study demonstrates that ivermectin is a generally well tolerated
and effective
therapy for strongyioidiasis of the gastrointestinal tract in immunocompetent patients. It
is associated with significantly fewer clinical adverse experiences than thiabendazole
with similar efficaq.
In additio~ ivermectin’s simple dosing regimen offers substantial
advantages over thiabendazole for patient compliance.
Overal~ the results of this tria!
suggest that ivermectin offixs a significant advance in the treatment of strongyloidhusis.
MW933U3C850.DOC
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D –2619
MK-0933 Prot. No.
020
Ivennectin
vs. Thiabendazole
-26-
V.
CONCLUSIONS
1. Ivermectin (200 mcgkg) as a single dose and as two doses on consecutive days and
thiabendazole (25 mgkg b.i.d. x 3 days) are effective therapies for Strongyloidiasis of
the gastrointestinal tract.
2. Ivermectin is generally well tolerated and associated with fewer clinical adverse
experiences than thiabendazole.
“
F. M. Ricci
Director
\
~.
Calandra, M.D., Ph.D.
T. tiO~
M.S.
Associate Director
CBARDS
Senior Director
Clinical Research
..-,
MK-0933WC850.IXIC
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-..
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
-.
-27-
VI.
LIST OF REFERENCES
1.
Strongyloidiasis
A Major Roundworm Infkction of Man E.&ted by David I.
2.
3.
4.
5.
6.
7.
8.
9.
Gove.
Published by Taylor & Francis.
Londo% New Yorlq and Philadelphi~
1989.
Neva F.
Biology and immunology of human strongyloidiasis.
J Infkct Ds
1986~:397+06.
Drugs for Parasitic Infections. Med Lett Drugs Ther 1992;34kue
865):17-26.
MINTEZOL@ (thiabendazole) Physician Circular, 1985.
MECTIZAN@ Program Notes, Published by MECTIZAN @ Donation Program,
One Copenhill, Atlant~ Georgi~ 30307, USA Issue 13 Mid-Year 1995.
White AT, Newland HS, Taylor ~
Erttmann KD, Keyvan-Larijani E, Nara &
Aziz ~
DAnna S~ Wdliams PN, Greene BM. Controlled tial and dose-finding
study of ivermectin for treatment of onchocerciasis.
J M&t
Dis 1987; 156:463-
470.
Mirck ~
van Meurs GK.
The &cacy
of ivermectin against Strongyloides
wesren”in foals. Vet. Quaxt 1982;5:89-91.
Naquira C, Jiienez
G, Guerra JG, Bemal ~
Nalin D% NW DC, Aziz MA
Ivermectin for human strongyloidiasis and other intestinal helminths.
Am J Trop
Med Hyg 1989@:304-9.
Freedman DO, Lujan ~ Nutman TB, Zierdt WS. The Efficacy of ivermectin in the
chemotherapy
of
gastrointestinal
helminthiasis
in
humans.
J
hfkt
Dk
1989;~(June
6):1151-53.
./,
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..
.-.
MK-0933 Prot. No. 020
Ivermectin vs. Thiabendazole
-28-
VI.
LIST OF REFERENCES (CONT.)
D –2621
(?
.
(5
10. Strongyloidiasis Laboratory Diagnosis of Infectious Diseases Principles and Practice,
~(102):979-986:
Bacterial,
Mycotic, and Parasitic Diseases,
Editors
Balows,
Hausler,
Ohashi, Turano.
Published by Springer-Verlag, New
Yorlq
Berli%
Heidelberg, Londo~ Paris, and Tokyo, 1987.
1I. fiena
J, Liu ~
Paress P, Schaeffer J, Cully D.
Expression of glutamate-activated
chloride cument in xenopus oocytes injected with C. elegans RNA
Evidence for
Modulation by Avermectin. Molecular Brain Research. 1992~:339-48.
12. Ivermectin and abamectin edited by William C. Campbell. Published by Springer-
Verlag,New York Berlin, Heidelberg,London, Paris,Tokyo, 1989.
13. Francis H, Awadzi ~
Ottesen EA.
The mazzotti reaction following treatment of
onchocerciasis with diethylcrubamazine: clinical severity as a function of infection
intensity. Am J Trop Med Hyg 1985;MQ):529-36.
.
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NDA 50-742
Page 70
Mectizan-’(Ivennec~in)
.
Strongyloidiasis
D. Medical officer findings.
As discussed above in the section entitled “Deviations horn protocol”, the medical officer agrees that
patients with a documented stool examination positive for SS at any time prior to enrollment are considered
evaluable. As mentioned, 10 of the 49 enrollees had> 30 days elapse between documentation of S-infection
and
enrollment in the trial. However, the medical oflicer cannot accept the outlier (patient-
whose only positive
stool pre-therapy is listed as being collected 102 days prior to enrollment.
The patient daa
by treatment group and day of parasitologic follow-up, are presented in the following
tables:
Disposition
and patient follow-up by treatment arm and patient number
Dreyer study 020
Timepoint
enrollment stool collected
>60 days pre-treatment
enrollment stool collected
>14 days but <60 days
pre-treatment
enrollment stool collected
s 14 days pre-treatment
total enrolled
.
day 7 (range 5-9)
post-initiation of therapy
day 30 (range 26-34)
day 90 (range 80-100)
day 180 (range 160 or
greater)
‘ootnotes:
Ivermectin
X 1
I
Ivermectin
X 2
I
Thiabendazole
o
0
(Patierl~
10
14
9
6
3
6
.
. . . .
17
I
17
I
15
14 (zero+)
17(1 +)
15(1 +)
14(4+)
16(1 +)
15(1
+)
,
6 (zero I+)
14(4 +)
13(5 +)
1
2 (zero+)
6( I +)
2 (zero+)
,
. .
..
. .
+ denotes positive stool for Strongyloides
stercoralis
by Baermann technique
0 denotes enrolled patient is HIV positive
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NDA 50-742
Mec[izm-’([verrnectin)
Page7 I
Slrongyloidiasis
If the criteria
for evaluabilit-yand cure that are discussed above are utilized (specifically, the requirement for three
consecutive negative stools to be called a cure, and the validity of the 30-day post-therapy timepcsintbecause of the
possibility of ‘re-infection),
the following results are obtained on a patient-by-patient
basis:
Medical officer evaluation of enrolled patients
by treatment group and patient number
Dreyer study 020
Patient#
Evaluable?
Reason
Cure?
Reason
Treatment arm:
Ivermectin X 1
yes
yes
yes
yes
no
yes
yes
yes
yes
yes
yes
yes
no
yes
yes
yes
no
Treatment arm:
Iverrnectin X 2
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
No
Yes
Yes
Yes
entry stool day -102
No
No
No
Yes
No
Yes
Yes
lost to flu
Yes
Yes
Yes
lost to th
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
+ Stool day 29
= stool Up to day I @
= StOOlUpto day 92
= Stool Upto day ]()I
+ stool day 29
+ day21; only 1= stool thereafter
~ stool day 29
- stool day 29
+ stool day 29
= StOO]Up to day 183
= stool Up to day 81
= stool Up to day 99
= stool day 25
- stOOlday 29
= stool Up to day 92
-
stool up to day ] 1s
- stool up to day ] ]s
=to&y87ti
= stool up to day 84
- stool up to &y 87 W
+day21; _X2;
+day 101
= Stoolup to day 183
= stool up to day 183
= Stool up to day 207
- stool up to day 28
= stool up to day !2!3
= stool up to day 93
_ stool up to day 85 d
‘t day 29
= stool up to day 29 d
- stool up to day 192
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NDA 50-742
Mcctizan-’ ([vcnnectin)
Page 72
SIrongyloidiasis
Medical oficer
evaluation of enrolled patients
by treatment group and patient number
Dreyer study 020
(Continued)
Patient #
Evaluable?
Reason
Cure?
Reason
Treatment arm: Thiabendale
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
Yes
Yes
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
= std
Up to day 19 I
= stool Up to day 94
+day
17,24; mday31-78d
= st~l
Up to day 93
+day31
= stool Up to day 186
= st~l
Up to day 94
= std
Up to day 92
= stool Up to day 94
= stool Up to day 93
_ stool up to day 29 V
= stool up to day 85 W
_ stool up to day 45 W
= stool up to day 82 V
yes
Yes
= stool up to da; 29
Footnotes:
O HIV+ enrollee
M reinfection or relapse (stools_
X 3 at or including day 30 but again positive at later follow-up)
The totals of the above chart are presented below:
Dreyer study 020
Results per Medical Oflicer
lvermeetinX 1
lvermectinX 2
Thiabendazde
Enrolled
Total
17
17
15
-
HIV i-
2
2
1
.,
Evaluable
per M.O.
14
17
15
Cure at day 30 (%)
9 (@%)
15 (88VO)
13 (87’%0)
Fail at day 30 (%)
5 (36%)
2 (12%)
2(13%)
Reinfections/reiaPses
o
(% of evaluables)
4 (24%)
5 (33%)
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NDA 50-742
Page73
Mectkan- (Ivcrmec[in)
.
Strongyloidiasis
Medical officer tindings: safety
[n the applicant’s summmary of the Dreyer study, a table on (applicant’s) page D-26 14 reveals that a
significantly higher number of thiabendazole-treated subjects reported clinical adverse experiences.~e
computerized patient-leveI data to corroborate these findings were included in the NDA submission (pages D-2795-
97) and were verified by the medical oflker.
As there were no deaths or discontinuations, nor were any events
considered serious in nature, no case report fotms were included in the NDA.
R is noteable that practically all of the adverse clinical events in the thiabendazole arm (19 evnets in 9
patients who reported them) were considered to be ‘definitely’ related to thiabendazole. This is somewhat striking;
investigators are not usualiy so adamant in their desire to ascribe causality. This would have been more convincing
had the study been conducted in a blinded fmhion.
The applicant reports that there were no Iaboratroy adverse experiences in this study. Patients were
assessed at one timepoint pre-therapy, and then once at day 7 or 8 post-therapy. Thus, the degree of follow-up is not
nearly as long-term as it was in the Gentilini study. Upon review of the submitted information, the medical officer
agrees that the investigator did not report any laboratory changes to be adverse events associated with study drug
administration. There were, nonetheless, several laboratory perturbations that were noted upon medical officer
review;
Subject #
lab finding (day of study)
Comments
lvermectin X 1
AST 17+43
(d7)
Thiabendazole
AST 18+38
(d8)
AST 17*43
(d8)
AST 19+38
(d8)
ALT 24+35
(d8)
,
WBC 4.7+ 2.2 (d7)
Ivermectin
X 2
AST 26+44
(d8)
AST 17+43
(d8)
AST 20+38
(d8)
Thus it can be seen that the only laboratory effects of ivermectin that were seen in this smaIl study with limited
laboratory followup was mild elevation in transaminases, particularly AST. This observation holds for thiabendazole
as well as both ivermectin atms. There were no appament perturbations in WBC count among the ivermectin-treated
subjects in this study, as were noted previously in the Gentilini study. The lack of laboratory follow-up past&e day
8 post-therapy timepoint makes it difflcuh to make any firther comment on this matter.
.,.
—
.
—
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NDA 50-742
Page74
Mectizan-’(Iverrnectin)
.
Strongyloidiasis
5. Study 014 (Berk) and 015 (Gann): An open, randomized study of the efficacy, safety. and tolerability of
ivermectin single dose and repeat dose (one day apart) vs. Thiabenda.zole (three-day course) in the treatment of
patients infected with Strongyloides
stercoralis.
These two studies were conducted in separate Ioeations but utilized comparable protocmls. Both study sites are in
the United States. Both utilized Baennann technique for processing of all stool speeimens. TimePoints of follow-up
were relatively comparable. On this basis, it would seem to be reasonable to combine the two studies.
The following summary of these studies is taken from pages D-2983 thru 2996 of volume 1.23 of the NDA
submission:
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D –2983
6’.75
MK-0933 Prot. No. 014/015
Dr. Berk and Dr. Gam
.
COMPREHENSIVE STUDY SUMMARY
An Open, Randomized Study of Efficacy, Safety, and Tolerability OF
Ivermectin Single Dose and Repeat Dose (One Day Apart) vs. Thiabendazole
(Three-Day Course) in the Treatment of Patients Infected With StrongyZoides
Stercoralis
I.
BACKGROUND
Tens of millions of people around the globe are currently
infixted
with Strongyioidks
stercoralis [1].
It is ~despread,
not only in moist rainy areas of the tropics and
subtropics, but also in some areas of southern and eastern Europe and Southeastern
United States.
StiongyIoides stercoraIis is an intestinal nematode that. usually causes a
limited intestinal infection.
Patients may remain asymptomatic but recurrent cutaneous
and gastrointestinal symptoms are common.
The intestinal disease is rarely fatal and
usually associated with eosinophilia.
Strongyloidiasis begins when inkctive larvae in contaminated soil penetrate intact skin
and cause an itchy e~hematous
rash at the point of entry. The larvae are then carried
in the bloodstream to the lungs where they ascend the bronchial tree before being
swal!owed.
They then enter the small intestine where they penetrate the mucosa and
mature into adult worms.
Eggs shed by fernale worms are transformed into lawae that
are excreted in the intestinal lumen. Most larvae are excreted in the stoo~ but some may
penetrate the mucous membrane of the lower bowel or perianal skin resulting
in
autoinbstion which intensifies and perpetuates the intestinal colonization [2].
This phenomenon of autoinfixtion is unique to S. sfercoralis and is not found in the
other nematode parasites commonly infecting humans. In this fo~
the dkease can be
perpetuated for an indefinite period of time.
World War II veterans who had been
fomwr prisoners of war in Southeast Asii as well as Vktnam veterans have been
diagnosed as having strongyloidiasis without being tier
exposed for periods of over
40 years [1].
Thiabendazole (TBZ) has been the “dreg of choice” for treatment of strongyloidiasis fir
almost 30 years since it has a wide range of action and is readily absocbed from the G.I.
-
tract.
However, it also is responsible for fkquent
and sometimes serious side effects
[3,4]. Albendazole, a more broad sp-m
anthehnintic, has efficacy in strongyloidiasis
-’
similar or slightly inferior to that of thiabendazole.
Albendazole is, however, better
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—..
D –2984
MK-0933 Prot. No.014/O15
Dr. Berk and Dr. Gann
-2-
1.
BACKGROUND (CONT.)
tolerated than thiabendazole.
Both drugs require administration of multiple dos=
[3].
Treatment failures occur with both albendazole and thiabendazole and a few patients are
not cured even when treated with increased amounts of drug for a rong time. A single-
dose drug with fewer side effects and increased efficacy would be usefid in the treatment
of strongyloidiasis.
Ivermecti% a derivative of avermectin 13,is an orally efikctive microfilaricidal agent.
It
has now been proven to be the current drug of choice for treating patients infected with
the nematode Onchocerca wbulus, which is a major cause of blindness .in inhabitants of
tropical areas [3].
More than 5.2 million people worldwide have received at least one single oral dose of
ivermectin at levels up to 200 mcg/kg for onchocerciasis [5].
Ivermectin given as a
single oral dose of 100, 150, or 200 mcgkg
has been found to be a relatively safe and
ef%ctive microfilaricide reducing O. vofvzdusskin rnicrofilaxiae counts
to near zero for
up to 12 months [6]. Based on the safety and tolerability evaluations from these studies,
150 mcg/kg was judged to be the optimal oral dosage [6]. Ivermectin was approved by
the French Regulatory Agency for the treatment of onchocerciasis in October 1987.
There is substantial evidence to suggest that ivermectin may be a usefid therapeutic
alternative for treatment of strongyloidiasis.
Ivermectin has demonstrated activity in
animal models of infection [7].
More importantly, ivermectin has been shown to be
effixtive against human strongyloidiasis in noncomparative studies [8,9].
Ivermectin
was well tolerated
and a single dose demonstrated
good activity.
Based on this
experience, we have undertaken a randomized, comparative trial of ivemwctin versus
thiabendazole in the treatment of Strongyloidiasis.
11.
SUMMARY OF PROTOCOL AND STUDY PROCEDURES
Protection of Human Subkets
This study was conducted
in conformance
with applicable
coun~
or
local
requirements regarding
ethical committee
review, itiormed
amen;
and other
statutes or regulations regarding the protection of the rights and welfwe of human
subjects participating in biomedkal research.
.m4933wc&.Doc
....
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D –2985
-.
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. GaM
B.
-3-
Investizators
Steven Beriq M.D. and C. Donald Howe, M.D.
Protow~014
East Tennessee State University
Veterans Administration Medical Center
.
Johnson City, Tennessee 37614
Peter ~
M.D. and Franldin Nev~ M.D.
-.
Protocol 015
Lowell General Hospital
“Lowell Community Health Center
c.
Lowell, Massachusetts
01852
Objectives
It should be noted that the primary objectives of the two protocols being combined
in this report were identical in the expressed need to measure efficacy, safety, and
tolerability of one or two oral doses (200 mcglkg) of ivermectin compared to a
3day regimen of thiabendazole (25 mgkg bid.)
in the treatment of SfrongyIoides
sfercoralis. However, other treatment comparisons were listed among objectives in
each study that rendered the two protocols somewhat different.
These differences
do not affect repoxting on the cumulative experience for the primary objective stated
above. The differences may be summarized as foilows:
f .7-T’
MK-0933U3C64.DOC
.
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D –2986
MK-0933
Prot. No.014/015
Dr. Berk and Dr. Gann
-4-
C. Obiectives (Cent)
Gann
-...
Berk
Protocol Objective
(Study 015)
(Study 014)
Compare the efficacy, safety, and tolerance of
one or two doses of ivermectin (200 mcg/kg)
to 3 days ofthiabendazole (25 mghcg b.i.d.).
Compare declines in specific antibody titers
over a 12-month period for the treatment
groups specified.
x
x
x
Compare
the times
for
stool
to
become
negative for the treatment groups specified.
Compare treatment results in hyperinfection
syndrome for the treatment groups specified.
—.
Although the above objectives were listed in each of the protocols as indicated, it
was not possible to consistently execute measurements dealiig with the Study 015-
objective of antibody titers; and frequent stool collections and cultures required to
compare the time rate of stools beuxning negative for S. stercoraks could not be
consistently
executed
as required
in Study 014.
In additio~
“hyperinfkction
syndrome” was not encountered in Study 014 and therefore not addressed.
Thus,
ordy the objective comparing the efficacy, tiety,
and tolerance of one or two doses
of ivermectin (200 mcg/kg) to 3 days of thiabendazole
(25 mgkg
b.i.d.) was
consistently addressed in both studies and this summary is limited to this single
objective.
if
.-7%
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-.
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—.
D –2987
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gam
-5-
D. Patient Selection
.
Inclusion Criteria
1. Patients were between 5 and 80 years of age.
.
2. An examination of the stool samples done 2 weeks or less before entry into the
study was positive for StrongyIoidess!ercoraiis kwae.
-3. No clinical evidence of disseminated strongyloidiasis (Study 015).
4. No treatment
for strongyloidiasis
within the previous 6 months (Study 015).
Exclusion Criteria
1. Age under 5 or over 80 years.
2. Women of childbearing potential (unless they have a negative HCG).
3. Medical history of mental illness, seizure, or other serious illnesses.
4. Abnormal levels of SGOT or SGPT greater than twice above the upper normal
limi~ matinine
greater than 2.0 mg/100 mL or grossly abnormal BUN or urine
analysis,
5. A history of an abnormal EKG or EEG (Study 015 only).
6. Moderate or severe anemi~ i.e., hemoglobin less than 10 g or hematocrit less than
30%; any abnormality of white blood cell count and/or
differential (except
eosinophilia).
7. Any pastor concumnt
medical illness which the investigator feels might influence
either the outcome of the study or interpretation of the data accrued.
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U –2988
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gann
4-
E. !%udvDesire
General Description
This was an opq
randomizedstudy in ambulatorypatients whihad strongyloidiasis
evidenced by microscopic stool examination or by positive stool culture. Using a
local allocation schedule patients were randomized into one of three groups to
receive either ivermectin(single or two dose) or thiabendazole.
Although duodenal
aspirates ardor
jejunal biopsies were permitted in Study 014 these tests were not
routinely pdomwd
nor were they used as confirmation of strongyloidiasis.
Only
Baermann stool examinations were used to assess strongyloidiasis in patients in
Studies 014 and 015.
Although the study was open in desigq stool specimens were examined by one
single expefi who was to remain blinded as to the treatment allocations.
The safety of ivermectin was evaluated on the basis of physical examinations and
laboratory tests prior to treatment and on Day 7 posttreatment.
Study 014 allowed
for an additional physical examination on Day 30 posttreatment.
In the event that mild or moderate reactions occurred,
they
could
be treated
with
aspirin and antihistamines; other medications were not to be administered during the
first week of dreg. administration except for necessq
treatment of patients with
severe allerfjc reactions.
Patient Allocation
Atler completion of the itionned
consent
procedures
and documentation
of
strongyloidiasis evidenced by stool examimtio~ patients were randomized to receive
either single dose of ivenn~
two single doses of ivexmectin 1 day apart or 3 days
of b.i.d. dosing with thiabendazole.
During the week prior to the study, the patient was screened to assure that hckhe
was in good physkal condition.
The patient had a physkd
examination and a
laborato~ screen. VitaI signs were recorded on Day -1 (the day before or same day
but before drug administration), Day 1 (the first day of drug administration), and
7 days later.
..
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—.
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gann
IL Study Desire (Cont.)
Treatment
-7-
D –2989
if
.%
I
Ivermectin and thiabendazole (TBZ) were provided as 6- and 500-mg commercial
tablets, respectively. The dose cIosest to that calculated on the basis of body weight
was utilized in order to achieve the targeted dose of 200 mcgkg
of ivermectin or
50 mghq$day of thiabendazole. A schedule of recommended mmbinations of these
tabIets is shown on the following page (see Table I).
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—..
MK-0933 Prot. No. 014/015
Dr. Berk and Dr. Gann
-8-
Il. Study Desire (Cont.)
Table 1
Dosage Reeonunendation by Weight
-
—
Ivemectin DosageRecommendedTablet
Combinationsfor 200-mc*
Dose
Numberof
PatientWeight (kg)
Tabkts (6 mg)
15to 24*
%
I
25 to 35
I
1
I
I
36 to 50
I
1% I
I
51 to65
121
I
66 to 79
I
2!4
I
I
80 and over
I
3
I
MK4933WC64.DCW
Thiabendazole(MINTEZOL)DosageTablet
Combinationsfor Daily50-rng/kgDose
Numberof
Patient Weight 0%)
Tablets (500 mg)
13.3 to 22.2
0.25 (%tablet)
22.3 to 33.4
0.5
(1tablet)
33.5 to 44.5
0.75 (1%tablets)
44.6 to 55.7
1.0 (2 tabks)
55.8 to 66.8
125 (2%tablets)
66.9 and over
1.5
(3tablets)
G Range not specified in either protocol; however, range was
necessary to accommodate
children down to 5 years of
age.
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D -2991
MK-0933 Prot. No.014/015
Dr. 13erkand Dr. Gann
.
F.
-9-
Clinical C)bsewations and Laboratow Measurements
Table 2 shows the schedule of clinical observations and laboratory measurements
during the study. In additio~ the patient was questioned dail~@y phone) regarding
adverse experiences with particular attention to evidence of allergic reactions (rash
itching, and anaphylaxis).
Table 2
Schedule of Clinical Obsaations
and Laboratory Measurements
Drug Administration
PhysicalExamination
Vital Signs
LaboratorySafety
StoolExamination++
lgG(ELISA)” I
Pre-
stud
1
x
or
x
or
x
xx
xx
x
x
x
x
1
6
12
xx
xx
Eosinophilia**
xx
Prestudy
within
14daysoftreatment,
S1OO1examinations for Study 014wereto include Post&ys 7, 14,21, and 30
~
2
—
x
x
—r
Day 7
3
(5-9
x
x
x
x
x
x
—
1
—
x
—
-1-1
M.hs
then monthly for 1 yeaq however, investigator was notable to co~istently
execute this schedule.
Study 015 only however, investigator not able to consistently execute this
requirement.
The anaIysisof eosinophilia was for Study 015 only. Although results were
coliected and submitted to MRL by the investigator the analysis was not
performed by MRL. However, the investigator performed the malysis and
concluded that eosinophil IeveIs returned to normal in 90?? of all subjects
bv 12 months 1111
I
I
...”
.MK43933U3CWNC
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D -2992
MK-0933 Prot. No. 014/015
Dr. Berk and Dr. Gann
-1o-
( . 5’+
F.
.
Clinical Obsewations
and Laboratory Measurements (Cont.)
Observations and measurements related to efficacy and sakty are descriied below:
EtTmcY Measures
All stool specimens were examined by individuals who were blinded to the patient’s
treatment.
-Parasitological cure was the primary measure of efficacy and was assessed using
repeated Baermam stool examinations during the follow-up period,
Any positive
Baerrnann stool examination afier Day 6 was considered a treatment ftilure.
The Baermann technique [1O] is a method of examining a stool specimen suspected
of having small numbers of Strongyloides larvae and uses the modified Baermann
apparatus.
The technique is dependent on the migration of active larvae out of the
fecal material, through a wire gauze covered with gauze padding and into water,
where they settle out. The procedure is as follows:
a.
b.
c.
Fill a fbrmel (six-inch) with water (attach xubber tubing with a pinch clamp to the
bottom of the fimnel) and place the wire gauze, one or two layers of gauze
padding on it, on the fimnel.
Place 50.to
100 g of fd
material on the gauze padding so that it is coverti
with water. If the fkcal material is too firq break it up slightly.
Mow the apparatus to stand for 2 or more how
draw off 10 ML of fluid by
releasing the pinch clamp, spin it down in a centrifuge and examine the sediient
with a magnifier or low power microscope to count and confirm the species of
the larvae.
The lamd counts obtained from the Baermann technique arethe basis for evaluation
of efficacy. Counts were done for pucposes of quantifyingthe level of infestation
(itensity of infkztion) per patient and important only to determine comparabdity of
trt!atmerltgrOUPS and emnine
whether there is an interactionbetween intensity of
infiiion
and clinical outcome.
This approach was not specifically stated in the
“
protocol; however, MRL believes that such an analysis between intensity of infixtion
..
and outcome is vflld.
However, for purposes of assessing clinical efficacy, stool
MK-0933U3C64.DOC
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r
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D –2993
f
. %4
MK-0933 Prot. No.014/015
Dr. Berk and Dr. Gann
-11-
F. ClinkaI Observations and Laboratow Measurements (Cont.)
exams for larvae were recorded
only as positive or negative; no quantitative
assessment of the intensity of infkctio~ as reflectd
in the number of lravae, was
made.
The investigators omsionally
used “word” or “plus” designations to quantifj the
number of lmae.
The following convention was applied to “word” or “plus”
designations:
‘Word” Decimation
Larvae Counts/innStool
“Plus” Desijznation
Rare
1to 15
+
Few
16t030
*
Moderate
31toloo
-l-l+-
Heavy
>100
Safety Measures
A complete physical examination was done during the week preceding study drug
administration and 7 days posttreatment.
Prestudy and follow-up samples for the
laborato~ safkty studies on blood and urine included:
a,
b.
c.
Hematology:
~lood Chemistries:
Urinalysis:
Hematoerit
Hemoglobin
White blood ce!l count, total
Differential counts will be made if WBC is abnormally low
or high.
Blood urea nitrogen
Serum creatinine
SGOT (AST)
SGPT (ALT)
Total bilirubin
Alkaline phosphatase
Urinalysis was petiormed in patients with abnormal serum
creatinitte values or with signskyrnptorns
of urinaq
tract
infkction.
MK41933u3c64.Doc
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u -2994
(7
.%6
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gann
F.
G.
-12-
Clinical Observations and Laboratory Measurements (Cont.)
The investigator cmdd cany out additiomd analyses as required by the hospital-or as
indicated for optimum patient care.
.
Vital signs (blood pressure and pulse rate, both supine and erect, respiration rate and
temperature) were recorded on Day 1 and Day 7.
Evacuation Criteria
1. Evaluability
2.
MK-0933V3C64.DOC
All patients whose data were received by September 1992 were classified by the
MRL clinical monitor as evaluable or unevaluable with respect to efficacy.
These evaluations by the MRL monitor, although not specified in the protocol,
were in keeping with the dictates of the protocol (i.e., inclusion and exclusion
criteria) and the exercise of good clinical judgment.
Thus, patients were
considered ewduable for efficacy if
a.
b.
c.
d.
e.
Strongyloidiasis was documented on stool examination.
The patient did not receive other effective anthehnintic therapy during the
study period.
The patient was compliant with therapy.
Adequate follow-up stool examinations were pdormed
for determination of
efficaq.
See details in next section.
There was no violation of inclusion and/or exclusion criteria that would
compromise efficacy evaluation.
E!Eswi
The primary measure of efficacy in this study was the absence of lame
in
posttherapy Baermann fd
examinations.
Cure was defined as the absence of
-
lame
in the follow-up stool examinations.
The detection of huvae on any stool
examination past 6 days posttreatment met the delinit.ionof treatment failure.
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—..
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. GanrI
-13-
G. Evaluation Criteria (Cont.)
The original protocols called for a number of posttreatment stool examinations.
Although a 12-month foIlow-up was planned at both sit~s, this was primarily
related to a parallel serological study at one site (Study 015). Three- to 6-month
follow-up was the main goal.
In general, fill compliance with follow-up
examinations outlined
in Table 2 was not possibl~
therefore,
the criteria
summarized
earlier
(II.G.1. Evaluability)
was
established
for
evaluability.
Patients with stool sampIes that were positive for Sr?ongy[oiti% tierwralis
larvaeanytime after posttreatment Day 6 were considered evaluable for efficacy
regardless of the total number of posttreatment stool examinations.
It is recognized
that these
changes
in evaluation
criteria differ from the
requirements
of the protocol;
however,
they are considered
by MRL. as
consistent with the treatment of patients ‘with strongyloidiasis given the natural
histo~
of the disease.
As such, MRL believes that the alterations from the
protocol as specified above do not impact on the validity of the results of these
studies.
3.
Safety
AU patients were evaluated for safety by physical examinations and laboratory
studies.
In additio~
the patient was questioned daily for 3 days (by phone)
regarding adverse experiences with p~icular
attention to evidence of allergic
reactions (rash itching, and anaphylaxis).
Adverse experiences were described
and recorded by the investigator who determined the durations, seriousness,
severity, and drug relationship as well as the eventual outcome of each adverse
experience.
IL Statistieal Plannhw and Analysis
Methods of Analwis
The primary measurement of efficacy was the cure rate.
Logistic regression was
used to determine if any concomitant
factors,
i.e., age, se% racx, severity of
infkctio~ intensity of iqftztioq
tiected
the cure rate. None of these factors was
related to cure rate at the a=o. 10 level of significance.
Thus, all were dropped
--
from the statistical model, leaving only treatment ~oup.
The treatment groups were
compared for the proportion of patients who were cured using Fisher’s exact test.
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..
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D -2996
MK-0933
Prot. No. 014/015
L
Dr. Berk and Dr. Gann
.
-14-
H. Statistical Plannin~ and Analysis (Cont.)
Baseline characteristics were analyzed using either Fkher’s
exact test ~r
the
Chi-square test or the Wilcoxon Rink
Sum test, as appropriate.
Cordidence
intends
were cakzdated using the method of Blyth and StiUfor N>5.
All statistical
tests for treatment-group differences were two-tailed (a=O.05).
L
CIinical Surndies
-Ivermectin in the form of 6-mg tablets (Lot C-WO11 17420) wzi used in both
studies and obtained through MRL facilities in West Point, PA
Thiabendazole
(TBZ) tablets (500 mg MINTEZOL)
were obtained through local drug supply
houses [4].
—.
MK4933u3c64.DOc
.<
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NDA 50-742
Page 89
Mectizan”’(Ivcmsectin)
.
S[rongyloidiasis
B. Devaitions from protocol
Despite the similarity in protocol design an$ most importantly, the similar methods of stool collection and
evaluation, it should be pointed out that there are several important differences between these two s~dy sites:
.
the site for Dr. Berk’s study was East Tennessee State University and its affiliated Vetrans Administration
Medical Center. ‘llms, the enrolled subjects at this site were all elderly males, many of whom presumably
were infected during their military service in the Pacific or SE Asia. (It should also be pointed out that this
area of the United States is known to have low-level endemic strongyloidiasis. Therefore, although
extremely unlikely, these study subjects would be potentially subject to re-infection post-therapy.)
G
the site for Dr. Gann’s study was a community health center in Lowell Massachusetts, a community
with a
large proportion of its population composed of immignnts from Southeast Asia. This group of enrollees
were generally younger, evenly distributed with regards to sex, and with a single exception, entirely of
Southeast Asian(predominantly Cambodian) origin.
.
the Berk protocol allowed for the entry of patients with disseminated strongyloidiasis, because of the
demographics of the patient population at the VAMC study site; the Gann protocol specifically excluded
subjects with clinical evidence of disseminated strongyloidiasis.
G
the Gann study specifically sought to follow and analyze specific anti-strongyloides antibody titers over the
12 months following therapy, whereas the Berk study did not.
-.
The actual implementation of these studies was similar enough to allow for their combined analysis. However, the
difference in demographics is striking:
Demographics of enrolled subjects
Studies 014 (Berk) and 015 (Gann)
Investigator, I
Demo
Site
t
Males
Ber~
Terrtwsaec
Females
1-
Males
Gann,
Massachusetts
I
Females
‘aphics
Number enrolled
Avemge age &s)
Number of deaths
Number enrolled
Average age(yrs)
Number of deaths
Number enrolled
Average age (yrs)
Number of deaths
Number enrolled
Average age(yrs)
Number of deaths
Ivermectin X 1
4
72
0
0
10
38
0
8
30
0
Ivermectin
X 2
5
70
I
o
8
46
0
11
33
0
Thiabendazole
6
65
1
0
6
42
0
10
32
0
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NDA 50-742
Page 90
Mectizan” (Ivennectin)
SWongyloidia.sis
.
The relatively
small numbers of subjects enrolled by Dr. Berk makes the difference in these demographics less
concerning. Furthermore, although this site was looking to enroll patients with disseminated disease, the applicant
states that no such patients were enrolled. The two deaths noted in this group, patients
died at days 84
and 57 of the study, respectively. Neither of these deaths were considered to be diug related. Patient ~
had severe
underlying COPD and prostatic cancer; patient ~-
had coron~
artery disease and COPD.
-
Comment: the case report forms for these two deaths were not submitted with the NDA,
In general, these investigators were more compliant than the previously-reviewed studies regarding the protocol
requirements for maximum allowable time between documentation of a positive stool and enrollment in the study.
Both protocols called for a maximum of two weeks to elapse between these two events. Dr. Berk did not violate this
paramete~ Dr. Gann enrolled 8 subjects whose stools had been collected between 2 and 4 weeks pre-enrollment.
These 8 subjects were not excluded from the medical oftlcer analysis. One Gann patient ~
was enrolled 79 days
following her only pre-therapy stool collection; this patient was not considered evaluable for efficacy by the medical
officer.
C. Applicant’s tindings
The applicant’s summary of the results of these combined studies is found on the following pages, as
excerpted from pages D-2997 to D-3022, volume 1.23 of the NDA:
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MK-0933 Prot. No. 014/015
Dr. Berk and Dr. GanrI
111. RESULTS
A. Patient Characteristics
-15-
Summaries of demographic itiormation for evaluable patien~as
we[l as all patients
entered into the trial we provided in Tables 3 and 4, respectively.
A detailed
summary of each patient’s treatment may be found in Appendix 1 (Summary of
Therapy).
There were no significant differences in the characteristics
of the
treatment groups.
Of a!] patients enrolled in the study, 8 of 22 patients in the single-dose ivermectin
gToup had secondary diagnoses as did 15 of 24 in the twodose
iverrnectin group
and 12 of 22 patients receiving thiabendazole.
Although more than haIf of the
patients had secondary diagnoses, no single body system accounted for the majority
of the secondary
diagnoses recorded in these studies.
A summary table of patients
with secondag diagnoses maybe found in Appendix 2.
A majority of patients (13 of 22 in the single-dose ivermectin group [59. l%], 12 of
24 patients in the two-dose ivermectin group [50.0%], and 15 of 22 patients in the
thiabendazole group [68.2VO))received concomitant therapy during the study.
No
patient received concomitant therapy with activity against S. sfercorak
Two
patients were treated
with prednisone.
C’(Study
015) was chronically
receiving 5 mg of prednisone per day and was considered evaluable. -(Study
014) was “treated with 30 mg of prednisone daily, which was considered potentially
immunosuppressive,
and was considered nonevaluable based on this concomitant
therapy.
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D -2998
(f-g2-
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gam
-16-
A. Patient Characteristics (Cont.)
Table 3
Patient Characteristics - Evaluable Patients
4
lvenne.ctin
One Dose
Two Doses
lliabendazole
Number of Patients
14
19
17
Study (ProtocoI)
Berk (014)
2
1
2
Gann (015)
12
18
15
Mean Age
40
42
42
Sex
Male [Age Range-Years]
9 [17-79] (64%)
7 [25-62] (37%)
8 [25-72](47%)
Female [Age Range-Years]
5 [2145 ](36%)
12 [17-50)(63%)
9 [8-56] (53%)
Race
Caucasian
2 (14%)
2 (11%)
2 (12%)
Southeast Asian
12 (86%)
17 (89Yo)
15 (88%)
htensity of Infixl.ion
1+
4 (29%)
4 (2 IYO)
3 (18%)
2+
2 (14%)
5 (26%)
4 (24%)
3+
2 (14%)
3 (16%)
6 (35%)
4+
6 (43%)
7 (37%)
4 (24Yo)
:Ollow-up stool Exam
Mean Number
4.9
4.6
4.3
Mean Duration (Days)
274
288
289
hre
wem no significant differences between treatment groups.
..
...-.
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MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Ga.n.n
-17-
.
A. Patient Characteristics (Cont.)
Table 4
.
Patient Characteristics - All Patients
.
Iw-metin
OneDose
Two Doses
Thiabendazole
Numberof Patients
22
24
22
Study (Protocol)
Berk(014)
4
5
6
Gann (015)
18
19
16
MeanAge
41
45
44
Sex
Male [AgeRange-Years]
14[17-79](64%)
12 [25-81](50%)
12 [25-86](55Yo)
Female[AgeRange-Years]
8 [1845 ](36%)
12 [17-50](50YO) 10[8-56)(45%)
Race
Cau&sian
4
(18%)
(25%)
(27%)
southeast Asian
18
(82%)
1:
(75%)
1:
(73%)
Mensityof Infection*
1+
6
(30%)
7
(32%)
5
(23%)
2+
2
(10??)
5
(23%)
6
(27%)
3+
3
(15%)
3
(14%)
6
(27%)
4+
9
(45%)
7
(32%)
5
(23%)
:Ollow-upstool EXam
MeanNumber
3.9
4.3
4.3
MeanDumtion (Days)
240
237
244
‘ Intensityof inf&lion may not have been necmled fir certain patients (as m the ease of a
negative pretreatment stool examination). Percentages relative to tots! number with
pretreatmentintensityof infkctionrecorded.
lkre wereno significantd.ifferen= betweentreatment groups.
<
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(1
&--
.....
MK-0933
Prot. No. 014/015
Il. Berk and Dr. Gartn
-18-
B. Patient Accounting
1. Accounting for Patients in the Study
TabIe 5 is a summary of patients who entered, completed, ‘id
discontinued the
study by treatment group.
Table 5
Accounting for Patients in the Study by Treatment Gfoup
..
Patients
Total Patients Entered
Total Patients Completed
Total PatientsDiscontinued
AdverseClinical Experience
AdverseLaboraloIYExperieno?.
Lost to Follow-Up
Patient Death
Patient Uncooperative
No ThCfapCUtiC Response
No Therapeutic ResponscJDeath
Ivermeetin
l-Dose
22
11
11
0
0
9
0
2
0
0
Ivermectin
2-Dose
24
19
5
0
0
4
1’
0
0
0
Thiabendamle
22
-
15
7
1
0
3
0
1
1
12
I
I
,
‘ Study 014,~
Patient actually completed treatment course and died 57 days posttreatment of
background diseasa (coronary artery disease and chronic pulmonary disease).
z Study 014, ~patient
considered to have no therapeutic response and died on Study Day 84 as a
red
ofunderiying @l10
nary di~,
the death was consideredto be not drug related.
.
2
Accountability for Patients in the Analvsis
Table 6 is a summary of the number of patients who were included m the
analyses of efficacy (evaiuable patients) and safety.
./’”
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MK-0933 Prot. No. 014/015
Dr. Berk and Dr. Gam
-19-
(’”
‘3s
.
B. Patient Accounting (Cont.)
Table 6
Accounting for Patients in the Analysis by Treatment G&p
.
Ivermectin
Ivermectin
Patients
I-Dose
2-Dose
Thiabendazole
Evaluablefor Eflkacy Anatysis
14
19
17
Nonevaluablefor EfficacyAnalysis
8
5
5
I&son
for Nonevaluability for Efficacy
Analysis:
Pretreatment Stool Exam. Negative
2’
22
0
Inadequate Follow-Up Parasitology
53
3s
34
Pretreatment StoolExam. >30 days
16
0
0
Patient Discontinued Too Early
o
0
17
Patient on High Dose
o
0
)s
hnrnunosuppressiveTreatment
Evaluablefor Safety Analysis
22
24
22
Patient Identities (Study/AN):
MK4933WC64.DOC
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——
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(?”
56
MK-0933 Prot.No.014/O15
Dr. Berk and Dr. Gam
-20-
B. Patient Accounting (Cent)
A total of 68 patients were enrolled in the trial (ivermectin one dose -22, ivefiectin
two
dose -24,
thiabendazole - 22).
AU 68 patients are included in the safety
analysis; however, 50 (74°/0)are included in the efficacy analysis.
Patients
who did not fidfill the evaluability
criteria
outlined in Section
XX.G.1. were
considered nonevaluable for efficacy. In certain circumstances, ftilure to satisfy the
entrance
criteria
in Section
11.D. did not necessarily exclude patients from the
‘analyses of evaluable patients if the evaluabili~ criteria were satisfied. The inclusion
criteria required that the time period from diagnosis (i.e., positive stool exam) to
initiation of therapy not exceed 14 days. In practice, this was not always possible.
Because the natural history of strongyloidiasis is one of persistence over time,
patients who received therapy within 30 days of a diagnostic stool examination were
considered evaluable.
It is rwognized
that these changes in entry/evaluation
criteria differ from the
requirements of the protocols; however, they are considered by MRL as consistent
with the treatment of patients with strongyloidiasis given the mturaI history of the
disease. As such, MRL believes that the alterations from the protocols as specified
above do not impact on the validity of the results of this study.
The study protocols
allowed the investigator to determine whether
a patient’s
underlying disease or concomitant therapy would interfere with evaluation of study
outcome (i.e., exclusion critefi).
Two patients enrokd
in the study received
concomitant steroid therapy.
One patient (Study 015, ~was
chronically
treated with only 5 mg of prednisone per day; this patient was considered evaluable
because of the low daily steroid dose. Study 014,~30
mg prednisone per day)
was considered an aweptable study candidate by the investigator.
The patient was
enrolled
in the
study
and
f~ed
thiabendazole
therapy.
Because
of
&dy
immunosuppressio~
this patient was considered nonewduable by the Merck clinical
monitor (this MRL decision was made independent of the clinical outcome for this
patient).
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f) –3003
MK-0933
Prot. No. 014/015
Dr. 13erkand Dr. Gann
.
-21-
B. Patient Accounting (Cent)
The daily doses of ivexmectin and TBZ were based on each patient’s body weight.
Ivermectin and TBZ were supplied as 6-mg and 500-mg tablet$ respectively, both of
which are scored to allow administration of half tablets.
Individual doses were
determined using Table 1 in Section I’I.E. These dosing guidelines were designed to
achieve as close to 200 mcg/kg/dose
and 50 mgkglday
as possible within the
physical Iirnits of tablet administration.
Ivemectin
was administered as single daily
doses for 1 day or on 2 consecutive ,days.
AN patients randomized to receive
-thiabendazole were treated b.i.d. for 3 days. With the exception of 1 patient (Study
$e%
aJlpatients received dosages
consistent
w-th those recommended
in
was somewhat underdosed having received a maximum of only 33
mg/kg/day
of thiabendazole
on
1 day
and a minimum of .22, mg/k*
of
thiabendazole on 2 days.
This patient was considered a clinical cure having had
repetitive
negative
stool
examinations
from
1 week
posttherapy
to
1-year
posttherapy. ~
was considered evaluable for efficacy.
Several patients had minor modifications or errors in their thiabendazole dosage
regimen,
(both in Study 015) received their sixth doses of
thiabendazole on Study Day 4 rather than on Study Day 3.
(Study 015)
received her last dose of thiabendazole on Study Day 5 rather than Study Day 4.
(Study 015) was moderately underdosed.
It appeared unlikely that any of
these irregularities would significantly impact the patients’ outcomes and no patient
was considered nonevaluable solely on the basis of these dosing modifications.
A single patient (Study 014,
was inappropriately recentered into the study
following a therapeutic failure with thiabendazole.
He was assigned a new allocation
number
and was re-randomized to be retreated with thiabendazole that was
again ineffective.
Because
patient re-entry
is not allowed
and because
the
experience represented by
is not an additional independent obsewatio~
is not considered an additional patient entry. Therefore
is not included in any
analysis.
Safkty data from
is considered to be a part of the continuing
observation for
To insme W] availabtity of dam
tionnation
collected
during the patient’s treatment
as
is included in tabulated information as a
-
second treatment phase for
MK-0933U3C64.DOC
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MK-0933
Prot. No. 014/015
Dr. 13erkand Dr. Gann
-22-
(?”
5 ‘o
B.
c.
Patient Accounting (Cont.)
Overal~ 14 of 22 patients (63.6%) randomizedto receive single-dose iverm~
19
of 24 patients (79.2Yo) in the twodose
ivenmctin treatment group and 17 of 22
patients (77.3%) assigned to thiabendazole treatment were considered evaluable for
efficacy.
There were no significant difkences
among
percent of total patients considered evaluable for efficacy.
treatment groups in the
1. Evaluable Patients
All evaluable patients (14/14) in the singledose
ivennectin group were cured
(100%)
compared to
18 of
19 patients (95%)
assigned to the
two-dose
ivermectin group and 16 of 17 (94Yo)of patients receiving thiabendazole.
There
were no signifkant differences between treatment groups in the proportion of
patients cured. Cure was not significantly related to age, se~ race or intensity of
infkction.
Table 7 contains the cure rates and 95% ccmtldence intemak
for
evaluable patients.
The mean number of posttreatment stool examinations and total duration of days
included in the follow-up period also did not differ among treatment gToups.
2. All Patients
For
the
analysis
of
efficacy
for all patients,
patients
without
adequate
posttreatment stool examinations were excluded as well as patients with negative
pretreatment stool examinations.
Thus, the following patients were excluded from the “all-patients” analysis of
eificacy
.
For simdedose ivennectin:
014/005 -
015/233 -
015/301 -
015/389 -
Negative pretreatment stool examination
No follow-up stool examination
No follow-up stool examination
Negative pretreatment stool examination
,.’
MK4933U3C64.DOC
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u
—2UUJ
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gann
-23-
C.. Efllcacv
(ConL)
.
For two-dose ivermectin:
014/006 - Negative pretreatment stool examination
.
015/262 - Negative pretreatment stool examination
.
For the thiabendazole RTOUP:
014/01 1 - Only posttreatment Day 9 stool examination
014/01 6 - No follow-up stool examination
MK-0933W64.DOC
Thus, in the group of patients with adequate pretreatment
and posttreatment
stool examinations, 18 of 18 (1OO??O)
patients in the single-dose ivermectin group
were cured compared to 2 I of 22 (95°/0) patients in the two-dose
ivennectin
treatment group and 18 of 20 (90’XO)patients assigned to receive thiabendazole.
The mean number of posttreatment stool examinations and total duration of days
included in the follow-up period also did not differ among treatment groups.
There was no significant difference between treatment groups in the proportion
of patients cured.
Cure was not significantly related to age, sex, race, or
intensity of infection.
Table 8 contains the cure rates and 95’% confidence
intends
for all patients with adequate follow-up stool examinations.
. ..
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d“”.
---
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gann
-24-
C
Eflkacy (ConL)
Table 7
Patients Cured - Evaluable Patients
.
MKJ3933Bc64.DOc
..
Ivcrmuxin
OneDose
TwoDoses
llliabcndazolc
cure
N
PCT
Cure
N
PCT
cure
N
~
OVaall
14
14
100
18
19
95
16
17
94
(58,100)
(72,100)
(69,100)
study
Bak
2
2
100
1
1
100
1
2
50
Gann
12
12
100
17
18
94
15
15
100
(53,100)
(72,100)
(58,100)
la
Male
9
9
100
7
7
100
7
8
88
(43,100)
(34,100)
(51,99)
Fanale
5
5
]00
1]
]2
92
9
9
100
(63,99)
(43,100)
km
Caucasian
2
2
]00
2
2
100
1
2
50
southeastA5iarl
12
12
100
16
17
15
15
100
(53,100)
(70?00)
(58,100)
maay ofIx&ion
]+
4
4
100
3
4
75
3
3
100
2+
2
2
100
5
5
100
4
4
100
3+
22
100
3
3
100
5
6
83
(36,99)
4+
66
100
67
86
44
100
(28,100)
(28,100)
herem
no Significafltdimrcnccsbctwcultnatmalt groups
= 95%aIlfmenCeintaval (for Ibs).
02FEB96
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~-0933
Prot. No. 014/015
Dr. Berk ~d Dr. ~
c. “-
(COn~)
-25-
‘d~~te
FmJfi...
up &OO] E=nation-
.
/In/.-I(62”W
‘ /‘L&o)
10
11
..
—__
—
—.
-.-. -.-,.
-
.,.-.—..—..
-.—.
.
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IJ —3UU0
.
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gann
-26-
C. Efllcacv (ConL)
A qualhy assurance audit was pdormed
for Study 015, 1% years fier
the
completion of the trial (reftience
Audit Information
Sheet - Appendix
3).
Persons who conducted the audit found uxtain GCP compliance issues relating
to organization of the study and study documentation.
Examples of their audit
findings included:
G
Lack of availability of signed patient consent fotms for 43% of all patients
and of those with signed forms 23°/0either did not have a date indicated or
the date that was indicated was not consistent with study start.
It should be
pointed out that almost all of the patients who entered the trial were
Cambodian refigees who were for the most part illiterate.
In additio~
the
investigator did not counter sign 810/0 of the patient consent
forms as
required by his IRB.
.
Laboratory safety data reported to MRL had discrepant dates with regard to
source laboratory reports and multiple laboratories were used during the
conduct of the trial without the approval of MRL.
G
Two additional patients
were treated at this site and
never reported to MRL.
Both patients had nonserious adverse experiences
repofied which were judged by the investigator to be drug related.
Both
patients received TBZ. Efforts made to obtain formal case .repofis on these
patients were unsuccessful.
Data from these two patients are excluded tim
t~s ~.
.
Finding a lack of complete supporting laboratory documentation
for stool
testing and some cases of Baermann results which were not reported to
MRL.
Subsequent to MRL leaning about the lack of complete laboratory
documentation for stool testing a second audit was ptionmd
wherein all
patients’ files were reviewed for the presetm
of Iaboratofy reports of stool
testing in support of the test results reported to Merck.
This subsequent
audit
showed
that
52°/0 of
the
patients
had
incomplete
suppotive
-
documentation on file for stool testing.
In this group of 52Y0,one to four
source reports were missing per patient, with most patients having had an
‘
average of 6 to 7 tests completed during the study course.
Admittedly, these
findings would be of great eoneem if the frequeney of positive stool tests
*
MK-0933U3C64.DOC
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D –3005
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. GaM
-27-
.
C. lNfkacy(Cont)
were hig~ howwer, this is not the ease for any of the three treatment groups
in this study.
All treatments
in this study d~playql,
for the most p-
negative stool tests. In general, what is not evident because of the “missing”
itiormation is confirrnato~ and repeated negative stool-testing results.
.
After the prestudy visit there was no routine field monitoring conducted
at this site.
.
There was no record of accountability for unused drug at this site.
Comparing the results of Studies 015 and 014 with those published in 1994
[11,12], the results summarized here indicate no substantive
difference.
Table 9 summarizes the differences between the two published reports and
the data in this summa~.
.
MK4933U3C64.DOC
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MK-0933 Prot. No. 014/015
Dr. Berk and Dr. Gann
-28-
C. E~cacy
(Cont.)
Table 9
Comparison BetweenData Received at MRL for Studies 014 and 015 vs. Two Independent
PubIic.ations(11, 12] by the Investigative Groups
-
MRL sumIna@
Publication*
Patient Accounting
IVxl
IVX2
TBz
rvxl
IVX2
TBz
Patients Entered - Total:
22
24
22
20
23
26
Berk (014)
4
5
6
4
5
7
Gann (015)
18
19
16
16
18
19
Evaluable Patients - Total:
14
19
17
20
23
26
Berk (014)
2
1
2
4
5
7
Gann (015)
12
18
15
16
18
19
NonevaiuablePatients - Total:
8
5
5
0
0
0
Berk (014)
2
4
4
0
-o
0
Gann (015)
6
1
1
0
0
0
We Rate+ - To(al:
14/14
18119
16/17
20/20
22/23
22/26
Berk (014)-
m
1/1
1/2
4J4
5/5
Sn
Gann (015)
12/12
17/18
15/15
16/16
17/18
17/19
G
IVxl=kmrwtinsin
gledoaeforlday.
IVX2=I vmncctin single dosefor 2 &ys.
T13Z= Thiabendazole 50 n@@iay
for 3 days.
+
Cure rates for “MILLSummary” are for )3duable Patienta only.
.,.
MK-09331Bc64.Doc
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MK-0933 Prot. No. 014/015
Dr. Berk and Dr. Gann
-29-
C. EfiieaeY (Cont.)
It is not clear why the total numberof patientsin Table 8 who entered into Study
014 differs by 1 patient between the MRL report and thg publication by Berk
(Study 014) [12]; however, data for only 15 patientswere ever received at MRL
for this study. What remains a puzzle is that for Study 015, wherein both reports
aee.ount for 53 patients; the number of patients per treatment group diffim
between the MRL summary and what appeared in the publication by Gann
(Study 015) [11]. Agai~ a comparison of the MRL database uwd in preparation
of this report with the case reports submitted by the investigator to MILL reveals
no discrepancies.
The major difference between this MRL summary and the two publications is the
exclusion of certain patients from the amlysis of efficacy.
Both investigators
included aI1their patients in their efficacy evaluation however, MR.L, used the
stringent criteria described earlier. Regardless of the approach taken for effieaey
evaluatio~
the cure rates described
in each of the publications
and this summary
are consistently
comparable.
Despite these GCP-related findings, h4RL believes that the basic scientific and
medieal conclusions drawn from these studies and described in this summary are
valid in that the data have been published in a peer-reviewed journal and the fact
that incomplete
source
documentation
for
some
of the
prirnay
effieacy
laborato~
data is outweighed by the high frequency of negative stool testing
results for a!l three treatment groups.
--
.?AK4933WC64.DOC
02FEB96
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MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gam
-30-
D. Safety
L Adverse Experiences - Clinieal
All patients were evaluated for safkty and tolerability.
“
a.
Overall Assessment of Clinical Adverse Experiences
Table 10 below is a surnm~
of the clinical adverse experiences.
Table 10
Clinical Adverse Experience Summary
Ivermeetin
Ivermectin
Single-Dose
Two-Dose
Tbiabendazole
Trea~ent Group
(?+=22)
(N=24)
(N=22)
Patients with clinical AE
3 (14%)
6 (25%)
19 (86%)
Serious Clinical AE
o
1+
1+
Discontinued Due to
Patient Death
o
1+
o
Diseondnuatim” Due to
clinical
AE
o
0
1*
Dimmtinued Dueto No
TherapeuticRespon@
o
0
1*
Dreg-RelatedClinicalAE
3 (14’YO)
5 (21%)
18(82%)
‘ Study 014,
- patient -idly
completedtreatrnmt eoursc and died 57
days posttmatmentof baekgrouriddiseases (eoronruyartery diseaseand chronic
pulmonarydisease);the death was not drug related.
“Study 014,
- Patient died on Study Day 84 as a result of underlying
pulmonarydisease the deathwas consideredto be not drug related.
‘ Study 014,
had study drug discontinued
after
1 day of therapy due to
severe
nausea
and
moderate
thuitus
considered
by the investigator
to be
definitely related to study drug.
MW933U3C64.DOC
.—
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0–3013
MK-0933
ProLNo.014/015
Dr. Berk and Dr. Gann
-31-
D. Safety (Cont.)
The difference in the incidence of clinical adverse experiences (AEs) between each
of the ivermectin groups and the thiabendazole group was significant (PcO.001 for
each comparison).
There was no statistically significant difference in the incidence
of clinical AEs between the two ivermectin treatment groups (p4.46).
There were
two serious clinical AEs (both patient deaths) as summarized above;
neither was
considered drug related.
“Drug-related
(possibly, probably,
or definitely related)
clinical AEs
significantly different between
the two
ivermectin treatment
groups
however,
the
difference
between
each
of
the
ivermectin ‘groups
thiabendazole group was significant(pzO.001 for each comparison).
Table 11 is a listing of clinical AEs by body system.
were
not
(p=o.70);
and
the
h4K-0933u3c64.DOc
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- ..
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Garm
-32-
D. Safetv (Cent)
Table 11
rl;n;f.ml AAx?arco wmtiCw’Mwx n!? nnav Cvcta=m
Ivennectin
Ivermedn
Body systeml
SingIc-Dose
Two-Dose
Thiabendamle
Diagnosis
(?4=22)
(N=24)
(?4=22)
Patients with AE
3 [3J
6 [5]
19 [18]
Body as a Whole
o
2 (8.3%) [1]
-
12 (54.5%) [11]
Asthenia/Fatigue
11 (50.070)[11]
Death
1(4.2%) [0]
1 (4.5%) [0]
Malaise
2 (9.lYO)[2]
Abdominal Pain
1(4.2%) [1]
Digestive System
2 (9.1%) {2]
1(4.2%) [1]
15 (68.2%) [15]
Anoretia
1 (4.5%) [1]
7(3 1.8%) [7]
Constipation
1(4.5%) [1]
Diarrhea
1(4.5%) [1]
1(4.2%) [1]
1 (4.5%) [1]
Dyspepsia
2 (9.1%) (2]
Flatulence
1 (4.5%.)[1]
Nausea
1 (4.2%) [1]
9 (40.9??) [9]
Salivation
1 (4.5%) [1]
Vomiting
1 (42%) [1]
3 (13.6%) [3]
Navous &Wm/i%yChiaQ’iC System
o
2 (8.3%) [2]
15 (68.2%) [15]
Disorientation
4 (18.2Yo)[4]
Dizziness
2 (83%) [2]
9 (40.9%) [9]
somnolence
7 (31.8%) [7]
vertigo
1 (4.5%)[1]
Winand Skin Appendage
3 (13.6%) ~]
2 (83Yo)[2]
1 (4.5YO)[1]
Pnuitus
1 (4.5%) [1]
2 (8.3%) [2]
1 (4.5%) [1]
Rash
1 (4.5YO)[1]
Unicalia
1 (4.5%) [1]
;pecial Scnaes
o
0
1 (4.5%) [1]
Tinnitus
1 (4.5~%)[1]
J.B.:Patien( counts and event counts may not be the same since some patients may have more than
one clinical AE event.
]
Numb
in brackets am those paticnta who had clinical A& which were considered possibly,
probably, or definitely related to studydrug.
,.”
,&’fW1933W264.Doc
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MK-0933 Prot. No. 014/015
Dr. Berk and Dr. Garm
-33-
D. Safety (Cont.)
The organ system most commonly involved among patients treat=
with
ivermectin repofiing clinical adverse experiences vqs
the skin (14Y0 of
patients receiving single-dose ivennectin and 8~0 of pat.irmts treated
with two
doses of ivermectin).
Pruritus
was the most frequent
slcin”sign or symptom.
Two
patients
in the
two-dose
ivermectin
treatment
group
repotied
mild
dizziness.
No other clinical adverse experiences were repotied by more than
1 patient treated with either ivermectin dosage regimen.
The organ systems most commonly involved in clinical adverse experiences
reported by patients
treated
with TBZ were
the digestive system and the
nenous/psychiatric
systems
(both
were
identified
in 68°A
of
patients).
Dizziness (9 patients),
somnolence
(7 patients)
and disorientation
(4 patients)
were
the most
common
symptoms
within
the nervous/psychiatric
system.
Nausea
(9 patients)
and anorexia
(7 patients)
were most frequent
within the
digestive
systemcomplaints.
The single most frequently reported
cIinical
adverse experience among patients treated with TBZ was asthenialfatigue,
occurring in 11 (50°/0)of patients.
halysis
was
also
performed
considering
only
those
adverse
clinical
experiences considered by the investigators to be drug related (relationship
of the clinical event to the study drug was rated as possibly, probably or
definitely related).
Using this definitio~ 3 of the 22 patients (1470)
in the
single-dose ivermectin group had one or more drug-related cliicd
adverse
experiences mmpared to 5 of 24 patients (21~0) of patients treated
with two
doses of ivermectin
and 18 of 22 patients
(82%)
in the thiabendazole
group.
The
dtiixence
between the two ivermectin
groups
was
not
significant
(p=O.70) but the difference
between
each of the ivermectin
groups
and the
thiabendazole
group was significant
@-@.001 for each comparison).
Most of the clinical AEs were considered drug related (possibly, probably, or
definitely) regardless of the treatment group.
Eight of the 9 (89?!) clinical
AEs among both ivermectin treatment groups and 18 of the 19 (95%) of the
thiabendazole group were considered drug related.
Thus, all clinical AEs
-
with the exception of the two deaths were considered related to study drug.
--
MK-0933U3C64.DOC
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D–3016
MK-0933
Prot. No. 014/015
Dr. Berk and Dr. Gann
-34-
D. Safety (Con~)
Two patients were considered to have had one or more serious c~ticaf
-. -
adverse experiences probably or definitely not related JO study drug
both
were in Study 014.~,
a 64-year-old male in the thiabendazole treatment
group; died as a result
of underlying
pulmonary
disease; the patient’s death
was considered to be definitely not related to thiabendazole therapy.
This
patient
was
scored
as “Dkcontinued
Treatment
Because
of Lack
of
Therapeutic Response/Death’’.~as
a 70-year-old male with coronary
artery disease and chronic pulmonary disease randomized to receive two
doses of ivermectin. The patient died on Day 57 of study the patient’s death
was
considered
definitely
not
related
to
ivermectin
therapy
by
the
investigator.
Although this patient
(014/012)
completed
his treatment
course, he was scored as discontinued from study because of AE (death),
b.
Serious
Clinical Adverse Experiences
Two serious clinical adverse experiences oecumd
during the trial.
Both
events were patient deaths (Study 014,
Both events were
considered definitely not related to study drug. Clinical descriptions of these
patients are provided in the preeedng paragraph
c
Patients Discontinued Due to ~inieal
Adveme Experiences
One patient (Study 014,
“ treated with thiabendazole had study drug
discontinued after 1 day of therapy due to a chical adverse experience.
The
patient reported severe nausea and moderate tinnitus on the first day of
thiabendazole administration considered by the investigator to be definitely
related
to
study
drug,
The
patient’s
symptoms
resolved
following
discontinuation of treatment.
Refkrence the above for
(Study 014) concerning patients who completed treatment course but were
scored
as discontinued
because of either “Death” or ~o
Therapeutic
ResponseAleath*, respectively.
MK-0933U3C64.DOC
02FEB96
——
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0-3017
-.
MK-0933 Prot. No. 014/015
Dr. Berk and Dr. Gann
-35-
D. Safetv (Cont.)
.
3.
4.
5.
2. Adverse Experiences - Laboratory
a.
Overall Assessment of Laboratory Adverse Ex~eriences
0
Iu
No patients in the singledose
ivermectin or twodose
ivennectin treatment
groups were noted to have any laboratory adverse experiences.
One patient
(Study 015
. treated with thiabendazole
(1 of 22, 4.5Yo) had
elevations of AST, ALT, and alkaline phosphatase, which all returned to
normal
without
intemention.
These
laboratory
abnormalities
were
considered
by the
investigator to be possibly related
to therapy
with
thiabendazole.
b. Serious Laboratory Adverse Experiences
There were no serious laboratory adverse experiences during the course of
this study.
c.
Patients Discontinued Due to Laborato w Adverse Experiences
No
patients
required
discontinuation
of
study
drug
due
to
a
laboratory
ad-verse experience.
Adverse Experiences - Other
There were no other adverse experiences.
Clinical Safety Measurements
No cliically significant changes in chkxd measures of saf~
were noted.
Laboratory Safetv Measurements
No consistent or significant changes in laboratory measures of safety were noted.
MK-0933V3C64.DOC
,
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u
—au
10
MK-0933 Prot. No. 014/015
Dr. Berk and Dr. Gam
-36-
Iv.
DISCUSSION
Ivemwctin is an 80:20 mixture of avermectin f31a and filb,
monocyclic
Iactones
produced by the actinomywte Streptomycesavennitilis. While its mechanism
of action
is not
fidly
understood,
ivemmctin
appears
to
exert
its activity
bj
inducing
a chloride
current
via a gkunate-gated
channel
in the parasite
resulting
in apparent
paralysis
and
death [13]. It is an orally effective antiparasiticagent which has been used in veterinary
medicine since 1981. Based on its efficacy and excdlent safkty profile, ivennectin has
achieved widespread acceptance as the treatment of choice for onchocerciasis (river
blindness) [3].
During trials aimed primm”ly at establishing ivennectin’s efficacy in onchocerciasis, a
number of uncontrolled obsenations
suggested that ivermectin had significant activity
against a number of gastrointestinal
nematodes
[14].
These clinical notes were
consistent
with
the
drug’s activity
in an animal model of
strongyloidiasis
[7].
Subsequently, noncomparative studies demonstrated that ivermectin is an effective agent
against strongyloidiasis [8,9].
Based on these observations as well as the need for a
more effective, less toxic therapy in strongyloidiasis, several studies, includlng this trial,
were undertaken.
This comparative randomized trial establishes conditions for evaluation of ivermectin’s
efficacy in strongyloidiasis.
All patients evaluated for efficacy had microscopically
documented S. sfercoralis infixtion and all subsequent follow-up stool examimtions
utilized a very sensitive technique for parasite detection.
Because the study was carried
out in areas with a low risk for patient re-infectio~ the foIIow-up period was longer than
that used in most previously published therapy triak in Strongyloidiasis.
Cure rates of 100% (singledose
ivetmectin),
95% (two-dose ivermectin) and 94%
(thiabendazole) were observed in evaluable patients, confirming ivermectin’sactivity in
this infixtion. There is no evidence that there is an advantage to two doses vs. a single
dose of ivexmectinin this patient population. It is importantto note that no patient was
severely immunocompromiwd or had evidence of infection beyond the gastrointestinal
tract. It is not possible to extrapolate fromthis trialto these otherpatient populations.
.
.,,
MK4J933U3C64.DOC
02FEB96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 119 of 382

V–5019
(?. m
-37-
MK-0933 Prot. No.014/015
Dr. Berk and Dr. Gann
IV.
DISCUSSION (CONT.)
Although efficacy did not differ among treatment groups, the incidence oFclinical
adverse experiences was substantially lower among patients receiving ivermectin. Three
of 22 patients (14°4) treated with single-dose ivemwctin were considered to have had
drug-related clinical adverse chical
events as compared to 5 of 24 patients (21%)
assigned to the two-dose
ivermectin group and 18 of 22 patients (82°/0) receiving
thiabendazole.
The difference between the two ivermectin groups was not significant
but the difference between each of the ivermectin groups and the thia,bendazole group
was significant.
Because this study was not conducted using methods to blind both
patients and investigators
to the therapy each patient received (i.e., aIl laboratory
personnel involved in Baermam
stooi examinations were to be blinded), it is not
possible to exclude some bias in repo~ing.and interpretation of adverse events.
Several
points suggest that these results are not due to such bias.
Similar patterns of clinical
adverse experiences are present at both sites and so are not specific to the investigator.
Furthermore, when all clinical adverse experiences are considered rather than only those
felt to be drug related, a significantly higher incidence of adverse events are still found in
patients treated with thiabendazole.
This analysis is independent of any interpretation of
events by the investigators.
Lastly, side effects in patients treated with thiabendazole is
consistent with other published repofis [3,4].
In onchocerciasis, many of the adverse effkcts that occur after ivermecti.ntreatment area
result of the patient’s immune response (IWwzotti reaction) to dead microfdariae and
usually appear within 3 days of the dose [15].
The severity of the response is directly
related to the initial intensity of 0. wlvuh.r
infkction.
The lack of Mazzotti-type
reactions in this trial following treatment of strongyloidlasis is consistent with previous
experience and would be predicted based on disease pathogenesis.
This study demonstrates
that ivemwctin is a well tolerated and effixtive therapy for
strongyloidiasis Iimited to the gastrointestinal tract in immunocompetent patients.
It is
associated with significantly fewer clinical adverse reactions than thiabendazole
with
similar eilk.acy.
Overal~ the results of this trial suggest that ivermectin offkrs a
significant advance in the treatment of strongyioidiasis.
./’”
.MIC-0933WC64.DOC
02FEB96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 120 of 382

---
MK-0933
Prot. No.014/015
Dr. Berk and Dr. Gann
-38-
V.
CONCLUSIONS
1. Ivenneetin
(200 mcg/kg) as a single dose and as two doses on consecutive days and
thiabendazole (25 mg/kg b.i.d. x 3 days) are effeetive therapy for strongyloidiasis of
the gastrointestinal tract.
2. Ivermeetin is generally well tolerated
and associated with fewer clinical adverse
experiences than thiabendazole.
Director
Associate Director
Regulatory Liason
CBARDS
./hLt%4/J
1
Ad
G. B. CaIandra, M.D., Ph.D.
- Senior Director
CIinical Research
MK-0933U3C64.DOC
.,
02FEB96
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NDA 50-742
Mcctizan-’ (Ivcrrncc[in)
Page I 15
.
Strongyloidiasis
Medics! oficer
Commeno:
D. Medical ol%eer findings
Medical officer evaluation
of enrolled patients
by treatment group and patient number
Berk 014/Gann
015
Patient #
Evaluable?
Reason/Comment
Cure?
Reason
Treatment arm:
Iverrnectin x I
# - stools
Berk
yes
yes
yes
yes
Gann
yes
lost to f/u till day +97
yes
yes
yes
no
pre-Rx stool> 60 days
yes
- yes
yes
yes
yes
no
yes
yes
no
yes
yes
yes
lost to ffu
lost to f/u
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
- Stoolto day 233
= Stool to day 264
= stool to day 126
= Stool to day 158
_ stool to day 232
= stool to day 19]
= stool to day 357
= stool to day 38 I
= WOO]to day 370
= stool to day 366
= stool to day 182
= stool to day 189
= stool to day 379
- stoolto day 186
= stool to day 296
= stooI to day 252
= StOOltOday 236
- stool to day 196
6
6
3
3
3
4
5
5
5
5
4
4
5
4
5
5
3
5.
no
only 2 stools post-w
Totals
.. .
enrolled 22
Cure 18
evaluable 18
Fail O
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 122 of 382

NDA 50-742
Page I I6
Mectizan” (Ivermcctin)
Strongyloidiasis
Medical oflicer evaluation
of enrolled patients
by treatment group and patient number
Berk 014/Gann
015 (con’t)
Patient #
Evaluable?
Reason/Comment
Cure?
Reason
# m stools
Treatment arm:
Iverrnectin X 2
Berk
yes
Yes
no
no + stool recorded
no
no flu past day 23
no
only 2 stools post-Rx
yes
Yes
- stool to day 35
_ stool to day 28
Gann
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
No
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
- yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
no
no pre-Rx stool +
m stool to day 365
_ stool to day 363
= stool to day 372
_ stool to day 378
+ stool day 35
_ stool to day 215
_ stool to day 180
_ stool to day 365
_ stool to day 329
_ stool to day 350
_ stool to day 225
_ stool to day 33 I
= stool to day 183
_ stool to day 267
_ stool to day 102
_ stool to day 231
_ stool to day 187
_ stool to day 208
5
3
5
5
5
4
5
4
5
5
5
5
5
4
5
3
4
4
5
Totals
Enrolled
24
Cure
19
Evaluable 20
Fail
I
.,”
.——
.—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 123 of 382

NDA 50-742
Page I I7
Mecti.zan- (Ivennectin)
.
Wongyloidiasis
Medical officer evaluation
of enrolled patients
by treatment group and patient number
Berk 014/Gann
015 (con’t)
—
-
Patient #
Evaluable?
Reason/Comment
Cure?
Reason
# - stools
Treatment arm:
Thiabendazole
Berk
yes
Yes
yes
No
no
_ stool to day 339
+ stool day 39,46
no
yes
no
only 1 stool post-Rx
only 1 stool post-Rx
lost to flu
Gann
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
-
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
yes
Yes
+ stool day91
_ stool to day 348
D stool to day 363
_ stool to day 381
_ stool to day 387
= stool to day 360
_ stool to day 351
_ stool to day 238
m stooltoday 354
_ stool to day 307
- stool to day 82
_ stwl to day 298
_ stool to day 268
_ stool to day 304
_ stool to day 94
- stool to day221
7
5
5
5
5
5
5
5
5
5
3
5
5
5
3
4
yes
Yes
_ stool to day 235
5
Totals:
Enrolled
22
Cure
17
Evaluable 19
Fail
2
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 124 of 382

NDA 50-742
!@c 118
Mectizarr”’(Iverrnectin)
.
Strongyloidiasis
Study 014 (Berk)/ 015 (Gann)
Resultsper Medical Officer
Ivermectin
X 1
Ivermectin
X 2
Thia~endazole
Berk
Gann
B&k
Gann
Berk
Gann
Enrolled,
Total
4
18
5
19
6
16
Evaluable
per M.O.
4
14
2
18
3
16
Cure at day 30
4
14
2
17
3
16
Fail at day 30
0
0
0
1
0
0
Cure at day 90
4
14
nla
17
1
16
Fail at day 90
0
0
nla
o
2
0
TOTALS
Cure (%)
18/18 (1OOY’O)
17/18 (94%)
17/19 (89%)
(day 90)
Fail (“A)
o
1/18 (6%)
2/19 (ll”A)
Medical officer findings: safety
The applicant’s summaty of safety results for these combined studies is found on (applicant’s) pages D-
3012-17. In this, the applicant reports that there were 3 clinical ADE’s in the singledose
iverrnectin arm, 6 in the
two-dose iverrnectin am; and 19 in the thiabendazole arm; this was repotted to be a statistically significant
difference between each of the ivermectin groups and the thiabendazole group.
The computerized patient listing for these adverse events was reviewed and compared with the tabular
presentation found in the applicant’s summary. The results as presented in Tables
10 and 11 of that summary were
found
to be consistent
with
the computerized
patient
listings.
As can be seen in Table 11, the most commonly
affected organ system in these clinical adverse events was skin and skin appendages in the ivermectin-treated
patients, and nervous system and digestive system in the thiabendazole-treated patients.
As can be seen in Applicant’s Table 10, there were two deaths and one discontinuation in these combined
studies. (All three of these events were among the subjects enrolled by Dr. Berk.) Although information is given on
these subjects in the text of the study summary, the case report forms for these three study subjects were not
submitted with the NDA.
The patient population enrolled by Dr. Berk was considerably older and had many more co-morbidities than
did the population of Cambodian immigrants enrolled by Dr. Garm. Thus is is not suqxising to see these adverse
outcomes predominantly in this’~oup of enrollees. A brief synopsis of these 3 cases follows:
,“
Early discontinuation:
Patient ~,Berk:
a 59 year old white male with pre-existing hypertension, hemiparesis, s/p
cerebrovascular accident and a history of alcohol abuse. Patient randomized to thiabendazole and had
severe nausea on the first day of drug administration.
He also had moderately severe tinnitus. Both of these
events were considered to be definitely related to thiabendazole administration and the patient was
withdrawn from the study.
.-
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 125 of 382

NDA 50-742
Page 1I9
Mcctizan” (Ivermec(in)
.
.Qrongyloidiasis
Death:
*
Patient
Berk: a 64 year old white male with COPD and prostate cancer, being treated concomitantly
with multiple medications including steroids. This patient was treated with an initial three-cJaycourse of
thiabendazole, with stools converting from 4+ positive to negative for Won~loi&s
larvae on days 10 and
25 post-therapy. He then was found tcthave larvae in the stool on day.39 post-therapy, and was started on a
second course of thiabendazole on day 44. Hecompleted this course of therapy. No further stools are
recorded in the computerized listings, but the patient expired on study day 84, reportedly from his
underlying pulmonary disease. The death was considered to be ‘definitely not related’ to study drug
administration. (It is unclear whether this patient died of or with disseminated strongyloidiasis.)
Patien~
Berk: a 70 year old white male with underlying coronary artery disezse and COPD who was not
taking concomitant steroids, randomized to the two-dose ivermectin arm. Hisstoolswere free of
So-ongy/okks larvae by day 3 post-therapy and were negative on three further exams. The patient died on
day 57 of study. The precise nature of this death is not clear from the study repo~ but the investigator
stated that it was ‘definitely not related’ to study drug. A review of this patient’s laboratory values only
presents lab data from study days 1 and 9, even though the death was considered to have occurred while on
study.
Laboratory adverse events which were considered worthy of mention by the investigator(s) include a single
event in patient-
a Gann patient in the thiabendazole arm who was found to have transaminase and alkaline
phosphatase elevations on day 9 post-therapy that were ‘possibly’ drug-related. Uponreview of these line listings,
the following additional perturbations were noted:
~
lab findino (day of stud
Comments
Iverrnectin X 1
Berk
serum creatinirie 1.I+ 1.8 (d7)
Gann
alkaline phosphatase 59+ 112 (dll)
Gann
alkaline phosphatase 34+ 147 (d7)
Gann
ALT36+
llO(dlO)
lvermectin X 2
GannW
ALT 33+66
(d12)
Thaibendazole
Gann
alkaline phosphatase 111+218
(d7)
Gann
AST 49-$126 (d9)
As mentioned in applicant’s summary
ALT 37+ 153 (d9)
alkaline phosphatase 52+ 150 (d9)
As can be seen from the above da% this study also reveals minor perturbations in transarninases and
‘-”
alkaline phosphatase levels but nothing else of note. It should be noted that the great majority of these patients only
had post-therapy labs included from day 7-10, and nothing thereafter. This is of some concern, particularly in the
case of the one patient (Berk~
who was considered to have died while in the study. No laboratory data from the
time approaching the patient’s ultimate demise is included in the computerized listings.
E. Conclusions
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 126 of 382

NDA 50-742
Pa:c I20
Mcctizan”’(Ivcrmcctin)
,
Strongyloidi~is
6. “WHO Study”: A comparative trial of a single dose Ivermeetin versus 3 days of albendazole for treatment of
S/rongyloides
s[ercorahs
and other soil transmitted helminth infections in children.
A. Study summary
This is a trial conducted under the auspices of the WHO in two villages on the island of Zanzibar, off the
eastern coast of Africa. llte applicant supplied study medication in the form of scored 6 mg tablets of ivermectin,
which was dosed at 200 ygkg as a single dose. The comparator drug, albendazole, was dosed at a fixed 400 mg qd
for three days.
Although this study is submitted by the applicant as one of the ‘pivotal’ adequate and well-controlled
investigations in support of the proposed product Iabelling for ivennectin, no primaty patient data is submitted. The
submission consists of a 20-page manuscript that has been submitted for publication in the American Journal of
Tro~ical Medicine and Hv~iene. (NB: subsequent to the filing of NDA 50-742, the applicant has reported that this
manuscript has been accepted for publication in that same journal.) The applicant maintains that the patient-level
data are not controlled by Merck, since the study was conducted not by Merck but by the WHO.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 127 of 382

NDA 50-742
Page I21
Meetizan-’ (Iverrnectin)
Slron@oidiasis
Study
setting:
two
primary
schools in two villages located in northern Zanzibar
Time of study: October to December 1994
Entry criteria
“male and female students z 10years ol~ including schoolteachers
- oral informed consent
. stool positive by Baermann technique for larvae of S. stercoralis
Exclusion criteria:
- No consent
“fever or other signs of acute illness
. severe neuroiogic disorder
. severe liver disorder
. pregnancy
Randomization: a randomized list of sequential allocation was prepared in advance. Afier entering the trial,
individuals were weighed and given their respective treatrnen~ with either ivermectin at a dose of 200 pglkg or the
first dose of albendazole at a dose of 400 mg. Both drugs were administered in the presence of a study monitor with
water. The subjects randomized to albendazole were given the subsequent daily doses under direct supervision so
that compliance with the three-day regimen was assurred.
Medical oflcer
comments:
no information is presented
to describe
which weight ranges were administered
which
combinations
of whole and half-tablets.
For comparison
to o!her studies submi!ted in supper! of this indication,
it is
importan[ to know whether subjects
of similar weights were dosed in a similar fashion.
AIso, the absorption
of
alben~-ole
is signij7cantly
affected by co-administration
with food.
Since it is unclear whether anthe[minthic
activi~
against intestinal parasites
is correlated
with serum levels as opposed to intraluminal
levels ofalbenda~ole
(or metabolizes),
the importance
of taking the comparator
with vs. without food cannot be determined
The app[icant
was asked to provide
this information, and in response a fm
was received
by this medical
oficer
on 26 August 1996.
Thefollowing
dosing information was provided
by the principal
investigator,
Dr. H.
Marti:
Patient weight (kd
)Vumber of6 m~ tablets
15 to 24
Z*
251035
1
36 to 50
1%
51 to 65
2
66 to 79
2$
80 and over
3
This dosing schedule
k identical
to that used in the Drqwr,
Berk and Gann studies but k dl~erentfrom
the
schedule
utiiized in the Gentilini stu~.
(The Gentiiini dosing schedule caused an inadvertent
underdosing
in the
ivermectin-treated
subjecfi,
who received
on average
169 pg/kg rather than the targeted
200 p~kg
dose.)
----
In this samefax,
Dr. Marti reaflrmed
that both stu@ medications
were dosed with water only; therefore
there was no food effect on &ug absorption
Follow-up: subjects were queried regarding medication side-effects at day 3 of the study, using a
questionnaire identical to that used at baseline. Three weeks following the first day of therapy, subjects were given a
stool specimen container and instructed to Tetum the following morning with a freshly-collected specimen. Upon
submission of this specimen, the subjects were questioned again regarding side effects of medication, using the same
questionnaire as previously.
Each subject was then given another container and told to submit a second specimen the
following day.
Endpoints: Subjects were considered cured if they had no evidence of Stron@oides
larvae in both follow-
up stool specimens, by Baerrnann technique. Individuals who did not provide both follow-up specimens were
excluded from the efficacy analysis.
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NDA 50-742
Page 122
Mectizan- (Ivcrmectin)
.
Strongyloidiasis
B. Applicant’s
findings
The applicant’s findings are summarized in the Ikwdts
section of the submitted manuscrip~ which begins
on page D-3560 of volume 1.24 of the NDA. The following table, taken from this manuscript prese~ts the
-
demographics and disposition of the subjects enrolled in this study
Demographics
and Disposition
of Enrolled Subjects, WHO (Marti) study
Patients examined
Males (age range 9-22 years)
545 (45.3%)
Females (age range 9-19 years)
659 (54.7%)
Pre-study evaluation
1204
Patients infected with S. slercoralis
419 (34.8?4.)
Males
207 (49.4%)
Females
212 (50.6Yo)
Excluded
for medical reasons
2 (0,5%)
Treatment
Ivermectin
Albendazole
Total
Eligible for trial
208
209
417
Incomplete questionnaire or treatment, or
45
39
84
Absence at last start of treatment
Evaluable for safety
163
I70
333
Evaluable for efficacy (both follow-ups completed)
152
149
301
Males
58 (38.2%)
67 (45?40)
125 (41.5%)
Females
94(6 1.8Yo)
82 (55Yo)
176 (58.5%)
Medical ojicer
comments:
in reviewing
the submitied manuscript,
it b impossible
to determine
the precise
-
accountabili~
ofa!l subjects randomued
in this trial.
For -mple,
how many were e.dudedfrom
arudysb
became
of incomplete
therapy?
What daes
‘absence at lmt start of treatment’ mean?
How ma~patients
wwe exc[uded
..-
form analysis because they presented
with one positive follow-up
stool, but did not have a second one collected?
This question was asked of the applicant,
who re[ayed it to the investigator.
Dr. A4arti supplied
the following
diagram
in his fa
communication
of 26 August 96:
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 129 of 382

NDA 50-742
page 123
Mectizm- (Iverrncain)
SWongyloidimis
.
SubjectaUocationinMartistudy,Zantibar
.
..
.
8
12a4
ptestudy evaluation
mediealfy excluded
419
Infested wftfrStsongyfoldes stercoralls
incomplete
treatment
absence at
last start of
treatment
I~m’z’d
7
Ztffi
fvermectin
o
6
2
treatment completed
202
no follow-up
39
163
oniy one
follow-up
11
@l
negative
10
positive
-4?
both fo[lmwrp stools
F
1
-.
6
%
202
32
h
170
21
13
As can be seen in thir diagram,
the inwrtigator
states that of the subjects who submitted
one, but not the second
folio+up
stoo!for
tawminatio~
10/1 I were negative in the ivermectin arm versus 13/21 negative
in the albendazole
arm.
The efficacy results, as reported in the study manuscript are presented in the following table (the results for
the other intestinal parasitic infections are not included since they are not relevant to the NDA currentlyunder ..
review):
Applicant’
s Efficacy Results, WHO (Marti) study
.
I
1
I
Cure rate
I
Parasite species
I
Ivermectin
I
Albendazole
I
Strongvloides
stercoraiis
I
82.9?40(126/152)
I
45% (67/149)
I
.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 130 of 382

.
NDA 50-742
l’a:c 124
Mectizan”’(Ivcrrnectin)
.
Strongyloidiasis
Medical oflcer
comment: the denominator
in these cure rates h the number of subjects in each arm who returned
for ~
foilow-up
stool aruujwes.
Ifthe subjects
whopresentedfor
one follow-up
stool are includd,
the rates
become 83.4 % (136/163) for ivermectin, and 47.1% (80/170) for a[benahzole.
Thus, the comparative
results are
not changed by the applicant’s
evaluability
requirement
oftwo
documentdfo!lo+up
SIOOLS.
It should be kept in mind that there eficacy
aizta are base on a three-week post-therapy
foIi~wup
timepoint.
As such, thb is the shortest dwation
ofpost-therapy
follow-up
of a~
of the submitted
studies in this
portion of the NDA.
The other study to be conducted in an endemic area (the Dreyer stu~,
which was conducted
in
Brazio attempted
to gather follow-up
stool samples at 30, 90, and 180 a@s post-therapy.
Because of concerns
over
possible
re-infection
of study subjects,
the 30-a@
et@oint
wa
considered
acceptable for this SIU4 (with a range of
26-34 days post-therapy).
The A4arti stu~
pruhes this primary study edpoint
up to 21 &ys post-therapy.
The safety data presented in this study were generated by questionnaires that were completed for all study
subjects at the time of enrollmen~ at the time of treatment and three days following the start of treatment (which for
the albendazole group would have been while still on therapy). Further safety information was collected by
questionnaire at the three-week timepoint as well.
The treatment-emergent signs and symptoms, as shown in Table 5 of the submitted manuscript (page D-
3573 of volume 1.24 of the NDA), are presented below (the table in the manuscript is entitled “Number of patients
developing new signs and symptoms within three days after treatment [Adverse effects]”):
Applicant’s
Safety Results, WHO (Marti) Study
7
Symptom
Albendazole (N = 170)
Iverrnectin (N = 163)
Abdominal distention
1
7$
Chest pain/tightness
o
7$
Loose stools
17
16
Headache
18
15
Cough, not with cold
8
11
Fever
7
10
Dizziness, vertigo
10
5
Nausea
6
5
Difise
itching
6
3
Watery diamhoea
3
2
$ p < ().05
..
C. Medical offtcer findings
The medical officer review of this submitted study, which the applicant considers ‘pivotal’ to the approval
of this indication, must be confined to a critical reading of the manuscript. The applicant was unable to provide any
source documental ion from this study, since it was conducted under the auspices of the WHO rather than Merck
Research
Laboratories.
The applicant participated in the conduct of the study only insofar as provision of study drug
(iverrnectin) was concerned.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 131 of 382

NDA 50-742
Page 125
Mectizan- (Ivennectin)
.
Strongyloidiasis
In a sense, then, despite the fact that the applicant considers this study to be ‘pivotal’ to the strongyloidiasis
indication, this clinical data is no different than the section of the NDA which provides literature references which
support the approval of iverrnectin for the strongyloidiasis indication (reviewed below). In fact, this study has not
yet been published in a peer-reviewed journal whereas the remaining literature submitted has, at the v~ry leas~ been
scrutinized in this manner.
Medical oficer
comment: shortly afler this NDA was submitted
the applicant
informed DAIDP that the manuscript,
which Dr. Marti had submitted for publication
in November
1995, had been accepted for publication
in the
American Jo urnaf of Tronical Medicine and Hvg iene. However, as the deadline for action on this NDA approaches,
the paper has ye~ [o appear in this journal.
The medical oficer
thus took the liber~
of calling Dr. Mc Wilson
Warren, editor-in-chief
of the aforementionedjournal,
on 29 August 1996. Dr. Warren contrmed
that the
manuscript had been accepted for publication,
and that the two peer reviewers
had provided
editorial
comments
but
that the actual data presented
in the manuscript
was identical to that which was to go to press.
He anticipated
the
appearance
of the Marti paper in the December
1996 issue of the American Journal of Tro~ical Medicine and
m.
If the reader refers back to the table on page 4 of this review, in which an overview of the submitted clinical
studies is presented, itcan be seen that the Marti study is, numerically, the study on which the strongyloidiasis
indication rests. In terms of total patients randomized, the Marti study includes 4 17/591 or 710/0of the subjects
studied in this portion of the NDA.
Methodologically, the Marti study is similar enough to the other studies to allow for pooling of the efficacy
data, particularly since Baerrnann analysis was used for all stool processing. However, there are two major
methodologic differences between this study and the other four reviewed above:
I test-of-cure stool examination was done at three weeks post-initiation of therapy and at no other time; and
I cure/fai] W~ determined on the basis of two stools collected within a few days of each other.
The reader will recall tha~ even in the other study performed in an endemic area (Dreyer, conducted in Brazil), a day
30 stool collection was considered acceptable by the medical officer tithere were a total of 3 post-therapy stool
collections documenting clearance of Strongyloides
larvae from the stool. One would expect such a study as Marti
to have a range of actual dates of stool collection, varying around the targeted three-week timepoint; thus, some of
the submitted specimens were undoubtedly collected earlier than day 21 of the study. Since patient level data was
not available for medical offker review, no further comment can be made.
D. Conclusions
The Marti study provides evidence of the short-term efficacy of singledose iverrnectin in the treatment of
intestinal strongyloidiasis. Even though the test-of-cure (ToC!) endpoint was shorter than in all the other submitted
studies, the observed comparative effkacy of iverrnectin versus albendazole makes it highly likely that a similar
difference would have been seen had the TOC stool samples been collected one week later. Furthermore, the
sensitivity of the TOC would have been improved had a third stool been collected in the post-therapy follow-up
period. Unfortunately, this study did not incorporate a thiabendazole arm for active comparison with the agent
currently approved for this indication in the US. Despite these shortcomings, this study is an important component
of the the NDA submission because of the large number of subjects enrolled and the substantially higher degree of
efficacy demonstrated as compared to the attive control, albendazole.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 132 of 382

NDA 50-742
pi3gC126
Mcclizan-’(lvcrrncclin)
.
.Wrongyloidiasis
7. Overview
of literature
references
submitted
in support of strongyloidiasis indication.
A. Applicant’s findings
The applicant has submitted a total of 13 literature references in support of the strongyloidiasis indication.
These references are broken down into compassionate treatments (4 references), anecdotal treatments (2 references),
and non-applicant-sponsored treatment studies (7 references).
The applicant’s summary of this literature, as found on pages D-3580-90 of volume 1.24 of the NDA,
follows:
._— —
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 133 of 382

Ivermectin
Clinical Documentation
D. Clinical Efficacy and Safety
II. References
B. Reference Documents
The purpose of this document is to summarize information appearing in the Literature that can
be used to fuxther support the use of ivermectin
in the treatment of strongyloidksis
of the
gastrointestinal
tract.
The information,
as published,
deals with the use of ivermectin
in
compassionate
treatments,
anecdotal
treatments
(i.e., patients
who~e strongyloidiasis
was
treated secondarily to a pnmag
treatment eoncem, e.g., treatment for onchocerciasis)
or non-
MRLsponsored
treatment studies.
In general, there were no safety problems encountered
in
the various citations covered that differed from what is presented in the safety analysis of
ivermectin
&ea@ent of patients within stronglyloidiasis
in this NDA.
Thus, this summary
deals on~y with presentation
of efficacy data that supports the claim for the use of iverrnectin
in the treatment of S. stercoralis infection of the gastrointestinal
tract.
In addition to citing references to the prim~
claim sought, this summary includes additional
case reports dealing with disseminated
S. stercora!is infections.
However,
these cases are
presented
for “information
purposes”
only
since
a claim
is not being
sought
for this
indication.
Many
of the publications
are in a foreign
language;
provided
for those citations that are used.
Numbers
in
attached to this report.
however,
English
summaries
[ ] refer to the references
that
are
are
Following
the summaries
of the published
eornmunieations
there is a table that summarizes
information
obtained
from these publications
regarding
the effkacy
of ivermectin
in the
treatment of strongyloidiasis
of the gastrointestinal
tracL
MK-0933U3W826.DOC
.-
25JAN%
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 134 of 382

.
;
D-
3581
Ivermectin
Clinical Documentation
D. Clinical Efficacy and Safety
II.
References
B.
Reference Documents
2
A.
Compassionate
Treatments
(1 -41
Four compassionate
treatments
using ivermectin
in the treatment
of strongyloidiasis
appear in the literature.
One patient (a 51-year-old
male with Cushing’s
syndrome)
previously
underwent
3
successive
10day
courses of albendazole
treatment,
each with relapse.
Ivemnectin
treatment
(12 mg per day for 2 days) eliminated
the parasites
with findings
still
negative at one year follow-up.
[1]
A 32-year-old
female (fotmer drug addict)
with HIV presented
with disseminated
strongyloidiasis
that was resistant to thiabendazole.
The patient received
a single
dose of ivermectin
(150 mcgkg);
however,
intestinal
obstruction
was present along
with severe electrolyte imbalance.
These symptoms worsened and diffuse mesenteric
adenopathy was found at laparotomy.
The patient died of septic shock (Pseudomonas
ueruginosa)
with meningitis.
The outcome
of ivermectin
treatment
in this patient
could not be determined.
[2]
A 45-year+ld
male with strongyloidiasis
that was resistant to various antiparasitic
agents received multipledose
ivermectin.
The patient was given an initial dose of
ivetmectin 12 m~ after 1 week the parasite burden was reduced.
The same dose of
ivctmectin was then given on 2 consecutive
days. No parasites were detected in stool
samples during 14 months of follow-up.
[3]
A 40-year-old
man who was unsuccessfully
treated with thiabendazole
evety 3-4
months over an 8-year period was given a single dose of iverrnectin
(200 mcg/kg).
Stool samples were clear of all larvae in 48 hours and remained negative for at least
one year after iverrnectiri therapy.
[4]
B.
Anecdotal Treatments
r5 - q
“During a mass treatment program of onchocerciasis
with ivermectin
in the rain forest
zone of Cameroon, 20 patients were found to have coincidental
strongyloidiasis
of the
gastrointestinal
tract.
Based on examjna(ion
of stools
1 month
after
treatment,
ivermectin
(single
dose
of
150
mcg/kg)
provided
a
cure
rate
of
10090 for
strongly loidiasis.
[5]
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 135 of 382

.
..
,.
..
.
D –
3582
-.
,—
Ivermectin
Clinical Documentation
D. Clinical Eftkacy
and Safety
II. References
B. Reference Documents
(?.31>3
B.
Anecdotal Treatments
[5 -61 (Cont.)
In a pilot study to determine the efficacy of singledose
iverrnectin in the treatment of
human gastrointestinal
helrninthiasis
in a hyperendemic
area of Central
Arneri~
12 randomly selected adults received a singledose
treatment of iverrnectin (140 -200
mcgkg).
Prior to treatment,
3 of the 12 subjects
had Strongyloides stercorulis
infestation;
based
on examination
of stools
1 month
following
administration
of
ivermectin, aIl 3 were successfully treated.
[6]
co
Non-MRL-Sponsored
Treatment Studies {7 -131
One series involved
9 HIV-infected
men, including
5 with AIDS-defining
conditions,
with evidence
of strongyloides
hyperinfection,
who received
either
a singledose
ivemw.ctin
treatment
(150-200
mcg/kg
in 2 of 9 patients)
or multiple
doses
of
ivermeetin
(200 mcg/kg on Days 1, 2, 15 and 16 in 7 of 9 patients).
All 7 patients
who
received
multiple
doses
of ivermectin
experienced
sustained
clinical
and
parasitological
cures
of their
Strongyloides
infedions.
One
of 2 patients
who
received singledose
ivermeetin relapsed on day 30 with both general, respiratory, and
GI symptoms.
This patient refised
finther tteatment
with ivermeetin and died 4 days
later with symptoms
suggestive
of sepsis and/or disseminated
strongyloidiasis.
The
remaining 8 patients remained in remission during follow-up periods from 7 months
to 3 years.
[7J
In a second study, 70 patients (41 males and 29 females) with strongyloidiasis
of the
gastrointestinal
tract were treated with ivermectin (6 mg on day one and another 6 mg
2 weeks later).
The eradication of S’.stercoralis was found in 60/68 (88.2%) 13 days
after the first dose (i.e., prior to dose 2); in 59/65 (90.8%)
13 days after dose 2; in
49/54 (90.7%)
1-2 months
late~ in 47/47 (100%)
3-4 months
lateq
and in 45/47
(95.7%) 5-6 months later.
Comparison
of patients who responded
to those who did
not respond showed significant differences between the groups in the amount of pre-
existing symptoms, anti-HTLV-1, eosinophil count, and IgE.
[8]
In a third study, in a highly endemic area of S. stercoralis
infection,
23 patients with
positive stool cultures
for S. srercoralis
were treated with iverrnectin
(single 6-mg
tablet on day one foIlowed by a 6-mg tablet 2 weeks later).
Two weeks after the
single treatment,
and prior to dose 2, parasitological
eradication
occurred in 18 of 21
patients
(85.7%).
Two weeks after the second ivermectin
dose one more patient
<ll~wefl nara<ifolnoiral
f=r2fiie2tinn
rol
—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 136 of 382

Ivermectin
Clinical Documentation
D-
3583
4
D.
II.
B.
c.
Clinical Efficacy and Safety
References
Reference Documents
Non-MRL-Sponsored
Treatment Studies [7 - 13] (Cont.)
In another
clinical
study,
a series
of
125 patients
with
strongyloidiasis
of the
gastrointestinal
tract (78 males and 47 females) were treated with ivermectin 6 mg on
day 1 followed by 6 mg on day 14. Parasito~ogical eradication
was achieved in 108 of
125 patients
(86.4%).
Of (he 17 patients who showed
persistence,
8 received a
furlher course of ivermectin and al! S. srercoralis in their feces was eradicated.
It was
noted by the authors that the positive rate of anti-HTLV-I
in the resistant group was
significantly higher (80.070) than in the eradicated group (29.2%).
[10]
A series
of 54 patients
(28 males
and 26 females)
in
another
study
received
ivermectin
(6 mg on day 1 followed by 6 rng on day 14) for strongyloidiasis
of the
gastrointestinal
tract.
For the patients with follow-up
stool examinations,
the cure
rate at 2 weeks after dose one (i.e., prior to dose 2) was 49 of 53 patients (92.5%) and
at 2 weeks after the second dose was 48 of 50 patients (96.0%).
[11]
An open trial of 100 patients with S. stercoralis infection of the gastrointestinal
tract
(57 maks,
43 females,
ages 3 - 94 years)
was done comparing
ivermectin
to
abendazole.
Patients were treated with singledose
iverrnectin (200 mcg/k&
N=53)
or albendazcde (400 mg for 3 days; N = 47).
Efficacy was evaluated in 85 patients
and cure rates were 42 of 43 patients in the ivermectin group (97.7%) versus 37 of 42-,
in the albendazole group (88.1 $ZO).The 6 treatment failures (1 iverrnectin and 5
albendazole) were re-~eated with iverrnectin and were cured. [12]
In a series
of 114 patiefits in Bangui, Central African Republic
(56 males and 58
females,
age range
5 to 70 years,
mean
age 26.3
some
with
mixed
parasitic
infestations
but
the majority
with
single
parasitic
infestations
[strongyloidiasis,
ascariasis
and/or
ancyjostomiasis]),
53
patients
(46Yo) were
shown
to
have
strongyloidiasis.
All patients received a single dose of iverrnectin
(200
rncg/kg)
and
follow-up parasitology
was evaluated at 7-10 days posttreatment
and again at 15 days
posttreatment.
Patients with strondyloidiasis
had nega[ive stool examjna(ions
al both
lime points [13].
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 137 of 382

Ivermectin
,.
Clinical Documentation
D. Clinical Efficacy and Safety
II.
References
B. Reference
Documents
I
5
Summary
of Published
Information That Supports the Use of Ivermectin
in the Treatment
of Strongyloidiasis
of the Gastrointestinal
Tract
4
.........++. :.-..% .-.’4:.-.’,
.“:+-:’
-
:“
~....
.>,
.,.:.,..
,~.,’,
,,
y,,;
,, d~;%j,;:
,..y.;ff
-!{,v,:<...: .,.~*.Jp.+~,
.’
. .:, ...-,,
,
,
$.-’-,
:.<:.,
~ERMECT~::
;/: ~~:y@ltJkm.
.,;!w;; ?
. . . . ,,
...<.*;5,.,.
>;~fit~():
npE
‘{~$~&!;~fiiltEdRENCE
[ ]*”X i’:W+$?r?boqj”
~~~
[$:: ~
(+oj
. .;.
‘2.% ,’... .. .. &~~fE~
q$:~y?;:;.:’;,:
., ..::.
COMPASS1ONATE
1
12 mgldayx 2 days
1/1(lCo)
Subjectwith Cttshing’ssyndrome
TREATMENT
previouslyunderwent3 failureswith
albendazolc
COMPASSIONATE
3
12mg/dnyx I day+
1/1 (loo)
After secondtreatment,definitecure
TREATMENT
12 mg/day x 2 days
wi[h 14 mo. posttreatmentfollow.up
COMPASS1ONATE
4
I x 200 mcgkg
1/1 (loo)
Chronic s[rongyloidimis
TREATMENT
unsuccessfully treated with TBZ over
an tt-ycm period was curedwith neg.
stoolsfor at least I yr. post!hcrapy.
ANECDOTAL
5
1 x 150 mcg/kg
20/20( 100)
Da!acollectedduringmasstreatment
TREATMENT
of onchoccrciasiswith i~ermectin in
Comcroon.
Twenty priticntshad
coincidentalstrongyloidiasisof the
gastrointestinaltract.
* Refcrencea [2] and [7]
me excluded from this summary since they represenI, respecliveiy, trcatmcnls of disscrnksted disease nnd
hyperinfection.
1
0
I
M K-0933\BW826.DOC — 25JAN96
II
,,,
“
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 138 of 382

Iverrnectin
.,
Clinical Documentation
D. Clinical Efficacy and Safety
II. References
B. Reference Documents
Summary of Published
Information
That Supports the Use of Ivermectin
in the Treatment of Strongyloidiasis
of the Gastrointestinal
Tract (Cont.)
.
. ., ANECDOTAL
TREATMENT
TREA1’’NlENT
STUDIES
8
6mgon Dayl+
I
6mgon
Day 14
I
* Referencca[2] and [7] are excluded from this summary since they rcpres
hypennfection.
MK.0933\I?W826.DOC
— 253AN96
CURERATE
,,,
”(%) ~~‘!’
3i3 (loo)
60/68 (88)
59/65 (9 I )
49/54 (91)
47f47 ( 100)
4s/47 (95.7)
.1 rcspectivcly,
Three of 12 randomlyselectedadultsin
a hypcrcndemic area of Central
America were positive for
S slerocomlis and treatedwith
ivcrmectin (140.200 mcgkg).
Stool examinationat:
!3 days Postdose1
13 days Postdosc2
1-2
monthsPostdosc2
3-4
monthsPostdosc2
5-6
monthsPostdosc2
,
satmcnts of disseminated disease and
6
.
u
I
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 139 of 382

I
I
Ii
ii
Ivermectin
.,
Clinical Documentation
D. Clinical Efficacy and Safety
Il.
References
B. Reference
Documents
Summary of Published
Information
That Supports the Use of Ivermectin
in the Treatment
of Strongyloidlasis
of the Gastrointestina!
Tract (Cont.)
.. .
. .
,,,,,,Q:;$
w~z$”,
:,,,,>:J,
<.,.
,
..j.
,
. . .. . .
.:.
,’S ~w%q,
,fe:~:’’:’>;;:;z:::NMvERMEcTN2&:L ,c~lw’m
,:2,:”.,:,,’
-.,,,,,;,,;, ~~ .’.,#&*;:
<
F?’
;::::?.
tfq?(j.NPE ‘$A$*. %u?
Iuw!E i 1*”X:;:$::,:;;~~sE
>};:;:,+
“ :; p%)
Iv;
,;,,:
,,:.:“:‘:’
COMMEW!’2W%Q.:’
“.“i’;
Stoolexfsmimstion at:
TREAT?vIENT
9
6mgon
Dayl+
18/21 (86)
Prior to Dose 2
STUDIES
6 mgon
Day 14
19/21(90)
TwoWeeksafter Dose 2
8 of 17 who failed received an
TREATMENT
10
6mgon Dayl+
108/125 (86)
additionalcourseof ivermeciinandall
STUDIES
6mgon Diry 14
8 werecured
S1001examinationitt:
TREATMENT
6mgon Dayl+
49[S3 (92)
Prior to Dose 2
STUDIES
II
6mgon Day 14
48150(96)
Two weeksaller DOSG2
* References [2] and [71 are excluded from this summary since they represent,respectively. treatments of disseminated disease and
hyperinfectiom
MK-0933\BW826,DOC
— 2SJAN96
7
c1
I
E
02
U-1
~’111
,,,,,
,8[,’1”
I
,,
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 140 of 382

Ivermectin
.,
8
Clinical Documentation
D, Clinical Efficacy and Safety
II, References
B. Reference Documents
Summary of Published
Information
That Supports the Use of Ivermectin
in the Treatment of Strongyloidirtsis
of the Gastrointestinal
Tract (Cont.)
K ;h:~:’~
-.jt~$#’Ji%
~
.s,..;
,-,,$&,,
,:,”,,
‘ ‘w
.Is?mzMEq;$’!”,,
**CURERA’rg
.;,;:
,,,
!. .,.,,
.,.
ti,’~:,’;:,j*~fi#pj
:&#, ! ~k fiKiN&
‘pc,::.:;’(?;~+,’’.~osjj
J;y+ii-..
:? ..?:(*y;
::;: :,<:.::,; ,, ‘Ai?r.~co~~xij;.k?ij%jii
‘“:::“%::i2 ,’;,.*.;,’*”:
::J-:;*,%:.~
TREATMENT’
1x 200 mcgkg
42143(98)
lvermeclin treatment
STUDIES
12
Albendazole(400 mg x 3 days)wasthe
comparativeagentin thistrialand
achieveda cure rate in 37 of 42
patients(88%).
The six treatmentfaiirsres(one
ivcrmcctin nnd five albentjazole) were
retreated with ivermcctin and were
cured.
TREATMENT
STUDIES
13
1x 200 mcg/kg
53/53(100)
Foliow-upstooiexamsconducted7-10
daysand 15daysposttreatment,
* References [2] and [7] are exciuded fmm this summary since they represent, respectively, treatments of disseminated disease and
hyperinfedion.
b
MK@933\BW826.DOC
— 25JAN96
.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 141 of 382

~....,
Ivennectin
Clinical Documentation
D. Clinical Efficacy and Safety
IL References
B. Refenmce Documents
4
5
Loutan, L., Goumaz, M. and Ga.illard, R. C. TRAITEMENT
AVEC
L’IVERMECTINE
DUNE HYPERINFESTATION
A
STRONGYLOIDES
STERCORALIS
CKEZ UN PATIENT AVEC
SYNDROME
DE CUSHING 4TlEATMENT
OF A
STRONGYLOIDES
STERCORALIS
HYPERINFESTATION
WITH
IVERMECTIN
IN A PATIENT WITH CUSHINGS
SYNDROME>
Schweiz Med. Wochenschr. 123(24):
1275, June 19, 1993 (French not
translated; however, English summary provided, in Sot. Proc.)
D –
3588
—
9
Couprie, R, Maslo, C., Bouchaud, O., Matheron, S., Saimot, A. G. and
coulau~
J. P. ANGUIJMJLOSE
DISSEMINEE
AU COURS DE
L’INFECT’JON PAR LE VIIl
LINE NOUVELLE
OBSERVATION
dXXWMINATED
STRONGYLOIDIASIS
IN A PATIENT WITH HIV
INFECTION
ANEW
CAS=
Presse Med. 22(20):
968, June 5,1993
(In Letters - French not translated; however, English summqy
provided)
Lyagoubi, M., Datry, A., Mayorg& R., Brucker, G., Hilmarsdottir,
1.,
Gaxotte, P., Neu, D., Danis, M. and Gentilini, M. CHRONIC
PERSISTENT STRONGYLOIDIASIS
CURED BY IVERMECI’IN
Trans. Roy. Sot. Trop. Med Hyg. 86(5):
541, Sept.-Ott.
1992( In Short
Reports)
de S. Wijesundew
M..and Sanmuganathan,
P. S. IVERMECTIN
IT-IERAPY IN CHRONIC STRONGYLOIIXASIS.
Trans. Roy. Sot.
lYop. Med. Hyg. 86(3): 291, May-June
1992 (In Shoxt Reports)
J40you, S. R-, Enyong, P. A. and Agnamey, P. RESULTS OF MASS
WERMECTIN TREATMEhT
ON THE ENDEMIC HELMINTHIASIS
UNTHE RAIN FOREST ZONE OF SOUTH WEST CAMEROON
4cra Leiden. 59(1-2):
466, 1990 (Abstract in Sot. Proc.)
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 142 of 382

.-.
D-
3589
8
.[3L
Ivermectin
10
CIinical Documentation
D. Clinical Efficacy and Safe~
II. References
B. Reference Documents
6
7
8
9
10
11
Freedman, D. O., Zierd~ W. S., Lujan, A. and Nutman, T. B. THE
EFFICACY
OF IVERMECTIN
IN THE CHEMOTHERAPY
OF
GASTROINTESTINAL
HE~
S1S IN HUMANS J. @feet. Dis
159(6): 1151-1153, June 1989 (In Communieations)
Torres, J. R, Isturiz, R., Munllo, J., Guzman, M. and Contreras, R.
EFFICACY
OF IVERMECTIN
IN THE TREATMENT
OF
STRONGYLOIDIASIS
COMPLICATING
AIDS Clin. Infect. ZXs.
17(5): 900-902,
Nov.
1993
Shikiya, K., Zaha, O., Niimura, S., Nakamura, H., Nakayoshi, T., Kochi,
A., Ueh~
T., Ueehi, H., Ohshiro, J., Kinjo, F. and Sai~o, A.
WERMECTIN
Nl YORU CHIRYOH NI TEIKOHSI-IIT’A
FUNSENCHUUSHOHKANSHA
NO ICENTOH dVERMECTIN
AND
DRUG-RESISTANCE
IN PATIENTS
WITH STRONGYLOIDLASIS>
Kzmwnshogaku 2ixsshi66(7}
935-943, July 1992 (Jan with Enrd, sum
Vot translated]
;hikiyz
K., Kinjo, N., Uehar~ T., Uechi, H., Ohshiro, J., Arakaki, T.,
Linjo, F., Saito, A., Iju, M. and Kobari, K EFFICACY
OF
VERMECITN
AGAINST STRONGYLOIDES
STERCOM.LIS
IN
WMANs
hten
Med. Jpm 31(3):
310-312, Mar. 1992
Clinical study on ivennectin
against 125 strongyloidiasis
patients]
Mkiya
~
Zaha O; Niimura
S; Uehara T, Ohshiro k Kinjo ~ Saito
k,
Asato R. Kan.senshogakuZmshi
Jan 1994, 68 (1) p13-20,
[Clinical study on ivetmectin
against Strongyloides
stereora.lis]
Wciya
~
Uehara T; ,Uechi H; Ohshiro J; Arakaki T, Oyakawa ~
Mugawa
H.; Kinjo F, Saito A; Asato R. Kansenshogaku Zasshi
Sep
1991, 65 (9) p1085-90,
h4K-0933U3W826.DOC
25JAN96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 143 of 382

Iverrnectin
Clinical Documentation
D. ClinicaI Efficacy and Safe~
Il. References
.
B. Reference Documents
I
13
I Tests J, Kizimandji-Coton
G, Delmont J, Di Costanzo B and Gaxotte P
TFUU7’EMENT D-EL’ANGUILLULOSE,
DE L’ASCARIDIOSE
ET DE
L’ANKYLOSTOMIASE
PAR L’IVERME-
(~~)
A
BANGUI (RCA) nREATMENT
OF STRONGYLOIDIASIS,
ASCARIASIS
AND ANCYLOSTOMIASIS
WITH IVERMEC’ITN
(MECTIZAN) IN BANGUI (CAR)]
Med Afr Noire 37(5): 283-284,1990
(French only. Not translated Only
English summary)
MK-0933U3W326. DOC
25JAN96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 144 of 382

NDA 50-742
Page.138
Mrxtizanq (Ivcrrncctin)
.
Strongyloidiasis
B. Medical ofllcer findings
1. Studies designed specifically to investigate strongyloidiasis
There are several studies in the literature which specifically examine the effkacy of ivermectin in the
therapy of strongyloidia.sis, in both immunocompromised as well as immunologically intact subjects.
Reference: Torres, J.R, et al. Efficacy of ivermectin in the treatment of strongyioidiasis complicating AIDS.
Source: clin Infect Dis 17(5): 900-2, 1993.
Type of study: open-label, compassionate use series
Treatment arms: Single-dose 150-200 mcg/kg, N = 2
Multi-dose 200 mcgkg on days 1~,15, and 16, N = 7
Number of patients: 9
Method of diagnosis: Baermann technique of stools (N= 9); sputum examination (N = 3)
Follow-up timepoints: at least seven months; up to three years
Results:
One patient with a CD4 count of 358 cells/mm3 and no evidence of disseminated infection was treated
with a single dose and was cured; the other single-dose patient had a CD4 count of 52 cells/mm3 and
evidence of disseminated disease (larvae in sputum); he refused fi.wthertherapy and died with
disseminated strongyloidiasis. The other seven patients were treated with multiple dose therapy. All
were cured of their strongyloidiasis, including two other patients with larvae in sputum and CD4
counts below 100/mm3.
Comments:
although open-label and compassionate in design, this study is of value because it utilizes
Baermann technique for stool examination, and provides prolonged follow-up of all subjects. It is
also a remarkable paper in light of the fact that immunosuppressed patients with disseminated
strongyloidirtsis have, in general, a very poor clinical response to thiabendazole.
The results of the
Torres study cited here should be compared to the recent review of the literature done by Celedon et al
(Systemic strongyloidiasis in patients infected with the human immunodeficiency virus: a report of
three cases and review of the literature. JUedicin~73(5) 256-63, 1994) which documents 14 cases of
HIV-associated
strongyloidiasis,
12 of whom died despite therapy with multiple, often prolonged,
courses of thiabendazole.
Reference: Scaglia M et al. [vermectin vs. Albendazole in the treatment of strongyloidiasis in Italian patients.
Source: Abstract tlom 1993 annual meeting of the American Society of Tropical Medicine and Hygiene, in
Am J TmD Med Hyg 49 (3, supplement): 262-3, 1993.
Type of study open-label
Treatment arms:
Ivetmectin 200 mcgkg single dose, N = 53
Albendazole 400 mg qd X 3, N = 47
Number enrolled: 100 patients with ‘uncomplicated’ Strongloidiasis
.
Method of diagnosis: ‘coproparasitological exam’ of fixed stool samples
Follow-up timepoints: one and three months post-therapy
...
Results: ten patients were lost to follow-up, and five died during the trial. Of the 43 evaluable iverrnectin patients,
42 (980%)were cured. In the 42 evaluable albendazole patients, 37 (88VO)were cured.
Side effects
were ‘negligible’ in both groups.
,
Comments: in this study, the eftlcacy of albendazole is considerably higher than in the previously-reviewed
studies. However, since the Baennann technique was apparently not used, Iow-level failures in both
arms may not have been detected.
Reference: Tests J, et al. Traitement
de I’anguillulose,
de I’ascaridiose, et de I’ankylostomiase
par I’ivermectin
(Mectizan)
a Bangui (RCA).
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 145 of 382

NDA 50-742
Page 139
Mectizan”’(Iverrncctin)
.
Strongyloidiasis
Source: M6decine d’Afnaue
Noire 37(5): 283-4, 1990.
Type of study open study
Treatment arms: Iverrnectin 200 mcg/kg single dose, N = 114 (total); N = 53 (infected with S. s(ercorafti)
Number enrolled: 114
Method of diagnosis: Tltree stool examination techniques, including Baermann technique
—
Follow-up
timepoints: 7-10 and 15 days post-therapy
Results: 53/53 patients with strongyloidiasis were cured at the 7-10 day endpoint; 18 of these 53 presented
for
the second (15-day) follow-up and all 18 were cured. No patients reported any adverse side-effects
(“Aucun
patient trait~ n’a d6crit d’effets secondaires apr$s la prise de I’ivetmectine.”)
Comments: multiple stool exam techniques make the possibility of false negatives unlikely;
however, a 15-
day
endpoint is relatively short.
Reference: Naquira C, et al.
lverrnectin for human strongyloidiasis and other intestinal helminths
Source: b m J TroD Med Hwg40 (3) 304-9, 1989.
Type of study: double-blinded, escalating dose-ranging study in patients with strongyloidiasis
in Peru
Treatment arms: patients were sequentially assigned to the following treatment groups:
Group A: Ivertnectin 50 mcg/kg (N = 18)
Group B: Ivermectin 100 mcgikg (N = 18)
Group C: Ivermectin 150 mcg/kg (N= 18)
Group
D: Ivermecting
200 mcg/kg (N = 17) =dosage used in MRL studies
Group E: Ivermectin 100 mcg/kg qd on days one and four (N = 18)
Group
F: ivermectin
200 mcgfkg qd on days one and four (N = 20) =
close to MRL dosage
Number enrolled: 110
Method of diagnosis: 24-hour stool collections were processed using Baerrnann technique as well as
additional
methods.
Follow-up timepoints: days 17-24 and 30-38 post-therapy. (Eighteen of the subjects cured at the 30day
endpoint, who lived in an area of Peru considered nonendemic for strongyloidiasis, were followed
additionally with three serial stool samples at day 90 post-therapy. The breakdown of these 18
patients by treatment group was not presented.)
Results: at 30 days post-therapy, the following cure rates were reported:
Group A. 10/15 (67%)
Group B: 11/15 (73%)
Group C: 16/17 (94?4.)
Group D: 16/17 (94%) =dosage used in MRL studies
Group E: 15/17 (88Yo)
Group F:20/20 (100%)
Additionally, all 18 of the cured patients who were followed up at three months post-therapy were
found to have remained cured of their infections.
Adverse events included constipation (4 subjects), elevation of transaminases, serum creatinine, and
alkaline phosphatase (1 each).
-..
Comments: Method of stool analysis is comprehensive and allows for comparison with ‘pivotal’ studies.
Excellent follow-up.
Despite conduct in an endemic area, used 30-day post-therapy
endpoint (unlike
Marti study).
Would have been of benefit if applicant had been able to submit patient-level
data for this study. Unfortunately, the two-dose regimens used in this study are not precisely the same
as those used in the MRL-6ponsored studies reviewed above (those doses were given in two
consecutive days [i.e., days I and 2] rather than on days one and four.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 146 of 382

NDA 50-742
Page 140
Mectimn”’(Ivcrnsectin)
Strongyloidiasis
The applicant has also submitted four references from the Japanese Iitemture.
All of these are authored by
the same group of investigators located on Okinaw% and all have the same first author (Shikiy%
K.).
When atmmged
chronological] y, these papers repoti successively larger numbers of subjects. Thus it is likely that these papem
represent successive accumulations of subjects and therefore the numbers repotied in each paper cannot be added
together.
The paper reporting the largest number of subjects, which presumably represents the cumulation of the
investigative efforts of this group, will be reviewed and tabulated. (One of the four papers was actually published in
English [Intern MedJcm31 (3): 310-12, 1992] and will be relied upon for procedural details of this series of papers.)
Reference: Shikiya K et al, Clinical study on ivermectin against 125 strongyloidiasis patients.
Source:
Kansenshoeaku Zasshi 68(l): 13-20, 1994.
Type of study: Open label, noncomparative study in an endemic area (Okinawa)
Treatment arms:
Iverrnectin 6 mg as single dose with repeat dose 2 weeks later. (Approximate dose range was 70-
160 mcg/kg for each dose.)
Number enrolled: 125 patients
Method of diagnosis: fecal samples were examined using the agar plate method
Follow-up
timepoin(s:
patients
were
seen and stoolsexamined2 weeks after the first and second doses, as well
as at or after one month following the second dose.
Results: of the 125 patients dosed with a single 6 mg dose, 112 presented for the two-week followup and 95 (85%)
were negative. Of those 95 (all of which were dosed with a second 6 mg dose at that two-week timepoint),
87 remained negative at the second follow-up stool. The 13 subjects lost to initial follow-up were all found
to be negative at this four-week timepoint. Therefore, at four weeks following the initial dosing, the cure
rate was (87 + 13)/119 or 84°A(six other subjects were lost to follow-up at the four week timepoint, making
the denominator 125-6 = 119). Side effects were reported by 9 (7.2°/0)patients following the first dosage,
and included dizziness in 3, nause and diarrhea in 2 each, and several other minor side effects in single
subjects. The English abstract also mentions that “although liver disjunction [sic] developed in 13.6% of
the patients, no symptoms occurred and no special treatment was required.”
Comments:
dosing regimen is non-standard. Although each individual dose appears to relatively underdose the
subjects (although data on the weight of the subjects does not appear in the article), when the total dose
over 2 weeks is calculated, these subject received a roughly comparable dosing regimen ( 140-320
mcglkg). Method of diagnosis is non-standard, although the agar plate method is considerably more
sensitive than a simple stool smear or formalin-ether concentration. The approximate amount of stool
used in the agar plate technique is less than that used for the Baerrnann technique, but is greater than
the amount used for a typical forrnalin-ether concentration. It is also of note that 43 out of the 125
patients treated in this study were HTLV-1 positive and therefore, to various degrees,
immunocompromised.
The investigators found a statistically significant correlation
between treatment
failure and HTLV-I status. Therefore, the overall eradication mte of 84°Ashould be considered lower
than would be expected had immunocompromised patients been excluded fkom enrollment.
2.
Studies not specifically
designed to investigate strongyloidiasis
Additional studies appear in the literature which have resulted from studies designed primarily to determine
the efficacy of ivermect in in the treatment ~f onchocerciasis.
Man y areas endemic
for onchocerciasis are co-endemic
for strongyloidiasi~ thus, several teams of investigators have studied the efficacy of ivermectin against intestinal
helminths in the context of mass treatment studies for onchocerciasis. The following studies were therefore not
specifically designed as strongyloidiasis studies but nonetheless contribute efficacy information that is relevant to
this portion
of the NDA.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 147 of 382

NDA 50-742
Page I41
Mectizan-’(Ivemwctin)
Slrongyloidiasis
.
Reference: Moyou SR et al: Results of mass ivermectin treatment on the endemic helminthiasis in the rain
forest zone of southwest Cameroon.
Source: Abstractof posterinActs Leiden59 (l-2): 466, 1990.
Typeof study:ancillarystudy in contextof masstreatmentcampaignfor onchocerciasis
Treatment arms: ivermectin 150 mcgllcg X 1
Number enrolled: a subset of 20 patients was found pre-therapy to have Strongyioideslarvae in stool
Method of diagnosis: not elaborated.
Follow-up timepoints: single stool exam one month post-therapy
Results: 20/20 patients with Strongyloides
larvae reported as cured
Comments:
lack of description of method of stool exam probably indicates a simple stool smear was performed;
therefore, low-level failures may not have been detected. Nonetheless, 30day endpoint is best that can
be asked for in this endemic area.
Reference: Freedman DO et al: The efficacy of iverrnectin in the chemotherapy of gastrointestinal helminthiasis
in humans.
Source: J Infect Dis 159(6): 1I51-3, 1989.
Type of study: ancillary study in context of mass treatment campaign for onchocerciasis in Guatemala
Treatment arms: ivermectin 140-200 mcg/kg X 1
Number enrolled: 12 randomly selected adults submitted stools, 3 of which were infected with S/rongvloide.s
Method of diagnosis: formal in-iodine concentration of stool and examination of entire sediment
Follow-up timepoints: one month post-treatment
Results: 3/3 strongyloidiasis patients were cured at the one-month timepoint
Comments:
Number is small. Difference in stool examination technique makes possibility of false-negative single
follow-up stool more likely. Nonetheless, these results are consistent with other studies using
Baermann technique.
Reference: Taticheff S et al: Effect of ivennectin (Mectizan~ on intestinal nematodes
Source: )?thiopian Med J 32(l): 7-15, 1994
Typeof study:
ancillary study in context of mass treatment campaign for onchocerciasis in Ethiopia
Treatment arms: ivermectin 150 mcg/kg X 1
Number enrolled: 231 patients with onchocerciasis, of which 7 were infected with Strongy/oide.s
Method of diagnosis: formalin-ether stool concentration
Follow-up timepoints: 15 and 90 days post-therapy
Results: 7/7 subjects were cured at the 3 month post-thempy timepoint
Comments:
Number is small. Difference in stool examination technique makes possibility of false-negative single
follow-up stool more likely. Nonetheless,
these results are consistent with other studies using
-
Baerrnann technique.
.,
In addition to these references, the’applicant has also submitted four articles that describe single case
reports of individual patients treated with ‘iverrnectin for strongyioidiasis. Because of the case repor( nature of these
references and the unusual clinical aspects of the particular cases that warranted publication, they are not considered
to be directly relevant to the NDA and will not be critically reviewed.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 148 of 382

NDA 50-742
Page 142
Mectizan* (Ivcnncctin)
.
Strongyloidiasis
Ile
submitted literature references which support the strongyloidiasis indication are summarized below:
Summary of literature references supporting strongyloidiasis indication
Referencq
Ivermectin
dose
Comparator
Method of
Eftlcacy at
HIV/HTLV
location
stool
timepoint
Patients
diagnosis
included?
Scaglia,
200 mcg/kg X 1
Albendazole
not
at three months:
“uncompli-
Italy
specified
lVER42/43(98%)
cated’’cases
ABZ37/42(88Yo)
only
Test%
200 mctdkgX 1
none
Baerrnann
at 15 days:
not
Central
IVER 18/18 (]()()~o)
mentioned
Africa
Naquira,
none
Baermann
at 30 days:
not
Peru
Gr A: 50 mcgkg X 1
Gr A: 10/15 (67%)
mentioned
Gr B: 100 mcg/kg X 1
Gr B: 11/15 (73%)
Gr C: 150 mcg/kg X 1
Gr C: 16/17 (94’%.)
Gr D: 200 mcgjkg X 1
Gr D: 16/17 (94%)
Gr E: 100 mcg/kg X 2
Gr E: 15/17 (88VO)
Gr F: 200 mcg/kg X 2
Gr F: 20/20 (1OO’YO)
Shikiya,
6 mg X 2, taken two
none
agar plate
at 28 days after first
43/125
Okinawa
weeks apart
dose:
patients
100/119 (84%)
enrolled
were
HTLV- 1 +
Torres,
200 mcgikg X I (n=2)
none
Baetmann
at 27 months:
all 9 were
Venezuela
200 mcgkg X 4 (n=7)
l/2 single dose
HIV+; 5 had
Given days
(50%)
CD4 s
1,2,15,16
7/7multidose
200/mm3
( 100%)
Moyou,
150 mcgkg X I
none
not
at one month:
not
Cameroon
specified
IVER20/’20(100IMo)
mentioned
Freedman,
140-200 mcg/kg X 1
none
Forrnalin/
at one month:
not
Guatemala
iodine
lVER3/3
mentioned
Taticheff,
I50 mcg/lcgX 1
none
Fonnalin/
at 90 days:
not
Ethiopia
ether
lVER717
mentioned
,/
.. .
The applicant seeks labeling that would indicate a single dose of 200 mcg/kg for the treatment of strongyloidiasis.
When the above references are compiled by those which studied doses of 150-200 mcg/kg as a single dose, and also
had at least 30 days of post-therapy follow-up, the efficacy rate is 9’7~0:
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 149 of 382

NDA 50-742
Page I43
Mectizan” (Ivcrsnectin)
Stfongyloidiasis
.
References using 150-200 mcg/kg X 1
and providing z 30 days of post-therapy follow-up
Reference
Patients cured/evaluable
Scaglia
42143
Naquira
16/17 (150mcg@X
1)
16/17 (200 mcgkg X 1)
Moyou
20120
Freedman
313
Taticheff
~
TOTAL
I04/107 (97%)
Not all of these studies utilized Baermann stool examinations,
thus raising the possibility of false negatives.
Furthermore, the ideal test-of-cure timepoint may well be longer than 30 days post-therapy.
BULsince all of these
studies were perfotmed in endemic areas where the possibility of reinfection exists, this timepoint is accepted as
being the most reasonable.
C. Conclusions
The published literature supports the applicant’s contention that ivermectin at a dose of200 mcgkg X 1 is
safe and effective in the therapy of uncomplicated strongyioidiasis.
8. Statistical considerations
Insert statsitical review and survival analysis here
./”
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 150 of 382

NDA 50-742
Page 144
Mec[izanw (Ivernwdin)
Swongyloidiasis
.
9. Overall conclusions
The sponsor has submitted four separate clinical studies in support of the strongyloidiasis indication for
which patient-level data (in the form of computerized case tabulations) has been made available. Ile
consolidated
results of these four studies, after the medical officer’s review, areas follows:
Study
Ivermectin X 1
Ivermectin X 2
Albendamde
Thiabendazole
30 day
90 day
30 day
90 day
30 day
90 day
30 day
90 day
Gentilini
24t26
21L26
12n2
10/22
Dreyer
9/14
15/17
13/15
Berk
4}4
4/4
212
313
1/3
Gann
14/14
14/14
17/18
17/18
16/16
16116
TOTALS
51/58
39/44
34/37
17/18
12/22
10122
32/34
17/19
(86%)
(89%)
(92%)
(94%)
(55%)
(45%)
(94%)
(89%)
Additionally, the applicant has submitted the manuscript of a study conducted by the WHO in Zanzibar (the Marti
study). This paper, along with the additional literature submitted in support of this indication, show the following
results:
Study
Ivermectin X 1
tvermectin X 2
Albendazole
Thiabendazole
30 day
90 day
30 day
90 day
30 day
90 day
30 day
90 day
Marti
1261152*
67/149”
Literature
i04/107
49/50
37142
(total)
TOTALS
130/159
49/50
67/149
37142
(82%)
(98%)
(45%)
(88%)
The clincal dam taken as a whole, support the applicant’s claim that a single 200 mcgkg dose of ivermectin is-safe
and effective in the treatment of uncomplicated strongyloidiasis in the non-immunocompromised host. The
statistical examination of these data performed by Dr. Sue Bell of CDER supports this claim. Therefore, the medical
officer concludes that this indication should be granted to the applicant.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 151 of 382

Iverrnectin in the treatment of Onchocerciasis
1. Tkdisease
A Lifecycle
tih~i~kti-tifwti
tideatibytih~~
ptitt?
Onchocenx
whdus.
This human parasite is a W&or-borne disease trmmmed
“
by the bite of the blackfly,Simulium.
In Ati@
the
*t
vector species is S &mnosum.
These insects require relatively high aquatic qga
Ievelafor their larval
pred
development
Thus, the lifecycle of the vector is closely -iated
with breeding areas in fkst-moving streams and
rivers where rapids provide adeqate oxygenation to auppoxtdevelopment of the water-borne Iawae.
Because of the association of the vector with streams and riv~
the disease in humans is epidemiologiealiy associated
with these bodies of water and has been texmed ‘river blindness’. (See Clinical mani~estitions,
below.)
Adult O. wlvulus males and f-es
are found in subcutaneous nodules of the infected human host. These
nodules are usually palpable and removablq upon removal and digestion in collagenase, a typical onchoeercsl nodule
can contain between 2-4 male and 3-6 female adults. The faale
measures 30-50 mm in kn~
whereas the male
measures 20-40 mm. The worms become tightly coiled within these nodules, which are usually palpable, measure 5-15
mm in diameter, and characteristically are located on the hips, joints of the arms or legs (in Mica
disease) or on the
scalp (in Central American disease). Nodules are less likely to be found in csucasian patients. They have been found in
children as young as one year of age in endemic areas. Adult Onchocema
cau live for over eleven years and are capable
of producing microfilariae for 9-10 years (Roberts JMD et ~ Bull WHO 37:195-212, 1%7).
Adult females within these noduks are in a sWe of constant kvipoaition.
First-stage lamae, Imownas
microfilariae, are discharged into the fibrous tissue aumoundingthe nodule and escape into subcutaneous tissue. These
rnicrofilariae (abbreviated mf) are relatively kmg-1.ivcdand may survive in the skin fbr up to 30 months (Duke BOL,
British Med Bull 28:66, 1972). When an infected human is bitten by an appropriate SimuIium vector, mfare ingested
when the fly imbibes tissuejuices fknn the skin. The ingested larvae penetrate the stomach of the fly and arrive m the
thoracic muscles, where they undergo two molts and become inketive third-stage larvae. These infective ]amae migrate
to the labium of the fly,where they-awaitthe fly’s next blood meal. When the veetor is fag,
infkctive larvae migrate
down the proboscis and enL5r-iheskin of the human host dining the feeding p~.
Following two additional molts,
adult worms become sexudy mature and mating paira coil up into nodules. Nodule development takes place in
proximity to the Iocatkmof the inketive Simufium bitq this ia why location of nodules varies between M&an and
American disease, as the biting habits of the local bkckily vectors varies by geographic area
B. Clinical mauifkstations
Although the adult worms Oftexlcause mauoacqic,
palpable masses, these amnottheksicmswhichpr educe
C~GddiSeSSe.
Itistheconstsnt
pmscnccofmigrating
auk@mem~
thehoatimmune lwWiontothesep&aai@&
dtimtipdApti*ti&
kti-dti*d--M~.
lb
migratingmfeausean intenaelypluritic delmatitia thathaabeenvarioualy
cham@&d
as liekiforrQ
eczeulatoia or
pigmented. Adenolymphocoele(%anging groin”) and acmtal ckphsntiasia has ah
beemdescribed as a complicado@of
this infection.
The most imporknt clinical manifestation of this infection occurs whm migrating mfinvade the atrucmm &
...
the eye. The mfmay invade the comes and be associatedwithapunctate,vasdar, orinterstitialsclerosing loxatitis.
Concornkmtly with the mi@ion
of the mfinto the orbit and paxtictdarly into the immediate vicinity of the optic nerve,
the patient ilrst txmplains of photophobia with evidemceof congestion andpunclatehemomhagearoundthelimbus of
the eye and congestion and edema of the conjun6tivaThisisfollowedbyMkmnationof the iris, ciliary body, *
and choroi~ exudate in the vitreous, resultingin gradually increasing 10ssof vision- The tinal stage, that of complete
blindness, results from the invasion of the optic n-e
by the mf(Fa@
Russel, and Jung Clinical Parasitolotw, 8th
editiou 1977).
It is estimated that some 20 million peopleinSubsaharsn Africa are infected with onchocerciasis, as well as an
additional one million people in scattered fmi in Central and South America. ‘his disease is considered to be the
second mos[ important infectious cause of blindness in Africa, following trachoma. Despite this prevalence in endemic
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 152 of 382

NDA 50-742
Page 2
Mcc6.zan ID(hmmtin)
.
.
O@wxmasls
areas of the world onch~ciasis
is not considered a major importd tropical *
in the United States. Acaxding to
the CDC, there are between 100 and 200 new cases annually in the United States (John Beac4 CDC Parasitic Disease
Drug Service, pemonal comrmmication).From one quarter toonehalfofthese
cases are in immigrants who have come
totheusfiom
endemic areas. *us-,ti=mm*hpttitim~mPa@
volunteers, missionaries, and others who had lived m endemic areas of the world fix adqmte
amouots of-tie
to acquire
a parasite burden of sexwdlymature Onchocenxz adults. The clinical manifestations of the disease am datively chronic
in nature, as opposed to other impmted tropical &eases (such as malaria) in which the infected patieat rapidly becomes
clinically apparent-
In endemic areas of the world such as West tiw
onchocerciasis has a major socioeumomic impact because
it incapacitates othexwisehealthy, potentially productive adults. This is one of the three major factors which led to the
WHO’s decision to initiate an onchocerciasis eradication campaign in West AiYicain the mid 1980’s. The mnaining
two factors which made this disease a candidate for a concerted eradication efhrt are 1) the aftmznentioned f~ty
of
the disease (i.e. its close asmciation with swiftly-flowingstreams and rivers); and 2) the recognition that ivermectin was
a suitable drug for use in population-based mass treatment programs.
C. Therapy
Dregs for the treatment of this disease are classified as either Iaxvicidalor adulticidal. According to the fourth
edition of Mandell’s Princimds and Practice of Infectious Diseases: “Traditionally, patients with skin disease have been
treated with diethylcarbamazine (DEC). This drug kills microfiltiae
but has little efkct on the adult worm. Severe
reactions such as rasi fever, generalized body pains, keratitis, and iritis may occur...”. DEC (Hetr~
L.e&le) was
discovered in the 1940’sand has been the mainstay of onchccerciasis therapy since the seminal articles on its effect on
microfiladerrnia were published by Mazzotti in 1948. This drug was approved by the FDA in November 1950 and
remains the only drug approved for this disease in the US to date.
Prior to the discovq
of PEC, the only dug found to be effective in this disease was Suramin This drug was
synthesized in Germany inlhe 1926’sas an antitrypanosomsl drug, following the observation that some am dyes
possc=d
trypsnocidal activity. It remains toti~tie~~~-
tik~dtititi~bti~ti
onchocerciasis. Suramin still has use in the therapy of Aliican trypanosomiasis. It must be given by slow intravenous
injecti~
and has a notoxiousaide effect pmfde which rncludeaperipheral naxopathy, albuminti
leukopea& ~
and renal failure. Because it has some larvicidal as well as adulticidal effects. tmatmed of on&xaTiasis
patialts with
suramin can evoke the constellation of signs and symptoms anmonly
mfe$redto as the Maizotd reaction (freer,
pruritus, *
adenitis, genemlized body pains, arthralgia). Suramin isavailable rnthe USunderan
INDheldbythe
Parasitic Disease Drug Service of the CDC.
~eMmtiw&mw=tiHk
tia-ofctid
ti&titiDEC.
Infi@thisreaction
iasucha
predictable ~
ofDEC ~
'onthatitia
kquent&used
asadiagnosdcchallcage
testincaacswhere
~&k_mtid
_@ptitil@cd_
~ti@bb_W.
llteaevai~
of this reaction is conaidexedto be pmportiemal to the rntensity of the iufkctk
Because the Mazzottircacticm can beaevere, tiemmmmded
doaingmgirnenfb!r onckemiasia
@uldelL
~cides
and practice of hlf~OUS
~,
F-Mtiq~M36)*fmmtiti
Wb(W@@)m
dayone, then50mgtidonday
2,then100mgtidon
day3, followed by3mg@tidfordays
4-2l.
(NB:thecurrent
product Meling reads “In Bancroft’s filsriasis, onchocerciasia, and loiasis, the usual dose is 2 mg5cgofbody weight 3
times a day immediatelyfollowing meals... when the disease is in the acute stage, lreatment should be maintained fm 3
to 4 weeks.” The DOSAGE AND ADMINISTRATK3N aecdon then p-
@~~
“WhCZL
ssapubfich~~
measure, it is desirable to treat large numbers of patients known to harbor rnicrcdilariae,the same dosage schedulemay
begiven for 3 to 5 days.”
The severity of the Mazzotti reaction and the need for multiple doses made DEC a suboptimal drug for use in
mass eradication campaigns. For this reasou the initial onchocerciasis control effcmsof the WHO were directed at the
Simulium vector. This massive spraying campai~
which began in 1973, wss
tithlly
SUUXSW
in reducing
transmission of the disease, but it became clear that ultimate success would not be achieved by this intervention alone. It
was at this critical time in the WHO’s Onchoccrciasis Eradication Program that iverrmxtin was recognized as a
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 153 of 382

NDA 50-742
Muaizan @ (kmcuin)
Page3
Potentidyimjxntant
SIlthdUdhiC
for human USC.
Ivamectinhado@inallybeendevelopedbyMedckthe
1970’sfmve&imuy
use. By 1986, ivennednhad
been registered in 47 aunties
for animal use. It was labeled fm the tmstment of eetoparasites (ticks, mites, and lice) as
well as nematode endoparasitea m a variety of auimal hosts (cattle, sheep, _
pigs, and do@.
—
Because ivermectinwasfbund to behighlyc4&tivernthe
tmatmc@of*ne@odes
(including the
horse parasite Onchoctvta
cervkdis),
usually as a single dose, studies of its saf’
and etlicacy in human parasitic
disease were undertaken. These clinical studies bcgau in 1980, and led to the marketing approval of ivameetin for
human onchocerciasis in France m 1987. These clinical studies form the basis of the clinical studies section of this
NDA. No clinical studies have been performed specifically in anticipation of an NDA filing with the FfM-
-
.,
2. Ovaview of submitted application
The applicant has mbmittd the following cliniea.1studies in support of the onchocerciasis indication:
1. Protocol 514: A muhicenter, rsndoa
doubleblind~
placeboumtrolled
comparative study of
ivcrmectin ( 12mg single dose, capsule formulation) versus DEC in the trestmemtof patients with onchocerciasis. This
study enrolled 149 male patients in four locations m Afi-ica. A dataset was provided to the statistical reviewer by the
applicant for this study, but the medical officerwas provided a study sumnuuy report in bard wpy only. A 34-volume
‘request for additional tiormation’ amendment was submitted to the ND~ dated 9 July %, which included four
volumes of individual patient data horn this study.
2. Protocol 519: A multicenter, ran-
double-blinds
placebo controlled study of ivcrmectin at three
doses (100, 150, or 200 mcgAcgsingle dose, capsule formulation) versus placebo in the treatmmt of onchoces-ciasis.
This lsrgephase 3 study enrolled !I%msles
and l19faslesat
sixlo@ionsinAfiiea
Adatasetfwthis
atudywss
provided for the statistical fiewer,
but the medical officer was provided a hard copy study summsuyonly. lle
9 July
% ‘additional information’ amendment to the NDA included 24 volumes of individual patimt data fi-omthis study.
3. Protocol 545: An open study of ivermectin (1S0 mcf+kg single dose, capsule fbmmlation) fa the treatment
of onchocerciasis in children 6-13 years old. This study was submitted to the French mgulatmy agcwy in 1988 as an
efficacysupplement to the already-approved ivennectin label. A dataset was submitted to the atatktical reviewer, but
the hard qy
summary of the Marketing Authorimtion Ap#ieation wss all that was submitted to the medical ofiiccr.
The 9 July% NDA ‘additional information’ submission included 3 vohnnes of individual patient data fbm this study.
4. Protocol S48: A Single-bin
plaoebo eontmiled study of the marketed tablet to assess the tolerabii,
aafkty,and eflicaey of single dose ivermectm“ (1s0-220 mcgkg) inthetreatmd
of onchocerch&.
Tbisstudywas
@-drntidemd
39 f~eptim@rna~e-ti(m~)
~~.
P.V_
Thedatasetfmuptothe
&y4@-ti~-tiw~~W
~titiAtim,
btimfd-_w~~tiU@b
applicant in the form of a completed study report. The ‘additional information’ submkaim to the NDA included one
volume of individud patient data ilmn this S@.
This study was not revkwd
by the medical officer.
Several additional studies are referenced in the applicatim but the above four studies are the clinical tisls
upon which the application rests. The design of these onchocereissis studies includes the following common f~tures:
.
the diagnosis of onchocercissis is madeonthebasis of skin snips, using a standardized instrument
.
the degree of microfiladcrrnia is quandfied in terms of number of microfilaria per gram of skin tissue, by taking
the average of four anatomically separate snips taken from standardized locations on the patient’s body
.
patients were treated with ivermectin for a single dose (or comparator) and then followed scriaIly for at least six
months
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 154 of 382

NDA %742
Page 4
Mcciizan @ (Wmwxin)
.
.
Ck&cuCmu
G
skin snips
were repeatedat speoitied times using the same technique as the baselinesamplesmentionedabove
G
~@
*Y
w~ IrMsumdasthc ckxeaseinmi cdibkmiahxn
that~atbaseline.
G
qproptiateophthalmological p~
inchding number of visible intraodar
microfilti
were monitored
M@titiyoftimmti*
h**krnti&,
a~-fmti-M
intraocular measuremeds of disease profpsion
or regmssiq
this is an appm@&ealdpoint
Suchmammmentsare
relatively well standardize and have been the acoeptedmethod fa diagooaiaand monitoring of onehcaw “ask patients
for many years. Thus it is appropriate to use this pammeter as ameasummat
of response to therapy.
Theclinicd
studies cited above followed ophthalmological endpoints as well. Since the spouaor requests labeling that caUsfor
repeated therapy at three month intew~
theprimaxy endpoint of interest in these studies will be &a-ease in
microfilade.nniaii-m baseline, at three months post-therapy.
several of these studies define ‘favorable response to therapy’ as a patied whose mics’ofilarialskin auip count
has dropped below 5 mfhng of tissue. The basis fm this measummm tliesinthefact
thatthesestudies weredesignd
primarily to examine the feasibility of using ivermectin in the setting of mass eradication campaigns.
If the &msity of
microfiladcnnia in the population can be suppressed below a certain Iin@ it is thought that trausmissiou of the iofkct.ion
back to the Simdium
vector can be interrupted. If this is accomplish~
then the t
“ ion cycle has been broken and
the eradication campaign has a much higher likelihood of success. Thus, for the pwposes of mass eradication tiles,
the 5 mt7mgtissue parameter is an important endpoint. However, at the individual patient level absolute eradication of
microfiladerrnia is the more important endpoint.
3. Medical offkzr review of submitted application
A. Study 514: Double-blind comparative studies of ivermectin (MK-933), diethylcarbamazine citrate (DEC-
C) and placebo in patiems with onchocerciasis.
i. Applicant’s wag
-. -
./-
—
,
—.
—
—
s
.
=.=
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 155 of 382

NDA 50-742
Mcdizan @ @WllCC@
Pas s
Odwcucissis
.
nzma
GMAR?
A
SOSIME
nzstAReff &mo*AToRl?s
~xmf?m-clmxal
S2uoYUPDRx
Q!K& lCJAM 7
?800UdX :
Xw~meetln
(IK-933)
CaPsuloC
Containing
6 m
MS-$33
and
DiethylcarbeuziM
Ci&et@
[DSC-C)
CSOSU1O*~ts!nins
50 M
0ss-s
and Mstetli tu
?Lteaba
c4PNhm
PSOXWOLC t:
DoutJIo+Blhd
Coapmetive
studios
of
Ivmmeetin,
Dicthylesrbemmzlne
8514-09
Cltrete
GISAPlceabo
in Patients
MM
Onehocareiacis
MVSSXICAYORS
Dr. M. Lerivim’e:Dekar.
senessl
c
snmY
c:
05002
DC. ti.
t.erivhre: Baeko.
ffali
Dr.
t.
Au8dzi:
Teulo.
Cbend
8s,
8.
Cmelse!
Crend -**9
Countv.
L Iberia
SYUDY 0SS109 :
Double-blind
vs
OSC-d
mid
ptSC,bO:
IDURA+IOM:Silsgh dove of
iwcmecthl
en
trem-t
Gsslgment
Gccording
to
G
I
Dey 1,
2 dally
doses
of
Dsc-c
en
Smys
1
randomized
Glloatlon
9ehedulo
hroush
8:
Gff!escy
foll~
for 1 year
DOSACS :
Xmrmeetimpatlentmreeciw~ds Gincleoral 12 x
dose en osy 1.
DSC-Cpatiomtc
roeeiwed 2 hilr
doca
tot~lln$
SO q
on
Dsy* 1
and
2
snd
200 q
cm Deys 3
thswsh 0.
PAtISSY POPULATION:
JPSR2fSCYI@
LA
mYSRSo:
MALI! (Mean
Age/xcarc)
50
(31.1)
S07R41
4:
(:2)
“’”
PSffALS (Mean
ARG/Yam9)
o
0
0
xoru
so
so
49
~LYTIMC
SYUOY:
44
45
44
kxYwDRAus:
6
s
s
SAY=Y (CLX81CALASO IA20RATORY)
O
0
0
“Rx fAIWRC
o
0
0
DYlrsR
4
s
s
SVALUAISOFOR
SYYICACY~ffAxIlfun)
:
47
49
46
A2mxRsE sxPl!lfIlmcss
{Patients)
CLI=ICAL
25
2s
11
UYJORAYORY
5
11
2
Rcsuus:
SYPICACY:
In thi9cmpsr-tivestudy
of
Avermectin
vs
OEC-C w
placebo
in hospitalized
OnchOcer-
eiosis
patients,
mm
skin
dcrofilarh
(of)
dencities
deeraased
sharply
by
Day
2 in
both Ivermectks
Gnd OfC-c
patientc 9nd
resehe4
GlmoStidmtical
low
levels
(.
XT. of
pretreatment)
by
Dey
0.
The C@ densities
then
decreasd
farther
in
the
iverneetln
patients
(mas
Eo
O)
over
the
next
3 tithe
but
imeraased
Bredually
in DEC-C pmtlentc
to Gbout14% of
pretreatment
lowal
in
S mnths.
Detueen
3
M4
12
menths
posttrest-
ment,
the
mf dem!t~cs
in
iv4rmectln
patients
$mdually
inemased
to
Gbout
S% of
the
pretrostment
level
eoqmred
to
20X
im the
OSC-C y+atlente
at
12
aths.
Xh9re were
Gstentldly--o
ehcnges
tith
placebotreatment.
Both
lv~-etin
mid
MC-C
Gltatneted
mf
from
the
Gnterior
chsmber
of
thv eye.
OSC-C-
traatod
Pathnts
cleed
d
fsster
than
lsermeetln-tr~ated
patients.
sum
:
the
lneldenee
of
elinieal
Glvers4
Gxperiences
in
the
fvameetln-treated
Gatients
WCS
tllchtl~
lower
than
in patients
treated
uith
DIN-C
(S0
V8
S6%).
More
DSC-C
pdhnt8
tied
G
uoreeni~
of
*ycteAc r4aAbne than
I-emctin
patients.
In
Gddithri
.
wee
Of!C-C
psthnts
cwqaked
steroid*,
8nti-inf
Iemeetery
&wg*
And analgesics
then
iver-
osctln
patldntc
to relieve •~tm
of
Gy9tAate
reactions
end
elhsleal
Gdvereo
Gxpbrieneac.
In
$enaral.
ophthelaolofic
Gsfcty
reeulto
vem
81mLlor
for
ive=tin
MA
OSC-C.
OfXC-C.
iwwevec,
eeu$ed
Gn
inereece
in
severity
of ltabiticandpwnctate
kesmtitis
in
=re
y+mtientc
durin$
the
f h-et
4 snd 14
StdAy
days,
mspectivoiy,
then
iverwctla.
tend
of
the
laboratory
Gdv-rse
Gp4rientaa
wm$ considered
Griouc
by
the
investi**-
tor4,
And no @Ant
me
dleeonthaed
trmithk Gtudydoe tv kdvereeqmrlenee.
she
OSC-C-treaM
*roup
hcd.
G
e~ctkr
*ert4nttg@
Of
**U4A
tith laboratory
*dwem*
Gxpetiencec
thm
the
isemeetin-tr~sted
- Croup.
2he
~rcatcte
of
patients
utth
incr4aeed
AST
in
thd
0SS<
Croup {2St)
*O
Glttslflcantly
;SWtar
thsn
In the ivea9cc-
tin &rom {221 Snll*lacoboIram
(4%) $ * <0.02.
COSCUISIOSS !
%he
following
cenehsebnd
ny
be
drem
from
the data presented
in
this
CSR:
(1)
lv~meetln
tiven
Ge * dngle 200 9t8/kg 0s41
4ose
is
en Gffective
~emfilarl-
cid~
in
the
trestment
af
onthotorel~el$
hd
is
Gt
Ieaet
G
6ffectiveGs the stmdwd
(May
eeorea
of
OtC+
{2)
lb
Gierofihrh
l~ml
resmh$
hlw
5 ti/~
ckin
for up
to $ months for G
lqtiw
@rSWitlge
Of
~vernectin
pstienti
then
ORC-C
patkmts,
end
the
tr4nd
eonthweq
for A
iamst12 mths:
(3) Ivomeetin hss G better
Gafety
pro-
file
in
onchoem-cimis
patients-
then
MC-C
with
ravpaet
to
Glle~ic
Gnd
inflmmstory
routbnc:
Gnd
(4)
The
troetment
of onchoeerckic with iwatntctln
is
swotiated
vtth
d
hwer
inchknte
Of
clinically
$ignif
icmt
~et~rioratlon
of
ophthalmologic
pwwmetert
then
WC-C,
~.4,
up to
bay
4 for
~lmb~th
snd up to
2 weeks
for
punctate
kerstith.
#
-$fL
(
4
(-iJuKqK&w&
Qe
)
J@+d’ (d’k !lt.l,!.4
carol
A.
Jatebsan,
S. S.
.L%
to.
. .
fs. P.n.
“ Hohemrd
A. Azlz. H.D., Ph. tI.
A8eoc .
wed .
Prog
.
coed
.
-
Senior
S
tlttielm
Ssnior
Olrector
Clin. Res. Intl.
CMRDS.
Intl.
ClIn. Rec. Intl.
.—.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 156 of 382

NDA 50-742
Mcx&m
@ (hwmech)
Page 6
Gdwxrciasis
ii. Medical offica eamments on study 514.
~s-w~tititifu~ma&
ti@rn W@ Wm(~dw
Utid-)d~
1984 and 1985. Each study site contributed appmximately 30 patieats (ten m eaeh &e&meatarm), with the exception of
Dr. Awadzi in GbanayWhO auded
59paticats.
~reauks
ofeachoftbese
study siteawere indqenbtly_pubkhedin
the peer-reviewed medical literature and f-an
impmtant eompnent Ofthe medical Iiteratum desuiiingthe
efhcy
of ivermectin in this disease. The publications that resulted fhmuthis study include:
.
Green BM et aI: Comparison of ivermedin and diethy]cd amazine in the treatment of onchocerciasis. ~
England Journal of Medicine 313(3): 133-8,1985.
.
Lariviere M et al: Double-blind study of ivermectin and diethylcarbamazine in M-
onchocerciasis patimts.
t- Lancet 2:174-7,27
July 1985.
with ocular involvement
Diallo S et al: A double-blind comparison of the eilkacy and safety of ivermectin and diethykarbamazine in a
..-
G
placebo controlled study of Senegakse patients with onckemiasis.
Transactions of the Roval Societv of
Tropical Mdicine and Hvgiene 80:927-34, 1986.
.
Awadzi K et al: The chemotherapy of onchocerciaaisXI: A double-blind comparative study of iverm~
diethylcarbaxnazine,and placebo in human onchocerciasis iu Northern Ghana. Annals of Trooical Medicine
and Parasitology 80(4): 433<2, 1986.
Each of these refmences are included in the NDA Submission found on pages D-3746 to D-3785 of volume
1.24.
In general, the design of this study is excellent. Afkr meeting the enrollment criteria patients were randomly
assigncxito one of the three treatment arms, and were supplied with identical-appearing treatment kits which contained
an eightday supply of medication consisting of a single dose of ivermectin (at a dose of 12rug) plus placebq an eight-
day course of DEC at a dose of 50 mg on day 1, 100 mg on day 2, and 200 mgdailyfwthe
remaining 6 day%or all
placebo capsules. Each patient took the same number of identictd.lyappearing capsules in tie morning and evening.
Patients and investigators were bligded as to the identity of the study medication.
All enrolled patients-were males with moderate to severe disease (defined as 220 mfper mg of skin) and
evidence of mild to moderate ocular involvement. Patients were followed daily in-hospital fa the first 2 weeks, tlm as
outpatients on day 28 and at months 3,6,9, and 12 post-therapy. Parasitologic pammetem followed included sldn Slips
at specified anatomic kxati~
as well as several ophthalmologic parametm (visual acuity, pu-ipheral visual fiel&
pupillary re5exes, color visi~
slit-lamp exam of the anterior and posterior chamber, intraocular pressure, ddated
fimdus exam with photography, and fluoresce.m angiography).
+ the formulation used was the capsule f-ulation
whereas the NDA rqueats approval of the tablet fbrrnulation
+thedoseofivermectin
atudied ka~t12~&,~ti~A_-mam~bfi.
&a
rough estimate, the baseline demographic cka&msb. .cs preaeated on page 22 of the study report @geD-1465
of
Volume 1.19) give a mean weight of approximately 56 kg in the tluee treatment arms. This means the average enrollee
received adoseof
214mcg/kg
whereas tlwNDAmquestsadoseof
150mc@g.
Theref~on
average, thepatientsin
this study received a higher dose of ivermectm. thanisrequested
+ the protocol makes no mention of nodulectomy as a component of this study, but the Merature reports that were
-
generated from thse studies specifically mention that onchocercal nodules were removed from numerous patients in all
arms of the study at various times post-therapy. This is potentially important because the removal of actively
larvipositing adult worms could cause a decre&
in microfihdermi% which may cmnfoundthe drug effect being studied.
There appears to be no attempt to control for this in the efficacy analysis, or to strati@the analysis by number of nodules
removed per patient. The graph presented on page 33 of the study report (page D- 1476, volume 1.19) shows that the
placebo group had a signitkant drop in microfiladermia at days 14 and 28. The applicant discusses this observation on
page D-1477. No satisfactory explanation is provided for this observation aside from the speculation that this was
‘<partiallydue to the ongoing Onchowrciasis Control Programme in Ghana”. Admittedly, the literature reports state that
nodules were removed from patients no earlier than one month post therapy; thus, the observed drop in microfdadexmia
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 157 of 382

NDA 50-742
Page 7
Mcu.izan @ (hmmcch)
Guhmaciasis
seen in the placx&
mm
of the @
preceded the nodulectomies that were perfii
Nonetheless. nodulectomy was
not planned to be a ~toftb.isstudy,
acardingto
thesubmittcd smdyreyert. Since suchaprocedure could have
afkctcd the parasitological cadpoid of in-
it should have been addmscd”Inthestudyreport.
+ thisistheoxdystudy
aubmittedrnti
NDAti&Wa
coqamtmarmusing
anFDA-approveddrug&rt
his
indication (DEC-C). Since the methodology used in this study is essentiallythe same as that used in the largezphase 3
@519,
itk~ableti~&d~~&
of&
DEW-of
&@titi~aq~&
of tie
ivexmec4inarmsofboth thisstudyas wellasstudy519.
iii. conclusions
Study 514 supports the safety and efheacyof ivcnned.n in the therapy ofonchocemiasis. The dose and
formulation used in this study are not identical
to that which
the applicant proposes in the pro@ct labeling, but these
diflkrenees do not invalidate the study. In this double-blindd
comparative, placebcontrolled
study, the applicant has
demonstrated that ivcrmectin has better eflicacy than DEC-C, when expressed as reduction in geometric mean
microfilariae per mg of skin from baseline. This difference persists beyondthe three month post-therapy timcpoint.
Furthermore, study 514 demonstrates that ivermectin (even at this higher dose) causes less severe Mazzotti-type
reactions than DEC-C, and that ivermectin does not exacerbate ophthalmological indices with the exception of a
transient increase in the number of anterior chamber microfdaria seen.
Please see the overall conclusions to this section of the NDA review for efficacyand safety results of this study
in comparison to the other studies submitted in this application.
B. Study 519: A multiclinic, double-blind study of ivcrrnectin (MK-933) and pIacebo in patients with
onchoccrciasis.
i. Applicant’s vary
..-
The applicant’s comprelxmsive study aunumuy fm this study is fbund on pages D-1523 to D-1605,
volume 1.19 of the NDA subrnissiom The reader is refkrred to this document fix a comprehensive description of the
study. The synopsis of the clinical study report is included on the following page
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 158 of 382

NDA 50-742
PageX
Mc.dbm @ (lvcrsncdio)
Ondmccrcissis
~YMOP21S--CLI8KAL
K2VOf RKPDRs
OASK:
20JAX67
R
27 FSB27
m MJ AM 7
“?Ri30um
Ivamcctln
00%93s) oral qlas
Contxinimco.7s. 1.0 or 4.0 w
Iv*rwctiss:
P1aeebo
mo20wL
& c:
A tkiltkllnie, Dmble-Blindstudyof Ivomeetln (IVAS13) and
#sl$40
Pl@caboin ?ctionts4fiLiI
0nehocwcia9i*
IP9SSSICA20RS
Six Inv*stA*atorsIn 6 eowtrlac
#soo3
& snfor f:
ssurm os21a:
A
doubl*-blimd,
rM4s=ized.
pkcObO-
~ WRAIIM:
Single
dose
Ivanectln
or
ph.
eontreihl,
mltieetat
Gtudy
eebo
09y
1:
GffLemY
fallOW+p
I
J.
t ad
12 months posttm-t-
*t
00SACS:
Cac?I patient
rec*ivwl
G slngl*
oral
dose
of
Iv.meetln
(100,
1S0
or
200 mrglkg
bodrvsight)
or plaeAo
on my
i
of th4Gtwly.
PATISU7
POPULAIZ02:
TOTAL
X)0
MCC/KC
mmso:
1S0 fYCC/KC
200 HCO/KC
PlAcx2m
MLS (ma*nAge)
1154 (31.0)
295 (30.9)
276
(31.1)
297
(31.8)
200
(30.0)
fmUL2 @aus AS*)
119
(37.2)
23
(s8.0)
44 (36.2)
2s
04. s)
27
(37.0)
CKUCIRR MO
ACE
3
1
2
0
0
TDru
1270
(31.61)
319
(s1.30)
322
(31.81)
unnoRAus:
322
(s1.98)
31s (31.Jo~
SAYST2 (cLIUICAL
AKO LABOP.AYORYI
o
0
0
0
Rx FAILURA
o
Q
o
0
OrHKA
SVALUATSO?OR
DST 3
1009
2S4
249
254
2s2
ff~l~ff
(YLAKIRUM)
:
ihmth
3
942
238
237
238
229
Month 4
91?
237
230
223
227
ADVKRW ssPmIAmc2s
(Pstlantc)
CLIMICAL
1s2
1s5
170
94
fA20RASDRY
i
1
0
0
R2SULSS :
SAYssi :
KPrlcAcr:
his
alticlinic.
double-blind
8M+IY compared
3 dosage
levels
of
iwercwctln
to
plae+bo
In
Iwspltdixed
onchorerciasis
pstlents.
She ndim
skin
-
densltiac
Gt
fmy 3 were
14.2,
0.4.
?.2
and 44. S for
tht100. 1S0. 200 mcK/ks
and plmeebo
trasta.nt
groups,
m8p4ctiv91y.
2h4
dscraase
continued
to
Ghost
cq14*
61idnstI-onof ths mf at ftonthsS and 4 for the ivamsctin Cmupc.
Durins elw
saw
period,placebopatients
had Algmlficcntlysnsliarchanges. 2hs 200 9c@kg
grouphsd G hozw v@d
Gfhet
Mmn
iOO
mc/kg
(p
< 0.0S1.
27svre-s
Mttle
dif-
ference
bet-en
the
1S0
and
200 xct/~
doses
with
mspcct
to
their
aierof
llmri-
eidal Gffact. In tha Glimhmthn
of micrqfllatlaofrox the xnterlorchaber of
tlsqGya.
I**mectin W*
GiCnifieAntly8uPcrior (p < 0.001) to placaba Gt
tJonth9
s mid4.
All
3 dos-s
(100.
1S0
4
200 OS**)
Of
ivaracctin
wsm
tenerally
wsll
tOlm-
Gtd.
-VCC,
ths
~~entqt
of
$Gtients
with
clinied
adverse
Gcperhncm
(prin8rily~algi8 And hbsdschejwas 41i*htlfhigherGt th4 kigherdose 10V4IC.
Motuof ttioaG&6r96 arjmionca mx
eof12i4Qcwd
9Gciox4.
lvomcctin trxa-t
4ms *enerAlly6u#4riorLO the pl~c~botremtit
mmdinc
tha pae4nt*c*$ *f
potiontsM*
*
~rov~t
In
li~itis,
cchrosi~
ksr9tit
1$,
8ntoriot
eh49b4r
demtilaris,
eoroeal
liv*
tie-f
ilxria.
cornea:
4*s4
9ier8fU4ria
md
punctat4
opacity
Gxp4cldlly
h
ths
~tion
of
9icro-
f ilmi*
in
th4
4ak*rietGksbar And tomos. M
fionths$ And S.
2vormectin
ems
$fsilir
to
plteobo
~srdin$
ehAn@4
b
&
otlwr
ophttilqie
=miabloc.
2uo
lvam4etin-troatod
pA+iont*
S44d t
Mwtitory
AdvW8*
axporionm
(not
8*ri -
OQse).
~
pa+htk
had s
Gpoestbiyc dtug-rdstodG-rim bilhubin
Glwatloa.
.
,
An&ha
patixntiud high uriawWCs.
frothmm
VGtedas mild.
C’D2CLUSIOKS
:
2hs
following
conelushnc
uy
be
drmm
from
the data
presented
In
this
CSR:
(11
Ivm=sctin
tlv-
Gs
9 *ingle
OS-AI dom
Gt
l*VOIC
@f
100.
150 ad
200 =rglkg
i*
a
Gffectivemicrofilirieide
h
the
t~shent
of
onchcmrciosis.
Migher
d0&9h- a,hchtd
V~tfIG s!(xAmid
Mod
Of Gff@Ct.
(2) Iwmectln
is GSSO-
elatod
with
Gild
•lle~lc
and
infls=story
resetions
uhich
increase
slightly
with
highsr
doco~ .
(3)
lverusctits
does
not
8Q$$J to
Pmcipltate
eajor
ocular
C~lic9timc
in
patiemtc
with
onehocdmiaslt.
(4)
Considering
the Gfficicy
Gnd
saf Gty
of
the
3 docaga
iweic
tasted.
1S0 mcgtkg
ivwmwtin
r+prasents
an opti-
mal
dosmge
for
the
treatment
of
onchoearci~sis.
(S)
ivenmctin
dministrstlon
is
not
naeded
mors
frequentlvthsn
once
in
6 ecisths.
/-i%nfi O.L c. -kLA..d 4-++
~/?.-
1.%,,
“-
. .
‘.:-’.-. . ...’~.
-J
U-. ..f”
Oonald c.
W-u.
8.$.
-Any
Ko, B’.i.,
M.P.H.
M&med
A. Asiz.
fl’. o.
,
Ph.D.
Smier
m-d. Prey,.
Coord.
Swlior
st*titt!ciul
S@nlor D(ractor
Cl In.
R*c.
Yntl.
CMRDS,
Intl.
Cl!n.
R-c.
Intl.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 159 of 382

..
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 160 of 382

NDA 50-742
Page 10
Mcc&an @ (kmKc&)
GKhocmSasis
As presented in Table 13 of the Clinical Study Report (page D- 1557, VOL1.19), the geometric mean percentage
redudion fiorn baseline of micmfihuiae per milligram of skin was 99.59’o at 3 months post tha-spy fbr the 1SOmcg/kg
m
of this study, with anN of 237.
Because this atudyuscd the capsule fmulatim
which maybe more bioavailable than the to-be-marketed
tablet formulation (see Biophannaceutics review of Dr. Philip CoIangelo, DAIDP), it is also imporhmt ti-~tice the
resukofthe
100mcg/kgannofthis
study. Thisarmhad an Nof238atthe3
monthpost-thmpy_d
demonstrated a 98.2% reduc$ionin microfihuia per milligram of skin tissue. Because the tablet fmulation
may be
slightly less bioavailable, the 150 mcgkg dose of tablet will most likely provide au efkacy rate that falls somewhere
between a 99.5% and 98.2% reduction in micmiiladexmia at the 3 month timepoint. This should be compared with the
efficacyresults for the DEC-C arm of study 514:
IOomcdlc gamlofstudv519
DEC arm if study 514
Nat entry
319
50
density ofinftztion
baseline (nd7mg,x [range])
47.3 (0.5-352.2)
57.1 (9.8-228.9)
day 4 (V.of baseline)
26.3’Yo*
3.8%
day 30
---.-
3V0
3 month
1.8V0
14%
6 month
2.9%
11%
Ginsludy519,1his
mcasuruncnl wasalday3post-lhuapy
ralhcftharl&y4
Thus inthis cross-studycomparkoILitappears that the lower dose of ivermectin still demonstrates a substantiallyhigher
efficacy rate in terms of clearance of microtladermia at three months post-therapy. This comparison is also notable for
the difference in rate of clearance l%lrweenthe two treatments at the 3-4 day post-therapy timepoiit- One can see that
DEC-C has a much more rapid killing effect on micrcdilariae, such that practically all the reduction in micmilhdamia
chewed
has taken place by day 4 post-therapy. In contr@ ivemectin clears micadilariae more gradually. The precise
mechanism responsible for this diikence
in kinetics is not know
but this ditkrence would seem to provide
parasitologic evidence which cxndmrates the difkmmtial rates of Mazmtti reaction between the two treatment
regimens.
In terms of safety, study 519 demonstrated that the 150 mcgllcgk
was, in gad
better tolerated and less
reactogenic than the 200 mc@g dose. Aside from disease-associated signs and symp~
the ivermecdn-treated
patients had more muscdoskeletal and nervous@sycb.iatricevents than did the plsoebtreated
patieots. Thess evcds
appeared to show a dose-sqmnse effect The adverse experience which was the most common ‘navow/p@hltric’
event was headache.
iii. Conclusions
Ivermectin at a singie dose of either 100 or 150 mcgAcgis safe and effkctivein the treatment of patients with
..
onchmxrciasis. Either do&is more efficacious and less reactogenic than the only currexdy-approved produa DEC-C.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 161 of 382

NDA 50-742
Pagell
Mcciizan @ (Ivmnedin)
GdKx=ciasis
.
C. Study 54.5:An open study of the tolerability, asfkty,and eftkacy of single oral 150 mcgfkg doses of
ivermectin (MK-933) in chil&en 5 to 12years of age with onchcwrciasis.
i Applicant’s~.
Following the marketing approval of ivermectin in France in 1987, the applicant proeeded to conduct a study
of ivermectin therapy in e-hildren The previous studies were conducted in adults only.
The Clinical Study Report fbrstudy S45 is found onpages D-1884 to D-2041C, volume 1.20 of the NDA_ The
synopsis of this report is fbund on the following page:
. .
--
..-
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 162 of 382

tJDASO-742
Page12
Mcdizan@(Ivrmncctin)
Ckhccrraasis
P~L
& 6:
An Open
Study
of
the
Tolar@bllity.
Safety.
GnA
Cffleoey
Of
Sin$le
Orel
GS45.00
150
meg/kg 00CSSof Ivamctin
(IW-S33)
in
cMldren
5
to
12 Yaarm
of
Ag@ uiht)nchoe~teiaoia
lSYI!STICATUR
Dr.
H.
Leriviere
4ss44
t snJoY 8:
7SDN Parle
Ca4cx
Ot
tranca
.-
2WOY
DEsxcU:
Open Gtucfy
I
DuRArxos :
?atienta
wore
clvan
1 orel
doca of
ivomactin
on
Day 1:
1
pathntt
fol~ovd
for 3. 6,
1
msAcl! :
md
12
mtho
poattmawt
lvormeetln.
1S0 mcg/kg
tingle
oral
dom
ACCOVSTIWC:
SYm2Qcrm
CRTSRIED:Total
103
?hle
(age
rmtt*--yemrm)
71
(6
to M)
?emele (age range--years)
32
(6
to 13)
CO?VL2TC!)
-Y:
103
ummRAuR:
0
EYALUATf!O
YUR t7tiCACY
102
(HA211!UHl:
WHXILTS:
~~ORS
:
~.
s.
Pappayliou.
H.s.
K. Khostovi,
SJ.A., R.A.
kalst.
Med. Prq.
Coord.
H.
A.
his.
N.D.,
Ph.D.
AseLat.
statistician
S4nlor
Director
Clin.
@es.
f!SASDS,
lntl.
Clin.
SOS.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 163 of 382

NDA 50-742
Page 13
Mdiz.an @ (Wcnmc&)
GlchooAasis
ii. Medical officer comments
This study was conducted so that community-basedmass eradication campaigns could safely include children
as well as adults. This is important not only so that the individual children might be spared the debilitating cfbts
of
infectionwith onchocerciasis, but also so that children cannot auve as reservoirs of disease within the Po@latim
making interruption of transmission all but impssiile.
Features of the design and execution of this study that are of particular note include the following
+ children fiofn ages 5 to 12 years, weighing 20 to 40 kg, were to be enrolled. These children had to have a
baseline skin mf density of at least 10 mi7mgakin and no ocdar involvement
. ..
+ The study was conducted by Dr. M Lariviere in Odienne, Ivmy CO*
West Africa. A total of 103 children
were enrolled.
+ Dosage of ivcrmectin was 150 mcg/kg, provided as cap.mdeformulation. The capsuks were provided in 1,
3, and 6 mg strengths. The study was open-label and there was no placebo control.
+ Following emollmcn~ patients were hospitalized at the time of drug administration and observed for seven
days, during which time clinical parameters (blood chemistries, CBC, urinalysis, akin biopsies, and ocular examinations)
were performed. Following discharge, patients were seen in follow-up at 3,6, and 12 months post-therapy.
+ Skin biopsy and ocular examination tdmiques
were identical to those utilizd in studies 514 and519 (no
fluorescein angiography was performed).
In general, this study win--designedand executed in a manner comparable to the previously-reviewed studies in
adults. Thus, relative efficaci= should be comparable across these studies.
As seen in table 9 of the Clinical StudyReport (page D-1903, volume 1.20 of NDA), the reduction in akin
microfilaria density, expressed as a permmtagereduction in geometric mean micdilariahng
of sl@ was 99.3% at the 3
month post-therapy adpod
This is similar to the results aeuI in aduh at this dosage.
With regards to safeq results m this study, ivemecdn therapy appeared to evoke the same constellation of
‘disease-associated’ signs and symptoms as were seen in adults. Within the iirst 1-3 days post-therapy, approximately
half of the children treated (49/103,48%) had fcv=, 16% (16/103) had pruriti,
and 2% (2/103) had lymph node
enlargement. These symptoms resolved by the time of the 3 month follow-up visit. The ophthalmologic parameters
revealed a similar pattern of response to ivermedb as seen in adults a transient incraseinanterior
ellamberand
corned microfihuiae in some patients at the three day post-therapy timepoint. At the three and six-month timqmints,
these ophthalmologic parameters have returned to baseline or improved.
Clinical adverse events, regardless of perceived relationabip to dxugdmhktmb ‘CnLWemrqOrted rn360fthe
103 childrq
and included 47 events. The most common event reported was headache in 24 (23%) of the childxvzL
followed by edema (either periphexai or not othemae‘
apeciiled)in11
(1l%), myalgiain9
(9?!), and ab&nnidpaiU
vomiting, and vexiigoin one patient each Clinical laboratory safktyresults were also similar to those seen in aduk
one
child had a decrease in WBC count of 50% or more h
baseline, two had increases from baseline of 100??oor more in
ALT, and 5 had increases of IOWAor more from baseline in AST.
iii. Conclusions
The safety and eflicaey of ivcrmectin at a single dose of 150 mcglkg appears to be the same for children 5-12
years of age as for adults.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 164 of 382

NDA 50-742
Page 14
.
D. Study 548: A single-blin~ placebo-cmtrolled study of the tolerability, safety, and &cacy of successive
single oral doses of ivemeetin spprox.imately1SOto 220 mcg/lcgin aduhs with onchocaeiasis.
i. Applicant’s summary
Thisstudywasdesigned
toexamine the el%eacyaud aafdy of the to-be-marketed tablet fmulation
of
ivermecti
and compare tbe results with those of the capsule f-ulatiom
The applie.ant’sClinieai Study Report ean
be found on pages D-181 1 to D-1838, volume 1.19 of the NDk the study synopsk is includedon the following page:
-.
.. -
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 165 of 382

NDA50-742
Page15
Median @(Ivumedin)
OdoaTCi&
#vOOPSIS--CLIUlCAL
STllOVREPORT
DAZE:
02rEs@7
TRooua:
Ivauethi,
tablet (6 x
ScoreA); Plocobo
TROTOCOL
& t:
?tUc*
111
0nchoeerslao194
Siagl*-Dlin4,
Plae*bo-4%ntmllo4
Study
0s4&O0
-
of theTolerability,
Ssfety0s4 Uficoey of
$UCC~CCiVQ $1w1o
Oral
Oosee of
Xmmeetin
(~-$~~)
Approxiutaly
2S0 to 220 xcg~
ict
Adult*
With tieheeo~
XSVESTICATOR
Dr.
P.
Viqtoin
S SSUDY8;
0ss4s
Xmtitut
D*Ophtldwl@o
2ropkola
Oo L* Afr@w
S.?.
240,
Sexcko,
UAli
Uortll-Co
Sruox
DSSICS :
A Gincla-bliad,
pl*eabo-comtrolle4
-l DURATSDS:3 yewo
Gtudy
I
DoSACC
:
Iveructin,
1S0 to 220 mc8/kg; S oueeeesive singia orol 40s0s Gt 6+ontb
Aoter-
Valc
?AXIPXIGOPUUTIOU:
Z=&
Jv-ffu
tu Clmo
RMTERXD:
SALSS
(Men
&e--Yearm)
ib
37 (s1.13
* (sO.s)
FUMES
(Ihen&e--Y0ers)
99
21 [s7.$)
12 (26.s)
mu
es
64
21
~LSTISC
STUDY:
S5
64
21
UISllDR#iW
:
0
0
0
s4YSTS(CLXSICAL MD LASORATOW)
Rx FAILURJ!
OTmsR
RVALUATEDFOR
71
Ss
16
~FF1CAC2
(nAxImm)
:
AOVKRSE
SSPCRISSCRS
(PationtS)
CU81CAL
4s
S*
s
LASOUTORY
o
0
0
RRSULTS:
PYFICACS:
90
f Oal-
Xno;yeis
of
as
data Um
porfomed
.
-Cy
GtStiOtles
of
tti
date
fer
tbe
fkot
4
4*7o
Qfta
tbo
fkot
do~o
Ouucot
tbst
ivormceth,
Gdministered
in kabl~t fo~. ro&eo4 ckim Slcrofiiork counts to new O lovois
uhlio
Gkln
mierofilarioe
doscweead
ooly
Glichtly
in ttn?loc*bo-*oto4
potiootx.SboGm-
pertkn of
~stl~to
vith
G fworoble
roxpemo
(< S ~/q
Gltla)
Gt Osy 4 peot-
tmotment wee SSfSS (S4.4%)and 2114 112.S%) for Ivomctio- ond placebo-trooted
.
petiento, rospoetivol~.
SAPsTr*
Clinical
odv~o
Gxporiencoo
roporte4
by
tbe
Lnvesti#etoc
Gre
lioted
below.
411
ware
troneiont. woe
um
eaaxiderod Gerhue.
?Otianto Onterod
64
8s G
Pathoto
Cqlotod
64
x
cliclico2 Aso
so (ss.4S)
s {2s.ss)
::
(so.sw
so loborotocyAU
W-
rop&to4.
mucLuslos:
Iv*mectia.in
G Glnslo
orsl
dose
of
1S0 to 220
msclkt
in
tablet
form.
opp+ers
to
be
Gafe
Gnd G
ffoctip 10 -dvciog Gkim dcrofilariocanto to mow
O 10V*IS
withins to 4 dayo.
.
I
L+Aiz6*
/ji’Ld/&+
@%wj#
c. Rupp.
R. S. Pqqmrliou.
H. A. Ati
,
m.c.
8.s.4
9.s.
S.A., m.P.
H.
U. O.,
Ph.D.
&9#0C. H*6.
tro~. Coord.
A9*0c . U*6. ?m~
. Cooti .
S*nior st*ti8ticie.n
Senior Sdrector
Clin. ~as. lntl.
Clim.
G.S.
Iatl.
‘
COARDS. Intl .
Clin.
R*S.
Intl.
-.
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NDA
50-742
Page 16
Meclizan @ (Ivermectin)
.
Orrchoeerciasis
ii. Medical officer
comments
This study is important because it is the only clinical study includedin the NDA which utilizes the to-be-
marketed formulation in the treatment of onchocerciasis. Unfortunately, the design and execution o~this study are
suboptimal:
+ there
is no direct
comparator
arm using the capsule formulation
+ there is no attempt to collect any clinical pharmacakinetic information
+ there are no data presented past the day 4 post-therapy timepoin~ although the study design calls for the
usual 3 and 6 month post-therapy timepoints.
The day 4 results from this study can be compared to the results seen in the above-reviewed capsule studies.
Specifically, the percent geometric mean reduction from baseline in microfilariae./mg of skin tissue was 97. I% and
the safety profiIewas sim-ilarto that seen in the previous studies.
DAY 4 POST-THERAPY
RESULTS
ALL CLINICAL
STUDIES OF ONCHOCERCIASIS
Study #
514
519
545
548
TrcatmcrrU
formulation
n
lvermeetin
capsules
DEC-C
Ivermectin
capsules
Ivermectin
capsules
Ivermectin
tablets
Geometric mean mf/mg skin
Percent
of pre-
Dose
N
post-treatment
Rx
pre-Rx
‘ (Gee.
day 3
day 4
Mean)
12 mg
47
60.5
3.6
6%
1350 mg I
49
I
55.9
I
I
3.8
I 7%
100
254 II
51.4
13.5
I
26.3%
mcglkg
150
249
47.8
8.1
I6.8%
mcgfkg
200
254
51.8
6.7
12.9%
mcglkg
150
101
36.4
2.1
5.8%
mcglkg
150-220
55
23.9
0.7
2.9%
mcgikg
.,
The day 4 results from study 548 show somewhat better parasite killing than was seen in the previously-reviewed
studies. This may in part be explained by ‘he fact that the patients enrolled in study 548 did not have as heavy a
parasite burden as did the patients enrolled in studies514 and 519. Furthermore, one additional day between dosing
and measurement of parasite killing would be expected to show more eradication of microfilariae in those patients
seen at day 4 as opposed to day 3 post-therapy.
At the very least these data indicate that the tablet form ulation
appears to be at least as effective as the capsule formulation in eradicating skin microfilariae.
Safety results from study 548 showed a profile of disease-associated signs and symptoms that is similar to
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NDA 50-742
Page 17
Mectkan@(Ivermectin)
Onchoccrciasis
that seen in the other ivermectin studies. For comparison purposes, the following table presents the resultsof the
most characteristic disease-associated and treatment-associated signs and symptoms across studies:
Study #
514
519
545
548
Treatment
I
Disease-associated signs and symptoms
I
Treatmen&associated signs and
sYmMoms
skh pruritus
fever
arthralgia/
headache
myalgia
synovitis
Iver 12 mg
19/37 (5 1%)
11/’29(38VO)
8!32 (25%)
13/50 (26%)
15/50 (30YO)
DEC
42/47 (89%)
25/34 (74Yo)
15/39 (38%)
1,9/50(38%)
19/50 (38’%.)
Iver 100 mcg
!
83/3 17 (26Yo)
54/3 14(1 7%)
27/3 16 (9%)
I 67/3 ]9 (21~,)
I
67/3 19(2 1%)
,
r
Iver 150 mcg
831318 (26%)
71/3 13 (2394.)
30/3 19 (9~o)
701322 (22%)
57/322 (18%)
Iver 200 mcg
99/3 19(3 1‘Y.)
93/3 16 (29VO)
331319(lo%)
78/322 (24?4.)
661322 (20%)
Iver 150 mcg
16/103 (16VO)
49/1 03 (48%)
3/103 (3~0)
24/103 (23Yo)
9/103 (9’%0)
Iver I50 mcg
27164(42%)
13/61 (21?40)
32/64 (50~o)
35/64 (55’%0)
9/64 (14%)
tablets
As can be seen in this comparative table, the rates of disease-associated signs and symptoms seen in study 548 were
somewhat higher than seen in study 519. This would be expected, as the killing of microfilariae (as indicated in the
previous table) was fairly rapid in this study. DEC, in general, has the most rapid killing kinetics and is more
reactogen ic than ivermectin.
Even though the symptoms ‘headache’ and ‘myalgia’ are referred to as “Treatment-associated signs and
symptoms” in this table, these symptoms are probably particular to onchocerciasis patients as well. They are
presented as a separate category in this table because they are outside of the constellation of signs and symptoms that
comprise the Mazzotti reaction. If headache and myalgia were truly treatment associat~
one would expect to see a
similar pattern of adverse events in the strongyloidiasis patients as well. This was not the case.
iii. Conclusions
Study 548 was the only study submitted in this NDA in which the to-be-marketed tablet fommlation was
studied in a field trial of onchocerciasis patients. Unfortunately, data were only submitted out to the day 4 post-
therapy timepoint. Overall, the safety and efficacy of the tablet formulation appears to be comparable to that seen in
the capsule formulation studies. From the results submitt~
there does not appear to be any evidence that the
bioinequivalence of the tablet as discussed in the biopharmaceutics review of this NDA, is of any clinical
significance. However, since the three month post-therapy timepoint was used as the primary endpoint for all other
studies mentioned in this review, no fhrther comment regarding comparative et%cacy (tablet vs. capsule) can be
made.
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NDA 50-742
Page 18
M@izan @ (Ivamcuin)
Ckhocerciasis
4. Medical officer review of litaature
h addition to the clinical studies reviewed above, the NDA con~
S,II~~ive
~o~t
of lit=a~e
submitted in support of the onchocerciasis indication. several of these key references have been cited above, as they
were the result of Merck-aponsod
studies 514 and519.
—
A separate volume of the NDA (vol. 1.25) is entitled ‘Tublished ClinicalIkmturc”.
The index to this volume
lists 404 references, all of which are submitted in abstract form. These ref?mmcesaddress a variety of aspects of the use
of ivermectin in the treatment of onchocerciasis. The reader is refkmed to this volume if tier
specific information is
sought. In general, these references support the use of ivem?mctinin mass treatment programs for onchoccrciasis. Most
G
of the investigations were perfbrmed with the tablet formulati~
and the results of these studies are consistent with the
results cited in the submitted clinical studies using the capsde formulation. Several abstracts refer to the use of
ivermeetin in returning travelers who have acquired onchocercib,
these abstracts support the safety and efficacyof
ivermectin in this setting, including the need for retreatment at 3 to 6-month intervals.
5. Statisticalconsiderations
As mentioned previously, the applicant submitted electronic datasets for portions of the onchocerciasis studies
reviewed above. These datasets were analyzed by Dr. Sue Bell of DATDP. The reader is referred to Dr. Bell’s portion
of this NDA review for her findings. IrIgeneral, her review confumed the applicant’s analysis of the data as presented in
their Clinical StudyReports.
6. Conclusions regarding Onchocerciasis indication
Since its introduction int~-clinicaluse in the early 1980’s, ivermed.n has become the drug of choice for the
treatment and control of onchocerciasis. The applicant has established the Mectizan Donation ProgranL through which
ivermectin has been donated to the WHO’s Onchocerciasis Control Programme since 1987. IXIthe ensuing 8 yam prior
to the submission of this ND&an estimated 36 million doses have been distributed to over 5.2 million pemons in
onchocerciasis-endemic areas of the world
The studies submitted by the applicant demonstrate that the capsule version of ivemectin is more effkctive than
DEC-C in eradicating skin micrdlariae,
is better tolerated than DEC-C in these patieds, and maintains its activity for
over three months following administration. The medical literature lends further suppat to these early clinical studies,
and indicates that the tablet formulation (which has been in use worldwi& since 1989) is as safe and efficacious as the
original capsule version-
How, th~
to address the Biopharmaceutical reviewer’s findings of bioinequivalence between the capsule and
the tablet? One possible way to resolve this finding would be to repeat the study,using a larger number of subjects to
see if the initial bioequivalence finding was partially the result of small sample size. Unfortunately, the capsules are no
longer available (and if any eadd be located they would be long since past theii expiration date) and thus the study
cannot be repeated. Is there another way to seek assurance from within the submitted studies that the tablet formulation
is amxptable?
Studies 514 and 519 used identical methodology for assessing parasite burden and response to therapy. IrIfact
these studies share several investigator in conhnon. Thus it is appropriate to do a cross-study comparison. Keeping in
mind that Dr. Colrmgelo’sbiopharrnaceutics’review suggests that the tablet may be less than 80V0of the capsule in terms
of bioavailability, and that the requested dose for onchoczrciasis is 150 mcg/kg, it is fortunate that the study design of
study 519 included a 100 mcg/kg arm. If the tablet truly delivers only 75°Aof the dose deliveml by the capsule, then the
100 mcg/kg mm is relevant since this represents 66% of the requested 150 mcg/kg dose. If this treatment arm of study
519 is wmpared to the DEC-C active contiol arm of study 514 (keeping in mind that this is the FDA-approved therapy
for onchocerclasis), one sees that wermectin compties quite favorably:
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NDA50-742
Page19
M-@
(kJYW@l)
100 rncdkt! arm ofstudv 519
DEC ann of studv 514
Nat entry
319
50
density of infection
baseline (mf%ng,x [range])
47.3 (0.5-352.2)
57.1 (9.8-228.9)
day 4 (VOof baseline)
26.3Yo*
3.8%
day 30
390
3 month
1.8Y.
14%
6 month
2.9%
11%
GiIlsaldy519, thismusmmaawas
atday3p0st4ha’apy mtIlcrtlam&y4
Additional information pertinent to this issue has been included in the ND~ to include the day 4 results of
study 548 and the large amount of medical literature that has been published since the introduction of the tablet
formulation to the Onchocerciasis Gmtrol Programme.
Therefore it is the conclusion of this medical officer that the finding of bioinequivalexiw does not render this
indication nonapprovable. The great preponderance of clinical informati~
as well as the cross-study comparison noted
above, suppofi the efficacy and safetyof the tablet formulation of ivermectin at a dose of 150 mcg/kg in the treatment of
onchocerciasis.
7. Recommendations
The onchocerciasis indication should be approv~
at a single dose of 150 mcg/kg in adults and children over
15 kg in weight. The labeling-shoiildalso state that repeated dosing at 3 month intervals is appropriate, sinm ivermeetin
has no activity againsl the adult parasites.
Reviewing Medical ~eer
HFD-520
.-
..-.
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NDA 50-742
Page 20
M&49
@csm@in)
OdnxUKiasis
.
cc:
NDA 50-742
HFD-520
HFD-5201’SMOKxisSa
%
HFD-520/MOICoyne
HFD-520/csoEogarq
HFD-520/CheXdbF=
HFD-520/Micro/KirLg
HFD-520&harrdAdeyemo
HFD-520/Biophaxm/Colangelo
HFD-520/Stats/Bell
HFD-344frhomas
Concurrence only:
ODE IV/OD/
HFD-520/AetDivDir/DFeigal
~~~
i(+d-y
HFD-520/DepDivDir/L.Gavrilovich
-.
--
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NDA50-742
Page17
Mcctizan@(hllldill)
.
safelyupdate
Medical ofJcer comment:
The individual nports
on each ojthese
15 elder~patients
have been camfidiy reviewed.
These patients ail
had extreme debili~,
and many appeared
to have begun a downward clinical spiraI well before the administration
of
ivermectin.
There were no concomitant medications
that appetnwd to have been administered
that watdd suggest a
possible
drug-dreg
interaction.
Thus, the medical oj%er
apes
with the conclusions presented
on page ]2 of the
Merck report.
‘Because this drug has been used in millions ofpatients
at doses simikzr to that used in the Wentworth Lodge
scabies outbreak
and appears to be exceeding~
safe when usedfor
its approved indications, it would seem to be
unlik+
that such a c[uster of deaths would be directiy aw”butable
to ivemtectin.
The confounding medical
conditions seen in these elderly institutionalizedpatients,
along with the wide range in time between dosing and death,
seem to argue convincing&y against any direct association
wilh ivermectin.
It should be noted that, although the reporting physician
(D-. Barkwel~ may have perjiormed a suboptimal
epidemiological
stu+
in his investigation
of these deaths, he at the vety least should be recognized
as seeing the
importance
of attempting some sorI of retrospective
case-control
stu~.
The investigation
by Merck
while making
great efforts to point out the inadequacies
of Dr. Barkwell ’sana~sis,
made no attempt to perform a case-control
study of a better design.
if Dr. Barkweil ’schoice of a control group was inappropn”ate, then perhaps
~heMerck
investigators
might have chosen a more appropn’ate contro[ group (perhaps age and sex-matched
controls from
wilhin the Alzheimer ’sunit). Furthermore, Dr. Barkwell was the physician on-site both before and during the
episode. His suspicion that his patients were declining and ~ing
at a rate that exceeded the norm seen at his
institution is a clinical hunch that men’ts recognition.
It appeam to be an unsubstantiated
hunch, but the obsewation
warranted
a complete evacuation.
The Canadian Health Protection Branch (HPB), immediateiyfoilowing
lhe reporting of this episode, placed
a clinical hold on their emergenq
release program for ivennectin treatment of scabies.
In prepan”ng this safe~
Update review, this medical oficer
contactedHPB
both telephonical~
and by electronic mail. Following the
Canadian
investigation
of this episode, HPB reached the same conclusions (i.e. that there was no causality identge~
and has reinstituted
the scabies emergency release program.
Them have been no further repo~
of ivermectin-
rdated
deaths from the Wentworth Lodge.
In conclusion,
then, this medical ofjcer
agrees with the Merck report found above.
There is insufjcient
information from this episode to wan-ant any addition to the Gen”ati”c Use section of the ivermectin product
labeling.
B. Nonfatal
serious AE’s: human use product
The one nonfatal serious AE reported to Merck during the repdng
period is detailed in WAES repofi
which describes the case of an 18-year old Cameroonian male who was treated with iverme.ctinin the
context of an onchocerciasis eradication program. The patient experienced joint pains 24 hours following a single dose
of ivertnectin, then two days later was found unconscious. He was hospitalized where he was found to be febrile and
mmatose, with spastic hypertonicity. Microtllariae of Loa loa were detezted in blood, urine and cerebrospinal fluid.
Over the following week his clinical status steadily improved. No t%rtherinformation was available.
Medical ojjcer
commen~:
It is unclear whether this case represents some sort of tokicity to ivennectin
(unlihz~), an immunologic event
related to the response of the patient’s
onchocerciasis
to ivermecfi”n therapy(unlikdy),
or an encephaiopathic
event
sometimes seen inpatients
who are infected with Loa ioa when treated with an anthe[minthic (most likely).
The report
comes from Yaounde, which is at the perimeter
of the loiasis-endemic
zone of Cameroon.
A relevant reference is included in Section 5 of the Safey
Update: “Five cases of encephalitis during
treatment of loiasis with diethylcarbamazine
“by Canne et al, found in A~
48(@: 684-90, 1991.
This article describes
the rare phenomenon
of treatment-induced
encephalopathy
when patienfi
with high -
microjlarial
loads are treated withjllaricidal
drugs.
AIthough this phenomenon
is of theoretical
concern in
ivermectin-treated
onchocerciasis
patients from areas co-endemic for loiasis, it does not appear to be of signljicant
—
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NDA
50-742
Mcztizsn @ (kMICdill)
Page 18
Wiay UFdalc
.
concern despite many pars
of use in such co-endemic awas.
C. Serious AE’s due to agriculturalheterina~
ivermectin exposure
Other formulations of iverrnedin have been available in the US and elsewhere for several years. The
agricultural product (abamectin) and the veterimy preduct (ivennectin for topical, injectable, and oral administration)
are extensively used for control of nematodes and ectoparasites. Occupational exposures occur with these products:
topical formulation sometimes splashes on the user’s face or hands, and agricultural product can also come in contact
with the user’s skin during handling and preparation.
The following cases were reported in which patients had serious AE’s after accidental (or intentional) exposure
to these non-human formulations of ivermectin:
WAES
43 yearold femaletim the UK with a history of delusional parasitosis had self-administered
6-gram doses of ivermectin (animal use) ffom 30 to 50 times over the course of one year. She also self-administered
furosemide and steroids. She was admittedto a London hospital for a full evaluation for parasitic infection, was found to
be cushingoid and hypokalemic, but checked out of hospital against medical advice. No follow-up was expected.
Medical ojjlcer commen~:
The scenario common~
referred to as ‘delusional parasitosis’
infers that a patient, despite multiple failed
a~tempts to discover a parasitologic
etiology for their symptom complex, has remained convinced that helshe is
infected with a parasi~e of some sort. Frequen#y, these patients are convinced they have an ectoparasite
such as
scabies orpediculosis.
Other parasitic
diseases implicated in this disorder include biasis,
onchocerciasis,
strongyloidiasis,
and myiasis.
Many of these diseases are potentially
treatable with ivermectin; thus, the use of
ivermectin by these patients is not unusual. The unavailabili~
of ivennectin on the US market has led some patients
(and theirphysicians)
to use veterinary product, according to intemet correspondence
reviewed by this medical
oficer.
If the histoy
of the above patient is accurate, it would at the ve~ least seem to attest to the relative safe~ of
ivermectin.
Aside from hypokaiemia
(which was most probably
due to furosemide
abuse), no other laboratory
abnormalities
were noted.
WAES
A male of unknown age committed suicide in Germany by ingesting multiple pesticides, as
well as iverrnectin. The reporter is listed as the police department in Traunsteti Ckmmmy. No additional information is
expected,
Medical ofjcer
comment:
Since this case involved exposure to multiple agents, it would be dtficult
to inteqowt even t~etiensive
additional
information were to become available.
WAES
A male of unknown age used topical ivermectin for animal use on his cattle in Oklahoma.
One day following use, the patient developed generalized body rash, swelling, andjoint pains which resolved 34 days
later. No accidental ingestion or topical exposure had been experienced prior to this event.
Medical officer comment:
The physician
treating this patient did not ascribe any causative role to ivermectin, but the event was
reported by the patient 5 wife. The symptoms experienced
by this patient are similar to those experienced
by
onchocerciasis
patients given ivermectin. ”
WAES
A 41 year old Argentineanmale ingested a bottle of averrnectin for animal use (??dose) along
with a liter of wine in an apparent suicide attempt. At the time of presentation to anemergency room, he “presented
obnubilation (sic) and slight mydriasis as a consequence of an acute intoxication”. Vital signs and exam were normal
otherwise. Appropriate measures were undertaken (lavage, activated charcoal, saline purge) and the patient was
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NDA 50-742
Page 19
Mcctizan@(klllW&l)
safety Updak
admitted to the ICU where he had an uneventfuland complete recavery.
Medical ofjcer
comment:
Pupil[ary dihztation has not been descnbedprevious~
with ivermectin.
it is unckr
whether a~
other
substances
had been ingested which may have prvduced
this e~ect. The noted slight mydriasis
may wX1 how been a
physiologic
response.
D. Serious AE’s included in Annual Report to IN’D
The applicant submitted the annual report to IND
on September 12, 19%. This report covers the
period 18 July 95 to 17 July %. Since the SafetyUpdate to the NDA included the timepcxiodupto31
May%, this
MD Annual Report captures an additionalone and one-half month of AE reporting.
In addition to the deaths reported by Dr. Barlcwellin Canada, which have been extensively reviewed above, the
Annual Report to the IND lists the followingdeaths:
WAES
A 44 yearold male patient with AIDS died of respiratory failure
WAES
An 83 year old male patient died of myoeardial infarction
No narrative summary informationwas included for these two deaths.
E. Non-serious AE’s included in Annual Report to IND
related to exposure to veterinary
ivermeetin
The applicant has also included a number of reports of exposure to various veterinary formulations of
ivermectin. A brief listing of the events as characterized in the narrative summaries follows:
WAES #
agehex
exposure
event”
41 M
topical
abdominal cramps, headache, increased ALAT
~F
topical
pregnant patient exposed at 16 weeks gestation
50 F
ingestion
-.
46 M
ingestion
--
30 F
ingestion
-.
36 M
injection
--
VM
topical
--
3’?7
ingestion
-.
‘??M
topical
--
??F
ingestion
see above (patient with delusional parasitosis)
65 M
topical
“Felt ghastly,decidedly grog#
??M
ingdon
intentional self-treatment of parasite infkction
35 M
injection
upset stomach
30 M
injection
r@ness, swelling, and pain
20 M
injection
--
??M
topical
splash in eyes resulted in erythem~ irritation
??M
i topical
splash in eyes resulted in imitation
2F
,
ingestion
-.
30 M
topical
splash in eyes without reaction
9M
ingestion
--
43 F
topical
--
?? F
topical
--
~M
topical
vomiting, diarrhea
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NDA 50-742
Page 20
Mcetizan @ (IVelmcclin)
safely Update
.
Non-serious
exposures
to animal
or agricultural
ivermectin
(con’t)
WAES #
agehex
exposure
event”
80 M
21 F
33 F
29 M
51 M
84 F
42 M
70 M
2F
31 M
37 F
?? F
50 M
34 M
‘??M
‘m
33 M
??M
56 M
‘???
25 F
23 F
62 F
62 M
2F
?? F
2M
?? M
4M
36 F
?? F
?? M
??M
29 F
38 F
??M
33 M
??F
75 M
??F
2F
30 F
2F
33 F
, ‘“ ingestion
accidental exposure in pregnant woman
TOTALS:
Ingestion
25
Topical
25
Injection
17
Inhalation
1
* Many of the reports have no associated adverse events reported, as depicted by the dashed lines.
topical
injection
injection
rnjection
topical
ingestion
injection
topical
ingestion
topical
topical
injection
injection
topical
ingestion
ingestion
injection
topical
ingestion
topical
topical
inhalation
ingestion
injection
ingestion
injection
ingestion
injection
ingestion
topical
injection
ingestion
topical
topical
topical
topical
injection
ingestion
ingestion
ingestion
ingestion
ingestion”
.
ingestion
dry eyes,changeineyesight
-.
.-
..
--
hypotensiom nause~ injection site swelling
erytherna, swelling of hands, vertigo, paresthesia
-.
nause~ anxiety, tremors
-.
--
-.
diarrhea
--
-.
numbness, swelling at site
shortness of brcati
--
rash
exposure in nursing female; no event reported
diarrhea, abdominal cramping, skin rash
--
rash, weight loss, fatigue
--
nervousness
--
swelling at site
--
splash into eye%nausea, drowsiness ensued
--
--
headache, fever, skin tingling
tntictia,
rash
splash into lefl eye led to severe pai.rLconjunctival
edema, eqtherna ulceration of cornea, nausea
stomach cramps, nausea, headache
swelling and pain at site
wamnheart f=ling, dry mouth
--
-.
--
--
--
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NDA 50-742
Page 21
Mcdizan @ (&lllC&l)
saidy
Updale
.
Medical oJJcer commenti:
There are numen-ws ingestion events of the 25 total, particular~
those in pediatric
subjects, that are the
result of accidental
ingestion ofveterinary
ivennectin kept in the household for thefamily dog.
In the majority of
these, no adverse events have beenreported.
The exact amount of drug exposure in these cases is not reported;
a
van”ety of dose sises are on the ma&t
that are intended for dlflemnt weight ranges of dogs.
—
The most striking aspect to these reports is the apparent im”tant effect of topical ivermectin when it is
splashed
into the eyes.
Of thefw
such events nported,
all had some degree of eye im”tation; one actually proceeded
to comeal
ulceration.
It is unckar whether this is due to ivermectin itself or one of the excipients in the fonrndation.
Several of these topical exposures resulted in systemic ~ptoms
such as nausea and headache, suggesting
that there may be some Wstemic absorption following
such topical exposure.
3. Conclusions
This Safety Update raises no new concerns over the safetyof human use ivermectin. The only finding of any
significance in this update is the episode at Wentworth Lodge in Ontario, Canada.
Any reported cluster of deaths warrants ciose scrutiny, particularly when the initial report claimed to show a
statistically significant association between ivermectin therapy and death. The applicant has thoroughly investigated this
event, generating WAES forms that are striking in their complete clinical documentation of each patient involvd.
Reading each of these cases leads one to the conclusion that these elderlypatients suffered ffom the debilities of old age.
4. Recommendations
The product labeling for ivermectin warrants no additional editing on the basis of the information submitted in
this stiety update. Therefore, no fbrther action is indicated.
(%W.D
Philip E. ~yn~
Jr., MD
Reviewing Medical 05cer
HFD-520
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 177 of 382

NDA50-742
Ihge2b’
. . .
~A
50-742
HFD-520
HFD-520/SMO/L.cissa ~
HFD-520M40/Coyne
HFD-520ES0/Fogarty
HFD-520/Chan/Tii
HFD-520/MicmKng
HFD-5201PharmfA&yemo
HFD-520BiophiumfC01angelo
HFD-520/’Ststs/BeU
HFD-344/rhomas
.
Concurmllce only:
ODE IV/OD/
HFD-520/ActDivDK/DFagal
*
11-zf.
“p
HFD-520/XlqllivDir/LOavrilovi
..
.,-,
-.
----
.,.
,/
,
—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 178 of 382

7!!i!!l
/’
~m.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 179 of 382

S@
31!X6’
CLINICAL
PHARMACOLOGY
/ BIOPHARMACEUTICS
REVIEVV
NDA:
50-742
Submission
Oate:
March 29, 1996
Product:
Ivermectin
6 mg Tablets
(MECTl~N@)
Sponsor:
Merck
Research
Laboratories
VVest Point,
PA
Type of Submission:
Original
NDA
\
Priority Category:
1P
1
OCPB Reviewer:
Philip M. Colangelo, Pharm.D.,
Ph.D.
L SYNOPSIS
Section
6,
Human
Pharmacokinetics
and
Bioavailability,
contained
the
following
studies
that were conducted by the sponsor (see also Table
l-l for details):
- Radiolabeled Metabolic Disposition Study in Healthy Male Subjects
- Single Dose Proportionality Crossover Study in Healthy Male Subjects
- Bioavailability of Clinical Capsule, Market Image Tablet, and Oral
Hydroalcoholic Solution in Healthy Male Subjects
- Single Dose Excretion into Breast Milk of Lactating Women
All of these studies were conducted between 1986 and 1988 to support the approval of
the 6 mg tablets in France for the treatment of onchocerciasis.
All initial tablet
formulations used
in these pharrnacokinetidbiopharmaceutics
studies did not include
antioxidants.
All tablet formulations used in the clinical efficacy strongyloides trials
contained small amounts of antioxidants (i.e., final marketed formulation).
Since the
clinical efficacy studies for the strongyloides claim were conducted exclusively with the
final market image tablet, no additional pharmacokinetics/biopharmaceutics
studies
were conducted with this formulation, i.e., either in association with the approval for
...
treatment of strongyloides in France or with this current NDA submission.
The results
of in vitro dissolution testing showed comparable and acceptable rates of dissolution for
the final market image 6 mg tablet (i.e., with antioxidants), the initial 6 mg tablet
formulation (i.e., without antioxidants), and the clinical 6 mg capsule formulation used in
the onchocerciasis trials.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 180 of 382

Table
I-1
L
Study
No.
Ref.
2
I
[1-s]
F
3s37
[1.6]
5s3s
[1-7]
E
5533
[1-8]
Table of Investigations”
I
StudyObjective/
Dosage
studyDaslgn
Fosms
EvaluMionof (3H)ivermeotin
14-mg kmectin
Capsule
sbaosptio~distributi~
metabolismandexcretion
Single-dosestudy
Evaluationof dose
3.rng IvennectinTablet
pfopoftionalityk?ingledoes
d-nsgkrntectln Tablet
@D$ threa.wayuossovas
MduationofPhase111
d-sngNenmctinCapsule
capauleandto-be-marketed
tabletvs.oralsolutionlSlngte.
6-mgIvermectinTatdet
dose,three-wayctowover
study
0.6 mg/mLhydroa!cAolia
Solutlon(40% ethanol)
Fomnulation
No.
(Batch Size)
R0933-DFC-002.
AOOI
(14)
E3806
(390)
11-3807
(230S)
E6086
(200)
E.3807
(230S)
E-3798
(S00 mL)
65885
(1000)
S4893
(1000)
Dose
14mg
(200pci)
6 mg
12m.g
15 mg
12 mg
12mg
12 mg
5 mg
12 mg
Numberof
Sullq:b($)
()
4s
(All M)
12s
(AllM)
12s
(AllM)
12s
(AllF)
Conclusions
MeanTmaxforivennectinwoo6 ~ correspondingt,A
was11,8 h, ~ax
oftritiatedmetabolizes
wastwice
Ihatofparentdug, Drugandmetabolizesareslowly
Iemeta6in bile andexmted In k.
No morethan
1.0% ofthedosewasexmetedin urine.
FollowingSD of 6,12, and 1Smg mean~ax
and
AUCweseproportional
to dosealthoughsubstantial
variability wasObSGSVd.
TIM oral solutlonshowedhigher(closeto twice)
bioavailabilitythaneitherof thetolld forms The
tabletformuhtion
showedcomparablebioaveilabilily
to thecapsulef~lation,
The relntive
bioavailabilityof thecapsulewss 113% of thetablet,
.
Orallyadministered
ivesmectinissecretedin human
milk
The highesteoncentmtionobsesvedwas
18.5 ng/mL a.fterthe12.mg dose, Dmg WM still
detectable1460V postdose.
MK-0933VIW934.DOC-
291vL4R96
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It is noteworthy from Table i-l, that
the
batch size of -2300
for the 6 mg tablets USed
in
the bioavailability study (i.e., Lot No. 3807) represented only -2-3?40of the
marketistability batches manufactured in 1987 (-83,000-97,000
tablets) and c 1YOof
the market/stability batches manufactured from 1989 to 1995 (+20,000-600,000
tablets). Thus, these percentages were substantially lower than the cwently
employed
ratio of-1 0% for bioavailabilii
batch sizes to production batch sizes.
—
The results of the radiolabeled metabolic disposition study indicated that systemic
exposure to dreg-related radioactivity, determined as ‘H+netabolite(s)
of ivermectin,
appeared to be greater than that of parent iverrnectin. The mean plasma Cmax for the
3H-metabolite(s) was approximately twice that of iverrnecth.
Also, the ‘H-metaboliie(s)
persisted longer in plasma than that of parent ivermectin and appeared to be related to
the slower rate of disappearance
of the ‘H-metabolite(s),
i.e., half-time of -3 days
compared to an effectiie T’!! of -12
hours for ivennectin. An effective T% was
determined rather than the true elimination T??since the plasma drug concentration-
time profiles showed evidence of enterohepatic recycling (see Section V1. 1. for
details).
No parent ivermectin was detectable in urine and only -0.6%
of the
radioactive dose was recovered in the urine at 4 days postdose. The predominate
pathway of excretion appeared to be fecal, with -50%
of the radioacthfe dose recovered
in the feces at 5 days postdose.
This suggested that some of the drug and/or
metabo!ites are excreted in the bile and ultimately eliminated in the feces.
Based on
the mean half-time of radioactivity of -3 days, it would take -12 days ( 4 x half-time) to
recover nearly all the radioactive dose (-95Yo) in the feces.
The results from the dose proportionality study (i.e., 6, 12, and 15 mg as tablets)
suggested increases in systemic exposure to ivermectin that were approximately
proportional to dose.
However, the overall variability in the AUC(O-72) and Cmax data
(i.e., as %CV) between subjects was wide, ranging from -50-70%
across all three
doses. The statistical analysis (ANOVA) of the dose-adjusted AUC(O-72) data (i.e., to
the 6 mg dose) detected a statistically signillcant difference in the 12 mg vs. 6 mg
comparison (p= 0.03), with the 12 mg dose producing a lower estimate.
No other
significant differences were detected in the dose-adjusted AUC comparisons and none
were detected in the dose-adjusted Cmax comparisons. This reviewer concurs with the
sponsor’s conclusion that the deviation from strict dose proportionality in AUC(O-72)
between the 12 and 6 mg doses would not be expected to be clinically significant.
in order to ve~
the -12
hour effective T% estimated from the small number of
subjects in the radiolabeled metabolic disposition study, this reviewer requested the
--
sponsor to determine this parameter for the 6 and 12 mg doses in the dose
proportionality study using the same calculation method as in the metabolic disposition
study (see Section V1. 2. for details).
The mean effectiie T% estimates for the 6 and
12 mg doses were similar at 16.8 and 16.7 hours, respectively, and were longer than
that determined in the metabolic disposition study. Thus, it appeared that the T?? of
ivermectin was at least -16
hours, if not potentially longer.
2
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The results from the bioavailabilii
trial
(i.e., 2 x 6 mg clinical capsules vs. 2 x 6 mg
market image tablets vs. oral solution 12 mg) showed significantly higher AUC(O-72)
and Cmax estimates for the sol~”on as compared to either the capsules or tablets (-2-
fold higher).
No statistically significant dtierences
were detected by ANOVA between
the mean AUC(O-72) and Cmax estimates.
Mean Cmax values following single 12 mg
doses were 50.6 ng/mI for the capsules and 46.6 rig/ml for the tablets, with_mean Tmax
at 3.7 and 3.6 hours, respectively.
The sponsor did not provide an evaluation of
bioequivalence between the tablet (as test fomwlation) and oapsules (as reference
formulation) using the 90% confidence intervals on the tabletkapsule
ratios calculated
based on the currently acoepted two onesided
test procedure.
Instead, posterior
probabilities and 95% confidence intervals for AUC and Cmax were calculated (see
Section W. 3. for details) using the ratio of capsuleltablet, i.e., using the tablet as the
reference instead of the test formulation. The sponsor ooncluded that any differences
in systemic availabilii
of the capsules vs. the tablets were most likely (i.e., -90Y0
probability) to be less than 30% and probably (i.e., - 80% probability) less than 25%.
However, the sponsor failed to note that differences of 20% or less had only a -70%
probability of occurrence.
The latter difference of 20% being that which the currently
accepted two one-sided test procedure for evaluation of bioequivalence is based upon.
The bioequivalence of the madcet image tablet relative to the clinical trials capsule
formulation was evaluated by this reviewer using the currently accepted two one-sided
test procedure, as mentioned above.
The 90% confidence intervals for AUC(O-72),
i.e.,
(66.8%,
117.1%) and Cmax, i.e., (75.3%,
120.5%)
indicated that the systemic
availability of ivermectin from the market image tablets was less than that from the
clinical capsules.
This finding of bioinequivalence should be weighed against the
results of the clinical efficacy and safety in the onchocerciasis trials in order to
determine the relevance.
The results from the breast milk excretion study indicated that ivermectin was present in
the milk of lactating women after a single dose of 12 mg (as capsules), maximum milk
concentrations occurred on the first day following the dose (mean 7.6 rig/ml at 4 hours),
and had substantially decreased thereafter, but remained detectable (> -0.1
rig/ml) for
up to 14 days postdose.
The maximum intake of drug by a nursing infant (3 kg body
weight) was estimated to be -3 mcg/kg on the first day of single dose ivermectin
administration and represented a minimal intake as compared to the recommended
2% of adult doses).
The mean intake of drug
adult dosages of 150-200
mcglkg (i.e., -
at 14 days postdose, the end of the study, was estimated to be +1
mcg/kg in a
nursing infant (i.e., -0.05%-O.07Y0
of the adult doses).
The sponsor commented in the Clinical Summary Section of this NDA that in light of the
limited information concerning the development of the blood brain barrier in newborn
infants, that treatment w“fi ivermectin in mothers who intend to breast feed be withheld
until at Ieast 1 week after the ~ifih of the child. This recommendation was also provided
for in the proposed labeling.
Thus, it appeared that the sponsor considered drug
exposure through ingestion of mother’s milk to the nursing infant to be of minor
consequence in infants with fully developedfintact blood brain barriers. The conclusions
3
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appeared to be appropriate based on the results of this study and of the oral toxicity
study conducted in neonatal monkeys (i.e., c 2 weeks old). In this species, which has
been reported to be more predictive of the human response to ivennectin than rodent
models, no evidence of toxicity was observed at doses up to 100 mcg/kg/day.
The studies in the Human Pharmacokinetics and Biopharmaceutics Section of this NDA
have been reviewed by OCPB.
In the bioavailabilii
study (NDA Study No. 5535), the
matket image 6 mg “wermectintablet formulation was found by this reviewer to be
bioinequivalent to the capsule fomwlation used in the onchocerciasis clinical efkacy
and safety trials. In light of the fact that ivennectin tablets have been distributed
worldwide for the treatment of onchocerciasis, it is urged that the reviewing medical
officer weigh this finding of bioinequivalence against the clinical evaluation (i.e., efficacy
and safety) of ivermectin in the treatment of this disease.
Comments 1 through 3
should be conveyed to and adequately addressed by the sponsor.
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TABLE
OF CONTENTS:
M
1.
II.
Ill.
Iv.
v.
w.
V1l.
Vlll.
SYNOPSIS
.
.......................................................................
Recommendation
.......................................................j
BACKGROUND
................................................................6
DRUG CHARACTERISTICS
& FORMULATIONS
1. Physical/Chemical
Characteristics ...............................6
2.
Formulations and Dissolution.......................................
ANALYTICAL
METHODS ..................................................O
HUMAN PK STUDY SUMMARIES
1. Metabolic Disposition..................................................ll
2.
Dose Proportionality ....................................................15
3. Bioavailability ...............................................................18
4.
Human Plasma&
Milk Levels ......................................21
IN VITRO
Metabolism
..................................................23
COMMENTS
TO SPONSOR ............................................24
Appendix
1: Proposed
Labeling ..............................................26
Included With Review
.
,,
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Ill. BACKGROUND
e
Ivermectin is a semisynthetic macrocyclic Iactone in the avermectin series of anti-
parasitic agents.
It possesses potent anthelmintic activity and has been registered for
agriculturallveterinary
use since 1981 for the treatment of infestations by Onihocema
and Wungykides
species of nematodes.
Ivermectin is not sold in the U.S. for human
use, but it is used in the U.S. and abroad in many countries for the clinical treatment of
onchocerciasis (a.k.a. river blindness). The 6 mg tablets are donated exclusively by the
sponor and distributed worldwide through the World Health Organization’s
Onchocerciasis Control Program.
In France, the drug was approved for use in
onchocerciasis in 1988 and was more recently approved for use in strongyloides of the
gastrointestinal tract in 1993.
The sponsor has filed this NDA to support the use of MECTIZAN@ 6 mg tablets for the
treatment of(1)
onchocerciasis at a single dose of 150 mcg/kg (not to exceed 12 mg
ivermectin/dose) and (2) strongyloides of the gastrointestinal tract at a single dose of
200 mcg/kg (not to exceed 18 mg ivermectin/dose) in humans.
IV. DRUG CHARACTERISTICS
and DOSAGE
FORMULATION
1. Physical
and Chemical
Characteristics
Ivermcetin is a mixture of two closely related homologies
(HZB1. and H2B1J of the class
of compounds known collectively as avermectins.
The mixture mntains at least 90%
H2B1. and less than 10% HzB1~. The chemical structures are as follows:
f)”
Ho,,,
J5
qc
o
“’0,,,
~“
..*Q3
.F
qc
o
“’o,,,
\
;0
‘“o
$$C’” ,
‘“H
R
‘“H
1;
H
,
I
G
9
OH
H,B,.(R=C,H,)GH,4J.: U.W.-675.10
HJBm@ =Ctf,):
GH+,.:
M W..U! 07
6
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Volubility is greatest in solvents of intermediate polarity. Ivermectin is insoluble in water
(< 0.001 g/L), but freely soluble (> 200 g/L) in solvents such-as methanoJ, ethyl acetate,
and methylene chloride.
It is soluble (1O-100 g/L) in ethanol, diethyl ether, acetone,
and aromatic hydrocarbons.
2. Dosage
Formulations
and
Dissolution
a.
Formu Iation History
During the course of the clinical program for onchocerciasis (i.e., to support registration
in France in 1988), the initial formulations were capsules of varying strengths, ranging
from
mg ivermectin and also 14 mg [3H]4abeled ivermectin.
All capsules,
except for the 14 mg [3H]-labeled ivermectin capsules, contained microcrystalline
cellulose and magnesium stearate as inert ingredients. The capsules were used in all
Phase Ill clinical onchocerciasis safety and efficacy trials and in the following
pharmacokinetics/biopharmaceutics
NDA studies: metabolic disposition (as 14 mg [3H]-
Iabeled ivermectin), bioavailability, and excretion in human breast milk.
The 3 and 6 mg tablets replaced the capsules and these were used in the dose
proportionality and bioavailability studies of the NDA. The tablet ingredients, which
show proportionality in composition, were as follows:
Initial Tablet Formulations
Ingredient
Amount
(mghablet)
I
Amount
(mgltablet)
I
Ivermectin
I
I
I
Microcq&alline
Cellulose,
NF
I
I
I
Pregelantinized
Starch, NF
Mg Stearate, NF
A bioavaiIability/bioequivalence
study was performed between the 6 mg tablet and the 6
mg clinical capsule to establish a link between the clinical trials and proposed marketing
formulations.
After the completion of the pharmacokinetics/biopharrnaceutics
studies
with these tablets and prior to submission of the original French registration package,
small amounts of antioxidants were added to prevent discoloration.
Thus, the final’
market image 6 mg tablet contained the following ingredients:
..’
7
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Final Market Image Tablet Formulation
<
Ingredient
Amount (mgltablet)
.
Ivermectin
Microc~stalline
Cellulose,
4___
NF
Pregelantinized
Starch, NF
-
I Mg Stearate, NF
I
I
I
Butylated Hydroxyanisole,
NF
I
I
1
ICitric Acid, USP
I
1
I
The addition of the antioxidant
represented -0.02%
of the total tablet weight and the
increase in microcrystalline cellulose from
mg represented -0.5?40 of the
total tablet weight.
This final tablet formulation, which has been distributed for use in onchocerciasis, was
used in the clinical safety and eficacy
studies to support the eventual French
registration of iverrnectin for the strongyloidiasis indication. Thus, no additional
pharmacokinetics/biopharmaceutics
studies with this final formulation were deemed
necessary by the sponsor. This was found to be acceptable by this OCPB reviewer
(see also Dissolution below for further support).
b. Dissolution
The initial dissolution specifications for the market image tablet were as follows:
Dosage Form:
Strength:
Apparatus:
Medium:
Volume:
Agitation:
Temperature:
Sampling Time:
Analytical Method:
Dissolution (tentative):
Compressed Tablet
6 mg
USP Apparatus II (paddIe)
Distilled water/n-propanol in ratio of 2:1
900 ml
50 rpm
.
37°c
45 min
..
HPLC with UV detection (247 nm)
Q =~!
in~min
A non-polar medium (i.e., 33?40v/v n-propanol) was required to maintain sink conditions
since ivermectin is nearly insoluble in water (< 0.001 g/L). Since this medium
apparently did not represent physiological conditions, the results of in vitro dissolution
8
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testing would serve only as a quality control check of the tablet manufacturing process.
During validation of this method, samples were repeated at 15, 30,
and 45 minutes (N
= 12 for each time).
The mean dissolution was 52% (RSD 36.8%),
89?40(RSD 7.2%),
and 98?40(RSD 3.5Yo) at 15, 30, and 45 minutes, respectively.
Thus, the specfkation
was set by the sponsor at ~A
dissolved (Q =@%)
at ~minutes
since the dissolution
gave an acceptable RSD only at this sampling time. The dissolution results for the final
market image tablet and other dosage fonm.dations(selected by the sponswr) used in
various NDA studies are presented below for this method.
Ivermectin
Dosam
Fmms:
Mean
% Di=sdutinn
lRsnnn\
.- --------
. . ----
- . . . .. .. .
...=-..
.- -----------
. .. . .
-
Dosage
Form
Study Type
%Q at 15 min
%Q at 30 min
VOQat 45 min
3 mg Tablet*
PK - Dose
106
(N=12)
Prop
(8~-?09)
(9;-:
1)
(98-1 13)
6 mg Tablet*
PK - Dose
101
104
(N=
12)
Prop; Bioavail
(839:06)
(97-105)
(98-107)
0.5 mg Cap
PK - Excretion
93.5
—-
(N= 2)
in Breast Milk
(8:!31)
(93, 94)
2.5 mg Cap
PK - Excretion
97.5
(N=
6)
in Breast Milk;
(83~:01)
(89-102)
–
Clinical -Oncho
Trial
6 mg Cap
PK- Bioavail;
100
(N=
12)
Clinical -
(929!03)
(909:05)
(90-106)
Oncho Trial
Market
Image
6 mg Tablet**
Clinical -
(N= 6)
Strongyloides
(88!;
01)
(99YOO)
(98~:00)
6 mg Tablet’*
Clinical -
103
103
(N= 6)
Strongyloides
(91~:06)
(100-108)
(100-107)
, ... . . . ..-
.. . ..
...
.
..
. .
. .
**Final market image tablet formulation with antioxidants
Dissolution for the market image tablets and the other formulations presented-in the
“
table above was acceptable.
In addition, dissolution results for the market image tablet
formulation (i.e., with antioxidants) and the initial tablet formulation (i.e., without
antioxidants) were comparable qt all sampling times.
According to the sponsor, this initial dissolution method was employed to control and
release ivermectin 6 mg tablets until March, 1994, when a more environmentally
9
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acceptable dissolution medium was developed.
The medium employed use of the
surfactant, sodium dodecyl sulfate (SDS), and was buffered $0 pH 7 with sodium
phosphate.
The current dissolution method and specification are as follows (changes in
bold):
Dosage Form:
Strength:
Apparatus:
Medium:
Volume:
Agitation:
Temperature:
Sampling Time:
Analytical Method:
Dissolution:
Compressed Tablet
6 mg
USP Apparatus II (paddle)
0.5% SDS/Distilled
Water,
O.OIM Monobasic
Na Phosphate,
pH 7
900 ml
50 rpm
37°c
45 min
HPLC with UV detection (247 nm)
Q =-!
in~minutes
This current method has been adequately validated with respect to accuracy, precision,
linearity, stability of ivermectin in the dissolution medium, and analytical specificity.
Dissolution in the two media (i.e., SDS vs. waterln-propanol) were acceptabe
and
comparable at 45 minutes for 3 production batches of tablets (i.e., 96% vs. 103Yo; 94!40
vs. 99Yo; 95% vs. 97’?40,N = 12 for each batch).
Based on these resufts, the sponsor
tightened the dissoultion specification for the SDS medium to Q =~Yo
in=
minutes.
Dissolution at ~minutes
with the SDS medium for the commercial batches of
ivermectin tablets manufactured after March 1994 ranged from
0/0dissolved.
V. ~NALYTl CAL METHODS
The method to quantify ivermectin in plasma and milk was by HPLC with fluorescence
detection.
Since there was only minimal excretion in the urine, no urine assay was
developed.
In all studies included in Section 6 of this NDA, the concentrations of only
the major component of ivermectin, i.e., HZB1,,were determined.
Although the assay
appeared to be selective enough to determine both the HzB1~and HzB1~components,
the sponsor noted that at lower total drug concentrations, the levels of HzB1~fell below
the limit of detection for the assay (-0.2
rig/ml). The validation of the assay in plasma
and milk was acceptable, and assay performance, with respect to interday precision
(“ACV) of the quality control samples was also within acceptable limits (i.e., < S?0%) for’
each of the studies in Section 6. It is noteworthy to mention that the performance
of the
assay for all studies was evaluated using only 2 levels of quality control samples (i.e.,
low and high), instead of the currently accepted 3 levels of quality control samples (i.e.,
low, medium, and high).
However, this does not represent a major deficiency in the
analytical methodology.
10
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It is also noteworthy that, for all the pharmacokineticdbiopharmaceutics
studies
included in Section 6, even though the limit of assay quanti$ation was
rig/ml in
plasma (as defined by the linear dynamic range of the assay), the sponsor reported a
limit of detection -0.2
rig/ml. Furthermore, no precision and accuracy data were
provided to support this claim, and it was also apparent that the AUC estimates
in the
various studies were determined using plasma concentrations between
rig/ml (i.e., extrapolation beyond the linear range of the assay).
In gener~
this did not
appear to effect the integrity of the AUC data or the overall results of the studies.
VI.
HUMAN
PHARMACOKINETICS
STUDY SUMMARIES
1. Dmg
Metabolism
Study #606:- Metabolic
Disposition
“An Open, Sinqle-DoseStudyinHealthySubiectstoDeterminetheMetabolic Dls~osition of Radiolabeled
Ivermectin” (R=port Date: January, 1986)
Objective:
To determine the absorption, metabolism,
administration to healthy male volunteers.
Formulations/Treatments:
and elimination of radiolabeled iverrnectin following single dose
[3H]-lvermectin Capsules 14 mg (200 PCi) - Lot #R0933-DFC-002-AOOl
Ratio of Components:
91.8% HzB,.; -8Y0 HzB1~
Position of Label: [22,23-3H]-lvermectin HZB1.;no label on HzBf~
Subjects:
Four healthy male Caucasian subjects, age range 2340 years (mean 30 yrs), weight range 60.0-75.0 kg
(mean 65.7 kg)
Study Design and Methods:
Each subject received a single oral 14 mg dose of the radiolabeled capsule with 240 ml of water after an
overnight fast of at least 8 hours. Blood samples for quantitation of parent ivermWin
concentrations, i.e.,
H261.only, and drug-related radioactivity in plasma were collected serially from O(predose) to 72 hours (3
days) postdose. Urine andfecalsamplesfor determination of parent and 3H-rnetaboIite(s) concentrations
were collected at specified intervals for up to 96 hours (4 days) postdose for urine and 120 hours (5 days)
for feces. Radiolabeled metabolize
concentrations were determined as the difference between total
radioactivity and unlabeled HZB1.as measured by HPLC (see below).
Assay Methods, Validation, and Pedonnance
(i) Iverrnectin (HQB,.)in Plasma and Urine - HPLC with Fluorescence Detection
Validated over linear dynamic range from 1-50 ng/mi in plasma. The limit of detection was
reported to be =0.2 rig/ml, but no data (i.e., accuracy and precision) was provided to substantiate
this claim. The lower limit of quantification was 1.0 ng~ml,however, it appeared that the sponsor
used plasma ivermectin concentrations between
rig/ml to calculate the AUC
..-”
estimates. Quality control (QC) samples were run with the ethical samples at two concentrations
(low and high), instead of the preferred three concentrations (low, medium, high). Th@interday
precision (%RSD) was acceptable for both the low(15 rig/ml) and high (35 rig/ml) QCS at 3.2%
and 7.9’Yo,respectively.
,
The assay of iverrnectin in urine was the same as that in plasma. No urine assay validation or
performance data was provided. According to the sponsor, no detectable levels of parent HzBt.
could be determined in urine.
11
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 191 of 382

(ii) Total Radioactivity in Plasma, Urine, and Feces
Total drug-related radioactivity in these matrices was measured by conventional liquid scintillation
counting. The potential for the radiolabel to associate with plasma water (i.e., 3H20)was
determined to be minimal, i.e., < 6V0of the total radioactivity was found in plasma water.
Results:
The individual and mean plasma concentration data for parent iveti”n
(HZB1=)and the 3H-rnetabolites
are illustrated in Figures 1 and 2, respectively. These figures indicated that, for all four subjects, individual
3H-metabolizemncentrations were higher and persisted bnger in plasma than parent ivermectin and the
between subject variabilii
in both parent and 3H-metabolizeconcentrations appeared to be wide. The
postabsorptive phase of the ivermectin profiles suggested enterohepatic recycling (i.e., double peaks),
which precluded accurate determination of the terminal phase rate constant(K) and TIA by conventional
methods. The estimate of T% was subsequently determined as the “effective” TYzusing the single-dose
method of Kwan, et. al. (In: Pharmacokinetics, Chp 14,p 147-162, U&net,
G Levy, B Ferraiolo, eds,
f984); see below for details. The pharrnacddnetic parameters in plasma are summarized in the following
table:
Mean t SD (Range)
Plasma
Pharmacokinetic
Parameters,
N = 4
Parameter
Ivermectin
(HZ81.)
3H-Metabolite(s~
Cmax
21.7*11.2 rig/ml (9.2 - 33.4)
54.2i26.6 ng.eq/ml (28.2 - 88.7)
[CV 52%]
[Cv 49%]
Tmax
6.0t4.O hr (4.0 - 12.0)
7.0*3.9 hr (3.0 - 12.0)
[CV 67%]
[CV 56%]
AUC(O-72)
329~196 ng.hdml (127-588)
ND-
[Cv 59.5%]
Effective
T%***
11.8* hr (9.8-14.3)
ND
Radioactive
Half-Time
ND
2.9@days (2.0-3.4)
GDetermined as the difference between the total radioactivii
munts and unlabeled H2B,ameasured by
HPLC
‘ND
= Not determined
‘Determined
as (in 2)/rl, where q = -(1/T) G [In(l - (AUC(O+AUC(O-72)))],
and T =
120r24hr
‘Harmonic Means
The mean plasma Cmax for the 3H-metabolite(s) was approximately twice that of parent ivermectin. The
mean Trnax estimates appeared to be similar for both species at -6-7 hours, but may be actually shorter
for the parent sinoe in 3 subjects Tmax was 4 hours, but was 12 hours in the fourth subject. This same
subject appeared to have a prolonged rate of appearance of the 3H-metabolite(s) as Tmax was also 12
hours. The apparent elimination of the 3H-rnetabolite(s) was substantially prolonged when oornpared to
parent ivermectin, as evidenced by the half-time for radioactivity of -3 days mmpared to the -12 hour
‘
effective TYzestimated for ivermectin.
12
As noted by the sponsor, no detectable levels of parent ivermectin (i.e., HzB,.) could be determined in
urine. The recovery of drug-related radioactivity in urine and feces are summarized in the following table.
_-——
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 192 of 382

Mean f SD (Range) Cumulative
Recovery
of Total Radioactivity,
N = 4
Time Postdose
Urinary
Recovery
.
Fecal Recovery
as YOof Dose
as ‘A of Dose
24 hours
0.252*0.091 (0.153-0.331)
29.03, 0.01 G
(Day 1)
[CV 36%]
0.06, 0.05””
48 hours
0.388t0.191
(0.206-0.632)
17.49ti9.22
(Day 2)
[Cv49%]
(0.18, 1.18,7.57, 61.04)
72 hours
0.500S244
(0.269-0.828)
31.31, 8.76”+”
(Day 3)
[Cv49%]
96 hours
0.606t0.311 (0-294-1.017)
37.45*30.03’
{Day 4)
[Cv51%]
(7.64, 36.63, 67.89)
120 hours
Not Collected
48.62*18.3
(Day 5)
(25.77, 43.60,56.64,
68.45)
GCollected 24 hours postdose for subjects 1 and 2
G*Collected predose (Day O)for subjects 3 and 4
“Walues
for subjects 2 and 4; no sample for subject 3; no value reported for subject 1
‘N = 3; no sample for subject 2
Urinary excretion of radioactivity appeared to be minimal, with a mean of -0.6?4.of the radioactive dose
recovered in the urine at 4 days postdose. Fecal remvery was greater with a mean of -50Y0 of the
radioactive dose excreted in the feces at 5 days postdose. As Figure 3 illustrates, fecal excretion was
minimal (i.e., < 10’%.)for up to -2 days postdose in subjects 2, 3, and 4, and appeared to continue to
increase through day 5, indicating that the length of the sample collection period was insufficient, i.e.,
based on half-time of radioactivity of-3
days, it would take -12 days ( 4 x half-time) to recover nearly all
the dose (-95’?40)in the feces. For subject 1, fecal excretion was -30Y0 at 1 day postdose and appeared to
remain constant at -7O’%Oat the foufth and fifth days following the dose.
Reviewem Conclusions:
Systemic exposure to drug-retated radioactivity, determined as 3H-metaboliie(s) of iverrnectin, appeared to
be greater than that of parent ivermectin (i.e., H,B,,).
The mean plasma Cmax for the 3H-metabolite(s)
was approximately twice that of ivermectin. Also, the 3H-rnetaboliie(s) persisted longer in plasma than that
of parent ivennectin and appeared to be related to the slower rate of disappearance of the 3H-
metabolite(s), i.e., half-time of -3 days compared to an apparent/effective T% of -12 hours for ivermecth.
The postabsorptive phase of the parent iverrnecth ptasma concentration-time profiles suggested some
enterohepatic recycling (i.e., double peaks), which prectuded accurate determination of the terminal phase
rate constants (K) and T% by conventional methods. The estimate of T% was subsequently determined
as the “effective” T%, which employs an estimation of drug accumulation (i.e., AUC(O-T)/AUC(O-inf) ratio)
associated with the recycling process. In calculating the effective T%, the sponsor assumed: (1) that-
AUC(O-72) approximated the AUC(O-inf) since plasma iverrnectin concentrations at 72 hours were either
at or below the lower limit of quantification of the assay (i.e., 1.0 rig/ml) for all subjects, and (2)-a dosing
,
interval, T, of either 12 or 24 hours. These assumptions and the method to determine T’%for parent
ivermtiln
were appropriate for this study.
No parent ivermectin was detected in the urine and only -0.6’Yoof the radioadlve dose was recovered in
the urineat4 days postdose. The predominate pathway of excretion appeared to be fecal, with -50Y0 of
the radioactive dose recovered in the feces at 5 days postdose. The results suggested that some of the
drug and/or metabolizes are eliminated in the bile and ultimately excreted in the feces.
Based on the
mean half-time of radioactivity of -3 days, it would take -12 days ( 4 x half-time) to recover nearly all the
13
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 193 of 382

radioactive dose (-95°/0) in the feces.
.
.
14
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 194 of 382

-—
.
FIGURE1
INDIVUX.ML
SUBJECTAND MEAN PLASMA coNCENIWiTIm
OF IVERMEc’ml
~lMElfT:
3H-XVEMECTIN
14 MC. 200
MICRO Ci.
ORAL
0
6
12
18
24
Iiouus
-
36
48
72
..
14 JUL86
....
..
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 195 of 382

FIGURE 2
0
6
12
18
24
HOURS
72
.
.,,.
14 JUL86
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 196 of 382

f-
i
,.
i
..
/’
.
FIGURE
3
CUMULATIVE FECAL RECOVERY OF RADIOACTIVITX
FOLLOWING ADMINISTRATION OF 3E-IVEMECTIN
80
60
Percent
of
Oose
40
2C
c
o
i
2
3
4
+
Subject
~
Subject
!+-
Subject
+
Subject
.
14JUL86
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 197 of 382

2. Drug Metabolism
Study #615:
Dose Propotilonality
“An Open, Three Period, Single Dose, Crossover Study in Healthy Male Subjects to Determine the Effect
of Dose on the Pharmacokinetics of Ivermectin Administered Orally as Tablets” (Report Date: June, 1986)
Objective:
To determine the effects of increasing the oral dose of ivermectin (tYom
rng) on its
pharmacokinetics.
Fonnulationflmatments:
Ivermectin Tablets
6 mg - Lot #E-3807
3 mg - Lot #E-3806
The 6 mg tablet was the market image.
Dissolution at 30 minutes was acceptable.
See Table 1 for details of formulation and dissolution
Subjects:
Twelve healthy male Caucasian subjects, age range 2141 years (mean 25.5 yrs), weight range 64.7-79.0
kg (mean 73.1 kg)
Study Design and Methods:
Open label, randomized, three period, crossover design. Each subject received the following three single
dose treatments of ivermectin tablets with 240 ml of water after an overnight fast of at least 8 hours:
A. 6 mg (1 x 6 mg tablet)
B: 12 mg (2 x 6 mg tablets)
C: 15 mg (2 x 6 mg tablets + 1 x 3 mg tablet)
Each treatment was separated by a 12 to 15 day washout intewal. Blood samples for quantitation of
ivermectin concentmtions, i.e., HzB,. only, in plasma were collected serially from O(predose) to 72 hours
(3 days) postdose.
No urine samples were collected.
Assay Methods, Validation, and Performance:
Iverrnectin (HZB1,)in Plasma - HPLC with Fluorescence Detection
Linear dynamic range from 1-40 rig/ml. The limit of detection was reported to be -0.2 rig/ml, but
no data (i.e., accuracy and precision) was provided to substantiate this claim. The lower limit of
quantification was 1.0 rig/ml, however, it appeared that the sponsor used plasma ivermectin
concentrations between
rig/ml to calculate the AUC estimates. Quality control (QC)
samples were run with the clinical samples at two concentrations (low and h~h), instead of the
preferred three concentrations (low, medium, high). The interday precision (%RSD) was
acceptable for both the low (2.5 rig/ml) and hgh (30 rig/ml) QCS at 9.2°A and 5.2Y0,respectively.
Data Analysis:
(i) Pharmamkinetic
AUC(O-72), Cmax, and Tmax were estimated by conventional model independent methods; ‘It
was obsewd
that the postabsorptie
phase of the ivemwctin concentration-time profiles
suggested enterohepatic recycling (i.e., double peaks), which precluded accurate determination of
the terminal phase rate constant (K) and T??by conventional methods. The estimate of VA was
subsequently determined for the 6 rng and 12 mg doses as the “effectiie” TYzusing the single-
dose method of Kwan, et. al. (/rt; Pharmacokinetics, Chp f4, p f47-f62,
LZ 13enet,G Levy, B
Ferraio/o, eds, 7984); see below for details.
,
(ii) Statistical
Statistical significance between the pharmacokinetic parameters AUC(O-72), Cmax, and Tmax
15
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 198 of 382

from the three dose levels was tested using an ANOVA for a three period design. Pairwise
comparisons (i.e., 6 vs 12 mg, 6 vs 15 mg, 12 vs 15 mg) oftheAUC(O-72) and Cmax estimates
were performed using both the actual and dose-adjusted (for the 6 mg dose) values. For the
dose-adjusted parameters, the 95!40confidence intetvals were also constructed for the cliometric
mean of the ratios (i.e., 12 mg:6 mg, 15 mg: 6 mg, and 12 mg:15 mg). The level of significance
was assessed at a = 0.05.
Results:
The mean plasma ivermectin (i.e., HzB1~mncentration-time data, unadjusted for dose, are illustrated in
Figure 1 and suggested an increase with the increase in dose. The descriptive statistics for all
pharmacokinetic parameters are summarized in the table below and the results of the ANOVA for Cmax
and AUC(O-72) are presented in Tables 2 and 3, respectively. The individual and mean unadjusted
AUC(O-72) and Cmax values are plotted as a timction of dose in Figure 2.
Mean t SD (Range)
Phannacokinetic
Parameters
(N = 12)
Parameter
6 mg
12 mg
15 mg
AUC(O-72)
347*195
513i209
820&555
(ng.hrlml)
(114-712)
(306-900)
(178-1871)
[CV 56%]
[Cv41%]
[Cv68%]
Dose Adjusted*
347*195
257t104
328*222
AUC(O-72)
(114-712)
(153450)
(71-748)
Cmax
18.3*9.7
30.6i15.6
48.5*35.2
(nglml)
(6.4-31.9)
(13.9-68.4)
(10.4-118.5)
[Cv 53%]
[Cv51%]
[Cv 73%]
Dose Adjusted*
18.3*9.7
15.3*7.8
19.4*14.1
Cmax
(6.4-31 .9)
(7.0-34.2)
(4.247.4)
Tmax
3.9io.79
3.8k0.87
3.821.19
[hr)
(34)
(3-6)
(245)
[Cv20%]
[CV 23%]
[Cv 31%]
Effective W**
16.8
16.7
ND-
[hr)
(14.0-21.0)
(13.3-20.5)
\djusted to 6 mg
‘Determined
as(ln 2)/rl, where q = <l/r)
G [In(l - (AUC(O-T)IAUC(O-72)))],and T =
24 hr. Mean values expressed as harmonic means.
G*Not determined
The increase in mean AUC(O-72) values approximated the increase in dose. However, the total variability
in AUC(O-72) between subjects (i.e., YoCV)was high across all 3 doses, especially the 15 mg dose. me
range of AUC(O-72) values varied -l O-fold for the 15 mg dose and from -3-to
6-fW
for 6 mg and 12 mg
(see Figure 2). The results in Table 3 indicated that no sgniticant difference was detected between the
mean unadjusted AUC(O-72) for the 6 and 12 mg doses (p = 0.08), but significance was attained between’
the 6 and 15 mg (p c 0.01) and the 12 and 15 mg (p < 0.01) comparisons. When adjusted for dose (6
mg), the mean adjusted AUC(O-72) for the 12 mg dose was significantly lower than that of the 6 mg dose
(p= 0.03). No significant differences were detected for the other dose adjusted comparisons (i.e., 6 vs 15
mg or 12 vs 15 mg). Although the geometric mean of the ratios for adjusted AUC(O-72) were close to
unity and the 95’%confidence intervals for these ratios all included unity (see Table 3), there was wide
variability between subjects for a given dose level. The individual dose adjusted AUC(O-72) ratios varied
-fold, with ranges of
for the
mg ratio.
for the 15:6 mg ratio, and
16
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 199 of 382

for the 15:12 mg ratio
Similar to AUC(O-72), the mean CmaX values also increased with the i~rease
in dose. AS me table
above indicates, the overall variability in unadjusted Cmax between subjects (i.e., as ‘ACV) was wide and
similar in magnitude to that obsewed for unadjusted AUC(O-72). The Cmax values varied over -1 O-fold
range at the 15 mg dose and -5-fold at 6 mg and 12 mg (see Figure 2). The results in Table 2 indicated
that a significant difference was detected between the mean unadjusted Cmax for the three dose
comparisons (i.e., p = 0.04 for 6 vs 12 mg; p <0.01 fbr 6 vs 12 rng and 12 vs 15 mg). Th&same
comparisons for the dose adjusted Cmax estimates were not statistically significant.
The geometric
mean of the ratios for adjusted Cmax were ctose to unity and the 95°A confidence intervals for these ratios
all included unity (see Table 2). The individual adjusted Cmax ratios varied
-fold,with ranges of
for the 12:6 mg ratio,
for the 15:6 mg ratio, and
for the 15:12 mg ratio.
Maximum plasma concentrations of ivermectin were attahed, on average, within -4 hours for all three
dose levels and no significant differences were detected in Tmax between doses. The mean effectNe
half-life estimates, calculated with T =24
hr, were similar for the 6 mg and 12 mg doses at 16.8 and 16.9
hr, respetiively.
However, these T% values were longer than those determined for the 4 subjects studied
in the metabolic disposition study (i.e., mean TYz= 11.8 hr, range 9.8-14.3 hr).
Reviewers Conclusions:
The sponsor provided the following conclusions:
Despite the substantial variability obsenmd in the estimates of AUC(O-72) and Cmax following
increasing single dose administration of 6, 12, and then 15 mg, this increase in dose did not result
in unpredictably high plasma drug concentrations/
systemic exposure to ivermectin.
The statistical analysis of the unadjusted and dose adjusted AUC(O-72) data suggested some
deviation from dose proportionality, but would not be expected to be clinically significant over this
dosage range. The analysis of the unadjusted and dose adjusted Cmax data suggested dose
proportionality was maintained across the three doses. The remarkable similarity in mean Tmax
estimates suggested no dose related differences in the rate of drug absorption from the
ivermectin tablets.
This reviewer is in agreement with the conclusions provided by the sponsor with respect to the
assessment of dose proportionality.
With respect to the method to determine the ‘effective” T% for ivermecth (i.e., (In 2)/q, where q = -(l/r)
G
[In(l - (AUC(O-T)/AUC(O-72)))]and T = 24 hr), the sponsor assumed that AUC(O-72) approximated AUC(O-
inf) since plasma ivermectin concentrations at 72 hours were either at or betow the lower limit of
quantification of the assay (i.e., 1.0 rig/ml) for nearly all subjects at the 6 and 12 mg dose levels.
Inspection of this concentration data revealed that 5 of 12 subjects at the 6 mg dose (42%)
and 7 of 12
subjects at the 12 rng dose (-58Yo) had plasma ivermectin concentrations at 72 hours postdose that were
-2 rig/ml or greater (actual range
nglml). From thk, it appeared that the assumption was not
appropriate for approximately one-half of the subjects for whom T!! was estimated. Furthermore,
inspection of the individual In concentration-time profiles suggested that a sampting schedule beyond 72
hours postdose may be needed to adequately characterize the terminal phase and accurately determine
T%. Thus, the estimates for effective T??determined in this study and the metabolic disposition study
may have underestimated the “’true” T% for ivermectin.
..-.
17
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 200 of 382

r.
.,!
.,
E!EwL
Formulation
and
analytical
measurements
for 3 nig and
6 mg
tablets
of Ivermectin used In dose proportionality study.
Ivermectin (MK-933) is
a mixture of no less than 80
Z 22c23-
dlhydroavermectln-B1a
(H2B1a)
and
no
more
than
20
$
22,23-
dihYdrOaVermeCtin-B1b
(H B b).
In
this
study,
the
drug
was
administered as the uiarkef~mage 6 mg, or submultiple 3 mg tablets.
6 mg tablet
3 Kg tablet
Lot number:
Formulation:
Ivermectin human use grade (90.2$)
?licrocrystallineCellulose
S\archo pregelatinised
Hagneslum
Stearate
Total
Meight
Assay Potency:
E-3807
E-3806
mg
mg
mg
Kg
mg
mg
mg
mg
mg
mg
Assay method:
FP-148
mean
5.82 mgttablet
3.00 mg/tablet
range
Dissolution test:
Test Method:
FP-148a
time
% dissolution (N-12)
mean
(range)
min.
min
min
a-
The method
used
in
the
dissolution
test
was:
USP XXI,
14ethod
II
(paddles
at
50
rpm.)
in
900
ml
of
33X
VIV
n-propanol
in
uater.
5
ml
samples
were
taken
at
15.
30
and
45 minutes
-
and analyzed using assay
procedure AM-211
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 201 of 382

4
FIGURE 1
MEANI-CTIN
CONCENTRATIONS
IN PLASMA
-
SINGLEDOSEOF DRUG
o
2
4
6
e
10
12
14
HOUR PosrDRuc
.—
.,,”
r
,4
170CT86
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 202 of 382

I
‘~
,.
.;,{,.
I
,~:,1..,,:,1,
I
I
,.’,!.
.,,
;4,
,.
*
.
N
“
Mean
Std
(!l{n,
max)
within
subject
std
Overall
treatment P-val
Pa{rw{se comparisons:
6 mg
With!’:subjectstd
(log
un{ts)
Overall
treatment
SUMMARY
STATISIXCS AM) RESULIS
FOROBSERVEDMAXIMUM
PLAStt4CONCENTRATION
(C
) of
IVERHECTfNA~TER
6,
12 ANfJ 15
t4G O~!S
Or
IVERtlECIIN
CWX-ACTUALVALUES(NG/ML)
C~@OSE-AOJUSTEDVALUESt(NG/ML)
~~
~—6&_~15HG
.
12
18.3
!;,6
:;. s
12
12
18,3
12
15,3
)9.4
(~:i
31.9)
(:;:;,
68.4)
(%!,
llB.5)
(~:~,
31.9)
(;:!,
34.2)
14.1
(4.2,
47,4)
t 0:01
0:16
0,04
<’0,01
G
{ 0.0)
NIA
0,17
~ O*2O
G
0,07
0,35
p-value (log un{ts)
MIA
Gm&rJ;
meanof the
> 0,20*
?
ax after
the
follow{ng:
reatments:
12 mg:6 mg
15 mg:6mg
0,88
15tn
:12mg
0.92
95% C! fOri
eometr{c mean
N/A
?
1.05
of
the
rat
o of Cm~ after
the following
treatments:
12 mg:6 mg
15 mg:6 mg
N/A
(0.65,1.19)
15mg:12mg
(0.68,
1.25)
(0.78,
1.42)
t Doseadjusted to,6mg
w
G All
patw{se
comparisons ) 0,10
2
~
‘,,
m
‘\.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 203 of 382

.
. . -.
---
. . .
-m-
@6aa3
.
.
.
000
---
N
G
--00.
.
00
—
!
/.
—
G
m
‘~—...
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 204 of 382

FIGURE
2
I
,
Drug Metabolism
Study #615
o
AUC(O-72)
vs.
Dose
(N = 72)
9nnn
a
6
9
12
15
18
Dose (mg)
Drug
Metabolism
Study
#615
Cmax
vs.
Dose
(N = f2)
. -A
J
6
9
12
15
18
I
—.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 205 of 382

3. Drug Metabolism
Study #616:
Bioavailability
“An Open, Three Period, Crossover Study in Healthy Subjects to Estimate the Relative Bioavailabiljty of
Iverrnectin Administered as a Capsule and as a Tablet Compared to Ivermectin Administered as an Oral
Solution” (Report Date: August, 1986)
Objective:
To estimate the relativebioavailability of a 12 mg single dose of ivermedn
when administered as
capsules, tablets, and an oral solution to healthy male subjects.
Fom?ulationflreatments:
Ivermectin Tablets 6 mg (market image) - Lot #E-3807
Ivermectin Capsules 6 mg - Lot #E+086
Mean dissolution at 30 minutes was acceptable for both tablets and capsules.
See Table 1 for details of formulations and dissolution.
Ivermectin Hydroalcoholic (40% Ethanol) Oral Solution6 mg/10 ml - Lot #E-3798
Subjects:
Twelve healthy male Caucasian subjects, age range 2248 years (mean 29.1 yrs), weight range 65-83 kg
(mean 72.8 kg)
Study Design and Methods:
Open label, randomized, three period, crossover design. Each subject received the following three single
dose treatments of iverrnectin with either 250 ml (for the tablets and capsules) or 230 ml (for the oral
solution) of water after an overnight fast of at least 8 hours:
A
12 mg iverrnectin oral solution (20 ml)
B: 12 mg iverrnectin capsules (2 x 6 mg)
C: 12 mg ivermectin tablets (2 x 6 mg)
Each treatment was separated by at least a 13 day washout interval. Blood samples for quantitation of
iverrneti”n
mncentrations,
i.e., HzB,. only, in plasma were collected serially ftom O(predose) to 72 hours
(3 days) postdose.
No urine samples were mllected.
Assay Methods, Validation, and Performance:
Ivermectin (H2Bfa)in Plasma - HPLC with Fluorescence Detection
Linear dynamic range from
rig/ml. The limit of detection was reported to be -0.2 rig/ml,
but no data (i.e., accuracy and precision) was provided to substantiate this claim. The lower limit
of quantification was 1.25 rig/ml, however, it appeared that the sponsor used plasma ivermectin
concentrations between
rig/ml to calculate the AUC estimates.
Quality mntrol (QC)
samples were run with the clh’iical samples at two concentrations (low and high), instead of the
preferred three mncentrations (low, medium, high). The interday precision (“ARSD) was
acceptable for both the low (6.25 rig/ml) and high (75 rig/ml) QC’S at 8.7% and 5.7Y0,respectively.
Data Analysis:
.,,
AUC(O-72), Cmax, and Tmax were estimated by conventional model independent methods. The AUC
and Cmax values were adjusted to the 12 rng dosages based on the assay potencies (see Table 1).
An ANOVA for a three period crossover design was used to determine statistical differences in the
pharrnacokinetic parameters between the three treatments. The most relevant statistical evaluations were
those between the capsules and tablets since thecapsules were used in the clinical onchocerciasis trials.
The AUC(O-72) and Cmax data were log-transformed for the pairwise ANOVA comparisons of solution vs.
18
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 206 of 382

capsules, solution vs. tablets, and capsules vs. tablets. The 95% confidence intervals were also
constructed for the geometric means of the ratios of solution:capsules, solution:tabiets, and
capsules: tablets for AUC and Crnax. In addition, posterior probabilities that the ttue mean difference in
AUC and Cmax of the capsules vs. tablets comparison were less than 40, 35,25, and 20°A of the mean
AUC and CmaX of the “standard”, i.e., tablets, were calculated.
It is noteworthy that the sponsor used the
tablets, instead of the capsules, as the standard or reference treatment when calculating the posterior
probabilities. Also, the sponsor did not perform an evaluation of bioequivalence between thh tablets (i.e.,
as the test treatment) and the capsules (i.e., as the raference treatment) based on the currentty accepted
two one-sided test procedure.
Results:
The mean plasma ivermectin concentration-time data are illustrated in Figure 1, which suggested that the
systemic availability of ivermectin from the 12 mg dose of the oral solution was greater than that from
either the tablets or capsules, especially up to 24 hours postdose. The mean plasma concentrations
resulting from administration of either the capsules or tablets appeared to be similar. The descriptive
statistics for the pharrnamkinetic parameters are summarized in the table below. The resutts of the
ANOVA and other statistical tests for AUC(O-72) and Cmax are presented in Table 2.
Mean k SD (Range)
Pharmacokinetic
Parameters
(N = 42)
Parameter
lverrnectin
Ivermectin
Iverrnectin
Oral Solution
Capsules
Tablets
(12 mg/20 ml)
(2x 6 mg)
(2x 6 mg)
AUC(O-72~
1291t330
782&302
726*41 1
(ng.hr/ml)
(954-1958)
(304-1334)
(287-1826)
(CV 26%]
[Cv 39%]
[Cv 57%]
Cmax*
82.9X?5.4
50.6t15.2
46.6S21.9
(nglml)
(42.9-139.7)
(26.3-71.0)
(16.4-101.1)
[Cv 31%]
[Cv 30%]
[Cv 47%]
Tmax
I
4.0*0.9
I
3.7*I.O
I
3.6i0.7
(hr)
(2.145.2)
(2.04.1)
(2.24.2)
I
[CV 23%]
I
[CV 27%]
1
[Cv 19%]
dalues for these parameters adjusted to the 12 mg dosages based on the assayed potencies given in
Table 1
As evidenced from the data above, the mean AUC(O-72) and Cmax estimates resulting from single dose
administration of the oral solution were -2-fold higher than those for e.kherthe capsule~ or tabie&
These
same estimates were only slightly hgher for the ivermectin capsules as compared to the tablets.
Mean
Tmax was similar for all three formulations at -4 houm and no statistically significant differences were
detected (p> 0.20). In Table 2, the ANOVA detected significantly higher AUC(O-72) and Cmax values for
the oral solution vs. either the capsules or tablets (p <0.01 ). No statistically significant differences were
detected in the ANOVA between the capsules and tablets for either AUC(O-72) or Crnax (p > 0.20). The
posterior probabilities for AUC and Cmax, calculated with the tablets as the standard instead of the test
formulation, were 0.71 that the true mean difference (i.e., for capsules vs. tablets) in either parameter was”
less than 20% of the tablet means, 0.84 for less than a 25% difference, and 0.91 for less than a 30%
difference. Thus, any differences in systemic availability of the capsules vs. the tablets were most likely
(i.e., -90% probability) to be less than 30% and probably (i.e., -80% probability) less than 25?40,but only
marginally (i.e., -70% probability) less than 20’Yo.The latter difference of 20’% br4ng that which the
currently accepted two one-sided test’ procedure for evaluation of bioequivalence is based upon.
The bioequivalence of the market image tablet relative to the clinical trials capsule formulation was
evaluated by this reviewer by calculating the 90% confidence intervals based on the currently accepted
19
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 207 of 382

two one-sided test procedure. The ratios of the tablet (test) to capsule (reference) and the 90’?40
confidence intervals (Cl) are summarized in the table below.
.
Bioequivalence
Summary
of Ivennectin
Tablets (N = 12) vs. Capsules
(N = 12)
AUC(O-72)
90% Cl for
Cmax
90% Cl for Cmax**
Ratio*
AUC(O-72)W
Ratio”
Arithmetic
Mean
0.97
(88.8%, 117.1%)
0.98
(755%,
120.5%)
Not 8ioequivalent
Not Bioequivalent
S.D.
0.42
0.40
Range
Geometric
Mean
0.88
0.88
GRatio of Tablets/Capsules
‘Cl
calculated based on the two one-sided test procedure; bioequivalence acceptance criteria (80V0,
125%)
These results indicated that, despite the apparent similarities in mean estimates of AUC(O-72) and Cmax,
the ivermectin tablets tilled to meet the criteria for bioequivalence when compared to the capsules. Thus,
the systemic availability of ivermectin from the market image tablet formulation was less than that from the
capsule formulation used in clinical trials.
Reviewers Conclusions:
The sponsor provided the conclusions that the bioavailability of ivermectin from the capsule used in
clinical trials and the market image tablet formulations appeared to be similar, with any difference probably
being less than 25%, and with drug from the capsule being slightly more bioavailabie than that from the
tablet.
Based on the statistical analyses of the phannacokinetic data performed by the sponsor (i.e., ANOVA,
posterior probabilities), these conclusions were valid. However, the results of the currentty accepted two-
one sided test procedure used to assess in vivobioequivalence, conducted by this reviewer, indicated that
the ivermectin tablets were not bioeauivalent to the capsules. This finding of bioineauivalence should be
...whA-
G-
A:----
.-~
L1---=-----
--+
-—~-~
: “.L—
-..
.
“.
–—,L
.-.,-,.
I
~uV
la70J
Walues for these parameters adjusted to the 12 mg dosages based on the assayed potencies given in
I
Table 1
As evidenced from the data above, the mean AUC(O-72) and Cmax estimates resulting from single dose
administration of the oral solution were -2-fold higher than those for either the capsules or tablets. These
same estimates were only slightly hgher for the iverrnectin capsules as compared to the tablets.
Mean
Tmax was similar for all three formulations at -4 houm and no statistically significant differences were
detected (p> 0.20). In Table 2, the ANOVA detected significantly higher AUC(O-72) and Cmax values for
the oral solution vs. either the capsules or tablets (p <0.01 ). No statistically signitkant differences were
detected in the ANOVA between the capsules and tablets for either AUC(O-72) or Cmax (p> 0.20). The
posterior probabilities for AUC and Cmax, calculated with the tablets as the standard instead of the test
formulation, were 0.71 that the true mean difference (i.e., for capsules vs. tablets) in either parameter was’
less than 20% of the tablet means, 0.84 for less than a 25’%odifference, and 0.91 for less than a 30?40
difference. Thus, any differences in systemic availability of the capsules vs. the tablets were most likely
(i.e., -90% probability) to be less than 30% and probably (i.e., -80% probability) less than 25’?40,but only
marginally (i.e., -70?40probability) less than 20Y0. The latter difference of 20% being that which the
currently accepted two one-sided test procedure for evaluation of bioequivalence is based upon.
The bioequivalence of the market image tablet relative to the clinical trials capsule formulation was
evaluated by this reviewer by calculating the 90% mnfidence intervals based on the currently accepted
19
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 208 of 382

Table
1
;
.
I
Fonnulatlon
and
Analytical
Measurements for Oral Solution
and for
6 UIgCapsules and lablet6 of Ivermectln
i
Used in the BioavailabllltyStudy
E
i-
/
IVC?~eCtin
(~-933)
$S a
=iXtUTe
Of
no
l@!66
than
80%
22,23-dihydro-
~mectln-Bla
(H2Bla) and no more than 20% 22,23-d~hydroaVennectin-
lb
(R2B1b).
6 mg Tablet
6 mgCapsule
Solution
Lot
number:
E-3807
E-6086
E-3798
Formulation:
Ivemnectin
human
use
grade
(90.22)
rlg
w
lng
<
Microcrystalline
cellulose
Qg
mg
Starch,
pregela~inized
ulg
~Magnesiurn
stearate
mg
w
nll
lr.1
TOTAL
mg
mg
ml
Assay
potency:
Assay
method:
R-148
FP-89
lW-l&9
mean
5.82
mgltablec
6.1
mglcapsule
5.9 mg/10 ml
range
Dissolution
test:
Test
method:
FT-148a
Ca4-39b
Z dissolution (n=12)
lime
mean
(range]
min
mln
min
.
USP XXI, Method
H
(paddles G t SO rpm) fzi900 ml of 33X v/v
n-propanol In water.
5 ml-samples were taken Gt 15, 30, and
45 minutes Gnd analyzed +ing
Gssay procedure AM-211.
,
b
USP XX, Method II (paddles at 50 rpm) in 9°0 ml of
33% ‘/v
n-propanol
In
water.
5 ad
samples
were
taken
at
1S.
30.
and
45 minutes
and
analyzed
using assay procedure AM-105.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 209 of 382

FIGURE 1
100
50
6a
u)
20
0
MEAN PLASMA CONCENTRATIONSOF IVERMECTIN (H2B~a)
(N=
12)
,-
,{
--------
H
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 210 of 382

‘-
f:<,..,
I
4
#. #..
...
,,
,,’ .,.
,A
.
.,
,,,
.
.
....,,.
,.,4
.
.
.
.
.,
I
N
~;n
II{n,
man
Wfth{n-subjeet
Std
overall
treatment
p-value
Pairw{se p-values
Solution vs
Capsules vs
Posterior
probabfl{ty
true meandifference
(caps Vs tabs)
{$
less than:
20%of stdb
25%of ttd
30%Of std
40% Of
$td
Log Un{ts
Wfth{n subject $td
Overall
treatfnent
p-value
Palrwtse
p-valuM:
Solution
vs
Capsules VS
Geometric
Mean/95%
Confidence Interval!
fWC(NGoHR/HL)
wJUQM_~~
12;;
12
782
330
7;:
302
954,
~958
30;j41334
28$ ’1826
( O.O1
( 0,01
( 0,01
> 0,20
0.74
0.84
0.91
0.97
0.33
( 0.01
< 0.01
< 0.01
) 0.20
Cw
(NG/HL)
~
;:.9
25,4
;;.6
;;,6
21,9
42.9,
139,7
26!;;271.0
16.4,
10t,l
17.1
c O.O1
t O,ot
> 0.20
0.74
0,84
0.91
0.97
,,
,,
‘A
.
,’
0.28
~ 0.01
c 0.01
t 0.01
~ 0.20
b
Solutton
to
capsules
$O?UtfOn
to
tablets
1.73/(1,28,
2,34)
CaP$u?esto
tablets
1.96/(1.43,
2.61)
1.65/(1.28,
2,12)
1.13/(0,84,
1.52)
1.88/(!.46,
z.41)
1,~4/(0.89,
1,46)
a See
Sect{on
11.b.2.
for
additional
information
assay,of
samples
on the
pharmacokinetlc parameters and
tfean of tablets
/
-... W.-..
,,.-.,.
.,,,-, .,,.<(
,,
f:.
, ‘U<
!,,.7
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 211 of 382

4. Protocol
No. 539:
Human
Plasma
and Milk Levels
“An Open, Single-Dose Study in Healthy Lactating Women to Determine Ivermectin Levels in Plasma and
Milk” (Report Date: April, 1986)
.
Objective:
To determine milk and plasma concentrations of ivermectin in lactating women following a single 12 mg
oral dose of ivermectin capsules.
Formulations/Treatments:
Iverrnectin Capsules 2.5 and 0.5 mg
Mean dissolution a&
*
minutes was acceptable for both strengths (i.e., Q ~Yo
for
mg;
~.
fo~mg)
Subjects:
Twelve healthy, nonpregnant, lactating African women who were not breast feeding or contributing to milk
banks, age range 17-37 years (mean 24 k 7 yrs), weight range 40-65 kg (mean 54 f 8 kg). Although
women weighing less than 50 kg or under 18 years of age were to be excluded, the study investigator
allowed 3 women weighing 40-44 kg and another 4 women 17 years of age to participate in the study.
Study Design and Methods:
Open label design in which each subject received a single 12 mg dose of ivermectin capsules (i.e., 4 x 2.5
mg + 4 x 0.5 mg; total of 8 capsules) at least one hour before breakfast. The subjects were hospitalized
for 14 days following drug administration and blood and milk samples for quantitation of ivermectin
concentrations, i.e., HZBI, only, were mllected as follows:
Blood
Day 1: Predose, 1,4, and 12 hours postdose
Days 2 and 3: Predose (i.e,, within 1 hour before breakfast)
m
Day 1: Predose, 1,4, and 12 hours postdose
Days 2 through 14: Predose (i.e., within 1 hour before breakfast)
Assay Methods, Validation, and Performance:
Ivermectin (H2Bt,) in Plasma - HPLC with Fluorescence Deteotion
Linear dynamic range from 140 rig/ml. The limit of detection was reported to be -0.2 nglml, but
no data (i.e., accuracy and precision) was provided to substantiate this tiim.
The lower limit of
quantification was 1.0 rig/ml, based on the range of the assay. Quatity control (QC) samples were
run with the clinical samples at two concentrations (low and high), instead of the prefemed three
concentrations (low, medium, high). The interday precision (%RSD) was acceptable for both the
low (2.5 nglml) and high (30 rig/ml) QC’S at 10.4% and 3.0%, respectively.
Ivermectin (H&)
in Milk - HPLC with Fluorescence DeteCtiOn
Linear dynamic range from 0.1-8 rig/ml. The limit of detection was reported to be -0.05 nghnl, but
no data (i.e., accuracy and precision) was provided to substantiate thk ctaim. The lower limit of
quantification was 0.1 rig/ml, based on the range of the assay. Quality control (QC) samples were
run with the clinical samples at two concentrations (low and high), instead of the preferred three
concentrations (low, medium, high). The interday precision (YoRSD)was acceptable for both the
low (0.5 rig/ml) and high (6.0 rig/ml) QCS at 10.6% and 4.6?40,respedvely.
Data Analysis:
No pharmacokinetic parameters from tither plasma or milk were determined by the sponsor.
21
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 212 of 382

Results:
Plasma
The plasma concentration data are provided in Table 1. Plasma levels of iverrnectin (HZB1.)were
quantifiable (i.e., >1.0 nglml) in allwomen from 1 hr postdose on Day 1 through predose on Day 3.
Maximum plasma concentrations were observed at 4 hrs postdose on Day 1 with a mean of 23 rig/ml and
ranged from 5.0 to 62 rig/ml. Plasma drug concentrations decreased substantially by Day 3 (47 hrs
postdose) for all but one subject-,
who had an elevated mncentration of 69 rig/ml. The total
variability in the plasma concentration data was wide at each timepoint (i.e., CVS of -65YOsnd greater).
Milk
=
concentmtions of ivermectin in milk are provided in Table 2 with the mean data plotted against time in
Figure 1. Coincident with the plasma data, the mean maximum drug concentrations in milk were also
observed at 4 hrs postdose on Day 1 at 7.6 rig/ml and ranged from
rig/ml. The highest
ivennectin milk concentration was obsenfed in subject-t
18.5 rig/ml which occurred at 12 hours
postdose on Day 1. Mean milk concentrations decreased by Day 2 postdose to 1.3 rig/ml and remained
approximately at this level through Day 6 postdose. From Days 7 through 14, milk concentrations
decreased further and remained between
, rig/ml. On Day fi4 postdose, milk levels were
quantifiable (i.e., >0.1 rig/ml) in 9 of the 12 subjects with a mean concentration of 0.6 rig/ml. Similar to
the plasma concentration data, the total variability in ivermectin milk mncentrations
between subjects was
also wide (i.e., CVS from -60 to -160Yo).
The sponsor estimated that the maximum intake by a nursing 3 kg infant on Day 1 would be -3 mcg/kg,
based on
e maximum ivermedn
concentration in milk determined in this studytobe-19
rig/ml (i.e.,
subject
&
~ nd the daily consumption of-500
ml of milk. This 3 mcglkg “dose” represented -2Y0 of
the recommended adult dosages for onchocerciasis and strongyloides (i.e., 150-200 mcglkg).
Mean
intake of ivermectin through the mother’s milk would be lower on Days 2 through 14 ranging from
mcgtkg.
.
Reviewers Conclusions:
The sponsor concluded that ivermectin was present in the milk of lactating women after a single dose of
12 mg, maximum milk concentrations occurred on the first day after the dose, and had substantially
decreased thereafter, but remained detectable for up to 14 days postdose. The maximum intake of drug
by a nursing infant (3 kg body weight) was estimated to be -3 mcg/kg on the first day of single dose
ivermectin administration and represented a minimal intake as compared to the recommended adult
dosages of 150-200 mcglkg. The mean intake of drug at 14 days postdose, the end of the study, was
estimated to be +.1
mcg/kg (-0.05Y04.070A of the adult dosages) in a nursing infant.
The sponsor also commented in the Clinical Summary Section of this NDA that in light of the limited
information concerning the development of the blood brain barrier in newborn infants, that treatment with
ivermectin in mothers who intend to breast feed be withheld until at least 1 week after the birth of the child.
This recommendation was also provided for in the proposed labeling.
22
Thus, it appeared that the sponsor considered drug exposure through ingestion of mother’s milk to the
nursing infant to be of minor consequence in infants with fully developedhtact
blood brain barriers. The
conclusions are approptite
based on the results of this study and of the oral toxicity study conducted in
neonatal monkeys (i.e., <2 weeks old). In this species, which has been reported to be more predictive of
the human response to ivermectin than rodent models, no evidence of toxicity was obsennxt al doses up
to 100 mcg/kg/day.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 213 of 382

. .
PLASMALEVELSOF IVERMECTIN
(H2Bla, NG/ML)FOLMWNG
ANOWLDOSE OF IVERMECTIN (12
MG)
SUBJECT
DAY 1,
DAY 1,
DAY 1,
DAY 1,
DAY 2,
DAY 3,
NUMBER
PREDOSE
1 HOUR
4 HOUR
12 HOUR
23 HOUR
47 HOUR
“
N
Mean ~ SD:
N.D.
1329
23$15
12~11
624
12 * 22
Median
N.D.
10
19
7
4
4
N.s.
= No sample.
N.D. = None detected.
a
b
c
d
Sample marked as plasma but was a milk sample.
Above range
of standard line--assay repeated on
a smaller sam-
ple volume.
Marked as Day 2, seven-hourPlasma 6.
Plasma 6 should be Day 3.
An
additional sample supplied marked Day 1,
seven-hour.
No
drug vas detected in this sample.
18DEC86
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 214 of 382

tlll~LEVELSOF IVERtlECIIN(H2Bla, NG/Ml.)FOLLONINGIINORAL00SEOF IVER!4ECTIN
(1211G)
.,
N
10
11
12
12
12
12
Mean* SO:
;.;.
12
10
12
1.6*
1,8
7.6 ~ 4,5
4*O i
5.3
163$2.1
I*3*
1.3
1.7*
1,9
1.2*1.1
1.2*1.1
Median
. .
O*9
?.2
2,5
.
O*7
?.0
0.7
1*O
‘
N,S, = No sample
N,O
= None detected
6 , Above ~an~eOf standard f{fle...a$$ay repeated on a Srnalter sample volum@
,,
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 215 of 382

-
&r~N~
.
.
MILK LEVELSOF IVERHEC71N
(H2EIla , NG/FtL)FOLLOWING
ANORALDOSE OF IVERflECTIN(12 flG)
N
12
10
12
11
10
12
..-
Iiean ~ SD:
0.9 * 0.8
004 *0,4
0.S ~ 0,6
O*S * 0.5
10
12
0.9*
0.7
O.e*
1.0
Med{an
0.9
0.3
0.3
0.s
0.7
0.4 G 0.5
:.! ~ 0.8
O*3
0.2
.
N,S.
s No sample
N,O
= None detected
h =Above range of standard I{ne-assay
repeated en a smaller
sampl@volume
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 216 of 382

FIGURE1
=
IVERMECTIN
(H2Bla)
LEVELS IN MILK FOUWING
12 ~
ORAL DOSE
G
!
G\
G \
_O”\
G-0,
‘\o__-,a#
———_
___
----
_ -
‘L,&
K &
/ ,“
./‘
18DEC86
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 217 of 382

VU. lN VITRO METABOLISM
.
As a follow-up to the radiolabeled metabolic disposition study (see Section
VI.), the
sponsor attempted to characterize further the metabolize profile of ivermectin using the
urine, feces, and plasma samples collected from the subjects in this study. A number
of polar and non-polar (or “drug-like”) metabolizes were tentatively identified or
postulated.
In urine, a group of polar metabolizes were identiied, with the fiajor
metabolize postulated to be a hydroxylated derivative of HzBt.. Another group of at
least 7 “drug-like” metabolizes were also postulated and resembled those identiied
in
the livers of pigs. In feces, the “drug-like” metabolizes were the primary group identiied
(-40-50%
of extractable residue), with the monosaccharide of H,B,a being a major
derivative of this group. The sponsor noted that all ‘drug-like” metabolizes obsewed
in
the feces were also present
in the urine, only at much lower levels. The unmetabolized
drug was also a major component of the extractable radioactivity in feces (-25-70%).
In plasma, only trace amounts of parent ivermectin were detected and -80%
of the
extractable radioactNity existed as non-polar metabolizes, with the majority postulated
to be derivatives of the monosaccharide of HzB1a. Approximately 12 polar metabolizes
in plasma were postulated, but the nature of these metabolizes were not investigated
any further.
The sponsor did not provide any data or related results of in vitro hepatic metabolism
studies of ivermectin in human liver miscrosomal or other hepatic tissues.
It appeared
that the in vitro metabolism of ivermetiln was investigated in rats and other animal
species.
In rat liver microsomes, CYP3A and possibly CYPIAI
may be involved.
In summa~,
although the data are not definitive, it appeared that ivermectin is
metabolized to a number of metabolizes and most likely by the liver. in light of the one-
time dosage regimen for either onchocerciasis or strongyloides, the potential for a drug-
metabolism or drugdrug
interaction would be expected to be minimal.
..
.,
23
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 218 of 382

Vlll.
COMMENTS
TO BE SENT TO SPONSOR
1. For the bioavailability study (NDA Study No. 5535), the sponsor was asked to re-
evaluate the bioequivalence of the to be marketed tablet formulation relative to that of
the capsule formulation used in clinical trials using 90% confidence intervals calculated
on the geometric means of the tabletkapsule
AUC and Cmax ratios based on the
currently accepted two one-sided test procedure.
In the initial NDA submis~on, the
sponsor calculated posterior probabilities and 95% confidence intewals using the to be
marketed tablets as the reference, instead of the test formulation. The request was
made since it is standard practice for the to be marketed tablet to be considered as the
test formulation and the clinical capsules as the reference formulation.
However, the
sponsor responded by providing 909f0confidence intervals on the capsule/tablet ratios,
i.e., the opposite of what was requested, and essentially the same as was performed in
the initial submission.
2. Has the influence of food on the systemic availability of ivermectin been assessed ?
The sponsor may want to consider examining this since iverrnectin, like albendazole,
is
nearly insoluble in water and appears to be poorly absorbed following oral
administration.
Yet, administration of albendazole with food for the treatment of
systemic parasitic diseases is recommended since systemic exposure appears to be
substantially increased.
If no such data or related results exist, then it is recommended
that the sponsor provide a statement in the labeling to indicate that the effect(s) of food
on the systemic availability of ivermectin has not been studied.
3. Labeling
Comment:
Under CLINICAL PHARMACOLOGY,
Phannacokinefics,
the last sentence in this
section currently reads:
24
Since in the dose proportionality study (NDA Study No. 5537), apparent/effectNe
half-
Iives of 16.8 and 16.7 hours
were
recently
calculated
for the 6 and 12 mg doses,
respectively, it is recommended to change the current wording to:
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 219 of 382

Philip
M. ~olahgeto,
~ha&.D.,
Ph.D~
Offi~
Clinical Pharmacology/6iopharmaceuti~,
Division of Pharmaceutical Evaluation Ill
RD/FT signed by Frank Pelsor, Pharm.D., Team Leader
t
Clin Pharrn/Biophaml
R view Attende es 08/29/ 96: Dr. Nicholas Fleischer (HFD-880),
Dr. Henry Malinowski (H;D-860),
Mr. John Hunt (HFD-870)
cc:
Div. File - NDA 50-742
HFD-520
(P. Coyne, MO)
HFD-520
(P. Fogarty,
CSO)
11
II
HFD-340
(Viswanathan)
HFD-205
(FOI)
#D-880
(Division
File)
#D-880
(Pelsor,
Colangelo)
@%g
file (Clarence
Bo% HFD-870,
PKLN RM 13B-31)
.,,
.
,
25
-
———.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 220 of 382

a.,
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 221 of 382

Review
and
Evaluation
of
Pharmacology
and
Toxicology
Data
Division
of
Anti.-Infective
Drug
Products,
HFD-520
NDA:
50-742
(formerly
NDA
20-721)
DRUG:
Mectizan
(Ivermectin)
CATEGORY:
Anti-parasitic
agent
SPONSOR:
Merck
Research
Laboratories
Sumneytown
Pike
West
Point,
PA
19486
CONTACT
PERSON:
Kenneth
R.
Brown,
M.D.,
Regulatory
Liaison
Phone
610-397-2552
NUMBER
OF
VOLUMES:
34
DATE
DATE
DATE
DATE
DATE
DATE
OF
SUBMISSION:
March
29,
1996
CDER
RECEIVED:
April
3,
1996
ASSIGNED:
April
8,
1996
REVIEW
STARTED:
June
17,
1996
FIRST
DIWFT
COMPLETED:
July
26,
1996
REVIEW
ACCEPTED
BY
INTRODUCTION/OVERVIE’W
Ivermectin
is
derived
spectrum
antiparas
itic
from
the
avermectins,
a
class
of
broad-
agents
isolated
from
the
fermentation
products
of
Streptomyces
avermitilis.
It
is
a
mixture
of
two
semisynthetic
macrocyclic
lactones,
which
are
designated
as
H2B1~
(ethyl
analog)
and
H2Blb (methyl
analog).
The
mixture
contains
at
least
90%
of
the
ethyl
analog,
and
not
more
than
10%
of
the
methyl
analog.
The
structure
of
ivermectin
is
shown
on
the
next
page.
Ivermectin
is
also
known
by
the
sponsor’s
code
number
MK
0933,
and
by
the
trade
name,
Mectizan.
The
drug
will
be marketed
in a tablet
dosage
form,
contai_n$_ng 6 mg_of
active
ln9re@$.?.QS:.
. ...._.—___
--t—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 222 of 382

.
Ho,,, #
qc
~c
~c
\\’‘
-’
ii
OH
Molecularformulas andrelative
molecularmasses:
H2B1a(R = C2H~): C4SHT40,4;M.W. -875.10
H2Blb @ = ~3):
c4THT@14;M.W. -861.07
Ivermectin
has
been
used
in
Africa
and
elsewhere
to
treat
onchocerciasis
(river
blindness)
and
strongyloidiasis
(a nematode
infection
of
the
gastrointestinal
tract ) .
Previous
human
experience
has
shown
that
the
compound
is
highly
efficacious
and
generally,
well-tolerated.
It
is
approved
in
France
and
several
other
countries
for
human
use,
and
in
the
United
States
for
veterinary
use.
In
the
U.
S.
it
is
used
for
prophylaxis
again-st
heartworm
in
dogs,
and
as
an
anthelmintic
in
several
species
of
farm
animals.
-This--NDA--eekapprovdldl
of
MecEizan-<er---Ehereaetwentnt
of
river
blindness
in
a
single
oral
dose
of
150
mcg/kg,
and
for
the
treatment
of
strongyloidiasis
in a single
oral
dose
of
200
mcg/kg.
2
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 223 of 382

PRECLINICAL
SAFETY
STUDIES
This
NDA
contains
reports
of
a
large
number
of
toxicology
studies
on ivermectin,
that
were
conducted
between
1977
and
1995.
The
data
from
most
of
these
studies
have
been
previously
reviewed
by
the
Center
for
Veterinary
Medicine
(USFDA),
and
are
summarized
in
the
next
section.
The
previously
unreviewed
studies,
are
reviewed
in
this
section.
1.
Ascending
Dose
Oral
Toxicity
Study
in Rhesus
Monkeys
This
was
a
GLP
study
conducted
by
the
sponsor
in
West
Point,
PA
between
March
and
September
of
1985
(study
TT-85-013-0).
Eight
rhesus
monkeys
were
caged
individually
and
maintained
under
appropriate
environmental
conditions.
At
the
start
of
the
study,
the
animals
were
two
to
three
years
old
and
weighed
between
2.4
and
3.2
kilograms.
TWO males
and
two
females
received
MK-0933,
while
four
other
animals
(two
of
each
sex)
received
another
compound
(MK-
0936)
.
The
compounds
were
administered
orally,
by
gavage,
in
sesame
oil
(5
mlikg)
.
The
doses
tested
were
0.2,
0.5,
1,
2,
4,
6,
8,
12,
and
24
mg/kg
with
intervals
of
two
to
three
weeks
between
doses.
Body
weights
and
food
consumption
were
recorded,
and
the
animals
were
observed
for
signs
of
toxicity.
The
eyes
were
examined
for
mydriasis.
Also,
blood
was
drawn
periodically
for
measurement
of
plasma
drug
concentrations.
Emesis
was
observed
in these
animals,
with
a dose-related
incidence
at
doses
of
2 mg/kg
and
higher.
Mydriasis
was
seen
at
doses
of
6
mg/kg
and
above.
Decreased
activity
and/or
sedation
occurred
at
24
mg/kg.
After
the
minimum
toxic
dose
of
2 mg/kg,
the
peak
plasma
drug
concentrations
were
highest
at
24
hours
and
averaged
110
nanograms/ml.
No
postmortem
or
microscopic
observations
were
reported
for
this
study.
2.
Two
Week
Oral
Toxicity
Study
in
Immature
Rhesus
Monkeys
This
was
a GLP
study
conducted
for
the
sponsor
by
(study
TT-85-9033).
Immature
rhesus
monkeys
(4/sex/group)
were
caged
individually
and maintained
under
appropriate
environmental
conditions.
At
the
start
of
the
study,
the
animals
were
13
to
21
months
old,
and
weighed
betwsen
1.9
and
3.2
kilograms.
MK-0933
in sesame
oil was
administered
once.
daily,
by
nasogastric
incubation,
at
doses
of
O,
0.3,
0.6,
or
1.2
mg/kg/day
(1 ml/kg)
for
14-16
days.
Evaluations
for
treatment-
related
effects
were
based
on
observations,
body
weights,
hematology,
serum
chemistries,
ophthalmogic
examinations,
gross
‘-–~altiology,
organ
weights”j’-an=-”rnicroscopic-listopathology.
—..—.—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 224 of 382

There
were
no
treatment-related
findings
in
these
animals.
Increases
in
serum
transaminases
occurred
.in three
animals,
but
these
increases
were
attributed
to hepatitis-like
viral
infections.
3.
Two
Week
Oral
Toxicity
Study
in
Neonatal
Rhesus
Monkeys
This
was
a
GLP
study
conducted
for
the
sponsor
by
-
(study
TT-86-9005).
Three
groups
of
neonatal
rhesus
monkeys
(5
males
and
3
females/group)
were
maintained
on
a
bottled
infant
formula
in
individual
incubators
in
the
nursery.
The
animals
were
examined
by
a veterinarian,
and
deemed
to
be
in
clinically
acceptable
condition.
At
the
start
of
the
study,
the
animals
were
7 to
13 days
old,
and
weighed
between
400-600
grams.
MK-0933
in
sesame
oil
was
administered
once
daily,
by
nasogastric
incubation,
at
doses
of
O,
0.04,
or
0.1
mg/kg/day
(1 ml/kg)
for
14
days.
Evaluations
for
treatment-related
effects
were
based
on
observations,
body
weights,
food
consumption,
hematology,
serum
chemistries,
ophthalmogic
examinations
(including
pupillary
light
responses)
,
gross
pathology,
organ
weights,
and
microscopic
histopathology.
No
treatment-related
effects
were
observed
in
this
study.
The
Mectizan
tablets
described
in
this
NDA
carry
a
three
year
expiration
date.
It has
been
determined
that
a loss
of potency
of
approximately
5-10%
occurs
during
three
years
of
storage
at
room
temperature.
The
loss
of
potency
is
due
to
the
formation
of
unidentified
oxidative
degradation
products
in
the
tablets.
The
following
two
studies
were
performed
to
evaluate
the
safety
of
the
degradation
products.
4.
Two
Week
Oral
Toxicity
Study
of
Stored
Tablets
in
Rats
This
was
a
GLP
study
conducted
by
the
sponsor
in
West
Point,
PA
during
June
and
July
of
1995
(study
TT-95-043-0).
Mectizan
tablets
that
had
been
stored
for
three
years,
were
ground
into
a
powder
with
a mortar
and
pestle.
The
crushed
powder
was
suspended
in 0-.5%
aqueous
methylcellulose,
and
the
suspension
was
assayed
for
concentration
and
uniformity.
The
suspension
was
administered”
orally
to Sprague-Dawley
rats
(15 males,
15 females)
once
daily
for
14
days.
The
suspension
was
given
‘in
a
volume
(5
ml/kg)
that
corresponded
to
10 mg/kg
of
ground
tablet,
and
a dose
of
0.5
mg/kg
of
ivermectin.
Another
group
of
rats
(lS/sex)
received
““a
comparable-volume
-of-~~~-met+y+aellulose,
and
served-as--a---control------
group.
Evaluations
for
treatment-related
effects
were
based
on
observations,
body
weights,
food
consumption,
hematology,
serum
chemistries,
ophthalmogic
examinations,
urinalysis,
gross
4
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 225 of 382

pathology,
organ
weights,
and
microscopic
No
treatment-related
effects
were
seen
in
5. Two
Week
Oral
Toxicity
Study
of
Stored
histopathology.
thins study.
Tablets
in Monkeys
This
was
a
GLP
study
conducted
by
the
sponsor
in
West
~oint,
PA
during
July
of 1995
(study TT-95-044-0).
Mectizan
tablets
that
had
been
stored
for
three
years,
were
ground
into
a
powder
and
suspended
in
0.5%
aqueous
methylcellulose,
as described
above.
The
suspension
was
administered
orally,
through
a nasogastric
tube,
to
rhesus
monkeys
(4 males,
4
females)
once
daily
for
14
days.
The
suspension
was
given
in a volume
(5 ml/kg)
that
corresponded
to
10
mg/kg
of
ground
tablet,
and
a
dose
of
0.s
mg/kg
of
ivermectin.
Another
group
of animals
(4/sex)
received
0.5%
methylcellulose,
and
served
as
a
control
group.
The
monkeys
were
approximately
two
years
old,
and
weighed
from
2.4
to
3.4
kilograms
at
the
start
of
the
study.
Evaluations
for
treatment-related
effects
were
again
based
on
observations,
body
weights,
food
consumption,
hematology,
serum
chemistries,
ophthalmogic
examinations,
urinalysis,
gross
pathology,
organ
weights,
and
microscopic
histopathology.
No
treatment-related
effects
were
seen
in
this
study.
TOXICOLOGY
PROFILE
OF
IVERMECTIN
The
following
summary
of
ivermectin
toxicity
the
CVM
reviews
of
the
earlier
submissions,
NDA .
Acute
Toxicity
has
been
derived
from
and
from
the
current
The
median
lethal
doses
(LD50s)
were
reported
as
follows:
11.6
mg/kg
oral-male
mice
24.6-87.2
mg/kg
oral-female
mice
(several
different
studies)
42.8-52.8
mg/kg
oral-male
rats
44.3-52.8
mg/kg
oral-female
rats
2.3
mg/kg
oral-infant
rats
(I-2 day
old
pups)
406
mg/kg
dermal-rabbits
(both
sexes)
The
signs
of
toxicity
obse~ed
in
rodents
were
ptosis,
bradypnea,
ataxia,
tremors,
and
loss
of
the
righting
reflex.
,.
A
study
was
conducted
in
dogs
using
single
oral
“doses
of
5-80
mg/kg.
Mydriasis,
ataxia,
and
tremors
occurred
at
10 mg/kg.
Two
‘“of the–’fo–u”r—doq=””-dosedat
80 mg/kg;-15ecaiiie”-c=iiaYosean-d died.
In
experiments
with
were
well-tolerated.
cattle,
subcutaneous
doses
of
up
to
6
rng/kg
However,
in
a
group
of
four
calves
that
- .-
5
..-. .
-. .’
—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 226 of 382

received
8 mg/kg
sc
(40
times
the
therapeutic
dose) , one
calf
died
and
two
others
were
sacrificed
moribund.
The. compound
was
thought
to
have
caused
CNS
depression
in
these
cattle.
Subchronic
Toxicity
A 14-week
study
was
conducted
in rats
(20/sex/group)
at tises
of
O,
0.4,
0.8,
and
1.6
mg/kg/day
orally.
(The
animals
used
in
this
study,
were
derived
from
dams
that
had
also
been
treated
with
the
compound)
.
The
no-effect
level
was
0.4
mg/kg/day.
At
higher
doses,
the
following
gross
and
microscopic
signs
of
toxicity
were
observed:
enlarged
spleens
with
congestion
of
the
red
pulp
and
extramedullary
hematopoiesis,
iron-positive
pigment
in
renal
tubular
epitheliums,
hepatocellular
vacuolation
and
pigment
in
Kupffer
cells.
Reactive
hyperplasia
of the bone
marrow
was
seen
in
the
animals
with
enlarged
spleens,
suggesting
possible
intravascular
hemolysis.
In dogs
(4/sex/group),
a 14-week
study
was
conducted
at doses
of
O,
0.5,
1,
and
2
mg/kg/day
orally.
The
no-effect
level
was
0.5
mg/kg/day.
The
signs
seen
at
higher
doses
were
salivation,
mydriasis,
anorexia,
dehydration,
tremors,
and
ataxia.
Some
of
the
animals
became
recumbent,
and
four
of
the
eight
dogs
in
the
high-
dose
group
were
sacrificed
in
poor
condition.
Reproductive
Toxicity
Several
teratology
studies
were
conducted
in
mice
(20-25
dams/group)
at
doses
of
O,
0.1,
0.2,
0.4,
0.8,
and
1.6
mg/kg/day
orally,
during
gestation
days
6-15.
Tremors
and
convulsions
were
seen
in
some
dams
following
doses
of
0.2
mg/kg/day.
Some
maternal
deaths
occurred
at
doses
of
0.4 mg/kg/day
and
higher.
Teratogenic
effects
were
seen
at
doses
of
0.4
mg/kg/day
and
above.
Cleft
palate
occurred
in the
fetuses
from
the
0.4,
0.8,
and
1.6 mg/kg/day
groups.
Exencephaly
was
seen
in
the
0.8
mg/kg
group.
A
teratology
study
was
conducted
in rats
(25 dams/group)
with
oral
doses
of
O,
2.5,
5,
and
10
mg/kg/day
during
gestation
days
6-17.
There
were
some
maternal
deaths,
and
some
pre-implantation
loss
in
the
high-dose
group.
Incomplete
bone
ossification
occurred
in
the
5 and
10 mg/kg/day
groups.
Cleft
palate
and
“wavy
ribs”
were
seen
in
the
10 mg/kg
group.
In rabbits
(16 dams/group)
the
teratology
study
was
conducted
with”
oral
doses
of
O,
1.5,
3,
and
6 mg/kg/day
during
gestation
days
6-
18.
In
the
high-dose
group,
there
were
losses
in
maternal
body
weights,
and
some
abortions.
There
was
also
an
increase
in
the
number-o&dead
fetuses.
Cleft
pa-lat-e--and---clubbforepawsepaws
occurred
in
the
fetuses
from
the’ 3 and
6 mg/kg
groups.
Some
additional
reproduction
studies
that
were
conducted
in
rats
6
-—. .. . .
.-----
?
,. ..,.
+.+:-..
.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 227 of 382

showed
that
ivermectin
produced
adverse
effects
in
neonates
(delayed
development,
increased
pup
mortality)
.
These
effects
occurred
at maternal
doses
of
1.6 mg/kg/day
and
above.
It was
also
shown
that
the
compound
was
secreted
in the milk
of
lactating
rats.
No
chronic
toxicology
studies
on
ivermectin
have
been
reported.
Ivermectin
was
non-mutagenic
when
tested
(with or withou~etabolic
activation)
in
the
Ames
Salmonella
mutation
assay,
the
mouse
lymphoma
(L5178)
assay,
and
the
unscheduled
DNA
synthesis
test
in
human
fibroblasts.
Carcinogenicity
studies
have
not been
conducted
with
the
compound.
PHARMACOKINETICSTUDIES
MK-0933
was
administered
orally
(in
sesame
oil)
to
two
groups
of
mice,
in
doses
of
0.1
or
0.5
mglkg/day
for
35
days
(Study
TT-82-
071-0)
.
Peak
plasma
drug
concentrations
were
5
and
20
nanograms/ml,
in
the
low-
and
high-dose
groups
respectively.
At
necropsy,
analysis
of
brain
tissue,
revealed
MK-9033
concentrations
of
35
ppb
in
some
animals
(because
of
technical
difficulties
encountered
in
the
brain
assay,
the
value
of
35
ppb
may
or
may
not
be
reliable)
.
In an acute
study
in mice,
a single
oral
dose
of MK-0933
(51 mg/kg)
was
administered
in
sesame
oil
(Study
TT-82-088-0)
.
This
dose
was
lethal
to
four
of
30
animals,
while
other
animals
became
moribund.
At
various
times
after
dosing,
blood
was
drawn
from
surviving
animals,
and
some
animals
were
sacrificed
for
analysis
of
brain
tissue.
The
peak
drug
concentrations
found
in this
study
were
5000
nanograms/ml
in plasma,
and
400
ppb
in brain.
In another
study,
MK-0933
in
sesame
oil
was
administered
orally
by
gavage
to
two
groups
of
four
female
Beagle
dogs
at
doses
of
either
0.5
or
2
mg/kg/day
for
35
days
(Study
TT-82-070-0).
Peak
plasma
drug
concentrations
of
175
and
1500
nanograms/ml
occurred
during
the
third
week
of
the
study,
but
then
declined
during
the
last
two
weeks
of
the
study.
One
dog
in
the
2 mg/kg/day
group
developed
tremors,
ataxia,
and
depression,
and was
sacrificed
moribund
on
day
24.
In
this
animal,
the
drug
was
detected
in
the
cerebrospinal
fluid
at
a
concentration
of
3
nanograms/ml.
In
the
other
seven
animals
sacrificed
on
day
35,
the
drug
was
not
detected
in
the
CSF
(detection
limit
1 rig/ml).
..
The
pharmacokinetic
data
obtained
in human
studies
is presented
in
Table
1-1
(attached).
. _+.—..-
7
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 228 of 382

CONCLUSIONS/RECO~ATIONS
TO
SPONSOR
.
Ivermectin
appears
to be
neurotoxic,
presumably
through
an
effect
on GABA
neurons.
The
compound
appeared
to be more
toxic
in rodents
than
in
subhuman
primates,
especially
with
regard
to
CNS
effects
such
as
tremors
and
ataxia.
In mice,
effects
were
seenst
doses
as
low
as
0.2
mg/kg/day;
in
monkeys,
mild
toxicity
(emesis)
was
observed
following
a dose
of 2 mg/kg,
which
is 10 times
higher
than
the
recommended
human
dose
of
200
mcg/ml.
At
these
doses,
peak
plasma
drug
levels
were
5.5
times
higher
in
the
monkeys
than
in
humans
(110
versus
20
nanograms/ml).
Ivermectin
is teratogenic
in mice,
rats,
and
rabbits,
and
should
be
labeled
as
Pregnancy
Category
C.
It
is also
excreted
in
the
milk
of
lactating
animals
and
humans.
Ivermectin
has
been
shown
to
be
effective
in
the
treatment
of
onchocerciasis
and
strongyloidiasis,
and
this
drug
will
be
extremely
useful
in
the
control
of
these
parasitic
diseases.
w
adequate
margin
of
safety
has
been
demonstrated
between
the
dose
toxic
to
subhuman
primates,
and
the
intended
single
(one-time)
human
therapeutic
dose,
Approval
of
this
NDA
is
recommended.
The
drug
should
not
be
used
by
pregnant
women
or
nursing
mothers,
unless
it
can
be
shown
that
the
benefits
of
therapy,
clearly
outweigh
the
risks
to
the
fetus.
?tL-4’ SiQ.4bL
Kenneth
Seethaler,
Ph.D.,
D.A.B.T.
Pharmacologist,
HFD-520
cc:
Original
NDA
50-742
Concurrence
Only:
HFD-340
HFD-520/L.Gavrilovich
HFD-520
HFD-520/R.0sterberg
HFD-520/Pharm/K.Seethaler
#l?@&4b
HFD-520/MO/P
.Co~e
HFD-520/Micro/J.King
p
.~kf
HFD-520/Chem/J.Timper
-HFD-52-O@Q+P.Fogarty
,
. .-..—
..---
HFD-520/Biopharm/P
.Colangelo
HFD-520/Biostat/S.Bell
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 229 of 382

,,
,,
!-!
1
lvermectin
,
SynopskofApplication
1,1Synopses
L
1,Human P~armacltinetfcs
andBioavaflability
Documentation
Table
I
~
Study
+_
11-5]
5537
[1-6]
5535
[1-7]
-
11-8]
~ations
StudyObkctive/
I
Dosage
StudyDealgn
I
Foti
Evaluationof @H)ivemsec!in
I 4.mg IvarmectinCapsule
absorptio~dia&ibutio~
metabolismendexcretion
Single-dosestudy
Evsduationofdose
pro~ionedity/Single dose
(Sb), three.waycroaeovec
study
EVeluntionof PheaeIll
ca$ule endto-be.marketed
tabletVS.oral solutloti Single-
do$is,three-waycrossover
study
3-mg lvennectinTablet
6-mg Mrsnectin Tablet
6.mg lvennectinCapsule
6-mg Mrmectin Tablet
0,6 mg4nLhydrotlcoholic
:olutkm (40% ethanol)
I
Eatiiation of ivermcctin’s
O.$mgIvennectinCapsule
sedretionIntohumanbreast
milk/Single-dosestudy
2,5.mg !vemvxtln Capsule
-
Fonnulellon
No.
(Batch Size)
R0933.DFC.002-
AOOI
(14)
E-3806
(390)
E.3807
(2305)
E-6086
(200)
E.3807
(2305)
E-3798
(500 mL)
E-5885
(tooo)
E-5893
(1000)
Dose
14mg
(200 pCi)
6 mg
12mg
lSmg
12mg
12mg
12 mg
Number of
Subjects(S)
Patients(P)
(;:M)
12s
(AllM)
12s
(AJIM)
12s
(ANF)
conclusions
Mean Tmax for ivamsectinwas6 IUcorrespondingt%
wea 11.8 h, ~ax
of tritintedmctnboliteaweatwice
thatofparent
drug,Drugandmetaboli~eswe rdowly
secretedIn bile endexcretedin feces.No moreihan
1,0% of thedoseweaexmetedIn urine.
FollowingSD of 6,12, endIS mg mean~ax
and
AUC were proportionalto dosealthoughsub@-antial
variability wasobserved.
The oral solutionahowedhigher(closeto twice)
bioavailabilitytheneitherofthesolidforms. The
tabletformulationshowedcomparablebioavailabili!y
!0 thecapsuleformulation, The relative
bioavailabilityof thecapsulewcs 113% of thetablet.
Smg
12mg
.
Orally dnhisteredivcnnectinis:ecretedin human
milk. The ~ghaat concentrationobservedwas
18.5 ng/mL afler the 12.mgdo~e,Drug wasstill
detectable14 dayapoaldose.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 230 of 382

k.-.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 231 of 382

NDA50-742MECTIZANW(ivermectin) oral tablets
1
STATISTICAL
REVIEW
AND
EV ALUATION
NDA:
50-742
Generic Drug Name:
Ivermectin
Drug Trade Name:
MECTIZANR
Formulation:
~>6~
oral tablets
Drug Class:
1P
Applicant:
Merck Research Laboratories
Indications:
1. Strongyloidiasis of the gastrointestinal tract
2. Onchooerciasis (a.k.a. River blindness)
User Fee Date:
October 1, 1996
Documents
Reviewed: NDA Volumes 1,28,29,30,31,32
dated March 29, 1996 submitted as NDA
NDA Volumes 3,7,29,
and 34 dated July 9, 1996 submitted as NDA
Safety Update Report dated July 31, 1996 submitted for NDA 50-742
Dataset provided August 23,1996 for Strongyloidiasis studies.
Dataset provided September 3,1996 for Onchocerciasis studies.
Draft of Medical Officets strongyloidiasis review.
Type of Review:
Clinical
Medical Offlcec
Phillip Coyne, M.D., HFD-520
Statistical
Reviewe~
B. Sue Bell, Ph.D., HFD-725
Project Manage~
Pauline Fogarty, HFD-520
O.Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
I.Background
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
11.Strongyloidiasis oftl-te gastrointestinal tract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
ll.A. Labeling claims and primary studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...4
11.B. Applicant’s Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...4
11.B.l. Protoco1004 (Gentilini/Datry).
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
11.B.l.a. Study Design
11.B.1.b. Efficacy Results
11.B.1.c. Safety Results
11.B.2. Protoco1014/015 (Berkand Gann)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
11.B.2.a. Study Design
11.B.2.b. Efficacy Results
11.B.2.c. Safety Results
11.B.3. Protocoi 020(Dreyer)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
ll,B.3.a. Study Design
11.B.3.b. Efficacy Results
11.B.3.c. Safety Results
!l.B.4. Wortd Health Organization Study (Martietal)
. . . . . . . . . . . . . . . . . . . . . . . . . . . 12
11.B,4.a. Study Design
11.B.4.b. Efficacy Results
11.B.4.c. Safety Results
ll.B.5. Dose ranging studies (Naquira) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
11.B.5,a. Study Design
11.B.5.b. Efficacy Results
Il.B.5.c. Safety Results
—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 232 of 382

NDA 50-742 MECTlZAN7~
(iverrnectin)oraltableta
2
.
lLC. Medical Officer’s integrated Summa~of
Effimcy
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
111.Onchocerciasis (a.k.a. River blindness) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . “’20
lll.A. Labeling cIaimsandprima~
studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
111.B.Protocol 514 (Document 5002)
Studies by LarMere (509, 510), Awadzi(511),
Green(512)
. . .=.
... . . . . . . . 21
111.B.1.Study Design
111.B.2.Efficacy Results
IILB.3. Safety Results
111.C.Protocol 519 (Documents 5003/5004) -
Studies by Green, Awadzi, Lariviere, Schulz-Key, Vingtain, Zea-Flores
. . . . . 23
111.C.I.Study Design
111.C.2.Efficacy Results
111.C.3.Safety Results
111.D. Protoco1548 (Document 5!545)- Study by Vlngtain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
111.D.1.Study Design
111.0.2.Efficacy Results
111.D.3.Safety Results
111.E. Protoco1545 (Document 5544) -Study by Lariviere
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
111.E.1.Study Design
lli.E.2.
Efficacy Results
111.E.3.Safety Results
IV. INTEGRATED SAFETY SUMMARY
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
V. SUMMARY AND Conclusions
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
V.A. Strongyloidiasis
of thegastrointestinal
tract
V.B. Onchocerciasis
O. Executive
Summary
The applicant is requesting approval of ivermectin for the treatment of strongyioidiasis and of onchocerciasis.
The recommended dosages are a single oral dose of approximately 200 or 150 pg of ivermectin per kg of
body weight for strongyloidiasis and onchocerciasis, respectively. Ivermeotin is to be supplied as 6 mg white,
scored tablets.
In support of the strongyloidiasis indication, five studies were submitted with two studies that used albendazole
as the comparator being considered pivotal by the applicant. The Medioal Officer considers negative stools
through 30 days of follow-up to represent a cure. Ivermectin was statistically superior to albendazole in both
pivotal studies with lower bounds on the 95% contldence intetvals of the difference in pmpottion
wed
of IO”A
and 27°4. However, in two U.S. studies and in one French study comparing single-dose and doubledose
ivermectin with thiabendazole, ivermectin was not statistically comparable to thiabendazole based upon the
DAIDPs Points to Consider document that requires that the lower bound be greater than or equal to -10%
if the cure rate is greater than or equal to 90”A. These studies were very small resulting in very tide
confidence intervals. Except for one treatment arm in one study, the point estimates of the proportion cured
by an iverrnectin treatment was either equal to or slightly greater than the point estimate of the proportion
cured by thiibendazole.
In mntrast, statistical analysis based on time to treatment fkilure showed that both
singledose
and double-dose iverm’bctin treatments were slightly better than thiabendazole based upon a
comparison of the 95% confiden~
intewals of cure rates. Graphs provided in the section titled Medical
Officer’s Integrated Summary of Efficacy show the consistency of the study results.
Concerning safety,
ivermectin was shown to be extremely safe in these studies and to have a better safety profile than
thiabendazole.
Therefore, based upon statistical review of the data provided by the sponsor and revised by the reviewing
medical officer, it is recommended that ivermectin be approved for the indication of strongyioidiasis.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 233 of 382

NDA 50-742 MECTIZAN*M
(iermectin)
oral tablets
3
.
In support of the onchocerciasis indication, 4 studies were submitted for review. The one pivotal study was
a multicenter, double-blind clinical trial with comparison to both a placebo group and a diethylcarbamazine
citrate
(DEC-C)
treatment
group.
The medical officer considers the reduction in geometric mean of
microfilaria (mf) density atone month to be the primary outcome with reductions at 3 months and 6 months
being of secondary importance. These time points are relevant because of the label’s rmmendation
for
possible retreatment at three months. Using nonparametric statistical methods to compare the percent of
baseline mf count shows that ivermectin is statistically superior to DEC-C at all three time points with a p-value
of 0.0001.
Further, DEC-C treatment causes severe systemic reactions as the result of the killing of the
microfilaria.
The number of ivermectin-treated patients with such reactions was statistically less. All other
studies were placebo controlled trials whiih demonstrated that ivermectin was superior with vefy few and very
minor adverse clinical experiences.
It must be noted that the onchocerciasis cJinicaltrials used a capsule that was found to be bioinequivalent to
the tablets in the clinical pharmamlogy/biopharmaceutics.
Otherwise, the statistical review of the applicant’s
data supports approval of ivermectin for the treatment of onchocerciasis.
1.Background
“MECTIZANR(Ivermectin) is a semisynthetic, anthelmintic agent for oral administration. Ivermectin is derived
from the avermectins, a class of highly active broad-spectrum anti-parasitic agents isolated from the
fermentation products of Streptomyces
avermitilis.”
“The drug has been registered for agricultural and veterinary use since 1981.“
“In 1987, ivermectin was approved in France for the treatment of onchocerciasis and is now considered the
drug of choice for the treatment of that infection.”
“As of mid-1995, greater than 36 million ivermectin
treatments (representing >5.2 million patients) have been administered for onchocerciasis.”
“In November 1993, the French government approved the use of ivermectin for strongyloidiasis.”
Ivermectin is available in 6-mg tablets. The applicant recommends administration of a single oral dose where
the dosage is dependent upon the indication and the weight of the patient. The applicant mnsiders the single
dose regimen to be one of the advantages of ivermectin since other agents used to treat these indications
require a multidose regimen.
Il. Strongyloidiasis
of the gastrointestinal
tract
‘Strongyloidiasis occurs chiefly in tropical and subtropical regions of the world.
However, endemic regions
also exist in southeast USA, Japan and southern and eastern Europe. Severe disseminated disease may
occur in immunocompromised patients.”
“The therapeutic arsenal available at present for the treatment of strongyloidiasis is limited to thiabendazole
and albendazole. Thiabendazole is effective in 75-96% of cases; however, it is frequently associated with
considerable clinical adverse reactions. Albendazole, the therapeutic alternative, is well tolerated and has a
cure rate of 42-100?40,depending on the dose schedule and length of follow-up.”
REVIEWER COMMENT: Exact statistical methods implemented in the software package StatXact3 will be
used to calculate 95% confidence intervals for the dflemnce in cure rates for this indication.
Because of the
relatively small sample sizes and high cure rates, the data from the majority of studies for this indication do
not satisfy the assumptions for using the normal approximation to the binomial distribution.
The Marti study
does have sufficient sample size for use of the normal approximation.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 234 of 382

NDA50-742MECTIZANTU
(iverrnectin) oral tablets
4
.
JLA. Labeling
claims and rximary
studies
me
recommended dosage of MECTIZAN
for the treatment of strongyloidiasis is a single oral dose designed
to provide approximately 200 pg of ivermectin per kg of body weight= ‘Patients should take tablets with water.
In general, additional doses are not necessary.
However, a follow-up stool examination to v=rify eradication
of infection should be performed.”
“Two controlled clinical studies using albendazole as the comparative agent were carried out in international
sites where albendazole is approved for the treatment of strongyloidiasis of the gastrointestinal tract, and three
mntrolied studies were carried out in the US and internationally using thiabendazole as the comparative agent.
Efficacy, as measured by cure rate, was defined as the absence of larvae in follow-up stool examinations.
Based on this criterion, efficacy was significantly greater for MECTiZAN (a single dose of 170 to 200 pg/kg)
than fbr albendazole (200 mg b.i.d. for 3 days). MECTIZAN administered as a single dose of 200 pg/kg for
1 day was as efficacious as thiabendazole administered at 25 mg/kg b.i.d. for 3 days.”
The applicant considers the Gentilini study and the Marti study as the two pivotal studies. Both pivotal studies
compared Ivermectin to Albendazole.
REVIEWER COMMENT Since the applicant is making a labeling claim that ivermectin is “as efficacious as
thiabendazole, ” the studies comparing ivermectin to thiabendazole are also reviewed in detail.
11.B. At3D!icant’s
Analvsis
11.B.I. Protocol
004 {GentilinilDatryJ
Protocol title:
“An Open, Randomized Study of Efftcacy, Safety and Tolerability of Ivermectin Single Dose vs. Albendazole
(3day course) in the Treatment of Patients Infected Wdh Strongy/oides Stercoralis (Study 004).’
Publication based upon data collected:
Datry A, Hiimarsdottir 1,Mayorga-Sagastume R, Lyagoubi M, Gaxotte P, Biligui S, Chodakewitz J, Neu D,
Danis M, Gentilini M.
Treatment of Stmng~oicfes stemordis
infection with ivermectirt compared with
albendazole: results of an open study of 60 cases. Trans Roy Soc Trop Med Hyg, 1994;88344-345.
JI.B.1 .a. Studv Desian
lWs study was an ‘Open, randomized trial in otherwise healthy ambulatory patients to compare the efficacy,
safety and tolerability
of ivermectin versus
albendazole
in the treatment
of strongyloiiiasis
of the
gastrointestinal tract.” “Although the study was open in design, stool specimens were examined by one-single
expert who was to remain blinded as to the treatment allocations.m The study was conducted in France.
Patients received either a single dose of ivermectin (target dose of 200 pg/kg) or albendazole (200 mg b.ild.
for 3 days). Because the iverrnectin dosage schedule included in the protocol was in error, the actual dose
of ivermectin was approximately 170 pg/kg. “The difference betwean the administered dose and the target
dose is not considered meaningful.’
Patients were included who were between 5 and 70 years of age and who were infected with Strungy/oides
stercoralis (SS). Infetilon status was determined by stml examination using the Baermann technique. Please
refer to the Medical Officer’s review for more details of the inclusionlexclusion criteria and for details of the
visit procedures.
REVIEWER COMMEN~: The published article also mentioned the exclusion of patients who had received any
other antifilaria/ drug in the 6 months, or other anfihelmintic treatment in the 72 hours, preceding the study.
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.
“After completion of the informed consent procedures and documentation of strongyloidiasis evidenced by
stool examination, patients were randomized to rece”wee“tier ivermectin or albendazole
according to an
allocation schedule. The patients were dosed at least 2 hours before breakfast.”
REVIEWER COMMEN~ According to the published article, informed oral consent was g~en rather than
written consent.
The applicant’s audit found no patient consent forms for 6 patients, 3 forms had not been
signed by the patients, and 4 of the signed forms were dated by the investigator.
The applicant’s study report considered all patients whose data was received by August 10, 1991. The
evaluability criteria were that strongyloidiasis was documented on stool examination, the patient did not
receive any other effective therapy during the study period, the patient was compliant with therapy, adequate
follow-up stool examinations were performed for determination of efficacy, and there was no violation of
inclusion and/or exclusion criteria that would compromise efficacy evaluation.
REVIEWER COMMEN71Thepublished article reports on 60patients entered into the trial while the applicant’s
report is for 56 patients. The applicant suggests that the discrepancy may have resulted fmm a cut-off date
imposed for the assemb/y of the French MAA.
“The efficacy and safety of ivermectin was evaluated on the basis of physical examinations and laboratory
tests prior to treatment and on Days 7 (5-9), 30 (26 to 34), and 90 (85 to 95) posttreatment.m Aspirin and
antihistamines were permitted for mild or moderate reactions to drug treatment. “Other medications were not
to be administered during the first week of drug administration except for necessary treatment of patients with
severe allergic reactions.”
“The prima~ measure of efficacy in this study was the absence of larvae in posttherapy Baermann fecal
examinations. The detection of larvae on any posttreatment stool examination meant failure. Patients with
adequate follow-up examinations which were all negative for Iawae were mnsidered cured. It should be noted
that although not specified in the protocol, parasitological cure (i.e., stool exams negative for lafvae) without
resolution of symptoms was counted as a clinical failure.”
Clinical failures were retreated using ivermectin.
REVIEWER COMMENT Contratyto thepmtocol, 2 ivermectin and 9 abendazole patients were fatreated afier
having a positive stool examination. A sensitivity analysis wi/1be performed on the Medical CMfhWs data to
assess the impact of showing the 6 albendazole patients, who were ratn?ated as eaffy as 70 days atter initial
treatment, as non-eva/uab/es in contrast to treatment failuras. The other 3 albendazole patients and the 2
ivem?ectinpatients were retreated approximately a month after initial therapy which was suficient time for the
drugs to demonstrate efficacy.
In a quality assurance audfi performed by the applicant 3.5 years after the completion of the trial, “certain
GCP compliance issues relating to insufficient documentation of informed consent, incomplete case report
form documentation at the site, protocol mmpliance, inmmplete regulatory documentation at the site and lack
of study monitoring” were found.
11.6.1.b. Efficacv
Results
.,,”
Atmlicant’s
results
“A total of 79% (22/28) of patients werewred
following ivermectin therapy compared to 43% (10/23) of those
receiving albendazole. This difference in cure rates is statistically significant (p=O.02). Logistic regression
analysis demonstrated that no other factor (age, sex, mce, clinical severity of infection, and intensity of
infection) was significantly related to treatment failure.” If those patients whose diagnosis was greater than
6 days prior to treatment are removed, similar results are seen with 76.9% (1Oof 13) of the ivermectin-treated
patients being cured and 33.3% (2 of 6) of the albendazoie-treated patients being cured,
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oral tablets
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.
RE V7EWERCOMMENT: The differena
between the percent curad fbr the two treatments is 43% with a 95%
confidence interval of 28.23 [8°A , 66% ] 7W,dB% This indicates that ivermectin cun?d a statistically greater
patcent of patients than albendazole in this study population.
“Similar results are seen if all patients, regardless of their efficacy evaluation status, ate considered for
analysis.” In this intent-to-treat analysis, 79% (23 of 29) of ivermectin-treated patients are cured and 48%(13
of 27) of albendazole-treated
patients are cured.
/?EVIEWER COMMENT: The difemnca between the percent cured tbrthe two fmatments in the intent-to-treat
analysis is 31% with a 95% conftience internal of ~z
[6Y0, 62°A ] ~,,w.
This indicates that ivermectin
cured a statistica//y gfeater percent of intent-to+eat
patients than a/bandazo/e in this study population.
As can be seen in Table 1, there is “no substantive difference” between the outcomes of the 56 patients
included in the applicant’s report mmpared with the outcomes of the 60 patients included in the published
report.
Table 1: Comparison between applicant’s data received from investigative site
and data published by the investigative team for protocol 004.
Applicant Summary
Publication
Patient Accounting:
Iv’
ALB*
ALL”
IV*
ALB*
ALL*
Patients Entered
29
27
56
32
28
60
Evaluable patients
28
23
51
29
24
53
(Efficacy)
Nonevaluable Patients
1
4
5
3
4
7
(efficacy)
Cure Rate
22/28
10/23
NIA
24/29
9/24
N/A
(%)
(79)
(43)
(83)
(38)
G IV= Ivermedln;
( ) = Percent cured
ALB = Albendazole;
ALL = IV p!USALB
Medical
Officer’s
resul&
Using a test of cure at 30 days post treatment and evaluating those patients with any recent positive stml
examination taken pretreatment without intervening treatrnen~ the Medical Officer fbund that ivennactin cured
24 of 26 (92%) evaluable patients and albendazole wred
12 of 22 (55Yo) evaluable patients.
A 95’%
confidence interval of the difference in proportion cured is ~.n [10’%, 65% ] ~2w,~~M.A lower bound greater
than zero indicates that ivermectin cured a statistically greater proportion of patients diagnosed with
strongyloidiasis than albendazole. Because the risk of reinfection in France is very low, a 90 day follow-up
is considered to evaluate the potential for relapse. At 90 days, the Medical Oflicer found that iverrnectin cured
21 of 26 (81%) and albendazole cured 10 of 21 (48?4.). A 95?40mnfidence
interval of the difference in
proportion cured ~,21 [3% , 64!’. ] ~lM,dB,~which continues to indicate that iverrnectin cures a statistically
greater proportion than albendazole.
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.
JI.B.1 .c. Safe tv Results
No patients were discontinued due to adverse clinioal or laboratory experiences. One patient from the
ivermectin group experienced mild nausea, fatigue, dizziness, sleepiness, tremors, and mild vertigo for one
to two days after treatment.
Although probably related to the study drug, it was not considered serious.
11.B.2. Protocols
014/015
(Berk and Gann}
Protocol title:
“An Open, Randomized Study of Efficacy, Safety and Tolerabiiii
of Ivermectin Single Dose and Repeat Dose
(One day apart) vs. Thiabendazole
(Threeday
course) in the Treatment
of Patients Infected With
Stmngyioides Stercoralis.”
Publications based upon data collected:
Gann PH, Neva FA, Gam AA. A randomized trial of single- and two-dose ivermectin versus thiabendazole
for treatment of Strongyloidiasis.
J Infect Dis, 1994;169:1076-1079.
Salazar SA, Berk SH, Howe D, Berk SL.
Ivermectin vs. Thiabendazole in the treatment of Strongyloidiasis.
Infect Meal, 1994;11:50-59.
11.B.2.a. Studv
Desian
“Open, randomized trial in ambulato~ patients with strongyloidiasis of the gastrointestinal tract. Following
diagnostic studies and laboratory tests, patients received either a single dose of ivermectin, two single doses
of ivermectin 1 day apart or thiabendazole twice a day for 3 days. Follow-up visits were weekly for 1 month
and monthly for 1 year (Study 014), or at Week 1, and Months 1, 3, 6, and 12 (Study 015).” “Although the
study was open in design, stool specimens were examined by one single expert who was to remain blinded
as to the treatment allocations.” The primary therapy period was from May 1990 through December 1991.
The Berk study (014) was conducted using patients from a Veterans Administration Medical Center in
Mountain Home, Tennessee. The Gann study (015) was conducted in
where there
is a large population of refugees from Cambodia and Laos.
Dosages were a single 200-mcglkg iverrnectin oral dose, two 200-mcg/kg oral doses of ivermectin 1 day apad
or 3 days of 25 mg/kg b.i.d. oral treatment with thiabendazole.
“After completion of the informed mnsent procedures and documentation of strongyloidiasis evidence by stool
examination, patients were randomized ...”
REWEWER COMMENT: The applicant @age 1549 of volume 30] reported that 4 of the 68 patients who were
randomized had negative pretreatment stooi examinations and were therefore considered nonevaiuable.
Beowse 2 of these 4 patients had at /east one positive pratreatrnent stocdexamination, the Medical Ofticer
wnsidered
these 2 patients to be evaluable.
‘Parasitological cure was the primary measure of efficacy and was assessed using repeated Baermann stool
examinations during the follow-up period. Cure was defined as the absence of Iawae in the follow-up stool
examinations.
A single positive stool after Day 6 was defined as a therapeutic failure.”
“The primary
measurement of eficacy was the cure’ rate.”
Patients were included who were between 5 and 80 years of age and who were infected with Sbongy/oides
stercoralis.
Infection status was determined by stool examination using the Baermann technique.
Please
refer to the Medical Officer’s review for more details of the inclusionlexclusion criteria and for details on the
visit procedures.
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.
J?EVIEWER COMMENT
There were inconsistencies between the prutocoh that required one year of fo//ow-
up and a statement in the study report that 7hrae- to &month foliow-up was the main goal.” The evaluability
criteria never explicitly stated what was considered “adequate fo//ow-up stool examinations.
The Medical
Of&er concluded that 30 days was appropriate for test of cure.
—
A subsequent
audit by the applicant “showed that 52?40of the patients had incomplete supportive
documentation on file for stool testing. [n this group of 520A,one to four source repofi
were missing per
patient, with most patients having had an average of 6 to 7 tests completed during the study course.
Admittedly, these findings would be of great concern if the frequency of positive stool tests were high;
however, this is not the case for any of the three treatment groups in this study.”
Rm EWER COMMENT
Them wem discussions concerning the lack of signed informed consent documents
for43% of all patients, It was conciuded that oral cwsent had been given, and that the problems had arisen
because “almost all patients who entered the tria/ were Cambodian n?fugees who wen? for the most part
illiterate.” Thejournal article by Gann et al specifically stated that the medical interviews were conducted in
Cambodian.
11.B.2.b. Efficacv
Results
“Aflevaluable patients (14/14) in the singledose
ivermectin group were cured (100%)
compared to 18 of t9
patients
(95?4.) assigned
to the twodose
ivermectin group and 16 of 17 (94’%.) of patients receiving
thiabendazole.
There were no significant differences between treatment groups in the proportion of patients
cured. Cure was not significantly related to age, sex, race or intensity of infection.”
REVIEWER COMMENT
The dfierence between the percent cured tirthe
single-dose ivermectin group and
the thiabendazole group is 6% with a 95% confidence interval of ,d,j, [-12Y0, 24% ] ,mM,w% The difference
between the percent cured for the double-dose ivermectin group and the thiabendazole group is 1% with a
95% confidence interval of
,9,,7
[-20%, 21%] g~%,&%In the DAIDP Points to Consider document,
equivalence, when the better of the two agents has a cure rate greater than 90%, is established when the
lower bound of the 95% confidence interval around the dfierence in the outwmes is notAS
than -70%. The
Iowerbounds of -12% and-20% miss this ttveshold for establishing equivalency. Howevefi it should be noted
that the studies were small which /ed to wide confidence intervals.
In a modified intent-to-treat analysis, the applicant included all patients “with adequate pretreatment and
posttreatment stool examinations.”
In this population, “18 of 18 (lOO”A) of the single-dose ivermectin group
were cured compared to 21 of 22 (950A)patients in the twodose
ivermectin treatment group and 18 of 20
(90%) patients assigned to receive thiabendazole.”
Table 2 presents the number of patients by treatment group who entered the study and the number of pdients
considered nonevaluable for clinical efficacy by reason for exclusion.
-.,
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Table 2: Accounting
by applicant
of patients entered
into protocols
014 and 015.
Patients
Ivermectin
Ivennectin
Thiabendazole
I dose
240se
Entered into Studies
22
24
22
Nonevaluable for Efficacy
8
5
5
Reason for nonevaluability for efficacy
Pretreatment stool exam negative
2
2
0
Inadequate follow-up parasitology
5
3
3
Pretreatment stool exam >30 days
1
0
0
Patient discontinued too earty
o
0
1
Patient on high dose
o
0
1
immunosuppressive treatment
Evaluable for Efficacy Analysis
14
19
17
Cure Rate
141j4
18/19
16/17
(%)
(loo)
(95%)
(94%)
Evaluable for Safety Analysis
22
24
22
Medical
Officer’s
results
Using a test of cure at 30 days post treatment and evaluating those patients with any recent positive stml
examination taken pretreatment without intervening treatment, the Medical Officer found that single-dose
iverrnectin cured 18 of 18 (1OOYO)evaluable patients, double-dose ivemwctin cured 19 of 20 (95Yo)evaluable
patients, and thiabendazole cured 18 of 19 (95%) evaluable patients.
A 95% confidence interval of the
difference in proportion cured between singledose ivennectin and thiabendazole is ,a,lg[-20Y0,37°A] ,W~,g5%.
A 95% confidence intewal of the difference in proportion cured between doubledose
ivermectin and
thiabendazole using the exact method is ~1~ [-28?40,30°A ] ~~x,~~x.
Because the risk of reinfection in the U.S. is very low, a 90 day follow-up is mnsidered
to evaluate the
potential for relapse. At 90 days, the Medical Officer found that singledose iverrnectin cured 18 of 18 (100%),
double-dose ivermectin cured 17 of 18 (940A),and thiabendazole cured 17 of 19 (890A). A 95% confidence
intewal of the difference in proportion cud
by singledose
ivermectin versus thiabendazole at 90 is
....
,e,lg[-16%, 43%] ,OOK,eQ%.
A 95% confidence interval of the difference in propodion cured by double-dose
ivermectin versus thiabendazole at 90 days is ,B,lg[-23°/0, 39°A ] M%,8Q.A.
JI.B.2.c. Safetv
Res Ults
,{
Two patient deaths that were not considered related to the study drugs were repotied.
One patient on two-
dose of ivermectin died 57 days posttreatment of coronary artery disease and chronic pulmonary disease.
One patient on thiabendazole
died on study day 84 as a result of underlying pulmonary disease.
One patient on thiabendazole had his treatment discontinued after 1 day of therapy due to severe nausea and
moderate tinnitus. The investigator considered these clinical adverse events to be definitely related to the
study drug.
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MECTIZANm
(ivemnectin) oral tablets
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“The difference in the incidence of clinical adverse experiences (AEs) between each of the ivermectin groups
and
the thiabendazole
group was significant (p<O.001
for each comparison).”
For ctinical adverse
experiences that were considered possibly, probably, or definitely related to study drug, there were 3 of 22
(14%) patients on single-dose ivermecth, 5 of 24 (21%) on two-dose ivermectin, and 18 of 22 (82%) on
thiabendazole.
11.6.3. Protocol
020 (Drever)
Protocol title:
‘An Open, Randomized Study of Efficacy, Safety and Tolerability of Ivermectin Single Dose (One or Two Day
Course) vs. Thiabendazoie (Ttweeday Course) in the Treatment of Patients Infected With Strongylcides
Stemora/is.”
11.B.3.a. Stu dv Desian
“Open, randomized trial in ambulatory patients with strongyloidiasis of the gastrointestinal tract. Following
diagnostic studies and laboratory tests, patients received either a single dose of ivermectin, two single doses
of ivermectin 1 day apart or thiabendazole W&
a day for 3 days. Follow-up visits were held weekly for 4
weeks.” The study was conducted in Recife, Brazil between May 1991 and December 1991.
Patients received either a single 200 pg/kg ivermectin oral dose, two 200-mcg/kg oral doses of ivermectin one
day apart or 3 days of 25 mg/kg b.i.d. oral treatment with thiabendazole.
Patients were included who were between 5 and 70 years of age and who were infected with Strongy/oides
stercoraks.
Infection status was determined by stool examination using the Baermann technique.
Please
refer to the Medical Officer’s review for more details of the inclusionlexclusion criteria and for details of the
visit procedures.
“The primary measure of efficacy in this study was the absence of larvae in posttherapy Baerrnann fecal
examinations. Cure was defined as the absence of larvae in the follow-up stool examinations. The detection
of larvae on any stool examination past Day 6 up to 36 days posttreatment met the definition of treatment
failure.“ “Since the study was conducted in a highly endemic area, a positive stool examination beyond 36
days posttreatment was not considered a clinical failure if all prior posttreatment stool examinations were
negative. ”
“All stool specimens were examined by one single expert who was to remain blinded as to the
treatment allocations.”
u.B.3.b. Efficacv
Results
A!mIicant’s
results
“Ten of 15 (67%) evaluable patients in the single-dose ivermectin group were cured compared to 14/17 (82%)
in the twodose
ivetiln
group and 13/15 (870A)of patients treated with thiabendazole.
There was no
significant difference between treatment groups in the propotilon of patients cured. A patient’s likelihood of
cure was not significantly related to age, sex, race, or intensity of infection.”
REVIEWER
COMME NT The dflerance between the pement cured fir the single-dose ivetmectin group and
the thiabendazole grvup is -2W0 with a 95% cont7denceintetval of,5,5 [-58%, 16%] ~m,Bm. The difference
between the percent cured for the dobble-dose iverrnectin group and the thiabandazole group is -5% with a
95% conftience inte~al of ~T,5[-36%, 27% ] ~~~,a~
The small study size resuks in very wide confidence
intervals with /ower bounds we// below the -75% required by DAIDPs Points to Consider to estab/ish
comparability.
“In order to estimate a ““worst outcome”” cure rate, efficacy was also evaluated by designating all patients with
any positive stool examination at any posttreatment time point (beyond Day 5) as treatment failures. By this
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criteria, 10/1 5 patients (67Yo) in the singledose ivermectin group, 10/17 (590A)of patients in the twodose
ivermectin group and 9/15 (60Yo) of patients in the thiabendazole treatment group were cured.”
REV *I
R COMMENT
The %vorstoutcome” resutis use the definition of faikn
that was used by Bark and
Gann (ptvtorwls 014 and 015).
The lower cum rates would be expected because of the ni
of reinfection.
Table 3 presents the number of patients by treatment group who entered the study and the numbers included
in the clinical and safety analyses.
Because Recife, Brazil is an endemic area, the cure rates for any
treatment failures after 36 days could have been due to reinfection.
REVIEWER
COMMENT
The Medics/ Oflicer used 30 days as test of cure.
Table 3: Accounting
by applicant
of patients
entered
into protocol
020 (Dreyer).
Patients
Ivermectin
Ivermectin
Thiabendazole
ldose
2dose
Entered into Study
17
17
15
Dismntinued
study
2
1
0
Completed study
15
16
15
Evaluable for Efficacy Analysis
15
17
15
Cure Rate (failure if positive stool days 6-36)
10/15
14/17
13/15
(%)
(67%)
(82%)
(87%)
Cure Rate (failure if positive stool after day 5)
10/15
10/17
9/15
(70)
(67%)
(59%)
(60%)
Evaluable for Safety Analysis
17
17
15
Using a test of cure at 30 days post treatment and evaluating those patients with any recent positive stool
examination taken pretreatment without intervening treatment, the Medical Officer found that singledose
ivermetiln cured 9 of 14 (65Yo)evaluable patients, doubledose ivermectin cured 15 of 17 (88Yo)evaluable
patients, and thiabendazole cured 13 of 15 (87%) evaluable patients. A 9!YY0confidence intewal of the
difference in proportion cured between singl~ose
ivermectin and thiibendazole is ,415[-59°A, 16°A] ~~w,m.
A 95% confidence interval of the difference in proportion cured between double-dose
ivermectin and
thiabendazole using the exact method is ,7.15[-31%, 39%] ~x,8%.
..
Because the risk of reinfection in Brazil is high, a 90 day follow-up is considered to evaluate the potential for
reinfetilon.
At 90 days, the Medk.al Officer found that singledose ivermectin cured 6 of 11 (550A),double-
dose ivermectin cured 10 of 16 (63%)/and thiabendazole cured 8 of 14 (57Yo). A 95% confidence interval
of the difference in proportion cured by single-dose ivennecth versus thiabendazole at 90 days follow-up is
,1.14[-50%,45%] 55%857%.A 95% confidence intewal of the difference in proportion cured by doubledose
iverrnectin versus thiabendazole at 90 days follow-up is ,G,l, [-36°A , 470/0] 630~,57%
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.
11.B.3.c. Safety
Results
There were no serious clinical adverse events or discontinuations due to clinical adverse events.
There was a statistically sgnticant dfirence
between the i*ce
of din”e! adverse ex@~e.nces between
the ivermectin groups and the thiabendazole group (P<O.001).
None of the 17 patients who received
ivermectin in a single-dose reported a clinical adverse experience.
Two of the 17 patients who received
ivermectin in two doses reported clinical adverse experiences that the investigator mnsidered
unrelated to
the study drug. Nine of the 15 patients who received thiibendazole reported clkkal adverse experiences with
8 patients having psychiatric/nervous system complaints and 6 of the 8 reporting dizziness.
“Each patient who entered the trial was asked to give an overall tolerance assessment
of their treatment.
Seventeen
of 17 (100%)
patients in the single-dose ivermectin group found the treatment to be Well
tolerated,” compared to 1? of 17 patients (1OO”A)in the twodose ivennectin and 6 of 15 patients (40%) treated
with thiabendazole.”
11.B,4.World Health Organization
Studv (Marti et. alJ
Protocol title:
“A Comparative Trial of a Single Dose Ivermectin versus 3 days of Albendazole for Treatment of Stmngy/oides
Stercom/is and Other Soil Transmitted Helminth Infections in Children.”
Publication based upon data collected:
Marti HP, Haji HJ, Savioli L, Chwaya HM, Mgeni AF, Hatz C. A comparative trial of a single dose ivermectin
versus 3 days of albendazole for treatment of !Wongyloides sterccmdis and other soil transmitted helminth
infections in children. Am J Trop Med and Hyg, (submitted November 1995).
11.B.4.a. Studv
Deskm
“A randomized trial carried out in rural Zanzibar comparing a single dose 200 pg/kg ivermectin and 400 mg
daily for 3 days of albendazole for treatment of strongytildiasis
and other intestinal nematodes.”
The study
was conducted October-December 1994. The participants were students at least 10 years old enrolled in
either one of two primary schools.
Included were students with S. stercom/is detected in a stool sample
provided by the student
Stool samples were evaluated in the laboratory on the same day as collection using
the Baerrnann technique. Excluded were students from whom consent was not given, who had fever or other
signs of acute illness, severe neurological disorders, severe liver disorders, or were pregnant.
A randomization list for the sequential allocation of the drugs was prepared in advance. Treatments were
administered under the supewision of a medical assistant.
Three weeks after the end of treatment, the
subjects were given a stool container and asked to bring a fresh specimen the following morning.
-
A standardized questionnaire was used by the medical assistant to assess side effects at baseline, at 3 days
after start of treatment, and at 3 weeks after the end of treatment.
11.B.4.b. Efflcacv
results
Armlicant’s
results
/
A total of 419 children were found to be infected with S. Stercoralis and were eligible for the trial. Of these,
2 children were excluded for medical reasons, 13 had inmmplete treatments, 32 had incomplete follow-ups
and 71 had no follow-up. The loss to follow-up was primarily attributed to an unforeseen closure of a school
just before the holidays, so that many pupils did not return to school. Of the 301 evaluable participants, 152
received a single dose of ivermectin, while 149 were treated with 3 days of albendazole.
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“Cure rates for S. stercwdis were significantly better with iverrnectin than with albendazole (82.9% vs 45.0%).”
Med ical Officer’s
results
Patient level data was not available for this study. Please refer to the Medical Officet’s report46r a qualitative
assessment of this study.
JI.B.4.c. Safety Resuftq
No severe adverse effects were recorded among the students in either treatment group.
“109 children
(32.7%) experienced adverse effects of either medication: 29.4% in the ivermectin group and 35.9% in the
albendazole group (n.s.). None of them was sufficiently incapacitated to be unable to perform normal daily
activities.
Abdominal distension and chest tightness or pain were recorded significantly more often after
ivermectin medication.”
11.6.5. Dose
ranaina
studv
[Naauira.
et.
al.)
Publication based upon data collected:
Naquira C, Jimenez G, Guerra JG, Bernal R, Nalin OR, Neu D, Aziz M. Ivemwctin for human strongyloidiasis
and other intestinal helminths. Am J Trop Med Hyg, 1989;40:304-309.
11.B.5.a. Studv Desian
“Seventy-four males and 36 females aged 11-74 years who had stcd examinations positive for S. Stermralis
larvae within 7 days of the study and who gave informed consent were assigned to 1 of 6 dose groups. All
received matching placebos on day 1 and then on day 3 a single oral dose of ivermectin. Sequential groups
of about 18 patients received single doses of 50, 100, 150, or 200 pg/kg ivermectin, followed on day 4 by
another matching placebo or, in 2 of the groups by another dose of ivermectin (100-100 or 200-200
pglkg).”
(page 2511 of volume 1.32)
“Ivermectin dose was assigned according to a double-blinded sequential dose allocation schedule,”
11.B,5.b. Efficacv results
Amdicant’s
results
Table 4 presents the numbers and percents of patiints treated and cured by dose level. “Strongyloidiasis cure
rates were significantly higher in recipients of doses >150 rncg/kg, but did not vary significantly above that
dose.’
...-
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NDA=742
MECTIZANW(ivermecth)oraltablets
14
.
Table 4: Cure rate (%) of strongyloidiasis patients treated with single ivermectin doses of 50-200
mcg/kg or with 2 doses of 100 or 200 mcg/kg in study conducted by Naquira et, al.
Patients cured/ total patients (%)
-
Total dose
Days post-treatment
(mcg/kg)
3
30
50
12/18 (67%)
10/15 (67%)
100
2/18(11%)
11/15 (73%)
150
7/18 (39?40)
16/17 (94%)
200
11/17 (65%)
16/17 (94%)
100 (x2)
11/18 (61VO)
15/17 (88%)
200 (x2)
9/20 (61%)
20/20(loo%)
All Doses
52/109 (48?40)
89/101 (88%)
Medical
Officer’s
results
Patient level data was not available for this study. Please refer to the Medical Officefs report for a qualitative
assessment of this study.
11.B.5.c. Safetv Results
“Clinical and laboratory adverse effects were chiefly mild and self-limited among the 200 patients in tits study.”
“There were 3 deaths of patients with severe complicating diseases: 1 with perforated gastric carcinoma, 1
with leukemia who developed a hernatologic blast cxisis,and 1 W-WKiebsiella meningitis. These patients died
at 10, 3, and 18 days after therapy, respectively.”
JLC. Medical
Officer’s
Integrated
Summarv
of Efficacv
The applicant provided patient level data for the Gentilini (004), Dreyer (020), Berk (014), and Gann (015)
studies. The protocols for these studies were fairly consistent including the use of blinded examination of
patient stools using the Baermann technique to assess infection with SWongyioicfessfercoralis.
Patients in
these studies were followed for an extended period with stool examinations generally occurring at 30,.60, and
90 days. However, these protocols had some inconsistencies in their definitions of evaluable patients and of
test of cure.
-’
The Medical Officer reviewed all the patient records provided and made an independent assessment of
evaluability and cure. Basically, any patient with a positive stool within a couple of months prior to treatment
was mnsidered evaluable. A few patie,ntshad been excluded by the sponsor because they had both positive
and negative stools prior to treatment&
Because it is possible for the Baermann technique to misdiagnose
light cases and because Strongyloidiasis is not known to be eliminated without treatment, the Medical Oticer
considered these patients to be evaluable. A few patients were excluded who had positive stool examinations
more than 100 days prior to entry into the study. Refer to the Medical Officet’s report for further discussion
on evaluability criteria.
For consistency, the primary efficacy outcome was defined as a test of cure at 30 days post treatment with
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 245 of 382

NDA50-742MECTIZANT”(iverrnectin) oral tableta
15
a secondary outcome at 90 days. The study by Dreyer was conducted in Brazil where Strongyloidiasis is
endemic to the area so there is the possibility of reinfection. The other studies were conducted in France by
Gentilini and in the United States by Berk and Gann where risk of reinfection is small.
For further analysis, the patient outcome data from the Gentilini, Dreyer, Berk, and Gann studies are being
pooled by treatment regimen. The studies started with very similar protoools. The Medical -r
has applied
consistent criteria for evaluabilii
and outcome assessment in his review. Respectively, for 30 days follow-up
and for 90 days follow-up, Table 5 and Table 6 compare the ivermecth
treatment regimens with the
comparator treatments for each study and for the data pooled by treatment.
Figure 1 and Figure 2 each
provide a graphical view of the 95% confidence intervals of the difference in treatment outcomes.
REVIEWER
COMMENT
DAIDPs Points to Consider document suggests when a standati
treatment has
90994eitiiacy or higher then the lower bound on the 95% confidence interval of the dflen?nce in the cure rates
should not be below-10% for approval. As can be seen in the following tables, tierrnectin is statistically better
than albendazole. A/though ivermectin’s cure rates ata comparable to”thiabandazole’s, the lower bounds are
genera//y around -20% at 30 days post treatment.
The confidence intervals are wide because of the small
sample sizes.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 246 of 382

NDA50-742MECTIZANW(ivermectin)oraltablets
16
Table 5: Summary of Medical Wtcer’s
assessment of efficacy at 30 days post treatment
Ivermectin
Comparator
95% cl of
cured/evaluable (%)
cured/evaluabIe (%)
treatment difference
Iverrnectin 1 dose versus Thiabendazole
Pooled Treatments
51/58 (88YO)
31/34 (92%)
[-22%
, 16%]
Berk (014)&
Gann (015)
18/18 (loo%)
18/19 (95%)
[ -20%, 37%]
Dreyer (020)
9/14 (65%)
13/15(87%)
[ -59%,
16%]
lverme~ln
2 doses versus Thiabendazole
Pooled Treatments
34/37 (92%)
31134 (92%)
[-19%,23%]
Berk (014)&
Gann (015)
19/20 (95?40)
18/19 (95?40)
[ -28%,
30% J
Dreyer (020)
15/17 (88%)
13/1 5 (87%)
[ -31%,
39%]
Ivermectin 1 dose versus Albendazole
Gentilini (004)
24/26 (92%)
12/22 (55?40)
[ 10% ,65%]
Marti (WHO)
126/1 52 (83%)
67/149
(45%)
[ 27% , 49%]
Figure 1: 95%
Confidence
Intervals
of Differences
in Proportions Cured of Strongyloidiasis
at 30 Days Post Treatment
I
Iven’nectin1 Dose versus Thiabendazole
PooledTreatments
~
Berk (014)& Gann (015)
~
Dreyer (020)
+
G
Ivermectin
2 Dose versusThiebendszole
Pooled Treatments
G
*
Berk
(014)&
Germ (015)
G
G
Dreyer (020)
G
G
Ivermectirr 1 Doee vemus Albendezoie
Gentiliii
(004)
~
Merti (WHO)
+
G
,
I
I
I
I
I
I
1
i
I
I
I
I
I
I
I
I
I
I
I
I
I
I
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
Wfswencain Proportion Cured
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NDA50-742MECTIZANTM(iverrnectin)oraltablets
17
.
Table 6: Summary
of Medical Officer’s assessment of efficacy at 90 days post treatment
Ivermectin
Comparator
95% c1 of
cured / evaluable (%)
cured / evaluable (%)
treatment difference
IvermWln
1 dose veraus Thiabendazole
-.
Pooled Treatments
45155
(82%)
25133
(76%)
[-14%
, 28%]
Berk (014)&
Gann (015)
18/
18 (100%)
17/19(89%)
[-16%
, 43%]
Dreyer (020)
6 ! 11 (55%)
8 t 14(57%)
[ -46%, 37%]
Ivermectin 2 doses versus Thiabendazole
Pooled Treatments
27 f 34 (79?%J)
25/
33 (76%)
[-21%,29%]
Berk (014)&
Gann (015)
17/
18 (94%)
17/
19 (89%)
[ -23%,
39% J
Dreyer (020)
10/
16 (63%)
8114
(57%)
[-31%,44%]
Ivermectin f dose versus Albendazole
Gentilini (004)
21126
(81Yo)
10/21 (48YoI
14Y0 ,61%]
Figure 2: 95?4.Confidence Intervals of Differences
in Proportions Cured of Strongyloidiasis
at 90 Days Post Treatment
Ivermectin1 DoseversusThiabandazde
,
Pooled Treatments
*
G
,,,
Berk (014)& Gann (015)
G
G
I
1
!
Dreyer (020)
4
G
I,
Ivermectin2 Dose versus Thiabemkde
~
I
PooIed Treatnwts
~
1,1
Berk (014)& Gann (015)
G
G
1#
Dreyer (020)
G
b
,
t
Iverrnectin 1 Dose versus Albendazole
;
,
Gentilini (004)
, ‘
1$+
G
1
I
I
I
I
I
I
I
i
I
I
I
i
I
I
I
I
1
I
I
I
-1.0
-0.8
-0.6
-0.4
4.2
0.0
0.2
0.4
0.6
0.8
1.0
Difference inProportionCured
——
..
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 248 of 382

NDA 50-742 MECTIZANW
(ivermectkt) oral tablets
18
A survival analysis can be used to analyze the time to an event.
In this &se,
the event is a positive stool on
follow-up examination.
A Kaplan-Meier analysis is a non-parametric method that can be used to estimate the
proportion cured and to provide a confidence interval about the proportion cured. For this analysis, patients
were pooled across studies by tneatmentregirmm. In the Gentilini study, a few patients were retreated within
a week or so of initial treatment
For the sutvival analysis, these patients are treated both as treatment failures
and as if they were lost to follow-up at that time (i.e. censored).
REVIEWER COMME WI! Six patients wefe Mraated with a/bendazo/ewithin10 days of initial treatment. It
is possible that the dmg had not had sui7icient time to complete its cure. It is a mom conservative case to
treat these patientsas 10sS6?S
ratherthan 8s failures ofalbendazok.
Note that in the Marti study albendazole
only cured 45%. At 30 days, Albendazole cures 55% if the early retraabnents am treated as losses and 43%
if the early retn?atments are treated as failures.
Basedon the Kaplan-Meier method, the 95°A confidence interval on the percent cured at end of follow-up is
the following for each treatment
albendazole [33%,76%] if retreatment
are failures and [49% , 96%] if
retreatment
are losses, singledose
ivermectin [68Y0,92Yo],doubledose
ivermecth
[66Y0,94Yo], and
thiabendazole [62%,92’3!.]. Figure 3 and Fgure 4 each provide a graphical view of the survival curves for each
of the treatments first with the Gentilini eariy retreatment
treated as tiilures and second treated as losses.
Figure 3: Kaplan-MeierAnalysis of lime to Treatment Failure for Strongyloidiasis
w“th early Gentilini retreatment treated as treatment failures
(\-
::;: ;-
..—-
-A-
-—+--++
—-t--
+tt--+i+t++-
++
---,
i,-,
1
---+
---
iHi+----
+----+
---
+--+
r
1
m
I
1
1
I
o
100
200
300
400
,
08Ys
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 249 of 382

NDA50-742MECTl~NTU(ivemdin)
orsl tabkts
19
.
Figure 4: Kaplan-MeierAnalysis of Time to TreaWent Failure for Strongyloidiasis
with early Gentilini ratreahenb
treated as censored events
o-“
— —
m
L -. +
I
0’
;#
l!:::
:~:
:+:
i
%’t-
~r
___
--—_
-—i+----++
.
~1
~-+---*-
—--t---*_
—++U*++
~
-0gw
--
+-----+
---+--+
o
z
E
/
.-g
I
[
Y.
I
o
I
1
/
j
Albendazok
—
hferme~i~l
m
I
o“ -
——
iverme~iti2
— --
Thiabend~o~
I
0
1
0-
1
/
0
I
100
I
200
300
400
~P
REvJEwER
COMMENT: AS the graphs illustrate, albendazole k closer in effectiveness to the other
tmahnts
when the early retreahents
are bated aslossesratherthanas failures. Howevec even withthis
WfiaPs
ovetiY consemative approach,iverm=tin
still demonstmtes effecttieness at /east as g~
as the
altematwes.
.,
.
—
-—
—..
—.
—_
—--—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 250 of 382

NDA50-742MECTIZANW(iverfnectin)oraltablets
20
J1l.Onchocerciasis
(a.k.a.
.
River blindness)
“Onchocerciasis is a major filatil
disease and one of the major causes of blindness in Third World countries.
This disease, caused by the filarial parasite Onchocerca VOIVUIUS,is transmitted to humans by blackflies of
the genus Simuiium.”
“The clinical manifestations of the disease, largely due to the host’s immune response to the dead microfilaria,
range from itching, weight loss, disfiguring skin changes, and eye damage which can lead to blindness.”
“Efforts
to reduce transmission
of onchocerciasis
by vector control have proven unsuccessful
and
chemotherapy of thii disease has been limited to the two drugs DEC and Suramin. These drugs often have
serious side effects and must be administered under close supervision making them impractical candidates
for mass chemotherapy.”
“During the development of ivermectin for animal health, it was discovered that the drug was highly effectWe
against the microfilariae of Or?chocemacankalis
in horses. Thus, it was postulated that ivermectin may have
activity in man against Onchocema vohdus,
the causative agent of onchocerciasis, also known as river
blindness.”
“In 1987, ivermectin was approved in France for the treatment of onchocerciasis and is now mnsidered the
drug of choice for the treatment of that inf~lon.”
IILA.
Labelinu
cIaims and mima w studies
“The recommended dosage of MECTIZAN for the treatment of onchocerciasis is a single oral dose designed
to provide approximately 150 pg of ivermectin per kg of body weight’
“Patients should take tablets with water.
In mass distribution campaigns in international treatment programs, the most commonly used dose interval
is 12 months. For the treatment of individual patients, retreatment may be considered at intewals as short
as 3 months.”
“The evaluation of MECTIZAN in the treatment of onchocerciasis is based on the results of clinical studies
involving 1278 patients. In a double-blind, placebo-controlled study involving adult patients with moderate to
severe onchocercal infection, patients who received a single dose of 150 pg/kg MECTIZAN experienced an
83.2?4.and 99.5% decrease in skin microfilariae count (geometric mean) 3 days and 3 months after the dose,
respectively. A marked reduction of >90Y0was maintained for up to 12 months after the single dose.”
“In a separate open study involving pediatric patients ages 5 to 12, similar decreases
in skin miorofilariae
munts were obsewed
for up to 12 months after dosing.=
JWVIEWER
COMMEN’C Applicant provided two sets of data for each of the following studies.
The effkacy
dataset only provided basic demographic data and supped for the density outcome of nn%ngof skin byralative
study day. The second dataset prvvided adverse clinical experiences. Note that systemic responses w@ra
excluded fmm the dataset since these wem oonsidemd to be the result of effective tn?atment rather than
unexpected adverse clinical expedences.
The statistical reviewer verified that rasults rapmted in the tVDAsubmission were consistent with results
produced by analysis of i%ese&tase,&.
Since the medical oficer did not rsciassify individual patients as to
evaluability or cure status, statistical mana/ysis of the data was /imited to application of a/temative statistic/
analysis to assess the robustness of the findings based upon the submitted data.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 251 of 382

NDA50-742MECTIZANW(Merrnectin)oraltabtets
21
111.B. Proto COI 514 (Document
500
)
2
.
Studies
bv Lariviere
(509. 510}. Awadzi (511]. Green
[512~
Protocol title:
“Double-Blind Comparative Studies of Ivermectin, Diethylcarbamazine Citrate and Placebo in Patients with
Onchocerciasis.”
_.
111.B.1.Studv Desian
The study was a double-blind, doubledummy,
comparative study of ivermectin, diethylcarbamazine citrate
(DEC-C) and placebo. Treatment assignment was according to a randomized allocation schedule. lvermectin
patients received a single oral 12 mg (two 6 mg capsules) dose on Day 1. DEC-C patients received 2 daily
doses totaling 50 mg on Days 1 and 2 and 200 mg on Days 3 through 8. The synopsis of the clinical study
report was dated 16Jan87. The study subjects were hospitalized onclmcerciasis patients located in Senegal,
Mali, Ghana, and Liberia.
The outcome was a measure of microfilana density that was the combined
measurements from 4 skin snips taken at the right and left iliac crest and at the right and left calf.
111.B.2.Efficacv
Re Sldts
AODlicant’s
results
“In this mmparative
study of ivermectin vs DEC-C vs placebo in hospitalized onchocerciasis patients, mean
skin microfilaria (mf) densities decreased
sharply by Day 2 in both ivermectin and DEC-C patients and
reached almost identical low levels ( - 2°Aof pretreatment) by Day 8. The mf densities then decreased further
in the ivenmectin patients (some to O)over the next 3 months but increased gradually in DEC-C patiints to
about 14°Aof pretreatment level in 3 months. Between 3 and 12 months posttreatment, the mf densities in
ivermectin patients gradually increased to about 5% of the pretreatment level mmpared to 20% in the Dee-C
patients at 12 months. There were essentially no changes with placebo treatment.”
“Both ivermectin and DEC-C eliminated mf from the anterior chamber of the eye. DEC-C-treated patients
cleared mf faster than ivermectin-treated patients.”
Figure 5 was provided by the applicant to graphically show the difference in the affect of the treatments on
the reduction in the geometric mean of microfilaria densities (mf/mg skin) over the one year of follow-up.
Table 7 shows the results for the outcomes that the Medical O~cer considered primary and semnda~.
FWVIEVVERCOMMENT
The Mectica/ Olfker considered the teduction in the geometric mean of the mth?g
one month posttmatmantto be the primaryoutoomefor assessmentof eficacy. Of secondary interestwas
the mdudion
at 3-months and 6-months posttmatrnent because of the labeling suggestion of possible
n?traatment at 3-months posttmatment.
As the applicant noted in the submission @ageD-1473 of volume 1.79],the data is neither normally distributed
nor log-normally distributed.
The applicant appropriately petionned nonparametnc analysis of the data in
addition to reporting the geomeb”c mean for consistency with otherpublications in this f~ld. In this mvieww%
nonparametric analysis of the data, results were consistent with the applicant in that there was not a
statistically significant difference between ivennectin and DEC-C in the actual reductions in the density
(mflmg). An alternative to analyzing the actual raduct.ionsin micmfilaria counts is to ana/yze the effect of the
treatments on the ratio of the micmfilaria count at a fo//ow-up time point to the microfilaria count at baseline
before tn?atment. The applicant referred to this measwe as pemantage of pretreatment.
Analysis of this
measure resulted in a statistically signifkant dfierence in the pementage of pretreatment baseline at all three
time points (p-value = 0.0001) based upon a kWcoxon Rank Sum analysis of the data provided by the
app/icant.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 252 of 382

NDA 50-742 MECTlZ4Nw (tverrnechn)oraltablets
21
.
111.B. Protocol
514 (Document
50 2}
o
Studies
bv Lariviere
(509. 510]. Awadzi {511}. Green (512J
Protocol title:
‘Double-Blind Comparative Studies of Ivermectin,
Diethylcarbamazine Ctite
and Placebe4n Patients with
Onchocerciasis.”
111.6.1.Studv Desian
The study was a double-blind, doubledummy,
comparative study of ivermectin, diethylcarbamazine citrate
(DEC-C) and placebo. Treatment assignment was accotilng to a randomized allocation schedule. Ivennectin
patients received a single oral 12 mg (two 6 mg capsules) dose on Day 1. DEC-C patients received 2 daily
doses totaling 50 mg on Days 1 and 2 and 200 mg on Days 3 through 8. The synopsis of the clinical study
repoft was dated 16Jan87. The study subjects were hospitalized onchocerciasis patients located in Senegal,
Mali, Ghana, and Liberia.
The outcome was a measure of microfilaria density that was the combined
measurements from 4 skin snips taken at the right and left iliac crest and at the right and left calf.
111.B.2.Efficacv
Results
Amiicant’s
results
% this comparative study of iverrnectin vs DEW2
vs placebo in hospitalized onctwcerciasis patients, mean
skin microfilaria (mf) densities decreased
sharply by Day 2 in both ivermetiln
and DEC-C patients and
reached almost identical low levels ( - 2°A of pretreatment) by Day 8. The rnf densities then decreased further
in the ivermectin patients (some to O)over the next 3 months but increased gradually in DEC-C patients to
about 14% of pretreatment level in 3 months. Between 3 and 12 months posttreatment, the mf densities in
ivennectin patients gradually increased to about 5% of the pretreatment level compared to 20% in the Dee-C
patients at 12 months. There were essentially no changes with placebo treatment.”
“Both ivermectin and DEC-C eliminated mf from the anterior chamber of the eye. DEC-C-treated patients
cleared mf faster than ivermectin-treated patients.”
Figure 5 was provided by the applicant to graphically show the difference in the affect of the treatments on
the reduction in the geometric mean of microfilaria densities (mfhng skin) over the one year of follow-up.
Table 7 shows the results for the outcomes that the Medical Officer considered primary and secondary.
J=vEwE R COMMENT The Medical Ot?icarconsidered the reduction in the geometfic mean of the mtimg
one month posh?eatment to be the primary outcome fix assessment of etikacy.
Of secondary intemsf was
the reduction at 3-months and 6-monMs posttmatment because of the /abe/ing suggestion of possib/e
retreatment at 3-months posttreatment.
..
As the applicant noted in the submission @ageD1473 of volume 1.19], the data is neither normally dis~buted
nor log-normally distntxded.
The applicant appropriately performed nonparametric analysis of the datajn
addition to @porting the gaomebic mean for consistency with other publicatins
in this field. /n this mviewets
nonpammetric
ana/ysis of the data, msu/ts wers consistent with the applicanf in that them was not a
statistically sign%cant dit7erence between ivermectin and DEC-C in the actual mcfuctions in the density
(mVmg). An a/temative to analyzing the actua/ faductions in microfilaria counts is to analyze the affect of the
tn?atments on the ratio of the mhmilaria
count at a fo//ow-up time point to the micrutlaria count at baseline
before treatment.
The applicant refem?d to this measure as pementage of pretreatment.
Ana/ysis of this
measum tw,dted in a statistica//y significant dflemnce in the percentage of pfetmatment baseline at all three
time points (p-va/ue = 0.0001) based upon a bWcoxon Rank Sum ana/ysis of the data provided by the
applicant.
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NDA 50-742 MECTIZAN1”(iverrnectin)oraltablets
22
.
Fgure 5: Geometric mean of microfilaria densities (mflmg skin) of onchocerciasis where the treatments are
ivermectin, DEC-C, and placebo.
1,
‘b.
\
-u
‘--w--=-
—.
.
Ik!ia
—..
Table 7: Summary of skin microfiiaria density (mf/mg skin) between-treatment comparisons
(pages D-1475 and D-1478 of volume 1.19)
Number of evaluable patients
Between-Treatment Comparisons
Median Change from Pretreatment
Percentage of Pretreatment@
Visit
Ivermectin
DEC-C
Placebo
Iverrnectin
Ivermectin
DEC-C
vs DEC-C
vs Placebo
vs Placebo
Day 28
38
39
36
N.S.
“
M*
41.7
-56.9
-24.9
1?40
3%
37%
Month 3
26
29
26
N.S.
-
w
-68.6Y0
49.1
-10.1
1Yo
149+0
86%
Month 6
44
45
43
N.S.
H*
G**
-49.9
43.2
-3.1
2%
11?40
929’o
@ Geometric mean of the percentage of pretreatment mf counts calculated as (follow-up mf
count / baseline mf count)
G 100Y0. ,
-
Significant difference between the respective treatment groups regarding median change
from baseline, p s 0.001
N.S. Difference between respective treatments was not significant, p >0.05
..~’
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 254 of 382

NDA 5G742
MECTIZANW
(ivennectin)oraltablets
23
.
In addition to the analysis of reduction in microfilaria density, the applicant performed an analysis using as a
test of cure a success being a reduction in the mf/mg of skin to less than 5 mf/mg skin.
‘It is generally
beliived, among the onchocerciasis experts, that a patient becomes “noninfective-
and will no longer serve
as a host for transmission of onchocerciasis when the microfilaria is reduced to less than 5 mfhng skin.”
[page D-1479 of volume 1.19].
Based on this criteria, ivermectin cured 36/38 (95%), 23&6 (88%), 31M4
(70%) at day 28, month 3, and month 6, respectively, while DEGC cured 25/39 (64%), 8/29 (28%), and 16/45
(36%) at day 28, month 3, and month 6, respectively. [page D-1480 of volume 1.19]
REV -R
I
COMME NT
The 95% confidence intervals about the dflemnce in pmpotfions witha favorable
response are ~,ag [ 1f %, 50%] ~~%,m%,~ Zg[37%,
85% ]W,m,
U 45[f3%,
57%1 Tmm
for day 28,
month 3, and month 6, respectively.
This reviewer performed the analysis also using cut points of 2.5 and
f.O mflmg with ivermactin showing even gn?ater ei?kacy in comparison to L3EGC.
JII.B.3. Safetv
results
“The incidence of clinical adverse experiences in the ivermecth-treated
patients was slightly lower than in
patients treated with DEC-C (50 vs 56Yo). More DEC-C patients had a worsening of systemic readlons than
ivermectin
patients.
In addition, more DEC-C patients required steroids, anti-inflammatory
drugs and
analgesics
than
ivermectin
patients to relieve symptoms of systemic reactions and clinical adverse
experiences.”
The most commonly reported clinical adverse experience was myalgia in 30% of the
iverrnectin-treated patients and 38% of the DEC-C-treated patients. Headache closely followed behg reported
by 26% of the ivermectin-treated patients and by 38% of the DEC-C-treated patients [page D-1503 of volume
1.19].
“In general, ophthalmologicsafety results were similar for ivermectin and DEC-C.m
“None of the laboratory adverse experiences was considered serious by the investigators, and no patient was
dismntinued from the study due to adverse experience.” There was not a statistically significant difference
between the number of ivemwctin-treated patients and number of DEC-C-treated patients with any adverse
laboratory experiences. The only statistically significant lab difference was AST that increased in 2% of the
ivermetiln-treated
patients and 22% of the DEC-C-treated patients (0.001<p<O.01).
JILC. Protocol
519 (Documents
5003 5004]
I
Studies
by Green.
Awadzi.
Lariviere.
Sc hulz-Ke~.
Vinatain.
Zea-FloreS
Protocol title:
“A Multiclinic, Doubl&Blind Study of Ivermectin and Placebo in Patients with Onchocerciasis.”
Protocol 5003 reported the results through 6 months of follow-up. Protocol 5004 is the posttreatment fbllow-
up through 12 months and includes all CRF data received as of June 30, 1987.
jll.C.l.
Studv
De sian
The study included 6 investigators (Greene, Awadzi, Lafi”iere, Schulz-Key, Vingtain, and Zea-Flores) in 6
countries
(Liberia, Ghana, Ivory Coast, Togo, Mali, and Guatemala).
The study was a double-blind,
randomized, placebo-controlled, muiticenter study comparing 3 dosage levels of ivermectin to placebo in
hospitalized onchocerciasis patients. Each patient received a single oral dose of ivermectin (100, 150, or 200
mcg/kg body weight) or placebo on Day 1 of the study.
Efficacy follow-up was through 12 months
posttreatment.
REVIEWER COMMENT
Note that three of the investigators (Larivien%Awadzi, and Greene) and three sites
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 255 of 382

NDA
50-742 MECTlZ4Nm
(iermectin)
oral tablets
24
(Liberia, Ghana, and Mah)are the same as fbrboth pnXocols 514 and 5i9.” Futther, these studies were being
conducted at the same time (cutoff date for 514 was December 26, 1985 [page D-1449 of volume 1.19] and
the cutoff data for 519 was February 28, 1986 [page D-1551 of vohme ?.f9J. This raises a question as to
whether then? is sui77cientindependence of the studies thm the two ptvtocols to sewe as independent
conthmation of the results.
“The overall efficacy assessment was based on reduction from baseline skin microfiiaria density and the
percentage of patients with a favorable response. Favorable response is defined as microfilaria reduced to
less than 5 mf/mg skin after the study drug administration.”
Patients whose baseline microfilariadensity was less than 10 mf/mg skin were excluded rather than the 20
mfhrtg that was specified in the protocol. The less stringent criterion was used ‘to avoid the exclusion of too
many patients”.
Because at six months Dr. Lariviere retreated 75 of his patients whom he felt were not
responding to therapy, his center was excluded from the efficacy analysis at 12 months. The skin snip assays
were not performed according to the protocol for Dr. Zea-Flores center, so the medical monitor decided to
exclude this center from the per-protocol efficacy analysis as well.
111.C.2.Efficacy Results
ADDiiCant’S reSUltS
Table 8 summarizes the efficacy of three dose levels of iverrnectin and of placebo at day 3, month 3, and
month 6 posttreatment. [page D-1561 of volume
1.19].
This study did not capture
data at month 1
posttreatment. There was not a statisticallysgnikant
difference among the ivermectin treatments while there
was a highly statistically significant difference (p s 0.001) between each iverrnectin treatment and placebo at
each time point.
Table 8: Summary of skin microfilaria density (mf/mg skin) between-treatment comparisons for
~rotocol 519.
Visit
Day 3
N
Median
9’0
Month 3
N
Median
‘%0
Month 6
N
Median
%0
(@Geometl
Number of patients evaluable for efficacy
Median change ftom pretreatment
Percentage of pretreatment@
100 mcg
150 rncg iverrnectin
200 mcg ivermectin
Placebo
ivermectin
254
249
254
252
-32.6
-34.0
-40.5
-2.9
26.2%
16.8%
12.9%
91.4%
238
237
238
229
47.9
-45.2
-48.0
-15.5
1.8%
0.5%
0.4%
60.8%
237
/
230
223
227
43.5
43.4
48.4
-18.0
2.9%
1.5%
1.1%
54.4%
mean of the percentage of pretreatment values
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 256 of 382

NDA 50-742
MECTIZANW
(iermectin)
oral tablets
25
.
jlLC.3. Safetv Resuls
“Clinical adverse experiences (drug related or not drug related) were reported in 152 (47.6%), 155 (48.1%),
170 (52.8%) and 94 (29.8’Mo)patients in the 100, 150,200 rncg and placebo groups, respectively.”
“None of
the adverse experiences was considered serious by the investigators and no patient was d13eontinuedfrom
the study because of the adverse reactions.=[page D-1586 of volume 1.19]. The two most common adverse
clinical events were myalgia and headache [page D-1590 of volume 1.19]. Myalgia was reported by219’o,
17.7Y0,20.5Y0,and 13°Aof the patients in the 100,150, 200 rncg, and placebo, respectively.
Headache was
reported by 21Yo, 21.7Y0,24.2Y0, and 10.2°A of the patients in the 100, 150,
200 mcg, and placebo,
respectively.
“Myaigia and headache are probably reactions caused by the death of the skin microfilaria,
which explains their frequent occurrences among the patients receiving ivermectin.
Only two patients, one in each of the 100 and 150 mcg groups, had any adverse laboratory experiences after
receiving the study drug. The patient in the 100 mcg group had high urine WBCS, and the patient in the 150
mcg group had increased total serum bilirubin. [page D-1593 of volume 1.19]
JII.D. Protocol
548 (Document
5545]
Study by Wnatam
.
.
.
Protocol title:
“A single-blind, placebo-controlled study of the tolerabilii, safety, and efficacy of successive single oral doses
of ivermectin (MK-933) approximately 150 to 220 mcgkg in adults with onchocerciasis””
111.D.1. Study Desian
The study was mnducted as a single-blind, placebo-controlled study. The synopsis of the clinical study report
was dated 02Feb87.
The intent was for the study to continue over a 3 year period, but “only data at the day
4 visit were in-house” at the time this report was prepared.
The dose level of ivermectin was 150 to 220 mcglkg of body weight. Five successive single oral doses at 6-
month intervals were to be administered.
Evaluability criteria was that baseline microfilaria counts be z 10 mf/mg skin rather than 20 mg/mg skin that
was specfied in the protocol.
JILD.2. Efficacv
Results
“No formal analysis of the data was performed. Summary statistics of the data for the first 4 days after the
first dose suggest that ivermectin, administered in tablet form, reduced skin microfilada counts to near O-levels
while skin microfilariae decreased only sliihtly in the placebo-treated patients. The proportion of patients with
a favorable response (<5 mf/mg skin) at Day 4 posttreatment was 53/55 (96.4Yo) and 2/16 (12.5Yo) for
ivermectin- and placebo-treated patients, respectively.”
In the study, 64 patients (37 males and 27 females) were treated with ivermectin and 21 patients (9 males and
12 females) were treated with placebo,
All 85 patients completed the study.
Seventy-one patients (55
ivermectin-treated and 16 placebo-treated) were evaluated for efficacy.
Nine patients from the ivecmectin
group and five patients from the placebo group were excluded because e.tier their baseline microfilaria counts
were too low or the patient lacked posttreatrnent skin microfilaria measurements.
REVIEWER
COMMENT
The difference between the percent cured in the iverrnectin-treated group versus
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 257 of 382

NDASO-742MECTIZANm(ierrnectin)oraltablets
26
.
the placebo-treated group is 85% with a 95% confidence inteNa/ of S.,6 [63%,
105% ] gfjx,lsz..
Cieaffy,
ivem?ectin is sfatisfical/y more efficacious than placebo.
flI.D.3. Safety
Resul@
The investigator reported chical adverse experiences for 38 of 64 (590A)ivermectin-treated patients and for
5 of 21 (24%) placebo-treated patients. No laboratory adverse experiences were reported.
111.E.Protocol
545 [Document
5544) - Studv bv Lariviere
Protocol title:
‘An open study of the tolerabilii,
safety, and efllcacy of single oral 150 rncg/kg doses of iverrnectin (MK-933)
in children 5 to 12 years of age with onchocerciasis.”
111.E.1.Studv Desian
This was an open study of 103 children (71 male and 32 female) aged 6 to 13 who had onchocetiasis
without
eye involvement and were otherwise in good health. Fifty-four of the 103 (52.4Yo)patients had a secondary
diagnosis of malaria.
Patients were given 1 oral dose of 150 mcg/kg of ivermectin on Day 1. Patients were followed for 3,6, and
12 months posttreatment.
All patients were hospitalized for at least seven days following administration of
iverrnectin.
“Evidence for the efficacy of the study drug was obtarned from skin biopsy samples taken on Days 3,4, or 5
and subsequently
during follow-up examinations at three, six, and twelve months after study drug
administration.” The relative day ranges for the vis”~ were -14 to predose for the pretreatment visit, 1 to 7 for
the Day 3 visit, 65 to 125 for Month 3 visit, and 141 to 225 for Month 6 visit. “If a patient had multiple data
within a day range, the valid data from the last visit in that interval were used in the analysis.”
JII.E.2. Eficacv
Results
fiDDIicant’s
results
“Ivermectin was effectNe in reducing skin microfilaria in children.
The median decrease from baseline
(median of 34.1 mf/mg skin) was significant at Day 3, Months 3 and 6 with changes of -29.3,-33.5,
and -32.7
(mf/mg skin), respectively. Greatest reduction from baseline occurred at Month 3. The percentage of patients
with a f5vorable response (< 5 mf/mg skin) was at least 70°Afor all vis-h.”
Based on an all-patients-treated analysis, as of Day 3,74 of 101 (73.3%) patients had a favorable response.
As of Month 3, 95 of 102 (93.10A) patients had a favorable response.
As of Month 6, 89 of 102 (87.3%)
patients had a favorable response.
,.
For the per-protocol analysis, one patient was excluded because a baseline skin biopsy was not pwformed.
A second patient was excluded from the Month 6 analysis because
the follow-up skin biopsy was not
performed.
IILE.3. Safetv Results
“Forty-seven clinical adverse experiences were reported in 36 (35.0%) patients.
Forty-six were mild, 1 of
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NDA SO-742 MECTIZANm
(ivennetin)
oral tablets
27
edema was moderate, none was serious. The most commonly reported Wereheadache (23.3%) and myalgia
(8.7Yo)followed by peripheral edema (5.8%) and edema (4.9%). The majority of clinical adverse experiences
had a drug relationship of ““possibly.”” Most patients did not have any of the disease-associated signs and
symptoms at baseline and remained symptom free after receiving ivermectin.”
“No Iaboratoty adverse experiences were reported.’
IV. Intearated
Safety Summa~
Combining the dlnical adverse experiences of patients treated for strongyloidiasis under protocols 004, 014,
015, and 020 [page J-88 of volume 1.1], 4 of 68 (6°4) single-dose ivermectin patients experienced an adverse
clinical event compared with 8 of 41 (20’Yo)double-dose ivermectin-treated
patients, 28 of 37 (76VO)
thiabendazole-treated patients [page D-91 of volume 1.28], and 2 of 27 (7%) of albendazole-treated patients.
No patients were discontinued from the ivermectin or albendazole treatment regimens due to adverse
experiences.
One patient was discontinued from thiabendazole treatment due to nausea.
For onchocerciasis, the disease-associated sgns and symptoms were presented separately from unexpected
events that were considered clinical adverse experiences (AEs). “No clinicalAEs were considered serious
by the investigators.*
“Clinical AEs, regardless of relationship to study drug, were reported in significantly
more ivermectin-treated patients regardless of dose (49.5Yo)than placebo patients (29.50A).” The applicant
states the these results ‘may be consistent with the profile of reatilons caused by death of skin microfilaria”
[page J-121 of volume 1.1]. Myalgia was repotied in 18% (218/1209) of the patients, and headache was
reported in 22.7%
(274/1209) of the patients [page J-127 of volume 1.1].
The applicant submitted a safety update report dated July 31, 1996 that included specific details concerning
the 15 deaths in a Canadian nursing home that were considered by the reporting physician to be possibly
.Nermectinrelated. There does not appear to be any pattern in the timing of the deaths or the causes of death
to indicate a relationship to ivermectin. The ages of the patients ranged from 77 to 90 with 7 males and 8
females.
The first death occurred 17 days after treatment and was due to pneumonia.
The other deaths
occurred 40 to 176 days after treatment. The most common cause of death was cerebral vascular accident
with 4 deaths occuning ftom 45 to 140 days after treatment, The second most common cause of death was
pneumonia with 3 deaths occurring from 17 to 123 days after treatment.
Other causes of death included
Alzheimets disease, congestive heart failure, corona~ artery disease, myocardial infarction, renal failure, and
respiratory infection.
REVIEWE
R COMMENT:
In the Onchocerciasis studies only 2 of 1437 patients were
over 65.
One
experienced eye pain 3 days posttreatment.
The other mpafed
no adveme clinical experiences.
In the
Strvngyloidiasis studies, 10 patier?tswem
over 65 yearn of age. Of these only one patient n?portedclinical
adverse experiences.
The adveme experiences @potted wem somnolence, tremor, vertigo, asthenia,
nausea, and dizziness f to 2 days posttn?atment.
—–
.—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 259 of 382

NDA50-742MECTIZANW(rvennectin)oraltablets
28
.
V. Summary
and Conclusions
VA
ro
oidias’
ea
~#
1. Based upon the evidence presented in the Gentilini study 004, the single target dos=of
200 pg/kg of
ivermectin was statistically more efficacious than albendazole (200 mg b.i.d. for 3 days) in the treatment of
strongytildiasis in patients 5 to 70 years of age (95°Aconfidence interval ~.= [1OY0,65Y0] *m,xX).
Further,
the World Health Organization’s study in children replicated the results with a 95% confidence interval of
152.149 127°\ot490~l
83%,45”&
Ivermectin
and albendazole
appear
to be equally safe with no serious adverse
clinical or laborato~
experiences noted for either treatment.
This reviewer concludes that the applicant has demonstrated that a singledose
treatment of ivermectin has
statistically superior efficacy and comparable safety to albendazole.
2. Using a test of cure as negative stools through 30 days of follow-up, neither single-dose of 200 pg/kg nor
doubledose (200 pg/kg for 2 days) treatments of ivermectin met the DAIDPs
Points to Consider document’s
criteria for establishing
comparable
efficacy to thiabendazole
(25
mg/kg b.i.d. for 3days).
Because
thiabendazole’s
pooled cure rate was 92Y0, a lower bound on the 95% confidence interval of the difference
in the rates should be no less than -1OYO.Except for the singledose
ivermectin arm of the Dreyer study, all
the remaining point estimates of cure rates for ivermectin equaled or exceeded the point estimates of the cure
rates for thiabendazole.
The small sample sizes of the studies resulted in very wide confidence intervals.
In contrast, the 95% confidence intervals for the cure rates based upon a Kaplan-Meier
analysis of the data
were slightly better for the iverrnectin-treated patients than for thiabendazole-treated patients with [68Y0,92Yo],
[66%,94%],
[62%,92%]
for singledose
ivermectin, for doubledose
ivermectin, and for thiabendazole,
respectively.
In regards to safety, the ivermectin-treated
patients consistently reported statistically fewer clinical adverse
experiences than the thiabendazole-treated
patients (p-value < 0.001).
Because ivermectin demonstrated both a statistically better safety profile than Utiabendazole and statistically
comparable efficacy based upon survival analysis methods, this reviewer considers ivermectin to be a
satisfactory alternative to thiabendazole for the treatment for strongyloidiasis.
V.B.
OnchocerciasiS
Based upon evidence presented in protocol 514 for the treatment of onchocerciasis, a single oral dose of 12
mg capsules of ivermectin was statistically comparable to DEC-C administered at a daily dosage of 50 mg
for two days followed by 200 mg daily for six days in the reduction of microtilaria density at one mon,ti
posttreatment.
Ivermectin maintained a lower level of microfilaria density through the one year of follow-up
than DEC-C.
Both treatments resulted in a statistically greater reduction in microfilaria density than placebo.
The safety profile for the two drugs was also comparable except a statistically greater proportion of DEC-C
patients experienced systemic reactions associated with the microfilaricidal action of the treatments.
The second study presented in support of the claim was protocol519
that was a dosing study comparing
ivermectin with placebo.
There was not a statistical difference between the 100, 150, and 200 pg/kg dose
levels of ivermectin in reduction in microfilaria density at 3 days, 3 months, and 6 months posttreatment.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 260 of 382

NDA 50-742 MECTIZANm
(iverrnectin)oraltablets
29
.
Because
protocol 514 demonstrated
that ivermectin was at least comparable in efficacy with DEC-C but with
a better safety profile and a much simpler dosing regimen and because the iverrnectin results were replicated
in other clinical trials, this reviewer concludes that ivermectin provides a statistically satisfactory alternative
to DEC-C for the treatment of onchocerciasis.
B. Sue Bell, Ph.D.
Mathematical Statistician, DOB IV
Concur
Daphne Lin, Ph.D.
Acting Team Leader, DOB IV
,j/+4f2$$w
Ralph H&kins,
Ph.D.
Division Director, DOB IV
cc
Archival: NDA 50-742
HFD-520
HFD-520/D. Feigal
HFO-520/B.
Leissa
HFD-7251R.
Harldns
HFD-725/D.
Lin
HFD-520/Medical
Officer/P. Coyne
HFD-520/Pharrn/K. Seethaler
HFD-520/Micro/J. King
HFD-520/ChenVJ. TimPer
HFD-520/Project Manager/P. Fogarty
HFD-880/Biopharm/P.ColangeIo
HFD-725/BioStat/S. Bell
HFD-344/Clin lnv/M. Thomas
Chron
This review contains 29 pages, 8 tables, and 5 figures.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 261 of 382

1!
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 262 of 382

NDA 50-742
Mectizan
Merck
.
Division
of
Anti-Infective
Drug
Products
(HFD-520)
Clinical
Microbiology
Review
Notes
#1
NDA
# 50-742
DATE COMPLETED:
10/4196
SPONSOROND)IAPPLICANT(NDA):
Merck
SUBMISSION
REVIEWED:
Proposed draft labeling
PRODUCT
NAMES(S):
Proprietary: Mectizan
Non-ProprietaryAJSAN:
Ivermectin
DISPENSED:
X
Rx _
OTC
INITIAL
SUBMISSION:
Received
by CDER:
N/A
Received
by Reviewer:
Review
Completed:
AMENDMENT(S)
Received by CDER:
9/30/96
Received by Reviewer:
10/3/96
Review
Completed:
10/4/96
Related
Documents:
The complete NDA
REMARR(s) :
l?his review
is written
to
bring
disposition
of this
NDA
to
closure
from
the
microbiological
perspective.
Microbiological
review
of
this
application
was
administratively
waived
at
the
request
of
the
Supervisory
Microbiologist
at
the
time
the
NDA
was
filed.
No
technical
review
of
microbiological
data
was
proposed
because
the
application
was
perceived
to
contain
no
microbiological
data.
Indeed,
no
technical
data
have
been
reviewed
in
accordance
with
admi.niatrative
agreements
determined
at
the
time .the NDA
was
filed.
Nevertheless,
proposed
draft
labeling
was
brought
to my
attention;
the
proposed
draft
labeling
contains
a MICROBIOLOGY
section
which
was
not
requested
by
a FDA
Microbiologist.
These
labeling
statements
have
not
been
verified
in
accordance
with
administrative
agreements
noted
above.
However,
these
labeling
statements
are
likely
to
be
accurate
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 263 of 382

NDA50-742
Mectizsn
Merck
scientifically because Merck has previously demonstrated a strong
commitment
to
providing
basic
scientific
information
to
the
FDA;
on
the
other
hand,
these
labeling
statements
have
not
been
reviewed
for
inaccuracy
due
to gratuitous
juxtaposition
of
otherwise
true
statements.
Overall,
no
outstanding
microbiological
issues
have
been
raised
within
the
context
of
the
administrative
agreements
pertaining
to
this
application.
CONCLUSIONS
and/or
RECOMMENDATIONS:
No
outstanding
context
of the
application.
SMicro/ASheldon
microbiological
issues
have
been
raised
within
the
administrative
agreements
pertaining
to
review
of this
DepDir/LGavri
lovich
cc:
Orig.
NDA
#
50-742
HFD-473
HFD-520/DepDir/LGavrilovich
HFD-635
HFD-520/SMicro/ASheldon
~
HFD-502
HFD-520
HFD-520/Micro/King
IiFD-520/MO/Coyne
HFD-520/Pharrn/
HFD-520/Chem/
HFD-520/CSO/Fogarty
James
R.
King
Microbiologist,
HFD-520
Printed
for
signatures
prior
to draft
concurrence;
10/4/96
—.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 264 of 382

A
... ..
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 265 of 382

!,!,
r-
=.
t..__
D /’/
DIVISION
OF ANTI-INFECTIVE
DRUG PRODUCTS
Review ofChemistry,Manufactig, and Controls
50
a 742
NDA #: #3+%F
CHEM.REVIEW
#: ]
SUBMISSIONflYPE
DOCUMENTDATE
ORIGrNAL
3/29/96
REVIEW DATE:
6114/96
CDERDATE
COMPLETED
DATE
411196
6/14/96
NAME & ADDRESS OF APPLICANT:
Merck ResearchLaboratories
P.O.Box 4,BLA-20
Sumneytown Pike
West Point,PA 19486
CONTACT: Kenneth R. Brown, M.D., Regulatory Affairs
610-397-2552
DRUG PRODUCT NAME
Prourietarv:
Mectizan
Established:
Iverrnectin
Code i%
MK-0933
PHARMACOLOGICAL
CATEGORY/iNDICATION:
Treatment of strongyloides of the gastrointestinal tract and onchocerciasis.
DOSAGE FORM: Tablets, immediate release
STRENGTHS:
6 mg
ROUTE OF ADMINISTRATION:
OraI
Rx/OTC:
Rx
——
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 266 of 382

,,,
,,,,,
,,,
,,,
,
1,,
I
.!
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 267 of 382

NDA
20-72l;J.Timper;
Chemistryreview#l;page3
Mectizan(lverrnectin);
.
Merck & Co.,Inc.
SUPPORTING
DOCUMENTS:
Two original IND were made for iverrnectin by Merck & Co. The fi.rstJN13
was filed on 9/13/84 in order to administer ivermectin to persons infected with S.
.
stercoralis or Ascaris hunbricoides or other gastrointestinal nematodes. The second,
was filed on 7/17/90 to specifically determine the safe~ and efficacy of
ivermectin in patients who were infected with S. stercoralis and other intestinal
nematodes. Following the filing of the second ND the first was withdrawn on
12/28/90.
RELATED
DOCUMENTS:
DMF
CONSULTS:
5/2 1/96: A consult for environmental assessment was prepared by this reviewer and
submitted to Nancy Sager, Environmental Scientist, CDER.
5/2 1/96: 2 method validation packages were prepared and submitted: Nick Falcone,
FDA U.S.CustomsHouse,room 900, 2“d& Chestnut St., Philadelphia PA 19106; Hank
Drew, DDA, room 1002, 1114 Market St., St. Louis,MO63101.
5/2 1/96: A consult was prepared and submitted for suitability of the trade name in the
labelingtotheLabelingandNomenclatureCommittee.
5/20/96: A consult was submitted for the fermentation process controlstoHFD-160,
Dr.
Peter Cooney.
An establishment evaluation request was submitted at the time of this review; The EER
number is 10248. The pertinent sites to be inspected are:
Fermentation
k petiormed
Extraction,
crystallization,
and isolation
ofavennectins
areperformedat
Hydrogenationandfinalpurification
stepsarepefionnedutilizing
thefacilities
located at
The manufacturing and packaging for ivennectin tablets are conducted at the facility
--
.
.
—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 268 of 382

NDA 20-721; J.T&per;
Chemise review#l;page4
Mecti~
(TvermeCti);
.
Merck & Co.,Inc.
REws/comms:
*~ecb’s
ase~wnthdicyan@4rn&tiCagentfor ml
admhismtim
Ivemecti
ISderived horn
the avemecti,
a cl=
of hi~y
active broad-spw~
antip~itic
agen~ isolated born fe~entition
produck
of &-ePfOmYce~~e~iri/iS.
me ~g
ha
been registe~d for agricd~
and vetfiq
use since 1981.
CONCLUSIONS
& RECOm~ATIONS:
The application
is not approvable
~fi
reg~d
to che~~,
m~~ac~g,
ad
contiols.
The comd@
itetized
on the pretiou
page
are incomplete
at this time:
envi.romenti
assessment fennentition process comdt; 2 method wdidation
packages;consdtforsti~bili~ofthetradenae
inthe]abelkgtotheLabelkg and
Nomenclatie Couitiee; establishment
evd~tion request.
comenti
to &
f~
with deficiencies to the application are cited in the sectiom: S.ntiesis;
Process Raw
Materials; Drug Product Component Composition; ExcipienG; Stabili~; Labelkg.
J. Timper, Review Chemist
—.
HFD-520~ivision
File
q~l
HFD-520/SBRoyfle@etier
HFD-520/jThper/Chem
6/14
7296
HFD-520/pCoWWO
HFD-520KS~&der@~
HFD-520~fi@cro
HFD-520/SBelVStit
HFD-520@Colmgeio~
ioph~
HFD-520/CktiotiCSO
~C-130/J~en
.
— —
—
—
—
———-’————————
—.
.-
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 269 of 382

---
*
I)MSION
OF
ANTI-INFECTIVE
DRUG
PRODUCTS
Review ofChemistry,Manufacturing,and Controls
NDA 50-742
CHEM.REVIEW
#2
REVIEW DATE:
9/16/96
SUBMISSION TYPE
DOCUMENT DATE
tiendment
(BZ)
8128196
NAME & ADDRESS OF APPLICANT:
Merck Research Laboratories
P.O. Box 4, BLA-20
Surn.neytownPike
West Point, PA 19486
.
Revision: 9/20/96
CDER DATE
ASSIGNED DATE
8/29/96
914/96
CONTACT: Kenneth R. Brow
M.D., Regulatory Affairs; 610-397-2552
DRUG PRODUCT NAME
Proprietary: Mectizan
Established: Ivennectin
Code # MK-0933
Chem. Type/T’her.Class: 1P
PHARMACOLOGICAL
CATEGORY/INDICATION:
Treatment of strongyloides of the gastrointestinal tract and onchocerciasis.
DOSAGE FORM: Tablets, immediate release
STRENGTHS:
6 mg
ROUTE OF A.DMINIST’IU4TION: Oral
.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 270 of 382

,
NDA 50-721; Chemistxy review #2;
page 2
Mectizan (Iverrnectin); Merck & Co., Inc.
.
CHEMICAL
NAME. STRUCTURAL
FORMULA.
MOLECULAR
FORMULA,
MOLECULAR
WEIGHT:
----
Ivermectin: A mixture of ivexmectin component Bl, and ivennectin component B1~.
Ivermectim CAS-70288-86-7;
Ivermectin component Bk: CAS-70161-1 14;
Ivermectin component B1~:CAS-70209-81-3.
Ivennectin
componentB1; CigH74014.
Component ofIvermectin.
(2aE,4E,8E)-
(5’S,6S,6’~7S,l
1~1 3~15S,17@20~20@20bS)-6’-(S)-sec-Bu~I-
3’,4’,5’,6,6’,7,10,11,14,15,1
7QO~O~20b-tetradeca.hy&o-20,20bdfiy&o~-
5’,6,8,19-tetramethy1~
17-oxospiro[l
1,15-methano-2H,13H,17H-furo[4,3z-pg]-
[2,6]benzodioxacyclooctadecin-l3,2'-[2Hlpyran]-7-yl
2,6-dideoxy-4-0-(2,6-
dideo~-3-0-metiyla-L-~bko-hexop~o~1)-3-O-metiyl-a-L-mbtio-
hexopyranoside.
Iverrnectin
componentB1~.C,&O~&
Component ofIvermectin.
(2aE,4E,8E)-
(5’S,6S,6’~7S,1
l~13~15S,17&20~20&20bS)-
3’,4’,5’,6,6’,7,10,1
l,14,l5,l7@O~O~2Ob-Tetradeca,hy&o-2O,2Ob-dihy&o~X'-
isopropyL5’,6,8,1
9-tetramethyl-17-oxospiro[l
1,15-methano-2H,13
H,17H-
fio[4,3,2-p~[2,6]-be~dioxacyclooctidech-l3,2'-[2~p~]-7-yl
2,6dideoxy-
4-O-(2,6-&deo~-3-O-metiyl-a-L-mbino-hexop~mosyl)-3-O-metiyl~-L-
arabino-hexopyranoside.
—.
,,
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 271 of 382

NDA50-721;
Chemistry review #2;
page 3
Mectizan (Ivermectin); Merck & Co., Inc.
.
SUPPORT~G
DOCUlW3~S:
Two original INDs were made for ivermectin by Merck & Co. The tirs~ IND
, was
filed on 9/13/84 in order to administer ivermectin to persons infected with S. stercoralis
or Ascaris lumbricoides or other gastrointestinal nematodes. The second, IND
was filed on 7/17/90 to specifically determine the safety and efficacy of iverrnectin in
patients who were infected with S. stercoralis and other intestinal nematodes. Following
the filing of the second IND the fust was withdrawn on 12/28/90.
RELATED DOCUMENTS:
DMF
.
CONSULTS:
5/21/96: A consult for environmental
assessment (EA) was prepared by this reviewer
and submitted to Nancy Sager, Environmental Scientist, CDER.
9/3/96: A consult with the response by the firm to the findings of the first
consulted EA review was prepared by this reviewer and submitted to Nancy
Sager, Environmental Scientist, CDER. The FONSI was completed 9/16/96.
(Comldete, acceMab]e)
5/2 1/96: 2 method
validation
packages
were preparedandsubmitted:
Nick Falcone,
FDA
U.S.CustomsHouse,room 900,2nd & ChestnutSt.,Philadelphia
PA 19106;Hank
Drew, DDA, room 1002,1114 Market St.,St.Louis,MO63101. The method validation
packagesarenotcompleteatthetimeofthisreview.
5/21/96: A consult was prepared and submitted for suitability of the trade name in the
labeling to the Labeling and Nomenclature
Committee.
6/20/96 (Comtdete, acce~table)
The committee reply stated no reasons to object
to the product name, Mectizan.
..
5/20/96: A consult
was submitted for the fermentation process controls to HFD-160,
Dr. Peter Cooney.
.,,
9/3/96: A consult with the response by the fm
to the findings of the first
consulted review was prepared by this reviewer and submitted to HFD- 160, Dr.
Peter Cooney,
.
9/11/96: (Complete, accer)tab]e) The second consulted review of the
fermentation process consulted review was completed with recommendation that
the information is acceptable.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 272 of 382

NDA50-721;
Chemistry review #2;
page 4
Mectizan (Ivermectin); Merck & Co., Inc.
6/14/96: An establishment evaluation
request was submitted at the time of this review;
The EER number is 10248. The pertinent sites to be inspected are: Fermentation is
petiormed
Extraction crystalliiatio~
and isolation of avermectins are
performed at
Hydrogenation and final purification steps are performed
utilizing the facilities located at
The manufacturing and
packaging for ivennectin tablets are conducted at the facility in
NDA 20-721; J.Timpe~ Chemistry review #l; page 4 Mectizan (Ivermectin); Merck &
Co., Inc. ThisisOPEN
atthistime.
REMAIU’WCOMMENTS:
This WA
50-742 was f~st pssigned @e number NDA 20-721. In June, 1996 the
product number was changed to conform to the numbering for fermentation products.
The firm should provide a translated copy of the drug substice
batch records and
address the lack of impurity controls in the drug substance fermentation and
subsequent synthetic step.
CONCLUSIONS & RECOMMENDATIONS:
There are still a few remaining deficiencies.
The method validation work is open.
The establishment inspection request is open. The firm’s request for 24 months
stability dating is not supported by the data; the stability data supports 12 months
expiration dating.
L+
~]+~
J. Timper,
.
NDA 50-742
HFD-520/Division File
HFD-520/BD@eamleader
(Acting)
HFD-520/JTimper/Chem 9/20/96
HFD-520/PCoyne/MO
HFD-520/KSeethaler/l%arm
HFD-520/DKing/Micro
HFD-520/SBell/Stat
HFD-520/PCokmgelo/Biopharm
HFD-520/Cintron/CS 0
HFC-130/JAllen
.,,
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 273 of 382

TO: NDA50-742
DATE:
10/7/96
.
RE: ADDENDUM TO REVIEW #2
The firm was requested to use the uninvested systematic chemical name. The prohibitive
length and room on the labeling was given as explanation for the request. The-response is
adequate.
The firm has proposed the inverted form of the systematic chemical name
developed by Chemical Abstracts Service (CAS), in general accordance with the
rules established by the International Union of Pure and Applied Chemistry
(IUPAC) and the International Union of Biochemistry (IUB), and employed in the
cument issues of CA. The name proposed is the names of two components of a
mixture of at least 900/0of
5-O-demethyl-22,23 -dihydroaverrnectin Al,
and less than 10°/0of
5-O-demethyl-25 -de(l -methylpropyl)-22,23 -dihydro-25-(1 -
methylethyl)averrnectin A,,
The drugproductcomponentsarecorrectly
giveninthelabeling
section,
“DESCRIPTION”.
The chemicalstructure
isgivencorrectly.
~“
J. Timper
NDA 50-742
HFD-520/Division File
HFD-830/BDunn/Deputy Div. Director, DNDC 111
d
qb
HFD-520/JTimper/Chem
~ ,o\q
HFD-520/PCoyne/MO
HFD-520/KSeethaler/Pharrn
HFD-520/DKing/Micro
HFD-520/SBell/Stat
HFD-520/PColangelo/Biopharm
HFD-520/Fogarty/CS0
HFC-130/JAllen
,
——
—--
—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 274 of 382

D1V1S1ON
OF
ANT1-lNFECTIVE
DRUG
PRODUCTS
Review ofChemktry, Manufacturing,and Controls
NDA 50-742
CHEM.REVIEW
#3
REVIEW DATE: 10/7/96
SUBMISSION TYPE
DOCUMENT DATE
CDER DATE
ASSIGNED DATE
Amendment BC
10/4/96
10/7/96
9/30/96
NAME & ADDRESS OF APPLICANT:
Merck Research Laboratories
P.O. Box 4, BLA-20
Sumneytown Pike
West Point, PA 19486
CONTACT:
Kenneth R. Brown, M.D., Regulatory Affairs; 610-397-2552
DRUG PRODUCT NAME
Proprietary: Mectizan
Established: lverrnectin
Code # MK-0933
Chem. Type/Ther. Class: 1P
PHARMACOLOGICAL
CATEGORY/INDICATION:
Treatment of strongyloides of the gastrointestinal tract and onchocerciasis.
DOSAGE FORM: Tablets, immediate release
STRENGTHS:
6 mg
ROUTE OF ADMINISTRATION:
Oral
Rx/OTC: Rx
SUPPORTING
DOCUMENTS:
IND
was filed on 9/13/84 in order to administer ivermectin to persons infected
-
with S. stercoralis or Ascaris lumbricoides or other gastrointestinal nematodes.
IND
was filed on 7/17/90 to specifically determine the safety and efficacy of
iverrnectin in patients who were infected with S. stercoralis and other intestinal
nematodes.
,
.
——
—
—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 275 of 382

NDA
50-742;
Chemistry
review
#3;
page
2
Mectizan
(lvermectin);
Merck&
Co., inc.
RELATED
DOCUMENTS:
FDA memorandum to Dr. Dunn from J.Timper regarding NDA 50-742 dated 9/27/96.
Letter to Philadelphia Regional OffIce from Merck, dated 9/18/96.
REMAIUWCOMMENTS:
This review is of Merck’s fax, dated September 30, 1996. There was a telephone
conversation with Merck Research Laboratories on 9/26/96, A fax was sent on
9/27/96 to summarize the FDA comments to the firm in that phone call.
In the fax, the firm has adopted controls at the extraction of averrnectin step that
occurs at
This control monitors the impurity Bz. to be Iess than 1.1VO in
the wet cake. The firm should commit to submit the results of the on-going
investigation of process failures at this step. The fiml states in the fax that they wi11
reject batches that show visible impurities or fail the Bz,specification.
CONCLUSIONS
& RECOMMENDATIONS:
The few remaining chemistry concerns should be addressed by the firm. The method
validation work is open. The firm’s request for 24 months stability dating is not
supported by the data. The stability data support 15 months expiration dating.
J. Timper
NDA 50-742
HFD-520/Division File
HFD-830/BDunn/Deputy Div. Director, DNDC 111
HFD-520/JTimper/Chem
,~y,
HFD-520/PCoyne/M0
HFD-520/KSeethaler/Pharm
HFD-520/DKing/Micro
HFD-520/SBell/Stat
HFD-520/PColangelo/Biopharrn
HFD-520/Fogarty/CSO
HFC- 130/JAllen
,/
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 276 of 382

TO:
NDA 50-742
DATE:
10/7/96
RE: ADDENDUM TO REVIEW #3
A memorandum dated October 4, 1996 was received by HFD-520. The memowdum
recommends to withhold application. It states the following deviations from GMPs:
G
Batch records are not routinely reviewed by Quality Assurance prior to product
release.
G
A limited review of batch production records found failures which were not
investigated to determine their cause nor were methods instituted to prevent their
reoccurrence.
G
Failure to validate changes made to established manufacturing processes and access
their effect on stability.
See attached.
NDA 50-742
HFD-520/Division File
HFD-830/BDunrdDeputy Div. Director, DNDC III@b
HFD-520/JTimper/Chem
HFD-520/PCoyne/MO
HFD-520/KSeethaler/Pharm
HFD-520/DKing/Micro
HFD-520/SBell/Stat
HFD-520/PColangelo/Biopharm
HFD-520/Fogarty/CSO
HFC- 130/JAllen
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 277 of 382

w‘5
REQUEST
FOR
TRADEMARK
~VIEW
To:
Labeling and Nomenclature Committee
Attention:
Dan Boring, Chair (HFD-530), 9201 Corporate Blvd, Room N461
From:
Division of Anti-Infective Drug Products
HFD-520
Attention: Bonnie B. Dum, Ph.D.
Phone: 827-2003
Date: October 4, 1996
Subject:
Request for Assessment of a Trademark for a Proposed New Drug Product
Proposed
Trademark: Stromectol
NDA/ANDA# 50-742
Established name, including dosage form:
Ivermectin; 6 mg immediate release tablet
Other trademarks
by the same fm
for companion products:
Mectizan (same drug product but donated else where than the U.S.).
Merck does not want
to use the same name as that used else where in the world because they don’t want to
confuse the donated drug program name with the “for sale” drug program in the U.S.
According to Frank Ricci of Merck Research Laboratories, this name is already registered
in the U.S. and France.
Indications
for Use (may be a summary
if proposed statement
is lengthy):
Treatment of strongyloides of the gastrointestinal tract and onchocerciasis (gastrointestinal
nematodes).
Initial Comments
from the submitter
(concerns,
observations,
etc.):
Note:
Meetings of the Committee’ are scheduled for the 4* Tuesday of the month.
Please
submit this form at least one week ahead of the meeting.
Responses will be as timely
as possible.
Rev. December
95
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 278 of 382

Consult #685 (HFD-520)
.
STROMECTOL
ivermectin immediate release table~ 6 mg
There were no look-alildsound-alike
conflicts or misleading aspects noted with the
proposed propriet.q
name. However, the Committee believes the established name for the
product is (ivermectin tablets) immediate release. The USP does not speciilcally~cognize
the term “immediate release” and to be in conformance with the USP established name
conventions, “immediate release” should either not be used at all or appear outside of the
parenthesis.
The Committee has no reason to fmd the proposed proprietary name unacceptable.
1
[(l[$@
, Chair
N~en&lature Committee
cc:
Original
NDA 50-742
HFD-520/Div.
File
HFD-830/Chem/DunnB
HFD-520/Chem/TimperJ
HFD-520/Chem/Ka
tagueD
HFD-520/PM/FogartyP
.-
,/ -
..
.,,”
,.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 279 of 382

DIVIS1ON
OF ANTI-INFECTIVE
DRUG
PRODUCTS
Review of Chemistry, Manufacturing,
and Controls
NDA 50-742
CHEM.REVIEW
M
REVTEW DATE: 10/22/96
SUBMISSION
TYPE
DOCUMENT
DATE
CDER DATE
ASSIGNED
DATE
Amendment BC
10/15196
10/16/96
10/17/96
NAME & ADDRESS
OF APPLICANT:
Merck Research Laboratories
..
P.O. Box 4, BLA-20
Sumneytown Pike
West Point, PA 19486
CONTACT:
Kenneth R. Brown, M.D., Regulatory Affairs; 610-397-2552
DRUG PRODUCT
NAME
Proprietary: Stromectol
Established: Ivennectin
Code # MK-0933
Chem. Type/T’her. Class: 1P
PHARMACOLOGICAL
CATEGORY/INDICATION:
Treatmentofstrongyloides
ofthegastrointestinal
tractand onchocerciasis.
.,..
DOSAGE
FORM:
Tablets,
immediaterelease
STRENGTHS:
6 mg
.,
ROUTE
OF ADMINISTRATION:
Oral
Rx/OTC: Rx
SUPPORTING
DOCUME~S:
was filed on 9/13/84 inordertoadminister
ivennectintopersonsinfected-‘
withS.stercoralis
orAscarisIumbricoides
orothergastrointestinal
nematodes.lND
was filedon 7/17190tospecifically
determinethesafetyand effkacyof
iverrnectin
inpatients
who wereinfected
withS.stercoralis
and otherintestinal
nematodes.
——.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 280 of 382

NDA 50-742; Chemistry review #4;
page 2
Mectizan (Ivermectin); Merck & Co., Inc.
REMARKS/COMMENTS:
The name “Mectizan” has been revised by the fm
to be Stromectol. ~~purpose
was to avoid confhsion in marketing. There was a consult to the Committee for Drug
Product Labeling and it was found acceptable. The formal review of the trade name
will be submitted to the file when it arrives.
The review #4 is the evaluation of the response by the firm to the FDA f~@ated
October 9, 1996)sent by Pauline Fogarty. This fax contained deficiencies noted to the
firm in chemistry review #3.
CONCLUSIONS
& RECOMMENDATIONS:
Recommend approval tier
acceptable establishment inspections. The research
needed to understand the production failures at the avermectins extraction and
purification step should be provided in a phase 4 submission.
..y-maItip’h=
J.Timper
NDA 50-~~2-:-=.
HFD-520/Divisi6n File
HFD-830/BDurdDeputy Div.Director,
DNDC
111~
‘olzq~qb
HFD-520JJTimperfChem
HFD-520/PCoyne/MO
HFD-520/KSeethaler/Pharrn
HFD-520/DKing/Micro
IIFD-520/SBell/Stat
HFD-520/PColangelo/Biopharm
HFD-520/FogartylCSO .“
HFC-130fJAllen
“
,,
,
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 281 of 382

Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 282 of 382

ENVIRONMENTAL
.
ASSESSMENT
FINDING OF NO SIGNIFICANT
IMPAC>
FOR
MECTIZAN@
(ivermectin
tablets)
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION
AND RESEARCH
DIVISION
OF ANTI-INFECTIVE
DRUG
PRODUCTS
‘
(Hm-520)
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 283 of 382

,-
-..<
FINDING
OF
MECTIZAN@
.
NO
SIGNIFICANT
IMPACT
NDA
20-721
(ivermectin
tablets)
–
The
National
Environmental
Policy
Act
of
1969
(NEPA)
requires
all
Federal
agencies
to
assess
the
environmental
impact
of their
actions.
FDA
is required
under
NEPA
to
consider
the
environmental
impact
of
approving
certain
drug
product
applications
as
an
integral
part
of
its
regulatory
process.
The
Food
and
Drug
Administration,
Center
for
Drug
Evaluation
and
Research
has
carefully
considered
the
potential
environmental
impact
of
this
action
and
has
concluded
that
this
action
will
not
have
a significant
effect
on
the
quality
of
the
human
environment
and
that
an
environmental
impact
statement
therefore
will
not
be
prepared.
In support
of
their
new drug
application
for
MECTIZAN@
(ivermectin
tablets),
Merck
Research
Laboratories
has
conducted
a
number
of
environmental
studies
and
prepared
an
environmental
assessment
in
accordance
with
21
CFR 25.31a(a)
(attached)
which
evaluates
the
potential
environmental
impacts
of
the
manufacture,
use
and
disposal
of
the
product.
Ivermectin
is
a semi-synthetic
drug
which
will
be
administered
orally
in the
treatment
of
strongyloidiasis
and
onchocerciasis.
The
active
moiety
is used
in the
U.S.
in approved
veterinary
products.
The
Center
for
Veterinary
Medicine
reviewed
an
environmental
assessment
and
issued
a
finding
of
no
significant
impact
for
the
approval
of
ivermectin
products.
Approval
of
this
product
for
human
use
will
result
in a very
small
incremental
increase
in the
use
of
this
active
moiety
over
that
which
is
currently
used
for
veterinary
purposes.
The
drug
substance
will
be
manufactured
at
Merck
facilities
in
Elkton,
VA,
Danville,
PA
and
Barceloneta,
PR.
The
drug
product
will
be manufactured
at
a Merck
facility
in
Haarlem,
Holland.
The
finished
drug
product
will
be
used
in
hospitals,
clinics
and
by
patients
in
their
homes
throughout
the
United
States.
Ivermectin
may
enter
the
environment
from
excretion
by
patients,
from
disposal
of
pharmaceutical
waste
or
from
emissions
from
manufacturing
sites.
The
environmental
fate
’and
effects
of
this
active
moiety
have
been
studied
extensively
because
of
its
use
as
a veterinary
product.
Rapid
photodegradation
and
oxidative
degradation
in
soil
have
been
identified
as
environmental
depletion
mechanisms.
Effects
on
standard
test
organisms
have
been
observed
at
concentrations
as
low
as
0.01
ppb.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 284 of 382

?-
%
Disposal
may result
from
production
waste
su’ch
as
out
of
specification
lots,
returned
goods
and
user
disposal
of
empty
or
partly
used
product
and
packaging.
Pharmaceutical
waste
will
be
sent
to
licensed
incineration
facility.
At
U.S.
hospitals
and
clinics,
empty
or
partially
empty
packages
will
be
disposed
according
to
hospital/clinic
procedures.
From
home
use,-empty
or
partially
empty
containers
will
typically
be
disposed
of
by
a
community’s
solid
waste
management
system
which
may
include
landfills,
incineration
and
recycling,
while
minimal
quantities
of
unused
drug
may be
disposed
of in
the
sewer
system.
Precautions
taken
at
the
sites
of
manufacture
of
the
bulk
product
and
its
final
formulation
are
expected
to
minimize
occupational
exposures
and
environmental
release.
The
small
incremental
increase
in
the
use
of
this
drug
that
will
result
from
this
approval
does
not
change
the
Agencygs
previous
conclusion
that
a
finding
of
no
significant
impact
is
appropriate.
The
Center
for
Drug
Evaluation
and
Research
has
concluded
that
the
product
can
be
manufactured,
used
and
disposed
of
without
any
expected
adverse
environmental
effects.
Adverse
effects
are
not
anticipated
upon
endangered
or
threatened
species
or
upon
property
listed
in
or
eligible
for
listing
in
the
National
Register
of
Historic
Places.
+>-”+
.
I
<
& ~~-
‘---
/!.
S4w___
D TE
PREPARED
BYfi
Nancy
B.
Sager
Team
Leader
Environmental
Assessment
Team
Center
for
Drug
Evaluation
and
Research
*
J3
-
,—
AE
CONCURRED
Charles
P.
Hoiberg,
Division
Director,
f
New Drug
Chemistry-1
Center
for
Drug
Evaluation
and
Research
Attachment:
Environmental
Assessment
,
2
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 285 of 382

lvermectin
Chemical and Pharmaceutical Manufacturing and
Control Documentation
I. Summary
F. Environmental Assessment
F- I
1. Lm
Jarnq
1,1996
2.
Nam
of Appl
e
icant/Petitioned
Merck ResearchLaboratones
Merck & Co.,Inc.
~-
Mk2ss:
Sumneytown Pike
West PoinLPA 19486-0004
4.
Pescrintion
oft.b
ePronosedActioT
a.
RN uestedAcho n
Merck Research Laboratories, Division of Merck and Co., Inc. has
filed a New Drug Application for MEC~
(ivermectin),
indicated
for the
treatment
of
strongyloidiasis
(threadworm
infection) of the gastrointestinal tract and onchocerciasis (river
blindness).
MECTIZAN will be available in tablet fomn (6 mg)
pac!~ed
in an aluminum foil strip. The composition of the foil
Mectzn.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 286 of 382

Ivemectin
Chemical and Pharmaceutical Manufacturing and
ControI Documentation
I. Summary
F. Environmental Assessment
F-2
.
strip is as follows (outside to inside); lacquered coa~g,
aluminum
foil (30 microns), primer, polyethylene sealant.
At
the
projected
annual US
patient
usage,
incremental production of ivennectin required is
the
maximum
estimated to be
extremely small (Confidential Appendix III, Part 1). This amount
is only a very small percentage (less than 0.1‘XO)of the estimated
amount of ivermectin used for human health purposes worldwide
and represents an even much smaller percentage of the ivennectin
produced for previously approved veterinary uses.
b.
Need for the Action
MECTLZAN (ivermectin), a semisynthetic
anthehnintic
ageng
offers effkctive therapy for the treatment of strongyloidiasis and
onchocerciasis.
While endemic in the tropics, these diseases also
occur to a limited extent in the United States especially where
unsanitary, crowded conditions prevail.
Strongyloidiasis is caused by the parasitic worm, Stron@oides
stercoralis.
The
recommended dosage
of
MECTIZAN
for
treatment of Strongyloidiasis is a single oral dose designed to
provide approximately 200 micrograms of ivermectin per kg of
body ‘weight.In general, additional doses will not be necessaxy.
Mectmdoc
;
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 287 of 382

?-
%.
Ivermectin
Chemical andPharmaceutical
Manufacturing
and
ControlDocumentation
I.Summary
F.Environmental
Assessment
F-3
—
Onchocerciads k caused by a pmash.icWormj Onchocera volvulus
and is a leading cause of blindness in certain tropical regions. The
recommended
dosage
of
MECTIZAN
for
treatment
of
onchocerciasis
is
a
single
oral
dose
designed
to
provide
approximately
150 micrograms of ivermectin per kg of body
weight
In mass distribution campaigns in international treatment
programs, the most commonly used dose interval is 12 months.
For treatment of individual patients, retreatment maybe considered
at intervals as short as 3 months.
c.
me Locations Where the Product will be Produced and Trees of
Enw‘ronrnents Adjacent to those I.ocatiou
The bulk drug substance (ivennectin) will be manufactured in the
applicant’s facilities. The fermentation steps will take place at the
Merck Manufacturing Division facilities in Elktoq
Virginia and
Danville, Pennsylvania (as avermectin broth).
The avermectin
broth produced at the Elkton facility will be shipped to the facility
in Danvil.le, Pennsylvania.
The Danville
site will complete the
isolation and purification of avermectin. The avermectin will be
shipped
to
the
Merck
Manufacturing Division
f=ility
@,
Barcelone@
Puerto Rico
for conversion to
ivermectin (drug
substance).
Meazn.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 288 of 382

Ivermectin
Chemical and Pharmaceutical Manufacturing and
ControI Documentation
1.Summary
F. Environmental Assessment
F-4
The
drug product (MECTIZAN)
will
be
ma=factured
and
packaged at the applicant’s facility in Haarlem, Holland.
Returned
goods will be disposed of at the Merck Manufacturing Division
facility in West Poin~ Pennsylvania.
The types of environments present at the locations mentioned
above, specific to the vicinity of drug substance (avermectin and
ivermectin)
manufacturing
or
drug
product
(MECTIZAN)
manufacturing
and packaging, are described
in the following
sections.
1) JWcton.Vinzinia
Route 340 South (P.O. Box 7)
Elkton, VA 22827
a)
Geomaph c Co
i
ndltions
The Elkton plant is heated on the south fork of the Shenandoah
River approximately three miles south of
ElktoL Virginia
in
Rockingham County.
Coordinates of the plant’s location qe
latitude38°23’ N and longitude 78°39’ W. The town of Elkton k
located approximately 3 miles northeast of
the plan~ has a
poptiation
of less than 1,935 people accmrding to the 1990 U.S.
Census Bureau.
Mectzn.doc
Jan.96
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Ivermectin
ChemicalandPharmaceutical
Manufacturingand
ControlDocumentation
I.Summary
F.Environmental
Assessment
F-5
The site is approximately 58 acres and employs about 700 people.
The
sumounding
neighborhood
includes
Merck’s
chemical
operations, fdan~
wooded acres, and residential homes.
b)
Air Resources
The plant is located in Virginia’s Air Quality Control Region II
which is in attainment with the National Ambient Air Quality
!hndads
(NAAQS) for sulfhr oxides, nitrogen
oxides,
total
suspended particles and ozone.
State air regdations
generally
incorporate standards and procedures required by the United States
Environmental Protection
Significant Deterioration
Standards
(NSPS),
and
Agency (LJSEPA). The Prevention of
(l?SD), the New Source Performance
the National Emission
Standard for
Hazardous
Air Pollutants
@JESHAPS) regulations
have
been
incorporated
into
the
state
air
regulations.
The
plant
is
approximately two kilometers from a Class I Area (Shenandoah
National Park). Prevailing winds near the plant are fin
the south-
southwest.
.
The mean summer tempemture is 23°C (73”F) and the mean winter
temperature is 1°C (33”F). /uumal rainfall is about 34 inches.
Mecun.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 290 of 382

Ivermectin
ChemicalandPharmaceutical
Manufacturingand
ControlDocumentation
I.Summary
F.Environmental
Assessment
c)
Water Resources
F-6
—
Separate sanitary, process and storm water sewer systems are
maintained
by the plant.
The
sanitary
wastes,
after
solids
separation and chlorinatio~ are mixed with the process waste for
additional treatment in the plant’s waste water treatment facility.
Water from the storm water system and non-contact cooling water
is mixed with the waste water treatment
plant eflluent
and
discharged to the South Fork of the ShenandoahRiverthroughthe
plant’s
VPDES
outfhll.
Thereareno injection
wellson theplant’s
property,
andtheonlystiacewaterwithin1000feetoftheplantk
theSouthForkoftheShenandoahRiver.The 100-yearfloodplain
elevationattheplantisapproximately973 f=t above mean sea
Ievel.One wellsuppliestheplant’s
potablewaterneedswithan
additional
wellasbackup.
d)
] and Resources
The terrainsurroundingthe plant is valley flatiand.. The E1.kton
plant is underlain by carbonate rocks of the Rome and Elbrook
formations, surficial deposits consist of fluvial sand and gravel, and
regolith of residual clays. The bedrock strata beneath the plant are
tilted and strike north 57° and dip to the northwest 45°. Handliig
and ‘disposalof solid waste streams at the Elkton plant is subject to,
and in compliance with, the Federal Resource Conservation and
Meazn.doc
Jan.96
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f--
‘%
Ivermectin
F-7
Chemkal andPharmaceutical
Manufacturing
and
ControlDocumentation
L summary
.
F.Environmental
Assessment
Recovery Act (RCRA), the Virginia Solid Waste ‘Management
Regulations
and the Virginia Hazardous Waste Management
Regulations,
which
are
administered
by
the
Department
of
Environmental Quality.
2)
Danvl“he.Pennsvbnia
P.O.Box 600
Danville,
Pennsylvania
17821
a)
Om phicCondition~
The Danvilleplantk locatedon a 180acresiteintheSusquehanna
Rver
Valley approximately70
miles north of Harrisburg,
PennsylvaniaintheBorough of Riverside.The plantislocated
adjacenttothesouthbankoftheNorthBranchoftheSusquehanna
River.Coordinates
oftheplant’s
location
arelatitude
40°57’N and
longitude
76°38’W.
b)
m
Resources
Annual rainfall at the WilliamsPort Airport (approximately
30
miles from theplant) is 41 inches. The mean summer temperature
is 22°C (72°F), while the mean winter temperature is -2°C (28°F).
The entire state of Pennsylvania has no significant nitrogen dioxide
Mectm.doc
Jan.96
..
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 292 of 382

Ivermectin
Chernieal and Pharmaceutical Manufacturing and
Control Documentation
I. summary
F. Environmental Assessment
F-8
pollution.
The
entire state of Pennsylvania is in~uded in the
Northeast Transport Region. The Danville plant is located in
NorthurnberlandCounty which is in attainmentwith the standards
for the National Ambient Air Quality Standards(NAAQS) for all
criteriapollutantsexcept ozone. The statehas incorporated into its
regulations the new source performance standards (NSPS), the
National Emission
Standards for
Hazardous Air
Pollutants
(NESHAPS), and the National Ambient Air QualityStandards
(N~QS).
Thereareno ClassI Areaswithin50 km of theplant.
Prevailingwinds near the plantare from the west-northwest
direction.
c)
WaterResources
Separate sanitary, process, and storm sewers are maintained at the
plant. The sanitary sewer flows to Danville’s wastewater treatment
plan~ while the process sewer flows to the plant’s waste water
treatment fmiiity.
Water from the storm sewer merges with the
effluent horn the plant’s waste water treatment system, and the
combined streams are discharged to the Susquehanna River through
the plant’s National
Pollutant
Discharge
Elimination
System
(NPDES) outfb.11.The only surface water within 1000 feet of the
plant is the North Branch of the Susquehanna River. There are no
injection wells on the plant prope~,
and the 100-year flood plain
elevation at the plant is approximately 460 feet above mean sea
Mectzn.doc
Jan.96
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Ivexmectin
ChemicalandPharmaceuticalManufacturingand
Control Documentation
I. summary
F.EnvironmentalAssessment
F-9
level. The plant derives its potable water entirely from an on-site
treatmentplant which uses the North Branch of the Susquehanna
River as its source.
The plant potable water quality meets all
requirementsof the Federal Safe Drinking Water Act and the
PennsylvaniaSafe DrinkingWaterAct.
d)
Jand Resourcm
The Danville site is located within the Appalachian
Mountain
Section of the Valley and Ridge Physiographic Province.
General
topographic trends of the region include long, continuous ridges
separated by valleys of varying width. The Danville site lies on a
fairly
flat
region
around
which
the
North
Branch of
the
SusquehannaRiver flows. MontourRidge is located directly across
the river from the Danville site, and rises to an elevation above
1000 fet
above mean sea level.
Elevations on the Danville site
range Iiom approximately450 to 470 f=t
above mean sea level,
withthe steepestslopes occuning along the banks of the river.
3)
Jhrceloneta. Puerto T&Q
.
Mectzn.doc
Merck Sharp& Dohme
Quimica de PuertoRico
,
Road #2, Kilometer 56.7
Barcelone@ PuertoRico
Jan.96
-.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 294 of 382

Iverrnectin
ChemiealandPharmaceutical
Manufacturing
and
ControlDocumentation
L summary
F. EnvironmentalAssessment
F- 10
a)
Geom-mhic Condition~
The Merck Sharp& Dohme Quimiea de Puerto Rico, Inc. (MSDQ)
facility is located on a 166 acre site in Bareelone@
Puerto Rico.
The city of Bareeloneta contains a population of approximately
20,000 people and is located 38 miles due west of San Juan and
three miles south of the Atlantic Ocean.
The MSDQ plant is
Ioeated at km 56.7 along state Highway 2.
Coordinates of the
plant’slocation arelatitude 18°25’ N and longitude 66°32’ W.
b)
Air Resour es
c
Puerto Rico generally has attainedNational Ambient Air Quality
Standards(NWQS)
althoughthereare problems with particulate
in the Catio
air basin. The Bareeloneta plant is located in the
Barceloneta air basin. The staterequires new source permits and
operating permits for all point sources.
Puerto Rico
has been
delegated authority over the National Emission Standards for
Hazardous Air pollutants prOgrilIll(NESHAPS).
..
Meteorological data for the area is collected at the Isla Verde
AirportinSan Juan (about47 mileseastofBarceloneta).Annual
.
rainfall
isnear60 inchesand themean ambienttemperaturevaries
Jan.96
.
Mcctzn.doc
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4-
1 .*
Ivermectin
Cherniealand Pharmaceutical
Manufacturing
and
ControlDocumentation
L summary
F. EnvironmentalAssessment
F-n
between24 and 28°C (76 and 82”F). An easterlytradewind is the
predominantwind pattern.
c)
WaterResources
The entirefresh water requirements for the plant are supplied by
one pumped well and two artesian wells.
The artestian wells are
used as the ptiary
source of plant water. No other well, or surface
water bodies, are located within 1000 feet of the facility. The plant
potable water quality meets all requirements of the federal Safe
Drinking Water Act.
Separate sewer systems exist for sanitaty,
process and storm water runoff. Process waste water flows into the
plant’s pretreatment system and then to the Barceloneta Regional
Wastewater Treatment Plant (BRWTP).
Sanitary waste from the
plant joins the effluent horn the pretreatment
system and the
combined streams flow to the BRWTP.
Storm water from the plant is collected in an independent trench
system, consisting of concrete dikes and swales and directed away
from the facility.
Surfhce water runoff from portions of the plant
discharge to the sinkhole system which is described in the land
resources
section
below.
The
MSDQ
plant
is
located
approximately 1.25 miles west of the Manati River and 70 meters
(230) f~t above mean sea level. The plant is located well above
the 100-year flood plain.
M~.doc
Jan.96
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Ivermectin
Chemical andPharmaceutical
Manufacturing
and
ControlDocumentation
I.summary
F. Environmental
Assessment
F- 12
d)
LandResourCes
The piantis located in an inter-mogotedepression. The depression
is elongated east-west over a distance of 2 km.
The mogotes are
asymmetricalhills thatare built of massive thick-bedded members
of the Aymamon Lmestone.
A seriesof sink holes and secondary
depressions are located to the east and tend in a northwesterly
direction from the site.
Bedrock beneath the plant site consists
primarilyof moderately solutioned, recrystallizedlimestone of the
Aymanmon Formation.
In depressions between mogotes
and
ridges, the Iirnestoneis overlain by the quaternaryblanket sands.
The blanket deposits consist mostly of silty or sandy clay which
underwentrapiddeposition in a subaerial fluvial plain environment.
Based on soil borings from the site, 20 percent of the soil is sand.
Red-brown to yellow silty clay comprises the dominant soil found
in the borings. Land use surrounding the plant includes industrial
and mixed industrial.
Other industries lie north and west of the
fiicility, the canrnunity of Trinidad lies north of the ficility, and the
rest of the surrounding area is undeveloped.
Mectzn.doc
Jan.96
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Ivermectin
ChemicalandPharmaceutical
Manufacturingand
ControlDocumentation
I.Summary
F.Environmental
Assessment
4)
~aarlem. Holland
F- 13
Merck Sharp & Dohme B.V.
Waaxdenveg 39
2031 BN Haarlem
The Netherlands
a)
~eomaDhic Conditions
The MSD
plantinHaarlem,Hollandk locatedinthemunicipality
ofHaarlem,neartheNorthSeacoastandapproximately
20 km (13
miles)hornthecityofAmsterdam. The plantisheatedeastofthe
cityof Haadem on 18 hectare(45 acres)of landnearthe river
Spaame. The plantislocatedintheareaofWaarderpolder,
which
k dedicatedtoindustrial
activi~only.The populationofHaarlem
isapproximately
150,000people.
b)
Air Resources
Dutch governmentlaws prescribeemission standardsfor hazardous
air pollutants. No significantairpollution generatingindustriesare
located in the vicinity.
Annual rainfall is about 0.75 meter (30
inches). Mean Jauuarytemperatureis 5-8°C (40-45”F).
Prevailing
wind,directions are west and south-west(sea wind) at a windforce
of 3 to 8 Beaufort.
-Mectzn.dw
Jan.96
———
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Ivermectin
ChemicalandPharmaceutical
Manufacturing
and
ControlDocumentation
I.Summary
F.EnvironmentalAssessment
c)
Water Resources
F- 14
All waterused for eansumptio~ process, and sankuy equipment is
obtained from the official county supplier. Water quality meets
standardsof potable water. Waterfor iirefightingcan be withdrawn
from the River Spaarne. There are no injection wells on the plant
property. The sanitmyandstorm sewer system are directly coupled
to the municipal sewer system, while the process effluents are
treatedbefore dischargeinto the municipalsewer. The discharge of
wastewater into the municipal sewer is covered by an agreement
with the Hoogheenwaadschap van Rynland.
All wastcwater is
treated in the public wastewatertreatmentplant managed by tie
Hoogheemraadschapvan Rynland. The effluent from the treatment
plantis dischargedintotheRiver Spaarne.
The land of the industrializedzone where the plant is located is
reclaimed (“polder”). The soil is composed of layers of clay, san~
and peat
Mw”tzn.doc
Jan.96
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Ivermectin
ChemicalandPharmaceutical
Manufacturing
and
ControlDocumentation
I.Summary
F.Environmental
Assessment
5)
West Point- Pennsvlvania
Meazn.doc
F- 15
SumneytownPike
P.O. Box 4
West PoinL PA 19486-0004
a)
Geo_graph
t o~
ic Condi i
The West Point plant is located on a site (-450 acres) in Upper
Gwynedd Township,Montgomery County,whichk approximately
30 milesnorthwestofPhiladelphia.
The centeroftheWest Point
plantk locatednearlatitude
40°12’54” N and longitude75° 17’
59”W. Land usesurrounding
theplantk primailyresidential
and
agricultural
withotherindustrial
sitesapproximate~y
one-halfmile
away.
b)
Air Resource$
Air quality
Protection
in this area is in compliance
Agency’s
(EPA)
National
with
the Environmental
Ambient
fi
Quality
Stidmds
(N&lQS)
of the Clean Air Act for total suspend~..
particuIates,SUMUoxides, and nitrogenoxides. This compliance is
based
on
monitoring
and
reporting
by
the
Pennsylvania
Departmentof EnvironmentalProtection(PA DEP)
under the
requirementsof the StateImplementationPlan. At thistime,
Jan.96
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Werrnectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F- 16
. .
Montgomery
County does not meet the ozone Standar;set
forth by
the NUQS.
The WestPoint plant lies within the outer zone of
the Southeast Pennsylvania
air basin.
Pennsylvania
is part of the
EPA Region III and PA DEP is responsible
for implementing
the
State Implementation
Plan which includes new stationq
source
permits for manufacturing.
Meteorological
data for the region is
collected at the Philadelphia
International
Airport. Annual rainfall
is approximately
42
inches
(107
cm)
and
the
mean
ambient
monthly
temperature
varies
between
33 and
77°F
(0.5 -25”C).
Predominant winds are from west to southeast.
c)
Water Resources
Potable water is supplied
to the pkmt operations
via an on-site
storage tank which is supplied by on-site wells and a public water
supplier, North Wales Water Authority.
The North Wales Water
Authority operates two public wells within a half-mile
of the plant
proper&y.
Storrnwater
drainage
is controlled
using detention
basins
which
maintain site runoff at levels estimated
for undeveloped
property
and to minimix
erosion.
This runoff is discharged
into either the
Towamencin Creek or the Wissahickon Creek.
Mectzn.doc
Jan.%
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Iverrnectin
Chemical and Pharmaceutical
Manufacturing
and
ControI Documentation
L summary
F. Environmental
Assessment
F-17
Wastewater generated as a result of on-site incineration
activity will
be
discharged
to
the
Upper
Gwynedd
Township
Authority
Wastewater
Treatment
Plant
(UGTA).
The
UGTA
discharges
treated effluent to the Wissabickon
Creek.
The location of the discharge from the UGTA is downstream
from
the
West
Point
site.
Pennsylvania
DEP
limits
the
wasteload
allocation
and
water
pollutant
limits
(established
by
the
Pennsylvania
Water Toxics Management
Sirategy) from the UGTA
by means of the National Pollutant
Discharge
Elimination
System
discharge
pexmit.
This wasteload
allocation
and water
pollutant
limit are used to determine
the allowable
contribution
limits from
tie
West Point site to the publicly
owned treatment
works.
The
treated wastewater is also regulated by the UGTA under permit and
local ordinance.
d)
JXUId Resourcw
The plant is underlain by Triassic age sedimentary
rocks, mapped
as the Brunswick
and Lockatong
formations.
These
formations
occur
as layered
beds
of red
and
very
dark
gray
shale
wi@
occasional
layers of sandstone.
Although
these rocks
generally
have
low
primary
porosities,
permeability
is
maintained
and
Mectzn.doc
improved by the presence of fi-actures and joint sets.
3an.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 302 of 382

Iverrnectin
Chemical and Pharmaceutical
Manufacturing
and
Controi
Documentation
I. Summary
F. Environmental
Assessment
.
F- 18
The plant site elevation
is about 361 feet above mean
sea level
(United States Geologic Survey datum).
d.
The Location Where the Product will be Used and Disposed Of
MECTIZAN
is intended
for use throughout
the United
States.
lvermectin
and other ingredients
used to formulate
MECTIZAN
will enter the environment
primarily
in domestic sewage which is
highly
diluted
during
routine
wastewater
processing.
Environmental
concentrations
of iverrnectin resulting from the use
of MECTIZAN
tablets will be many orders of magnitude
below
levels
of environmental
significance.
When
compared
to the
expected
environmental
concentration
(US-use)
for treatment
of
strongyloidiasis
and
onchocerciasis,
aquatic
toxicity
endpoints
born
studies
conducted
with
ivermectin
produce
differences
(assessment fmtors) which are well in excess of 1000.
Merck & Co., Inc. has a returned goods policy which involves the
return
of
any
unused
market
packages
to
the
West
Point
Pennsylvania
facility
for disposal.
This
results
essentially
in. a
single
controlled
location
for
product
disposal.
Thermal
destruction is used to treat wastes containing finished product
On-
.
site inci.nemtion facilities are used to handle the majority
of this
Mectindoc
——
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 303 of 382

Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F- 19
waste.
Any
off-site
incineration
is conducted
a~a
permitted
facility.
5.
lden tification of Cheroical Substances that are the Subiect of the Promsed
Acbon
Ivermectin
is produced by fermentation
(Strepfomyces
avennitilis)
aud subsequent
chemical hydrogenation
and is a mixture
of two
closely
related
homologies
belonging
to a class of compounds
known
as
avermectins.
The
chemical
names
of
the
two
homologies
are:
22,23-dihydroaverrnectin
B]a
(R=C2H5)
and
5-O-DemethyL25-de(
l-methylpropyl)-22z3
-dihydro-25-(1 -methyl
ethyl)
avermectin
B 1a (R=CH3).
The latter
is also
known
as
22,23dihydroaverrnectin
Illb.
The Chemical
Abstracts
Registry
(CAS) number assigned to ivermectin is 70288-86-7.
The
structure
and
properties
of
ivermectin
are
given
below.
Formulation
ingredients
and excipients
are listed
in Cm.fIdential
Appendix - Part 2.
,,““
Meazn.doc
.,.”
;
hn.96
—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 304 of 382

Iverrnectin
Chemical and Pharrnaceutieal
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-20
Oq
b
HO,,+,
oq
WC
o “’’’04,h.
WC
o ““’’’0,,$
i
OH
Molecular Formu 1a
Molecular Weipht
@=
C2H5) C48H74014
875.10
(R= CH3) C47H72014
861.07
Ivermectin
contains at least 90% of the compound
in which R in
the above structure
is the ethyl group and less than
10% of the
compound in which R is the methyl group.
~ote:
Iverme.etin was
previously
defined as containing at least 80?? of the compound
in
which R is the ethyl group and less than 20% in which R is the
methyl
group.
Based
on a historical
data
review
and
process
capability,
the
component
proportion
was
changed
to
that
indicated.]
Ivermectin
is a white to yellowish-white
crystalline
.
powder and has an ill-defined melting point of about
155”C.
The
Mectzn.doc
kin.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 305 of 382

,..s
Iverrnectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-21
material is optically active and has a specific rotation
[a]~,
of
approximately
-19“ (C=2.5, CH30H).
The ultraviolet
absorption
spectrum
in methanol
is characterized
by a maximum
at 245 nm and clearly defined shoulders
at -237
and
-254
nm.
Ivermectin
is very
insoluble
in water:
The
concentration
of a saturated aqueous solution is 4 ppm.
Iverrnectin
has been shown to be stable for at least six months
when stored under ambient conditions.
In solution,
ivermectin
is
photolabile.
Ivermectin
contains
at least 95% of the two compounds
shown
above as determined
by W
absorption and liquid chromatography.
Based
on radioactivity
measurements,
the octanol-water
(@3 7
buffer) partition coefficient
KD, for ivermectin
is 1651.
The present
assessment
supplements
ivermectin
data
with
data
generated
with avermectin
B1.
The structure
of aven.nectiri
B1
(AVM)
only differs from that of ivermectin
(IVM)
by a double
bond at position
2243.
Ivermectin
is produced
from averrnectin
by ca$alytic reduction
of this double bond.
Physical
properties
of
ive~ectin
and avermectin are compared below.
Mectzn.doc
Jan.96
—
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),
%..
Ivermectin
Chemical and Pharrnaceuti~l
Manufacturing
snd
Control
Documentation
L summary
F. Environmental
Assessment
F-22
.
mmrmon of IVM and AVM Ph
._
vsical ProDerheS
Aw
Molecular Weighta
875
873
Octanol/Water
Partition Coef.
1,651
9,900
KoCb
12,600-15,700
a4,000
Aqueous Solubilityc
4 ppm
8 ppb
E (Lmax), Methanol
30,100 (245)
31,850 (243)
aMolecular weight of the Bla component
b
Different soils used
c Different methods used
Both
compounds
possess
low
water
volubility,
high
octanol/water
partition
coefficients
and high ~
values.
Compounds
with ~c
values >1000 are considered
to be
irnmoblle in soil.
Additional
information
cmweming
the
molecular
-
structure,
chemical
names,
laboratory
codes,
generic
-
name, trade name, physical-chemical
properties as well as
a summary
of the environmental
fate and effects data for
ive~ectin
carI be found in Appendix I.
Mectmdoc
lan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 307 of 382

Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
6.
Introduction
of SubStan
.
ces into the Envuo nment
F-23
A surnmq
of the permit numbers applicable to the mantiacture
of
MECTIZAN
(ivennectin),
discussed
below,
is
given
in
Cotildential
Appendix III - Part 3.
a.
Asa Result of the Manu facture of MECTIZAN
(iverm ectinl
6 mg
1)
J3kton. Virpinia
a)
Air Emissions Control sand Citations - Bulk Dn.w Substanc eM anufacture
The fermentation
step genemtes fermentation
off-gases that contain
typical
respiration
byproducts,
including
carbon
dioxide
(COJ
The on-site
incinerator
emissions
consist
of typical
combustion
products.
Air emissions
are subject to, and in compliance
wi~
the Virginia
Regulations
for the Control and Abatement
of Air Pollution.
The
on-site trash incinerator
is in compliance
with the Commonwealth
of Virginia
Regulations
for the Control
and Abatement
of Air
Pollution.
No new permit limits are anticipated
as a result of the
proposed action and approval will not impact the facility’s ability to
comply with all applicable permit condhions.
Meetmdoc
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-24
b)
kiquid Emissions Controls and CIMOJIS
- Bulk
Drup
subm~
.
.
The manufacturing
process generates aqueous waste streams horn
fennentor
vents, fermenter
sample fimnels, equipment
washes and
floor drains.
All aqueous waste is collected via piping or collection
sump in a 20,000 gallon collection
tank or directly transferred
to
either holding tanks or tank trucks.
From the collection
tanlq the
waste
can
be
transf~ed
either
to
an
evaporator
system
to
concentrate the liquid waste prior to shipment off-site or directly to
a tank truck.
The liquid
waste
is then
sent to the
appkant’s
Danville,
Pennsylvania
facility
for treatment
and disposal.
The
specifics of wastewater treatment employed
at the Danville facility
are described in the section (2) below.
On a limited case-by-case
basis,
liquid wastes
that have been
determined
through
process
knowledge
and detailed
analysis
to contain
less than a threshold
concentration
of avermeetins
will be sewered to the site’s advanced
activated sludge system (wastewater treatment plant).
Effluent from the facili~s
wastewater treatment plant is discharged
directly
to the
Shenandoah
River
under
the
Virginia
Pollutant
Discharge
Elimination
System
(VPDES)
Permit
#VAOO02178
(expiration
date: 6/6/99).
The VPDES
permit is administered
by
the Virginia Department
of Environmental
Quality.
The effluent
curren~y has maximum
daily limits of TSS S338
kgld and COD
<17,246 kg/d and pi-l limits between 6.5 and 9.5.
No new permit
Mectzn.doc
Jan.96
.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 309 of 382

+-
..*
F-25
Iverrnectin
Chemical and Pharmaceutical
Manufacturing and
Control
Documentation
I. Summary
F. Environmental
Assessment
limits are anticipated as a result of the proposed action and approval
will not impact the fid.ity’s
ability to comply
with all applicable
permit conditions.
c)
sol id Waste Controls and Cltatlons -
.
.
Bulk Drug Sub stance Man ufacture
Burnable,
non-hazardous,
solid
wastes
containing
“de rninirnis”
amounts
of avermectin
may consist of paper,
aluminum,
plastic,
and drums.
Such
wastes
are incinerated
on-site
or
sent to a
permitted
incineration
facility able to accept such waste streams.
Other non-hazardous
wastes which cannot be recycled are disposed
of at a state licensed landfill.
Disposal
of
non-hazardous
solid
waste
is
subject
to
and
in
compliance with Permit #183 (no expiration
date) issued under the
Virginia
Solid
Waste
Management
Regulations.
There
are no
numerical permit limits on solid waste generation
and no additional
permit conditions are anticipated as a result of the proposed action.
d)
Ovee protectlo~
Material Safety Data Sheets (NISDS) are
available
on-site for all
chemicals as required by the Occupational
Safety Act of 1971, the
Hazards Communication
Act of 1985 and Title 29 Code of Federal
Regulations
(CFR)
Part
1910.
Employees
associated
with
the
Me.azn.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 310 of 382

4-
,.,
lvermectin
Chemical and Pharmaceutical
Manufactig
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-26
manufacture of drug product have appropriate -MSDS;available
for
their
review.
Employee
protective
clothing,
such
as
gloves,
uniforms and safety glasses are used during the packaging
process
to assure compliance with the Occupational
Safety Act of 1971 and
the
Hazud
Subpti
I.
2)
Dan
“Ile. Pennsvl vani~
Communication
Act
of
1985
and
Title
29
CFR
a)
Air Emission Controls and Citations - Bulk Drug Substan ce Manufacture
The fomentation
step generates fermentation
off-gases that contain
typical respiration byproducts, including carbon dioxide (COJ.
Air
emissions
generated
ffom
the
avermectin
isolation
consist
of
volatile
organic
compounds
(such as hexane,
methanol,
ethanol,
and
toluene)
and
dust.
Volatile
organic
emissions
from
the
avermectin
production process are controlled by condensers.
Dust
in the process buiiding will be filtered with HEPA filters to control
the introduction
of avermectin and dust into the ambient air with an
efficiency greater than 99.90A.
.’
Air emissions
applicable
to the production
of avermectin
are in
compliance
with the regulations
of the Pennsylvania
Department
of
.
Environmental
Protection
(Title 25, Part I, Subpart C, Article
III,
Mectzn.doc
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
Mectzn.doc
F-27
Air Resources)
and Operating
Permit
#49-31 3-032~
(expiration
date: 10/3 1/99).
b)
Liauid
F
“ -
alsslons
Controls
and
Citatim.s
-
Bulk
Drug
Substan ce
Man ufactur~
The
avermectin
manufacturing
process
generates
two
types
of
liquid-waste
streams: one, a combination
of solvent-based
waste
streams, the other, a combination of aqueous waste streams.
The
solvent-based
waste
streams
horn
the
averrnectin
manufacturing
process are generated in the isolation step and in the
recovexy of solvents used for the isolation.
They contain discarded
organic compounds
(e.g., avermectin) dissolved
in solvents such as
toluene, methanol,
ethanol, hexane.
Solvent-based
liquid streams
will
be recovered
within
the process
to the
extent
faible
to
minkize
any
potential
release
of
organic
compounds
to
the
environment.
Solvent-based
wastes will either be sent off-site
for
disposal
to a pexmitted
facility,
or
disposed
of
in
an
on-site
permitted incinerator.
The incineration process is subject to and in
compliance
with the Pennsylvania
Rules and Regulations
for the.,
Protection of the Environmen~ Title 25, Part I, Subpart C, Article I,
Land Resources,
Chapter 75, Solid Waste Management
and Article
III, ~
Resources
and 40 CFR
Parts
264
and
265,
Standards
Applicable
to
Owners
and
Operators
of
Hazardous
Waste
JaxI.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
F-28
Control
Documentation
1. summary
F. Environmental
Assessment
Treatmen~
process
is
Storage
and
Disposal
Facilities..
me
incineration
also
subject
to and
in
compliance
with
the
site’s
hazmdous
waste (RCRA) permit #PADO03043353
and Operating
Permit #49-301-018
(expiration date: 4/30/98).
The aqueous-based
waste
streams
consist
of spent
fermentation
broth
and
wash
waters
that
contain
unconsumed
fermentation
nutrients,
unrecovered
by-products
and traces of avermectins
and
dissolved
solvents such as hexane, methanol,
ethanol, and toluene.
The aqueous-based
streams are treated using caustic
in an on-site
high pressure, high temperature reactor designed to destroy residual
avennectins.
The effluent from the high pressure reactor is fiut.her
treated
in an on-site two-stage
biological
waste
water
treatment
plant
before
being
discharged
into
the
North
Branch
of
the
Susquehanna
River. The final plant effluent is discharged
under the
requirements
of and in compliance
with NPDES
Permit
No. PA
0008419
(expiration
date:
9/99)
which
is administered
by
the
Pennsylvania
Department
of
Environmental
Protection.
The
amount of avermectin released into the Susquehanna
River is below
levels of environmental
concern based on toxicity testing.
c)
sol id Waste Controls and Citations - Bulk Jhug Substan ce Manufacture
Dry solid waste (such as paper, trash
and HEPA filters) from the
avermectin
production
process
is disposed
of by either on-site
or
Mectm.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 313 of 382

4-
..
‘
F-29
.
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
1. Summary
F. Environmental
Assessment
off-site incineration.
On-site incineration
of solid a
is subject
to and operated in compliance with the regulations
for air emissions
of the Pennsylvania
Department of Environmental
Protection
(Title
25, Part I, Subpart C, Article III, Air Resources).
d)
Material
Safety Data Sheets (MSDS)
are available
on-site
for all
chemicals required by the Occupational
Safkty Act of 1971 and the
Hazards Communication
Act of 1985.
Employees
associated
with
the manufacturing
of avermectin have appropriate
MSDS available
for their review.
Employee
protective
clothing,
such as gloves,
uniforms,
and safety
shoes,
aud protective
equipmen~
such
as
safety glasses, are used during the manufacturing
process to assure
compliance
with the Occupational
Stiety Act (OSHA) of 1971 and
the Hazards Communication
Act of 1985.
To
minimiz
worker
exposure
to
avennect@
the
following
monitoring
activities are conducted:
(l).
At least hi-annual
monitoring
of dust levels
for averrnectin
..
where avermectin powder is handled; and
(2) At ~east monthly wipe test on equipmenq
floors and production
bottles in the production area.
Meetzn.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 314 of 382

Ivermectin
Chemical and Pharmaceutical
Manufi@uring
and
Control Documentation
I. summary
F. Environmental
Assessment
F-30
3)
Barceloneta.
PUerto RicQ
a)
”-”
~
Ce
uce
Air emissions
generated during the production process will consist
of volatile
organic
compounds
such as ethanol,
formamide,
and
toluene
which
will be controlled
as appropriate
by condensers.
Exhaust air in the process building and the fommlation
and sterile
areas
will
be
filtered.
h
emissions
are
subject
to
and
in
compliance
with the Puerto
Rico Environmental
Quality
Board
under the “Regulations
for the Control of Atmospheric
Pollution.”
Manufacture
of
drug
substance
is
also
in
compliance
with
conditions under permit number PFE-09-1291-1668-I-11-O.
b)
Liquid
Emissions
Conti
Is
o
and
Citations
-
Bul k
P
Subs tance
Marl ufacture
The manufacturing
process
generates
two types
of liquid
waste
streams:
a combination
of solvent-based
waste
streams,
and
a
combination
of aqueous waste streams.
..
./”
The solvent-based
streams are generated in the chemical processing
steps.
They will conti
discarded organic compounds
dissolved
in
.’
solvents
such
as ethanol,
formamide,
toluene
and
water.
—
solvent-based
streams will be destroyed
by incineration.
The
l-he
on-
Mectzn.doc
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-31
site incineration
process will be subject to and in coliipliance
with
the Puerto Rico Environmental
Quality Board (EQB) Regulations
for
the
Control
of Atmospheric
Pollution
and
the
U.S.
EPA
regulations
for the control of hazardous
waste, 40 CFR Parts 264
and 265.
Currently, the solvent incinerator operates under a permit
number
PRD
090028101
issued by the EQB
Hazardous
Waste
Program
and
under
EQB
Permit
No.
PFE-09-1291-1668
-I-111-O
issued by the EQB Air Program
The aqueous-based
waste stream consists of wash waters generated
by equipment
washings.
Holding
tanks
are provided
to contain
these
washes
prior
to testing
and disposal,
Depending
on the
ivermectin
concentration,
the
holding
tank
contents
will
be
managed in one of two ways:
(1) Contents are tested for ivermectin and recycled through a filter
until a specified
level is reach~
and then are discharged
to the
chemical sewer, or
(2) contents are incinerated.
.,
Effluent from the Barceloneta plant is discharged to the Barceloneta
Regional
Wastewater
Treatment
Plant
(BRWTP)
under
permit
#~,A-93-202-045.
The BRWT’P operates under the requirements
of NPDES permit #0002137 which is administered
by EPA.
Mectm.doc
Jan.96
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Ivermectin
F-32
Chemical and Phannaceuticd
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
c)
solid Waste C@ols
and Citations - Bti
DNP Sub-cc
~
.
.
ufacture
SoIid wastes,
such as paper,
tmsIL and HEPA-type
filters
etc.,
generated
at the BarceIoneta
plant as a result of drug substance
manufacture
are subject to, and in compliance
wi~
the regulations
for solid waste disposal of the Puerto Rico Environmental
Quality
Board (EQB).
Non-hazardous
solid waste (general
trash, paper
and plastics)
is
dkposed
of on-site in a solid waste incinerator.
The incinerator
is
subject to and in compliance with the Regulations
for the Control of
Solid Waste administered
by the EQB and permits
PFE-09-1291-
1668-I-111-O issued
by the EQB
Air
Program
and
S1-93-0004
(expiration date: 4/14/96) issued by the EQB Solid Waste Program.
d)
Emglovee Protection
MateriaI Safety Data Sheets are available on-site for all chemicals
required by the Occupational
Stiety
Act of 1971 and the Hazards
(hnmunications
Act of
1985.
Employees
associated
with
the
manufhcturi.ng of drug product have appropriate
MSDSS available
for their review.
Employee
protective
clothing
(such as gloves,
uniforms, tiety
glasses, safety shoes, and protective
equipment)
is
used dpring the manufacturing
process of drug product
to assure
compliance
with
the Occupational
Stiety
Act
of
1971 and the
Mectin.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 317 of 382

Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
Hazards
F-33
Communication
Act
of
1985.
To
minimiz
worker
exposure to ivermectin,
the
conducted:
following monitoring
activities will be
(1) At least semi-annual
monitoring
of dust levels where ivexmectin
powder is handled;
(2) Wipe tests are performed
to veri$
the cleanup of spills in the
manufacturing
area.
4)
Hml
m. Ho
e
hand
a)
Air Emissions
Controls
and Citations
- Druz
Product
Formulation
and
?rim.v Packa~ing
Air
emissions
generated
during
the
formulation
of
human
iverrnectin consist of volatile organic compounds
(such as ethanol)
and dust.
Air fbm
the process
building,
formulation
area sterile
facility is exhausted through HEPA-type
filter prior to discharge to
the
atmosphere
to
control
particulate
emissions
of
iverrnectin
powder (drug substance).
The manufacturing
is regulat~
and in
compliance with the Air Pollution Act.
Mectzn.doc
Jan.96
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?--
\.
“.
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-34
.
b)
Liquid Em-
Controls and C-
- Dxug prOdUCt F=
ulation and
?rimq
Packapi~
Liquid waste
streams containing
ivermectin
are generated
in the
formulation and packaging of the drug product.
Small quantities
of
organic
solvents,
such
as ethanol
and
water,
from
equipment
cleaning and wipedowns are generated.
Waste organic solvents are
collected and sent to the Rotterdam incinerator.
The disposition
of
organic solvents is in compliance
with the Hazardous
Waste Act
and the Waste Act.
Any aqueous waste resulting from manufacturing
the drug product
will be collected and treated with an activated
carbon purification
unit to remove
the ivermectin.
The wastes
will then
enter the
plant’s general waste system which includes domestic sewerage and
will go via a neutralization
pit (pH X5)
to the municipal
sewerage
treatment
plant”
This
plant
operates
under
the
control
of the
ibogheemraadschq
Van
Rynkmd.
MSD
has
a
permit
#1420(’86)V26580
(gmnted June 11, 1987 with no expiration
date)
from the municipality
for entering
the sewerage
treatment
plant
with their plant effluent.
The wastewater
discharge is regulated by,
and
in
compliance
wi~
the
“Wet
Verontreiniging
Oppervlaktewateren”
which includes tie Waste Water Regulations.
Spent activatwl carbon from the filter system will be collected
in
Meam.doc
Jan.96
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4-
\,
Ivermectin
F-35
Chemieal and Pharmaceutical
Manufacturing
and
Control
Documentation
1. Summary
.
F. Environmental
Assessment
c)
d)
Mectn.doc
Pltic
bags, put into drums, and handled as a hazardous
waste as
described below.
Simons
Controls and C@@gms - Dnw Pro
.
.
.
.
.
duct Fo rrnulation
and
Solid waste resulting
from production
and packaging
of the drug
produc~ such as HEPA-type filters and spent activated
carbon, will
be combined
with
other
plant
trash
and transferred
via closed
vehicle to the Rotterdam
incinemtor.
A permit
for transport
and
incineration
is issued by the provincird authorities
under the laws
regulating transport and processing of solid wastes.
Management
of solid waste from manufacturing
is regulated,
and in
compliance
wi~
the “Wet Milieubeheer”
which includes:
the h
Pollution
Act
the Hazardous
Waste ACG the Waste Act
and the
Waste Regulation.
Employ=
Protetion.
Material Safety Data Sheets (MSDS) are available for all chemids.
required by the Dutch Safety Law (Arbo Law) and the Dutch Safety
Rules for Industry and Workshops.
Employees
associated
with the
formtiation
and packaging
of ivermectin
have appropriate
MSDS
available
for
their
review.
As
additional
worker
protection,
Ja.n.96
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4
...
Ivermectin
Chemid
and pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
monthly
F-36
swab tests are performed
for ivermectin
on equipmen~
floors, and production bottles in the production area.
Manufacturing
is regulated by, and in compliance,
with the Dutch
Stiety
Law (Arbo
and Workshops.
5)
West Po in~ Penn svlvania
Law) and the Dutch Safety Rules for Industry
a)
Air Emission Controls and Citations - Dnw Product Disr)osal
The
on-site
incineration
facility
employs
necessary
operating
conditions as to ensure compliance with permitted
emission
levels.
As a contingency,
off-site
incineration
will
be conducted
at a
permitted facility.
The air emission controls for the disposal of this product meet the
requirements
of
the
Pennsylvania
Air
Pollution
Regulations
under Title 25 of the Pennsylvania
Code,
Department
of
Environmental
Protection
(PA
DEP),
121-141.
Approval
of the proposed
action
ability to comply
with the above
will
not
impact
the
stated requirements.
Control
Part I-
Chapters
.,’”
facility’s
No new
petit
limits are anticipated as a result of the proposed
action.
Mecvn.doc
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
L summary
F. Environmental
Assessment
F-37
b)
Liquid Waste Cm trols and Citations - Drug~sx
The liquid from incineration operation
will be discharged
into the
site wastewater
collection
system
and wiIl undergo
pretreatment
along with other sanitary waste.
This wastewater
is discharged
for
fiuther treatment to the UGTA.
The treated effluent is discharged
horn the UGTA under NPDES Permit Number
PA 0023256.
This
permit is administered by PA DEP.
The
wastewater
is
subject
to,
and
in
compliance
with,
the
pretreatment
standards for existing sources of the Pharmaceutical
Manufacturing
Category
under Title 40 of the Code
of Federal
Regulations
Part 439.
The wastewater
is also regtdated
by the
UGTA and is in compliance
with the existing
contract
and the
“Rules and Regulations
Governing
the Discharge
of Sanitary
and
Industrial Wastewaters
into the Public Sewem of Upper Gwynedd
Township
Authori~.”
These
regulations
are
based
on
the
requirements
of the Federal
Clean Water Act and Pennsylvania
Clean Streams Law.
The cumnt
contract with UGTA (expiration
9/30/98) limits plant efiluent to a flow (calculated
from a monthly
average)
of
1.255
million
galh~
BOD
=
250
mg/L
(daily
maximum);
TSS = 300 mglL; and pH between 5.5-9.0.
Approval
of the proposed
action
will not impact
the facility’s
ability
to
/
comply
with the above
stated requirements
and no new permit
limits are anticipated as a result of the proposed
action.
Mecnn.doc
Jan.96
,.
—.
—
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4-
..*
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-38
c)
Solid Waste Controls and Citations - Dn.w Product Dmo.sal
.
Appropriate
controls for the disposal of unused market packages
are utilized as part of the site solid waste management
program.
The waste
is incinerated
at permitted
disposal
facilities.
Ash
generated horn the on-site incineration process is disposed
of at a
permitted facility and is monitored to mnfirrn its acceptability
with
prevailing solid waste regulations.
Solid
waste
management
at
the
West
Point
plant
requires
ccmformance
with
conditions
set
forth
in
Permits
400674
(expiration
6/16/2005)
(expiration
date:
1/25/2003)
aud
400459
(expiration
date:
issued
by
PA
DEP
and
Permit
PADO02387926
date:
4/15/2002)
issued by both EPA and PA DEP.
These requirements
assure comprehensive
control for management
of waste throughout
the plant including returned market packages.
The requirements
of the Pennsylvania
Code,
Title
25, Part
I -
Department
of
Environmental
Protectio%
Chapter
75,
are
the
prirmuy regulations
which impact solid waste management.
The
regulations
are subject to the requirements
of the Federal Resource
Consemation
and Recovery A@ the Federal Hazardous
and Solid
Waste
Amendments,
and
the
Pennsylvania
Solid
Waste
Management
Act.
Mecta.doc
Jan.96
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j--
%..
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
L summary
.
F. Environmental
Assessment
F-39
Approval of the proposed action will not impact the facility’s ability
to comply with the above stated requirements.
d)
Emplovee Protection
Material Safety Data Sheets are available on-site for all chemicals
required
by the Occupational
Stiety
Act of
1971, the Hazards
Communication
Act
of
1985
and
Title
29
Code
of
Federal
Regulations
Part
1910.1200.
Employees
associated
with
the
manufacture
of drug substance have appropriate
MSDSS available
for their review.
Employee
protective
clothing,
such as gloves,
uniforms,
and safety glasses are used during
the manu.fhcturing
process to assure compliance with the Occupational
Saf&y Act of
1971 and the Hazard Communication
Act of 1985 and Title 29
Code of Federal Regulations,
Subpart I.
b. As a Result of th
Use of IWECTIZAN (
e
ivennect@
The projected use Ofmcm
(ivermectin)
for the treatment
of
strongyloidiasis
and onchocerciasis
involves oral administration
of
a single dose consisting of one to three 6 mg tablets depending
on,
the patient’s
body weight.
The annual demand
for MECTIZAN
(iverrnectin),
6 mg for use in the treatment
of Strongyloidiasis
and
onchocaciasis
in the United States will be very low.
Based on the
indicated dose, this corresponds
to an extremely
small quantity
of
Mectzn.doc
Jan.96
“,.
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>..,
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
ControI
Documentation
I. summary
F. Environmental
Assessment
Mectzn.doc
ivermectin
annually on an incremental use basis
F-40
(se=Confidenti@
Appendix
III - Part
1).
This
amount
is only
a very
small
percentage
(less than 0.1‘XO)of the estimated amount of ivexmectin
used for human health purposes worldwide and represents
an even
much smaller percentage of the ivermectin produced
for veterinary
use. Human health use of ivermectin will not result in emissions
to
either the terrestrial or atmospheric compartments.
c.
Asa Result of the Dis~ osal of MECTIZAN
6mE(I vermectin. MSD)
The Merck West Point, Pennsylvania
incineration
facilities
will be
used to treat returned product.
On-site incineration
facilities
will
handle
the
majority
of
this
waste
with
resulting
combustion
efllciency of at least 99.9°/0 on an hourly basis.
In the event that the
West Point facility is unable to accept such waste, the wastes will
be disposed
of at an alternate
permitted
off-site
facility.
The
expected emissions from the disposal site are described
below.
(1)
Air Emissions
- Particulate
and vapors
(carbon
dioxide,
water
vapor,
etc.)
are
expected
to
be
emitted
into- the
atmosphere
from the incineration
of returned
goods.
The.,.”
on-site
West
Point
facility
incineration
operation
is
in
compliance
with all applicable standards
and pexmit limits.
Any off-site incineration
will be conducted
at an equivalen~
permitted facility.
Jm.96
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4-
‘%
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
Mectzn.doc
F-41
(2)
Liquid
Emissions
- Any
wastewater
genemted
from
the
incinerator
operation
will be discharged
into the sanitary
sewer which undergoes on-site pretreatment
for equalization
and
is
discharged
for
off-site
biological
wastewater
treatment at the UGTA.
(3)
Solid
Emissions
-
All
returned
and
outdated
market
packages
and residual ivermectin
waste horn operations
at
West Point will be incinerated at on-site or off-site facilities
permitted to handle such waste streams.
d.
Effect
A@lca~on
.
.
Appro
al
Com@nce
.
of
v
on
With
Cumen t
Emissions
Reuuiremen~
Merck & Co., Inc. states
etiorceable
schedule
to
requirements
set
forth
that it is in compliance
wi~
or on an
be in
compliance
with,
all
emission
~
Wts>
consent
decrees
and
. .
admmstmd “ve orders applicable to the production
of ivermectin
at
its facilities
in
Elkto~
Wrgin@
Danville,
Pennsylvania
and
Barcelonekq
Puerto
Rico
and
the
production
of
MECTEZAN
(ivemwctin)
at Haarle~
Holland as well as emission requirements
set
forth
in
applicable
ftieral,
state,
and
local
statutes
and
regulations
applicable
to
the
production
of
iverrnectin
at
its
facilities
in
Elktou
VirginiA
Dauville,
Pennsykmkq
and
Barcelone~
Puerto
Rico and the production
of MECTIZAN
at
Jan.96
..
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-42
Haarlem,
Holland
and the incineration
of returned
goods
at its
facility in West Poin~ Pennsylvania.
7.
Fate in the Environm ent
MECTfZAN
(ivermectin)
is derived from the avermectins,
a class
of highly active broad-spectrum
antiparasitic
agents isolated from
fermentation
broths of liltrep~onzyces avemzitilis.
Environmental
assessments
have previously been prepared in connection
with the
approval
of the use of avermectins
in veterinary
and agricultural
applications.
Environmental
Assessments
for ivermectin
submitted
to the FDA (CVM) have universally
resulted
in “findings
of no
significant
impact” (FONSIS).
Moreover,
detailed assessment
of
ivermectin’s
effect
on
the
environment
has
been
a
major
component
of the overall
program
to develop
ivermectin
as an
antiparasitic
drug for fd
producing
animals.
Extensive
studies
have
been
conducted.
These
were
specifically
designed
to
determine
the extent of ivexmectin’s impact on the environment.
Ivennectin’s
mobility,
distribution
and stabiity
in soil and water
were measured.
Other studies investigated
the drug’s effect on a
variety of environmentally
important organisms including Imcteri&
invertebrates,
fid
plants,
etc.
Combined
with the clinical
use
pattern
of ivermectin
in livestock
and m-
these
provide
the
means to assess ivennectin’s environmental
impact.
Mectzn.doc
Jan.96
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Ivennectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
.
F. Environmental
Assessment
F-43
Information
which supports the present Environmental
Assessment
can also be found in assessments
prepared for previously
approved
products including:
EKK!!M
NNAQA
&w-Md
IVOMEC (ivexmectin)
Injection for Cattle
128-409
02/1 3/84
EQVALAN
(iverrnectin)
Paste for Horses
134-314
05/21/84
IVOMEC (ivermectin)
Injection for Swine
135-008
07/22/86
IVOMEC (ivermectin)
Pour-On for Cattle
140-841
12/04/90
Relevant sections of those assessments
have been summarized
and
are included herein.
a.
Photodefzradation
Halley
(1990) used a high-pressme
xenon
arc lamp to simtdate
sunlight
and calculated
that ivennectin
would photodegrade
near
the surfkce
of opeIL flat bodies
of water
under
clear
skies
in
summer and winter
sunlight
with half lives of 12 and 39 hours,
respectively.
This rapid photodegradation
in water should effect
Mectzn.doc
Jan.%
..
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‘%
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
L summary
F. Environmental
Assessment
swifl elimination
of ivermectin
from the
Based upon data from a preliminary
study,
F-44
aquatic environment.
ivermectin
undergoes
photodegradation
as a thin, dry fihn on glass with an estimated t%
of about 3 hours in summer sunlight
(Yeager and Halley,
1988).
Av-hn
Bla possesses
an absorption
maximum
similar to that
of
ivermectin
(Sec.
5),
with
less
intense
longer
wavelength
absorption
at approximately
290 and 350 nm (Halley,
1990), and
photodegrades
on soil TLC plates with a hrdf He of 21 hours (Ku
and Jacob, 1983a).
Rapid photodegradation
is consistent
with the
rapid loss of avermectin B la from cotton leaves (Bull et al., 1984).
b.
Soil Binding
Ivermectin
has been classified
as “tightly
bound”
to soil
~c
12,578 with clay loam soil (Iowa)] and hence considered
immobile
(1-kdley, 1985).
Consequently,
the possibility
of translocation
of
ivermectin through soil from one site to another in the environment
is remote.
It was also demonstrated
that toxicity
of ivermectin
(Ostlincl and
Cifelli,
1980)
and avermectin
B1 (Forbis,
1989)
toward Daphnia is greatly attenuated (99Yo) in the presence of soil.
These results agree with the known irnmobolization
of ivemwtin
..
(Halley, 1985) and aveqnectin
B1 (Ku and Jacob,
1983a) on soil.
When ivexmectin was partitioned
between water and Iowa soil, a
soil to water distribution
of 333 was foun~
predicting
that 99.7%
Mectzn.doc
Jan.96
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Ivennectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
1. summary
F. Environmental
Assessment
F-45
of the drug would be boun~
with only 0.3V0 in so~tion
(Halley,
1985).
c.
Fate in Soil and Ve~etatio~
Laborato~
studies
(Bull
et al.,
1984) have
shown
that
under
aerobic conditions in soil [31-Ijavermectin Bla degrades
to at least
thirteen radioactive products; half lives for the drug (at 1 ppm) in
Lu&in fine sandy loam, Houston clay and coarse sand soils are 14-
28, 28-56,
and
56 days, respectively.
The
major
degradation
product
is an approximately
1:2.5 equilibrium
mixture
of
8a-
hydroxyavennectin
Bla (an acetal)
and the cmespondi.ng
ring-
opened aldehyde.
At all treatment
levels
in Lufkin
fine sandy
loam, 90% degradation
of [3Hlavermectin
B]a occurs
within
168
days of exposure.
Avermectin
B la is strongly adsorbed
by ditch-
bottom sludge (VOnk and Van den Hove~
1985) and other soil
types and is immobile (Ku and Jacob, 1983b).
Low levels @O.1ppm) of radioactivity
were found in the leaves
and sterns of cotton seedlings
grown in Lu.fkin fine sandy loam
containing
10 ppm
of
[3HJavexmectin
B]a;
some
mdioactivity
(23 ppm) was found on the seedling
roots,
but whether
it was
absorbed or adsorbed was not detennimd
(Bull et al., 1984).
Little
radioactivity
from labeled
avermectin
Bla or its degradates
was
taken into the vascular system of the cotton seedlings.
This low
Mecun.doc
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-46
level
of
uptake
is
consistent
with
the- obse~ed
lack
of
phytotoxicity
for a number
of other plant species
grown in soil
containing
avermectin
B1. The
obsemed
lack
of
pronounced
systemic insecticidal activity for ivermectin and averrnectin B1 also
indicates little or no uptake of these compounds by plants.
Tntiated avermectin Bla was found to undergo rapid depletion
and
degmdation when applied to the leaves of cotton plants (Bullet
al.,
1984).
Little more than half of the applied radioactivity
was still
present on the leaf at 2 days post treatrnen~ and only one-third of
this was averrnectin.
At this time, roughly
5V0 of the applied
radioactivity
was found within the leaves.
By eight days post
treatment
only 13% of the applied radioactivity
was found on the
leaf surfaces, and only 15’%0of this residue was avermectin;
8% of
the dose was within the leaves.
The authors suggest that the rapid
loss of applied labeled avermectin Bia and its instability
are related
to
the known
photolability
of this
compound.
A
non-polar
photodegradation
product of avennectin
Bla has been identified as
the Ag’g-immti
(Ku and Jacob, 1983).
The slight uptake by cotton seedlings
of radioactivi~
from soil
containing
[3H]avennectin
Bla, repoti
by Bull
et al. (1984),
suggests
that if soil were to contain
the close structural
analog
ivefiecti
uptake of the latter by plants grown in the soil would
also be minor.
Data from Bull et al. (1984) concerning
lack of
Mecwn.doc
Jan.%
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-47
uptake
of
radioactivity
by
grass
from
a
plot
treated
with
[14C]avermectin
B]a
ant
bait
fonmdation
also
support
this
contention.
In additio~
studies comparing the pesticidal
activities
of dimxtly
applied
vs. systematically
applied
(soil)
avermectin
demonstrated
little or no uptake of the agent from soil.
Moye and coworkers (1987) reported radioactive
residues in crops
(sorgh~
lettuce, carrots and turnips) grown in three types of soil
to which [14C]avermectin
B 1a had been applied 3 to 12 times at
0.025
to
0.030
lb/acre/application.
Radioassay
of
the
crops
indicated a maximum total residue of 14 ppb.
~
only 4.4°/0 of the
total radioactive
residue
in a lettuce
leaf was extractable
with
acetone, it is clear that most of the residual radioactivity
is either
chemically
different iiom avermectin B la or present in a strongly
bound form (probably
incoqxxated
into the vegetable
matter
as
small molecules resulting from breakdown of the avermectin
B1 ~.
Iwata et al. (1985) reported that the initial rate of avemnectin
Bia
degradation
on citrus iiuits and leaves is very rapid.
Total residue
dissipation
half lives were 50 days (lemon leaves), 58 days (orange
tid)
and 36 days (lemon rind).
timparison
of total radioactive,
residues
with
percentage
ayerrnectin
Bla
showed
continuing
degradation
of the actual avermectin
Bla present
in the residues.
Comparison
of pulp and rind radioactive
residues indicated
lack of
translocation
from the rind into the e&ble portion
of the fruits.
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control Documentation
I. Summary
F. Environmental
Assessment
Mectmdoc
F-48
Residue
levels
(total radioactivity)
were less than-0.004
mcg/g
(limit of detection)
in new growth leaves from tips of branches
whose mature leaves had been immersed in a [31+javennectin
B1a
solution (3 mg/rnL) 91 days earlier.
It is reasonable to assume that
the extent of translocation
(both leaf to leaf, and rind to pulp) of
ivermectin
would also be very slight.
Ivermectin
would also be
expected to exhibit a short persistence on fruit surfaces because of
photodegradation
d.
Fate Summary
Photodegradation,
combined
with
oxidative
degradation
in soil
under aerobic conditions, will diminish the extent of environmental
contamination
by ivermectin.
Human drug use of ivermectin
is
unlikely
to
result
in contamination
of
surface
water
and,
as
movement
of ivermectin
through soil is sligh~ contamination
of
surface and subterranean
water is highly improbable.
Binding
of
iverrnectin
to soil sediment
in water greatly reduces
its eff6ctive
concentration.
Based
on the discussion
of
soil
binding,
soil
metabolism
and
photodegradatio~
it
can
be
predicted
that
ivennectin
present
in the environment
would not be expected
to
undergo
significant
movement
or translocation,
and
should
not
accurm.date.
Given
its
environmental
fate
characteristics,
,
ivermectin
will
be
readily
eliminated
from
the
aquatic
environment.
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4--
k.
“.
Ivermectin
Chemical and Pharmaceutical
Manufactig
and
Control
Documentation
I. summary
F. Environmental
Assessment
8.
Effect on the I%rironm ent
F-49
a.
A! uatic To-
The effects of iverm~
avermectin and related compounds
upon
a number of aquatic species (including I)aphnia),
as determined
in
laboratory
tests,
are
reported
in
Table
1.
Ivermectin
and
avermectin
B 1 show
comparable
aquatic
toxicity.
However,
ivermectin
is more
toxic
to daphnids
than
is avermectin
B 1.
Daphni~
the
freshwater
aquatic
species
most
sensitive
to
ivermect~
have been used for risk assessment
purposes.
The
concentrations
at which toxicities are observed in these tests should
be regarded as ‘worst-case” values because factors (i.e., binding to
soil and other particulate
matter, and photodegradation)
known to
reduce exposure under field conditions are absent.
Iverrnectin
and
averrnectin
show
comparable
mammalian
toxicity
(Lankas
and
Gordo~
1989).
I)
Daphnia
a)
~oxicity
,,
The 48-hr LC50, 48-hr NOEL and calculated 21-day MATC values
for ivennectin
toward Daphnia are 0.025, -0.010
and 0.004 ppb,
respectively
(see Table 1).
As indicated
in 7.b., the presence
of
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7..
,
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-50
soil in the test system
reduced
the toxicity
of ~ermectin
and
avermectin B1 toward Daphnia.
It is clear that the environmental
and the very limited use of the
fate characteristics
of ivexmec~
drug in humans,
make it highly
unlikely
that
environmental
concentrations
as
a result
of the
proposed
action will reach levels toxic
to any
aquatic
species,
including
Daphnia.
Data in Table
1 also support
the view that
ivermectin-related
compounds
such
as its monosaccharide
and
aglycone
and
feces/soil
column
percolates
which
contain
ivermectin
degradation/metabolites
are much
less toxic than the
parent compound
(based on 48-hr. LC50 data for the former, and
48-hr. NC)EL data for the percolates).
Avermectin
B 1 is less toxic
toward
Daphnia
than is ivermec~
and the known
degradation
products
of avermectin
B la (i.e., the A899 isomer
and the 8a-
hydroxy
compound)
are also much
reduced
in toxicity
toward
Daphnia compared to their parent compound
(Forbis,
Georgie and
Burgess, 1985a and b, respectively).
a)
Toxicity
Fis~’are at ieast 100-fold less sensitive to the toxicity of ivermectin
than are Daphnia.
Ivermectin
96-hr LC50 values,
corrected
for
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Ivermectin
Chemical and Pharmaceutical
Manufacting
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-51
assay, (Table 1) for rainbow trout and bluegill sunfish are 3.0 and
4.8 ppb, respectively,
fm higher (factor of at least several orders of
m~de)
th~
the extremely low concentrations
that might occu
with ivermectin
in ponds and streams because of the use of this
drug in the treatment
of Strongyloidiasis
and onchocerciasis.
In
general, the acute toxicity
of avermectin
toward fish [e.g., LC50
values
of 3.6 and 9.6 ppb for rainbow
trout (Sous~
1981) and
bluegill
sunfish
(Wlson,
1981), respectively]
is similar
to that
exhibited by ivennectin.
b)
J3ioconcen tration in Sunfish
The bioconcentration
of [3~avermectin
Bla by the bluegill sunfish
is modest
and occurs gradually
(Forbis
and Franklin,
1983).
In
water containing
0.099 mg of test compound per liter (0.099 ppm)
the daily bioconcentration
factor for whole fish was only 19 to 69,
with an uptake tissue concentration
for whole fish of 1.9 to 6.8 ppb;
accumulation
ceased by about day ten. A 95 percent clearance rate
of radioactivity
for whole fish was found for a M-day deputation
period; the whole-fish
concentration
dropped from 6.8 to 0.32 (day
14). This bioconcentration
value of less than 100 and the rapid rate
of deputation
are favorable, as they demonstrate
that concentration
and retention
of avermectin
Bla (and hence
ivermectin)
in fish
,
shouid not be an environmental
concern.
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,
‘-=.
Iverrnectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
1. summary
F. Environmental
Assessment
Mectzn.doc
F-52
3)
Toxicity Toward Other Aauatic Snecie~
The toxicity
of ivermectin
and
avermectin
toward
other
aquatic
species is also presented in Table 1. Iverrnectin has a moderate effect
upon the growth
characteristics
of Clzlorella pyrenozdosa,
a fresh
water
unicellular,
non-motile
chlorophyte,
at the
relatively” high
concentrations
of 1 to 10 ppm (Halley et al., 1989). Avermectin
B 1
exhibits
14- and 9-day
EC50
values
of 3,900
and
100,000
ppb,
respectively,
with duckweed
and a freshwater
algae,
Selenastrwn
capricornutum (see Table 1).
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Ivermectin
Chemical and Pharmaceutical
Manufacting
and
Control
Documentation
I. summary
F. Enviro~enti
Assessment
TABLE 1
F-53
EFFECT OF IVERMEC~,
~~~.c~
AND ~J,ATFD
CO~O~S
WON
AOUA~C
SP
coMPo~
SPECIES
IF,s
EFFECT
Ivermectin
Ivemecti
(H2BIJ
monosaccharide
Ivermectin
(H2BId
aglycone
Ivermectin
Feces from ivermectin-
dosed stee;/soil column
percolates
Ivennectin
Ivermectin
Avermectin
B]
Avermectin
Bla
Avermectin
B1
Daphnia
Daphnia
Daphnia
Daphnia
Daphnia
Bluegill
Sunfkh
Rainbow
Trout
Daphnia
Bluegill
Sunfish
m“
48-hour
LC50 0.025 ppb
48-hour
LC50 0.400 ppb
48-hour
LC50 >17 ppba
48-hour NOEL
-Q.OIOppb
48-hour
NOEL -3.2 ppbc
96-hour
LC50 4.8 ppb
96-hour
LC50
3.0 ppb
48-hour
LC50 0.34 ppb
Estimated btha.1
Threshold 6.7 ppb,
NOEL 2.3 ppb
@ynamic
7-Day
Toxici~
Study)
96-hour
LC5042
ppb
Halley et al., 1989
Halley et al., 1989
Halley et al., 1989
Haley
et al., 1989
Halley et al., 1989
Forbis, A.D., 1983
McAllister,
W.A., 1986
Surprenant
& LaBlanc,
1981
Forbis, 1983
.,
Douglas and Pen, 1985
Mectzn.doc
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4-.
1-*
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
Avermectin B]
Averrnectin B1
Avermectin B1
Avermectin B]
Avermectin B1
Avermectin B1
A839-Avermectin
B]a (@otochemical
degradation product of
avermectin Bl~
8a-Hydroxyavermectin
B]a (aerobic soil
degradation product of
avennectin
B@
Avermectin B1
Ivermectin
F-54
TABLE 1 (Con
nued]
ti
Channel
Catfish
Mysid
shrimp
Sheepshead
Minnow
Oyster
Bluegill
Sunfish
Rainbow
Trout
Daphnia
Daplmia
96-hour
McAllister
et al., 1985
LC50
24 ppb
96-hour
Surprenan~
D., 1988a
LC50 0.022 ppb
96-hour
Ward, 1985
LC5015 ppb
48-hour
War~
1983
EC50 430 ppb
96-hour
Wdson,
1981
LC50 9.6 ppb
96-hour
so-
J.V., 1981
LC50 3.6 ppb
48-hour
Forbis et al., 1985a
LC5014 ppb
48-hour
LC5026
ppb
Forbis et al., 1985b
Daphnia
21-day MATC
Surprenanq
D.C., 1984
(Life Cycle)
0.03-~.09 ppb
ACR
6.5
Dap&a
Estimated MATC
Calculated
value’
(Life Cycle)
0.004 ppb
Mectzn.doc
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.-
‘.>
Ivermectin
Chernicd
and Pharrnaceuticzd Manufactig
and
Control
Documentation
I. Summary
F. Environmental
Assessment
Avermectin B]
Avermectin B1
Avermectin B]
Iverrnectin
TABLE 1 (Continuedl
Averrnectin B 1
Mysid shrimp
(Life Cycle)
Rainbow
Trout (ELS)
DuckWeed
Selenastrum
capricornutum
Chlorella
pyrenoidosa
F-55
28day
MATC
Surprenan~D.C.,1988b
0.0035-0.0095
ppb
ACR 3.8
MATC 0.52-0.96
McAllister,
W.A., 1986
ppb ACR 4.6
14-day
Hollister,
1981a
EC50 3900 ppb
9-day EC50
Hollister,
198 lb
100,000 ppb
Maximum tiOWth
Halley et al., 1989
Rate, No Effkct
at 10,000 ppb
Mectzn.doc
..
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“.
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4-
-...c
lvermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Notes:
a
b
c
d
c
L~50
could
Assessment
F-56
not be determined
accurately
as the highest
concentration
of the aglycone
studied W=
17 ppb.
Feces from steers dosed with radiolabeled
ivermectin were mixed with soil and applied to the
tops of soil columns.
Water was allowed to percolate through the columns;
collected
water
contained no (<0.01 Oppb) ivenmctin,
which binds to top of column.
Because the low concentrations
of ivermectin-related
compounds
in the faes/soiI
column
percolates Iimited the extent of testing, suilicient
data could not be collected to calculate the
LC50 value accurately.
ACR
=
Acute
to
Chronic
Ratio;
LC5@4.ATC
(Maximum
Acceptable
Toxicant
Concentration).
An estimated MATC for ivermectin
was calculated from the 2 l-day MATC for avermectin
(0.03 to 0.09 ppb; geometric
mean
of 0.052 ppb) and the ratio of the ivermectin
and
avermectin
48-hr.
LC50 values
for Daphnia
(0.025 and 0.34 ppb, respectively):
X/52
=
25/340; X = 0.004 ppb.
Mecm.doc
Jan.96
—.—
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
b.
other
F-57
An overview
of the pharmacology
of ivermectin
and Mormation
on the toxicity
of ivermectin
to soil microbes,
plants,
various
aquatic organisms,
nematodes,
arachnids, insects, and annelids,
as
well as a literature
review,
can be found in the Environmental
Assessment
for
lVOMEC@
(ivennectin)
Injection
for
Swine
(MDA
135-008).
The
present
Environmental
Assessment
supplements
this
with
recent
information
on
ivermectin
and
supporting
information on avermectin B 1.
The low phytotoxicity
toward six plant species (cucumber,
lettuce,
soy-
perennhd
ryegrass,
tomato,
and
wheat)
has
been
demonstrated
with ivermectin
in both a seed germination
and root
elongation
study
(Feutz
and
Stuennan,
1995a)
and
a seedling
growth study (Feutz and Stuerman,
1995b,).
The results
(NOEC
values) from the studies are presented
below.
All NOEC values
were based on mean measured concentrations.
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Iverrnectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
Table 2: Seed Germination
and Root Elongation
Phytotoxicity
Study with Ivermectin
Species
NOEC, ppm
F-58
Germination
Root Elongation
Cucumber
>980
98
Lettuce
>980
z980
Soybean
>930
>930
Perennial Ryegrass
>980
98
Tomato
>980
>980
Wheat
>930
>930
Table 3: Seedling Growth Phytotoxicity
Study with Iverrnectin
in Sand
Species
NOEC, ppm
Shoot Length
Shoot Weight
Root Weight
Cucumber
0.68
0.68
>790
Lettuce
6.9
0.68
>790
soybean
~790
6.9
2790
Tomato
0.68
0.68
0.68
Wheat
6.9
0.68
0.56
In additio~
a seedling growth study was conducted with perennial
ryegrass
in sand
and
sandy
loam
soil
(Feutz
and
Stuennan,
1995b). The low phytotoxicity
of ivermectin to perennial ryegrass
was tier
reduced by approximately
2000-fold,
as measured
by
Mcctzn.doc
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
.
F. Environmental
Assessment
F-59
the NOEC
for shoot weight
(the most se)isitive
parameter)
in
sandy loam soil relative to that in sand.
Table 4 Seedling Growth Phytotoxicity
Study for Perennial
Ryegrass with Ivermectin
Growth Medium
NOEC, ppm
Shoot Length
Shoot Weight
Root Weight
Sand
7.7
0.57
2780
Sandy Loam Soil
>1 ]00
>1100”
>1 ]00
Both ivermectin
and avermectin
are toxic toward a wide variety of
agricultural
pests
including
the Mexican
bean
beetle,
Southern
army worm,
aphids,
and mites.
The effect of ivermectin
upon
animal ectoparasites
including flies, fleas, lice, ticks, and mites has
also been determined
(Fisher and Mro~
1984).
A review article
by Strong and Brown
(1987) discusses
the avermectins
control.
Avermectin
B1 has no effect upon vitrification
in humic
loam soils at up to 0.4 mg/kg
soil, or 0.4 ppm (&rug
in insect
sandy or
and” Van
Agtere~
1985).
There
was
no
effect
upon
notification
or -
respiration
(Halley et al., 1989) for soil containing
30 ppb of fecal
ivennectin
and
metabolizes
from
subcutaneously
dosed
(300
Mectm.doc
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Ivennectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-60
mg/kg) steers.
These are much greater concentratio~
than would
be found in the environment from human health use.
Avermectin B1 was found to impair the total gas production
and the
methane production
of anaerobic methane-forming
bacteria above
a concentration
of 1000 mg/L @mstvei~
et al., 1985) (1000 ppm,
the NOEC).
The EC50 for total gas production
was determined
(by extrapolation)
to be >>3200 mg/L; a significant
inhibition
of
methane
production
rate
could
not
be
detected.
These
are
concentrations
f=
above
any
anticipated
to
arise
in
the
environment.
The LC50 earthworm
toxicity
for ivermectin
is 315 mgkg
soil
(315 ppm) and the corresponding
96-hr. NOEL is 12 ppm @lalley
et al., 1989). These are much gnater
concentrations
than would be
. .
found in the environment
horn human health use.
Because
of 1) the very limited amount of ivermectin
introdumd
into
the
environment
through
its
use
as
an
anthelmintic
for
humans,
and 2) its rapid elimination
from the environmen~
there
will be no undesirable,
adverse effkct of this drug with respect to
aquatic species or other life forms in the environment.
Me.ctzn.doc
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-61
Ivermectin
has been tested for acute oral toxicity
in a variety
of
laboratory animal species (Lankas and Gordo~
1989). Acute toxic
effects
are
characterized
by
signs
of
CNS
toxicity
including
tremors,
mydriasis,
and lethargy.
The acute
oral LD50
values
range from about 80 mg/kg in dogs to about 30 mg/kg
in mice.
The
derrnal
LD50
values
for
ivermectin
following
24-hour
occluded
exposure
in
rabbits
and
rats
are
406
mg/kg
and
>660 mf$lsg, respectively.
The oral LD50 of ivermectin
in mice is
approximately
30 mgkg.
In assessing the toxicity of ivermec@
it is important
to note that
rodents,
and mice in particular,
are poor models
for predicting
effects of ivermectin in humans.
For example, doses of ivermectin
of 0.2 mgkg
produce
clinical signs of drug effects (tremors
and
ataxia) in mice (Lank
and Gordo~
1989). This dose (0.2 mg/kg)
of ivennectin
is used to treat onchocerciasis
infections
in humans.
Since 1982, millions of people have been treated for onchocerciasis
(0.15 -0.2 mgkg)
with no serious drug-related
adverse eff&ct.s.-
,.
A comparison
of acute
exposure
data in rhesus
monkeys
with
humans suggests that primates are abetter
model for predicting
the
effects
of ivenmctin
exposure
in humans.
In
monkeys,
the
minimum
acutely
toxic
oral dose is 2 mg/kg
based
on a 25°/0
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:.*
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-62
incidence of emesis in treated animals (Lankas and ~ordoq
1989).
Peak plasma levels at this dose were 110 nghnl or about 5-fold the
human therapeutic plasma concentmtion.
Doses of 8-24 mg/kg in
monkeys
produced
mydriasis
and sedation
in addition
to emesis
with no deaths, despite plasma levels up to 680 nghnl.
These signs
are similar to those reported in a carefidly documented
case of a
child
after
accidental
ingestion
of about
8 mg/kg
iverrnectin.
Emesis, mydriasis,
and sedation were reported
in this individual
followed by complete recovery.
Therefore, the primate is a better
model for predicting
the effects of human exposure to ivermectin
than rodents.
In addition, a 2-week repeat dose study in monkeys
with ivermectin
administered
at dosage levels up to 1.2 mg/kg/day
produced no evidence of toxicity.
Ivennectin
was
not genotoxic
in vitro
in the Ames
microbial
mutagenicity
assay
(Salmonella
typhimurium
strains)
with
and
without rat liver activatio~
the mouse lyrnphoma cytotoxicity
and
mutagenicity
assays and in the unscheduled
DNA synthesis
assay
inhuman
fibrobh.sts.
Ivermectin had no adverse el%zts on fertility
in rats at doses of up to eighteen times the maximum
human-dose
@ased on mg/kg/day).
Long-term studies in animals have not been
petiorrned to evaluate the carcinogenic potential of ivermectin.
.
Developmental
toxicity studies cxmducted with ivermectin
in rats,
rabbits, and mice have shown that the drug is not selective y toxic
Mectzn.doc
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-63
—
to the fetus.
No-effect
levels for embryo/fetal
toxicity were at w
near
those
that
produced
severe
matemotox.icity
(Larks
and
Gordo~
1989).
Therefore,
a risk assessment
for developmental
effects based on maternal exposure will provide even greater safety
margins
for developmental
toxicity.
This is supported
by target
animal safety studies conducted
in a variety
of domestic
animal
species treated at 2-fold or 3-fold the recommended
use level of
ivermectin
with
no
evidence
of
developmental
toxicity.
In
addition, extensive clinical use of ivermectin
in these same species
with over a billion
doses administered
to cattle,
sheep,
horses,
swine, and dogs has confirmed
the safety of this drug in pregnant
animals.
There
are, however,
no adequate
and well-controlled
studies in pregnant women.
e.
?harrn
CO1OW
a
Ivermectin
is metabolized
in the liver and iverrnectin
and/or
its
metabolizes
are excreted almost
exclusively
in the f-s
over an
estimated
12 days with less than
lo/o of the administered
dose
excreted in the urine.
The plasma half-life of ivermectin
in man is
about 12 hours.
Ivermectin
inhibits
intemeurons
to the
stimulating
release
signal
transmission
from
the
ventral
cord
excitatory
motor
of the
inhibitory
neurons
in nematodes
by
neurotransmitter,
gamma-
Mectzn.doc
Jan.%
.
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4-
7.
.
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
9.
F-64
aminobutyric
acid (GABA)
from presynaptic
nerve terminals.
In
arthropods, a similar mechanism
inhibits signal transmission
at the
neuromuscular
junction.
Ivermectin
does not readily penetrate the
CNS of mammals,
and thus, does not interfkre with mammalian
GABA-dependent
neurotransmission.
In animal species studied (dog, swine, cattle, sheep), liver and fat
contained the highest residues of ivermectin and little was found in
muscle and kidneys.
The unaltered drug was the major residue in
the liver.
The high degree of extractability
indicates that there are
few, if any, macromolecukuly
bound drug or metabolize residues.
In various species, virtually
all of the excreted
drug-residue
was
eliminated in the feces.
Use of Resources and Enerw
The raw materials
used to manufacture
MECTIZAN
(iverrnectin)
are common
organic
compounds
and phannaceuticxd
excipients
which are generally
regarded
as safe (GIUN3).
The amounts
of
these which will be used for production
of the human dosage form
will be insignificant
compared to the amounts consumed
for other
applications.
Energy requirements
for dosage form production
is
nominal and without
environmental
impact.
Energy will also be
used to transport
the
drug
product
and
to
dispose
of wastes
associated with this production
but the amounts involved will also
Mectm.doc
Jan.96
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4-
‘-.
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
ControI
Documentation
I. summary
F. Environmental
Assessment
10<
F-65
be negligible.
The land to be used for production
of the drug
substance and the dosage form is already committed
to production
of other similar products.
Approval
of the intended use of ivermectin
for the treatment
of
Strongyloidhsis
and onchoceriasis
will
have
no
effect
on any
endangered or threatened species or upon property listed or eligible
to be listed in the National Registry of Historic Places.
h4iti~ation Meas ures
The measures
taken
to avoid
potential
adverse
environmental
impacts
associated
with
the
manufacture
of
MECTIZAN
(ivermectin)
include proper disposal of liquid and solid waste as
described
in
Section
6
of
this
Environmental
Assessment.
Moreover, the distributio~
use and destruction
of returned
goods
takes place under highly regulated and controlled
conditions
which
further mitigate against adverse environmental
consequences.
11. Alternatives
to the Proposed Action
.,
MECTIZAN
(ivermectin)
has been demonstrated
to be generally
well
tolerated
in
the
treatment
of
both
strongyioidiasis
and
onchocerciasis.
From
an
environmental
prospective,
use
of
MECTEZAN will result in negligible release of drug substance
or
Mectzn.doc
Jan.96
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?-
\..
lvermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-66
active metabolizes and thus poses no environmental
risk.
Approval
of MECTIZAN
(ivennectin)
for the indicated
use
is therefore
prefmble
to non-approval,
the only alternative
to the proposed
Meet.zn.doc
action.
Jan.96
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4
-.
7 .=
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-67
12. J,ist of Prerxtrer~
Stuart Bather
B.S. - Chemical Engineering,
1961
Columbia University
New York, NY
M.S. - Chemical Engineering,
1964
Columbia University
New York, NY
Director, Developmental
Technology
Merck Research Laboratories
Bruce A. Halley
B.A. - Chemistry,
1970
The College of Wooster
Wooster, Ohio
Ph.D. - Organic Chemistry,
1977
The University of Caltiorni%
Santa Barbara
Santa Barbaray CA
Senior Research Fellow,
Drug Metabolism 11
Merck Research Laboratories
Mectzmioc
Jan.96
.
.“.--
.
.
.—
-
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
h4ectzn.doc
Diane Krell
B.S. - Chemical Engineering,
1989
Pennsylvania
State University,
University Park PA
Project Engineer,
Central Environmental
Resources
Merck Manufacturing
Division
G. Lankas
A.B. - Chemistry,
1971
Princeton University
Princeton, New Jersey
Ph.D. - Toxicology,
1977
Universi~
of Cincinnati
Cincinnati, Ohio
F-68
Senior Director,
Department of Safety Assessment
Merck Research Laboratories
Jan.96
;
—
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>..
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environrmmti
Assessment
Steven Wittmer
B.S. - Civil Engineering,
1975
Universi~
of Delaware
Newark
DE
M.S. - Environment
Engineering,
1980
University of Delaware
Newar~
DE
Director, Environment
Affhirs,
Merck Manufactig
Division
F-69
Mectzn.doc
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Sumnuuy
F. Environmental Assessment
13. Certih3tion:
The
undersigned
official
certifies
that
the
information
presented is true, accurate and complete to the best of the
knowledge
of the firm responsible
for preparation
of the
environmental assessment.
*
Date
Vice President,
Safety & the Environment
Merck & Co., Inc.
F- 70
Meztm.&c
Jan.96
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4-
....
Ivermectin
Chemical and Pharmaceutical
Mantiacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
14.
“t
L1 erature Cited
F-71
Barug, D. and R. van Agteren.
1985. “Influence of Avermectin
B1
on the Soil Vitrification”,
Study Report - Netherkmds
Organization
for Applied Scientific Research.
Bull, D.L., G.W. Ivie, J.G. McConnell,
V.F. tiber,
C.C. K%
B.H. Arisen,
J.M. Stevenson
and W.J.A. VandenHeuvel.
1984.
“Fate of avermectin
B1 a in soil and plants”.
J. Ag. Food Chem.
32:94-102.
Campbell,
W.C. 1991 “Ivermectin
as an Antiparasitic
Agent
for
Use in Humans”.
Annu. Rev. Microbiol. 45:445-74
Douglas,
M.T.
and
I.B. Pen.
1985.
“The
Acute
Toxicity
of
Avermectin
B1
to
Carp
(Qprinus
carpio)”,
Huntingdon
Research
Center,
Huntingdon,
England.
Study
Report
-
Carnbridgesh.ire,
Feu@ E. and L. Stuerrnan.
1995a
“Determination
of the Effects of
Ivennectin
on Seed Germination
and Root Elongation”.
Analytical
Biochemistry
Laboratories,
Inc. Coh.unbi~ MO 65202
Mectm.doc
Jan.96
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Iverrnectin
F-72
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
.
F. Environmental
Assessment
Fe@
E. and L. Stuerman.
1995b. “Determination
of the Effects of
Ivennectin
on Seedling
Growth of Terrestrial
Plants”.
ha.lytical
Biochemistry
Laboratories,
Inc. Columbi~
MO 65202
Fisher, M.H. and H. Mrozik.
1984.
“The avermectin
ftily
of
macrolide- like antibiotics”.
In, It4acrolide Antibiotics,
Chemistry,
_
~
-,
S. om~
Ed., Academic
Press, New York.
pp. 553-602.
Forbis, A.D.
1983.
“Dynamic
Acute Toxicity
of Avermectin
B 1~
to
Bluegill
Sun&h
(Lepomis
macrochirus)”,
Study
Report
-
Analytical Biochemistry
Laboratories,
Inc. Columbi~
MO.
Forbis, A.D.
1989.
“Acute Toxicity of Soil-Bound
3H-Avermectin
B] to Daphnia
mazna;
Acute
Toxicity
of 3H-Averrnectin
B 1 to
B
-s
studY Rewrt
- Analytical
Biochemistry
Labs,
Inc., Columbi~
MO.
Forbis, A.D. and L. Franklin.
1983.
“Uptake,
Deputation
and
Bioconcentration
of
3H-Avermectin
Bla
by
Bluegill
Sunfish
(k.Wmis
~acrochim
)“, Study Report
- Analytical
Biochemistry
Labs, Inc., Cohunbi~
MO.
Mectm.doc
Jan.96
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IVermectin
F-73
Chemid
and Pharrnaceutiml
Ma.nufacting
and
Control
Documentation
L summary
F. Enviro~enti
Assessment
%
Forbis, A.D., L. Georgie and D. Burgess.
19$5a.
“~cute
Toxici&
of Delta 8,9-cis Averrnwti
B la to Dan~ia
~a_gna”, Study Repo~ -
Analytical Biochemi~
Labs, Inc., Colurnbi4
MO.
Forbis, A.D., L. Georgie and D. Burgess.
1985b.
“Acute Toxicity
of 8a-Hydro~
Averrnecti
B la to Daphnia mama”,
Study Report -
Analytical Biocherni~
Labs, Inc., Cohunbi~
MO.
Halley, B.A.
1985.
“Sorption/Desoption
of Ivermectin
with Iowa
Soil”, Intend
Report - Merck Research Laboratones.
Halley,
B.A.,
T.A.
Jacob
and
A.Y.H.
LU.
1989.
“The
environrnenti
impact
of the use of ivermectin:
Enviromenti
effects and fate”.
Chemosphem
18:1543-1563.
Halley,
B.A.
1990.
“The
Photodegra&tion
of
[3HjIvemecti
Under
Artificial
Light
(AEDM-72)”,
Internal
Report
-
Merck
Research Laboratories.
Mectzn.doc
Jan.96
HanstveiG A.O., H. Oldersm& M.A.H.L. Pullens and L. Pot.
1985.
“The
Effixt
of Avennecti
B1 on Anaerobic
Meihane-Fofig
Bacteria”,
Study
Report
- Netherlands
Organization
for Applied
Scientific Research.
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4-
-..1
Iverrnectin
Chemical and Pharmaceutical
Manufacturing and
Control
Documentation
I. summary
.
F. Environmental
Assessment
F-74
Hollister, T.A.
198la.
“The Effect of Avermectin
B 1 to DuckWeed,
-
pm.,
Study Report - EG&G Bionomics
Marine Research
Laboratory, Pensacol~
FL.
Hollister, T.A.
1981b. “The Effkct of Avermectin
B 1 to the Fresh
Water Alga Selenastrum
cauricomu turn”, Study Report
- EG&G
Bionomics Marine Research LaboratoV,
Pensacol~
FL.
Iwa~
Y., J.G. MacConnell,
J.E. Flor, I. Putter and T.M. Dinoff.
1985. “Residues
of averrnectin
B1 a on and
in citrus
fruits
and
foliage”.
J. Ag. Food Chem. 33:467471.
Ku, C.C. and T.A. Jacob.
Bla
in Water
and Soil
Research Laboratories.
KU C.C. and T.A. Jacob,
1983a
“Photodegradation
of Avermectin
Environment”,
Internal
Report
- Merck
1983b.
“Mobility
of Averrnectin
Bla in
Soils”, Internal Report - Merck Research Laboratories.
Lankas,
G.R.
and
L.R.
Gordon.
1989.
“Toxicology”.
In,
Jverm ectin
~
Abamectin.
W.C.
Campbell,
E.D.,
Springer
Verlag, New York. pp. 89-143.
Mectm.doc
_—
. .———-
.-
.-. —
Jan.96
—
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.-
,...
Ivennectin
Chemical and Phannaceutica.1 Manufacturing
and
Control
Documentation
.
I. summary
F. Environmental
Assessment
F-75
McAllister,
W.A.
1986. “Early Life Stage Toxicity
of Avermec@n
B1 (MK-0936
Technical) to Rainbow Trout (SalmQ gairdnefi)
in a
Flow-Through
System”,
Study Report
- Analytical
Biochernkry
Labs, Inc., Cohunbi~
MO.
McAllister, W.A., J. Bowman and P. Cohle.
1985. “Acute Toxicity
of MK-0936
Technical
to Channel
Catfish
(Jctalurus
punctatu@”,
Study Report - Analytical Biochemistry Labs, Inc., Colurnbi~
MO.
McCauley, J.A.
1979. “Aqueous Volubility of MK-0933”,
Internal
Report - Merck Research Laboratories.
Moye, H.A., M.H. Malagodi, J. Yob, G.L. Leibee,
C.C. Ku and
P.G. Wislocki.
1987.
“Residues
of avermectin
Bla
in rotational
crops
and
soils following
soil tieatment
with
[14C]avermectin
Bla~~. J. Ag. Food Chern.”35:859-864.
OstlinL
D.A. and S. Cifelli.
1980.
“MK-933:
The Effect of Dirt
Treatments
on the
Ability
of
Concentrations
to
Kill
D2
x,
~temd
Report-
Merck Research Laboratories.
sow
J.V.
1981.
“Acute Toxicity of L-676,863 -OOV50 Technical
to
Rainbow
Trout
(salmo
gairdneri)”,
Study
Report
- EG&G
Mectzn.doc
Bionomics,
Wareharn, MA.
Jan.96
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F-76
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control Documentation
.
I. Summary
F. Environmental
Assessment
Strong, L. and T.A. Brown.
1987. “Avermeetins
in insect control
and biology: a review”.
Bull. Ent. Res. 77:357-389.
Surprenan~
D.C. and G.A. LaBlanc.
1981.
“Acute
Toxicity
of
L-676,863 -OOV50 to the
Water
Flea
(Dardmia
~a_ma)”,
Study
Report - EG&G Bionomics, Wareharn, MA.
Surprenan4
D.C.
1984.
“The Chronic Toxicity
of 3H-Avermectin
to Daphnia
magna”, Study Report - EG&G Bionomics,
Wareham,
MA.
Surprenan~ D.C.
1988a. “Acute Toxici~
of 3H-Avermectin
B 1 to
Mysid
Shrimp
(Mvsidopsis
lmhia)
Under
Flow-Through
Conditions”,
Study Report - Springbom
Life Sciences,
Wareharn,
MA.
!hrprenan~
D.C.
1988b.
“Chronic Toxicity of 3H-Avermectin
B 1
to Mysid Shrimp @fvs idogsi~ ~ahia)”, Study Report
- Springbom
Life Sciences, Wareh~
MA.
Vow
J.W. and A.M. van den Hoven.
1985.
“Adsorption
of
Averrnectin B la to Ditch-Bottom
Sludge Particles”,
Study Report -
The Netherlands
Organization for Applied Scientific Research.
Mectzn.doc
Jan.96
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4-
-...
Ivermectin
ChernicaI and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summa.qv
.
F. Environmental
Assessment
Ward,
G.S.
1983.
“Acute
Toxicity
of
F-77
MK-0936
Technical
to
Embryos-Larvae
of Eastern Oysters (Cmssostrea
V@ ‘nica)”, Study
Repoxt - Environmental
Science and Engineering,
Inc., Gainesville,
FL.
Ward, G.S.
1985.
“Acute Toxicity of MK-936
Technical
to the
Sheepshead
Minnow
(C- -
vurinodon
varie ~atus)”,
Study
Report
-
Environmental
Science and Engineering, Inc., Gainesville,
FL.
Wilson,
B.F.
1981.
“Acute
Toxicity
of
L-676,863-OOV50
Technical
to Bluegill
(Lepomis
macro chirus)”,
Study
Report
-
EG&G Bionomics, Wareharn, MA.
Yeager,
R.L.
and
B.A.
Halley.
1988.
“Photodegradation
of
Ivermectin (MK-0933)
(H2Bla
Component)
as a Dry Thin Film by
Sunlight”, Internal Report - Merck Research Laboratories.
15. ~uortimz
Inform ation
a
A.Dproved Ivennectin
prod cts
u
Information
which supports the present Environmental
Assessment
can be found in assessments
prepared for the following
previously
Mectzn.doc
approved products:
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-78
.
GIVOMEC@
(ivermectin)
Injection
for
Cattle,
N-DA
128-409;
Approved 2/13/84 Federal Re~ister, Vol. 49, No. 30, Februay
13,
1984, p. 5344
GEQVALAN@
(ivermectin)
1.87°/0 Paste for Horses,
NADA
134-
314; Approved 5/21/84 Federal Register, Vol. 49, No. 104, May 29,
1984, p. 22275
cIVOMEC@
(ivermectin)
Injection
for
Swine,
NADA
135-008;
Approved
7/22/86
Federal
~e@ter,
Vol. 51, No.
136, July
16,
1986, p. 25686
GIVOMEC@
(ivermectin)
Pour-on
for
Cattle,
NADA
140-841;
Approved 12/04/90
./‘
/
Mectzn.doc
Jan.96
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4-
-. .
.
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
Appendix I
A.
Mectzn.doc
F-79
1.
Nli
clature
International
Non-Proprietary
Name
Ivermectin
U.S. Adopted Name
Ivermectin
Chemical Name
Ivermectin
is
a
mixture
of
two
closely
related
homologies
belonging to a class of compounds known as avermectins.
Ivermectin contains
90’% (rein):
22z3-dihydroavermectin
B1.
10% (ma):
22~3_&hydroavermec@
B~b
Laboratory Codes
MK-0933
Ja.n.96
__—-———.
———
—
——.
—
__———=.
.. ..
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1..<.
Ivennectin
Chemical and Pharrnaceuticd
Manufacting
and
Control
Documentation
I. Summary
F. Environmental
Assessment
Other Names
MEcmw
Eqvalan@
Ivomec@
Htigard
30@
Chemical Abstracts Service (CAS) Registry No.
70288 -86-7
2.
Description
Structural Formula
OCH,
b
HO,,
.
oc~
qc
o
““’’’o,,
b
...
WC
o
‘“”’’O(,,
qc
‘“”’”
HOH
F-80
Mectzn.doc
‘.<
Jan.96
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Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
Molecular Foxmula/MolecuIm
Weight
component B,~
C@~~O,~
875.10
component B,~
Ca7HnOlq
861.07
3.
~ vir
a.
solubilitv.
Aqueous
4 mg/L
K~= 1651
Melting Point
-155°C
d.
UV - Visible SWXtru.m (Methanol)
F-81
Maximum
at 245
nm
with
shoulders
at -237
and
-253
run
with Al*Al cm values of about 382, 349 and 248 respectively.
Mectzn.doc
-------
. ...
Jan.96
‘+.
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4-
,..
*
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Contiol
Documentation
I. Summary
F. Environmental
Assessment
F-82
Ivennectin
is susceptible
to photodegration
in aqueous
media.
Calculated half-lives under clear sky conditions are
summer
12 hours
winter
39 hours
4.
Environmental
Effects
a.
Aa uatic ToxiciN
There is an extensive bodj of literature on the aquatic toxicip
of
ivermectin
and
the avermectins.
Representative
studies
with
ivermectin are summarized below:
1)
DaDhnia ma$?na
48-hour LC~O =
0.025 mcg/L
NOEL
-0.010
mc@
2)
Blu egill Sunfis h LLeDomismacrochirusj
96-hour LC~O=
4.8 mcg/L
Mcctzn.doc
Jan.96
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“%.
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
3)
Rainbow Trout @.ncorhvnchus mvkzss+j
.
96-hour LC~O=
3.0 mcg/L
b.
Tti~
96-hour LC~O=
315 mg/kg soil
NOEL = 12 mg/kg soil
/
hkcun.doc
.
F-83
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 368 of 382

lvermectin
Chemical and Phannaceutid
Manufactig
and
Control
Documentation
I. Summary
F. Environment
Assessment
Appendix II
MSDS
Mectmdoc
*!.
Jan.%
..
F-84
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 369 of 382

lverrnectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-85
MATERIALSAFETYDATASHEET
PRODUCTNAME:
IVERMECTIN
PAGE: 10F 9
PLANTMSDSCODE: PR-020
Date: 1/96
1. ChemicalProduet and Company Identification
Manufacturer---
MERCK SHARP& DOHME
QUIMICA DEPUERTO IUCO, ~C.
P.O. BOX601
BARCELONET&PUERTO RICO; 00617
EmergencyTelephoneNumber—
(809) 846-3620 (P.R)
1-908-594-5555 (U.S.)
LabelName--–-—-–—
Ivermectin
ChemicalName———––––
Ivermectin(activeingredient)is a mixture of not less than
80% component Bla (5-O-demethyl-22,23dihydro-
avemwctin Al a) andnot more than 2070
component B1b
(5-Odemethyl-de( 1-methylpropy1)-22,23-dihydro-25-(l -
methylethyl) averrnectin Ala).
Synonyrns——————
Ivomec
MaterialStatisticalNumber———
Notavailable
MaterialProductNurnber---
SP-2097
Intended Use—-—————
Antiparasitic agent
2. Composition/Information
on Ingredients
Molecular
Mokeular
Comx)onent
Es?m2!&u
CAS Number
Percent(“Al
lvennectin (hmp. Bla
C@@]4
875
70288-86-7
CS.100
Comp. B1b
C@@14
861
(mixture)
EC Label
Not applicable
3. Hazards Identification
Appearance—————
Clear, moix off-white to slightly yellow powder
Emergency Overview
CAUTION!
Antiparasitic agent.
Toxic if swallowed.
Hannfid in contact with skin
May be harmful if inhaled.
,
Very toxic to aquatic organisms.
*** Continued on nextpage ***
Mectm.doc
Jan.96
———..—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 370 of 382

7. .
Iverrnectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F- 86
PRODUCT
NAME:
lVERME~
PAGE: 2 OF 9
-
–
PLANT MSDS CODE:
PR-020
Date: 1{96
Avoid contact of spilled material with soil. Do not allow
any water potentially contaminated with ivermectin
including storm water, runoff fbm spills and fire fighting
activities and contaminated wastewater to enter any
waterway, drain or sewer.
PotentialHealthEffects————
4. First-Aid Measures
Eye Contact—— -—-----
Skin Contact
----
Inhalation
—-
Ingetion
..——
Overexposure to ivermectin may cause drowsiness,
depressed motor activity, slowed breathing, dilation of the
pupils, tremors, vomiting, anorexia and incoordination.
Flush with plenty of water for
attention if irritation occurs.
15 minutes. Seek medical
Wash with soap and water. Seek medical attention if
symptoms appear.
In case of accidental overexposure, get to fresh air. If
irritation occurs get medical attention.
If ingested, call a physician or Poison Control Center
immediately. Drink one or two glasses of water and
induce vomiting by gently touching the back of the
throat with finger. Repeat until vomit fluid is clear. Do
not induce vomiting or give anything by mouth to an
unconscious person.
NoteiOPhysicians———
Sinceivermectink believedto produceeffectsthatmimic
enhancementof GABAactivityin animals,it is probably
wiseto avoiddrugsthat enhanceGABAactivity
(barbiturates,benzodiazepines,valproicacid)in patients
withpotentiallytoxicivcrmectinexposure.
../’
5. Fire-Fighting
Measures
FlashPoint(Wl%+—————
Not applicable
Flash Point Test Method--
Not applicable
*** Continued on next page ***
Mectzn.doc
Jan.96
—
.—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 371 of 382

—..
c
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-87
PRODUCT NAME:
IVERMECTIN
PAGE 3 OF 9
PLANT MSDS CODE: PR-020
Date: 1/96
Flammable Limits-LEL (%)—
Not appkable
-UEL (%)—
Not applicable
Autoignition Ternpemture (O(YF)-
Not available
Oxidizing Propeties—
Not available
Combustibility information—
Not available
Dust Explosivity Information—
Not available
Shock Sensitivity-----
Not available
FireiExplosion Hazards-------
Materialwill bum if ignited. Can form explosive mixture
with air in dusty conditions.
ExtinguishingMedia—---
Use water spray or all purpose dry chemical. Water
contaminated with iverrnectin should be contained and not
discharged to any waterway.
Special Fire Fighting Procedures-
Avoid creating significant airborne dust. Use fill
protective clothing and self-contained respiratory apparatus.
Contain all water potentially contaminated with ivermectin.
All exposed personnel and equipment should be
dccataminated
at the site.
HazardousDecomposition Products Resulting From a Fire-If
involved in
a fire, toxic gases including carbon monoxide and carbon
dioxide may be generated.
6. Accidental Release Measares
Personal Preeautions—
Immediately contact emergency personnel. Keep
unnecessarypersonnel away. Use suitable protective
equipment. (Section 8) Follow all fire fighting pro-es
(Section 5).
Environmental Precautions—
Ivennectin is very toxic to certain aquatic species. Avoid
--
contact of spilled material with soil. Do not allow any
water potentially contaminated with iverrnectin including
storm water, runoff fi-omspills and fire fighting activities
and contaminated wa.stewaterto enter any waterway, drain
or sewer.
*** Continued on next page ***
Mectm.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 372 of 382

4-
\.
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-88
PRODUCT NAME:
IVERMECTIN
PAGE: 4 OF 9
~
PLANT MSDS CODE:
PR-020
Date: 1/96
Methods for Cleaning Up—
If emergency personnel are unavailable, vacuum or
carefidly scoop up spilled material and place in an
appropriate container for disposal by incineration. Avoid
contact of spilled material with sod. Do not allow any
water potentially contaminated with ivermectin including
storm water, runoff from spills or fie fighting activities and
contaminated wastewater to enter any watenvay, drain or
sewer. Residual surface material should be removed with
towels moistened with methanol.
For additional assistance in the U.S., CHEMTREC provides a toll-free
Hotline for chemical emergencies
regarding spills, leaks, exposure or accidents:
1-800-424-9300.
7. Handling and Storage
Flandling——————
Compound should be handled in a contained area with
access limited to authorized personnel and managed so that
material is prevented iiom entering unregulated areas.
Storage———
—
Store in a tightly closed container in a cool, dry well
ventilated location.
Other-———
Protective clothing must be removed prior to leaving the
controlled area. Showers are required after handling the
material at the end of the workday. Always wash hands
with soap and water prior to eating, drinking, or smoking.
8. Exposure Controls/Personal
Protection
OSHA
ACGIH
Merck
Permissible
Threshold
Exposure
Exposure Lmit
Limit Value
Control Limit
QmQQW?X~_fXLXl_
.~.
Ivermectin
Not established
Not established
0.08 mg/m3
(8hr-lwA)
***
continued on next page ***
Mectm.doc
Jan.96
—
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 373 of 382

Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. summary
F. Environmental
Assessment
F-89
PRODUCT NAME:
IVERMECTIN
PAGE: 5 OF 9
PLANT MSDS CODE: PR-020
Date: 1/96
-----
.
.
9.
Lnstmeenrw ~on rrol~
Ventilation
PersonalProtective EauiDment
Respiratory—----
HanddAnns————
-.
EyefFace–—----
Additional Protective Equipment-
Physieal and Chemical Properties
Appeamnce
—
Odor/Threshold Level @pm)—
pH
Boiling PointfRange (oCJW+——
Melting Point/Range (°C/OF)—
Volubility in water
Partition Coefficient (ICowj--
SpeCificGravity (Wa~l)---
,
Vapor Density (Air= l)---
Loeai exhaust ventilation must be provided where dust may
enter the workroom environment. Containment areas
should have dedicated exhaust and dust collection systems
(HEPA filtersor eolleetors).
An approv@ properly fit teste~ HEPA filtered
cartridgerespirator,or a respiratorof greaterproteetio~
is requiredfor handlingthe powder.
Latex gloves, or gloves providing greaterprotectio~ are
required.
Safety glasses are required. Goggles, face shield or
other full-face protection is required if potential exists
for direct exposure to dust or aerosols.
FuIl body garments should be worn when
handling this compound. Disposable clothing including
tyvek suits, head cover, arid shoe protectors should be
worn.
Clear, moi.sgoff-white to slightly yellow powder
Odorless
Not applicable
Not applicable
Approx. 150°C (302°F)
Negligible
Not available
Not applicable
Not applicable
*** ~ntinued
on next page ***
Mectzn.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 374 of 382

4-
-.. *
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-90
PRODU~
NAME:
IVERMECTIN
PAGE: 6 OF 9
-
PLANT MSDS CODE: PR-020
Date:
lt96
Vapor Pressure (rnrnHG @ O@F)---
Not applicable
Volatile Components (VOw/w)–—
0%
10. Stability
and Reactivity
Stability—---–––
Stable compound under reasonably foreseeable conditions
of storage and use.
Conditions to Avoid——---
None known
Incompatibilities
—
Can be hydrolyzed by strongcaustic solution.
HazardousPolymerizations———
None known
HazardousDecomposition Products-
11. Toxicological
Information
J%imarvRoute(s) of Entrv--
Toxicitv Data
JVERMECTIN
I&I
LD50
LD50
LD50
LD50
LD50
LC50
LD50
LD50
LD50
LD50
Irritation
Imitation
SEEc!Es
Mouse
Mouse
Rat
Rat
Rat (infant)
Rat
Rat
Rabbit
Dog
Rhesus monkey
Rabbit
Rabbit
If involved in a fire, toxic gases including carbon monoxide
and carbon dioxide may be generated.
Inhalation:
Yes
Ingestion:
No
Skin Contact: Yes
Rom
old
Intraperitoneal
oral
Intraperitoneal
Inhalation
Dermal
Dennal
oral
ocular
Dermrd
REXJLT
25 mgllcg
30 mgikg
50 mgfkg
55 mglkg
2t03mg/kg
*
More than 660 mg/kg
406 mg/kg
About 80 mgllcg
More than 24 mgkg
Very slightly irritating
Non-irritating
*Maximum attainable concentration of 5.11 mg/liter produced tmnsient
irritation of mucous membranes but no deaths or other signs of toxicity after 1 hour exposure.
G ** Continu& on next page ***
Mectm.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 375 of 382

Iverrnectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summaxy
F. Environmental
Assessment
F-91
PRODUCT NAME
IVERMECTIN
PAGE: 7 OF 9
—
PLANT MSDS CODE:
PR-020
Date: 1/96
Effects of Acute ExDosurQ
Eye Contact
Slightly irritating to the eyes in animal studies.
Skin Contact
Non-h-hating in animal studies. Prolonged or repeated
contact may cause irritation andlor drying and cracking
of the skin.
Ingestion——————
An acute inhalation study demonstrated a low order of
toxicity in animals by this route but this is accounted for
by the large particle size of the sample used in this test.
Inhalation is considered the primary route of exposure
to the dry solid compound.
Iverrnectin is considered highly toxic in acute animal
studies although rodents were shown to be more
sensitive to ivermectin compared to other species.
Ivermectin is used at a therapeutic dose of 0.2 mg/kg,
without signs of toxicity, in a variety of species
(including humans).
Based upon studies in animals and cases of accidental
ingestion in humans, overexposure to ivemwctin may
cause drowsiness, depressed motor activity, slowed
breathing, dilation of the pupils, tremors, vomiting,
anorexia and incoordination.
Fff Ctsof Chr
e
onic Exnosure—
lkre
were no grossor histologicchangesobsenwl in dogs
treatedwithivermectin for 3 months or in monkeys treated
for 2 weeks. Changes in the’spleeq bone marrow and
kidneys were reported in rats treated fa 3 months. Signs of
toxicity reported in these repeatdose studies were similar
to those observed following acute overexposure. The
lowest no-effect level reported was 0.4 mgkgklay.
Iverrnectin produced developmental toxicity in animals
only at or near dose levels that were matemally toxic. No
evidence of genotoxicity was found in a battery of assays.
;** Continued on next page ***
,
Mectzn.doc
Jan.96
;
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 376 of 382

-..
F-92
Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
&sessment
PRODUCT NAME:
IVERMECTIN
PAGE: 8 OF 9
PLANT MSDS CODE:
PR-020
Date: 1/96
Carcinogen Designation—
Not listed as a carcinogen by NT’P,IARC or OSHA.
Medical Conditions Aggmvated by Exposure- None Imown
12. Ecological Information
EnvironmentalFate———
Ivermedin photodegradesrapidly in the environment and is
metabolized in the soil. Water volubility is limited and it
binds to soil very tightly. It does not bioconcentrate in fish
and is not takenup from soil into plants. Both aquatic and
terrestrialstudiesconfirm the rapid degradation of
ivermectin in the environment and its lack of accumulation
and persistence.
EnvironmentalEffects-—--
Ivermectinis very toxic to certainaquatic species.
LC50 - Daphniarnagn~ 48 hours
= 0.025 ppb
NOEL (No-Obsemtble-Effect Level) - Dadmia mama = 0.010 ppb
LC50 - rainbowtrou496
hours
= 3.0 ppb
LC50 - bluegill sunfkh, 96 hours
= 4.8 ppb
13. Disposal Considerations
Waste Disposal Information—
Iverrnectin
is very toxic to certain aquatic species.
Avoid contact of spilled materialwith soil. Do not
alIow any waterpotentially contaminated with
ivermectin including stormwater, runoff from spills and
fire fightingactivitiesandcontaminatedwastewaterto
enteranywaterway,rhainor sewer. Residualsurface
materialshouldberemovedwithtowelsmoistenedwith
methanol.
Incinerate all spill materials and residues at temperatures
greater than 600°C.
,*’*
G ~ntinued
on next page ***
Mectm.doc
JsI-I.96
_--—
—.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 377 of 382

Ivermectin
Chemical and Pharmaceutical
Manufacturing
and
Control
Documentation
I. Summary
F. Environmental
Assessment
F-93
PRODUCT NAME:
IVERMECTIN
PAGE: 9 OF 9
PLANT MSDS CODE:
PR-020
Date: 1/96
14. Transport Information
ShipninzDescrintion
U.S. DOT-
Toxic soli~ organic, N.O.S. (ivermectin), 6.1, UN281 1,
PGII
IATA/TCAO———
------
Toxic soli~ organic, N.O.S. (ivermectin), 6.1, UN28 11,
PGII
IMO——
—
Toxic soli~ organic,N.O.S. (ivermectin), Class 6.1,
UN2811,11
ADR-RID–—-——–——
Not available
15. Regulatory Information
U.S. FederalRemdation~
Not available
~ntemationalRezulations—
Not available
StateRemdations
Not available
16. Other Information
DatePrepared———
June 1989
Last Revision Date-
January 1996
MSi)S Coordinator
1-908423-7926
Merck &Co, Inc.
One Merck Drive
P.O. BOX I(M),WS2F-48
Whitehouse &atio~ NJ 08889-0100
U.S.A.
Disclaimm While this information and reaunrnendationssetforth
arebelieved to be accurate as of the date hereof,
MERCK & CO, INC. makes no warranty with respect hereto
and disclaims all liability horn reliance thereon.
Mectrn.doc
Jan.96
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 378 of 382

~LT H
~“
@
‘“
+%
;~
+
(
~
DEPARTMENT
OF HEALTH
& HUMAN SERVICES
:(
z
.
Public Health Service
.2.W
>
~$
*
Food and Drug Administration
.&~W$
,’c, .“
‘-. o
%.~?’”’
Center for Drug Evaluation
and Research
..O USA
‘-
.- ““”
MEMORANDUM
4
Mectizaa was submitted
to the Division of Anti-infective
Drug Products on March 29, 1995. The
document was reviewed by the Supervisory
Microbiologist
prior to assignment
and it was determined
that no microbiological
data had been submitted
with the document.
There were two possible
administrative
decisions that could
be made regarding the fileability of this submission.
The first was to
make the NDA nonfileable
because a microbiology
section was not submitted
with the NDA.
This class
1P drug would then have been returned to the applicant
with a portion of the user fees deducted
according to convention.
The other possibility
was to accept the NDA even though the microbiology
section was missing.
The possibility
of accepting the Mectizan NDA was discussed with the medical officer.
The focus of the
discussion was to determine what additional
information
could have been required for microbiology
that
would cast doubt on the efficacy of iverrnectin.
It was reasoned that the establishment
of
microbiological
efficacy was provided
for in the clinical study since the establishment
of efficacy was
based on microscopic
examination
of stool (Strorzgy/oidiusis
) samples or skin microfilariae
(Onchocerciasis)
geometric mean counts.
Thus, clinical and microbiological
eflicacy could be
-
assessed.
The problem was then viewed horn the labeling perspective.
The question was asked”
What
statements were being made in the microbiology
section of the package insert (PI) that require
verification?”
In fact, no rnicrobiology,section
was provided
for in the original PI. The information
that
was included in the PI, at the request of the FDA, was “reviewed”
by microbiology.
The information
appears reasonable but verification
of the truthfulness
must reside with the person requesting
its
inclusion.
From the microbiological
perspective
the NDA can be approved.
_
_..——
.—.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 379 of 382

NDA
MEMOIUNDUM
OF TELEPHONE
CONVERSATION
50-742
Drug
:
Ivermectin
DATE :
November
21,
1996
SUBJECT
:
CMC
issues/Phase
4
commitments
BETWEEN :
Representative
of
Merck
& Co,
Inc.
Kenneth
Brown,
Regulatory
Affairs
Frank
Recci,
Regulatory
Affairs
Danville,
PA:
David
Long,
Tech.
Operations
John
Graves,
Tech.
Operations
Michael
Kovach,
Tech.
Operations
Randy
Hall,
Plant
Manager
Rahway,
NJ:
Richard
Steinbach,
CMC
James
Buckley,
CMC
AND:
Representatives
of
the
Division
of
New
Drug
Chemistry:
Bonnie
Dunn,
Ph.D.,
Chemistry
Representatives
of
the
Division
of
Anti-infective
Drug
Products:
James
Timper,
Chemistry
Pauline
Fogarty,
Project
Management
Staff
Background:
An
approvable
letter
was
issued
on
October
8,
1996,
with
CMC issues
to
be
addressed
by
the
applicant.
On
October
15,
1996,
the
applicant
responded
to
the
approvable
letter.
Upon
review
of
the
response
Mr.
James
Ti.mper
felt
that
further
elaboration
was
required,
however,
this
could
be
accomplished
through
a
phase
4
commitment.
The
attached
was
faxed
to”the
applicant
and
a
teleconference
was
held
in
which
the
issues
were
discussed.
P4erck
stated
that:
1.
The
particulate
impurities
found
in
failed
batches
of
avermectins
bulk’
intermediate
have
been
identified
as
triglycerides
and
phospholipids
that
are
produced
in
competition
with
the
avermectins
in
the
fermentation
step.
1
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 380 of 382

2.
The
observation
of
the
insoluble
brown
particles
in
the
avermectins
bulk
intermediate
would
warrant
rejection
Of
the
batch
for
human
use.
3.
They
would
submit
to
the
NDA
representative
chromatograms
showing
the
resolution
and
detection
limit
of
the
process
impurity
B2=.
DAIDP
agreed:
that
the
applicant’s
explanation
was
satisfactory.
Therefore,
the
application
can
be
approv~d
without
a
phase
4
Commitment.
The
teleconference
concluded
amicably.
cc
:
NDA
50-742
Div.Fi.le
HFD-520/Coyne
:R=:::f::::::
>~\++6
HFD-830/ESheini.n
HFD-830/BDunn
e
li\2+~
HFD-520/Fogarty
TELECON/PF.11/22/96
50-742.them/11/22/96
&f
\
P
uline
Fo
arty
egula
Heal
h
Manager
Concurrence
Only:
HFD-520/JBona
2
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 381 of 382

Ivermectin
50-742
Commitment:
Attempt
to provide
an in-process
control
to assure
that
failed
batches
of the avermectins
bulk are identified.
*
This
can be demonstrated
by providing
information
on the following:
/
I. An HPLC
chromatogram
of the
avermectins
toluene
extraction
could
be an
adequate
in-process
control
when
the chromatograms
of failed
batches
are
significantly
different
than
the
chromatograms
of acceptable
batches.
Please
provide
A representative
chromatogram
of a failed
and acceptable
batch.
(1) Please
identify
those
aspects
of the chromatogram
that
identify
a possible
failure.
(2) In the failed
batch
chromatography,
please
identify
the impurity
Bti.
Il. An HPLC
chromatogram
could
be an adequate
in-process
control
for release
of
the finished,
purified
avermectins
intermediate
bulk,
when
the chromatograms
of
acceptable
batches
are significantly
different
than
batches
that
contain
&ible
brown
particles.
(1) Please
provide
a chro-matogram
of an acceptable
and a failed
batch.
(2) Please
identify
new
peaks
or enhanced
peaks
in the chromatograms
batches.
(3)
Please
identify
the
impurity
Baa
of failed
Ill. Continue
the
effort
to identify
the compounds
that
constitute
the
brown
particles
found
in the
failed
batches
of avermectins
bulk.
Provide
evidence
of the
resolution
of the
impurities
in the
chromatogram
which
is used
to control
the
isolation
of avermectins.
.
Case 3:22-cv-00184   Document 1-11   Filed on 06/02/22 in TXSD   Page 382 of 382

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