CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-409
`
`Pharmacology Review(s)
`
`

`
`PHARMA COLOG Y/TOXICOLOG Y COVER SHEET
`
`NDA number:
`Review number:
`
`21-409
`1
`
`000; 9/28/01; original submission
`Sequence number/dateltype of submission:
`); No (
`)
`x
`Information to sponsor:
`Yes (
`Sponsor and/or agent:
`Merck Research Laboratory, Rahway, New Jersey
`Manufacturer for drug substance:
`The same as above
`
`Reviewer Name:
`Division Name:
`Division Code:
`
`Luqi Pei, Ph.D_
`Pulmonary and‘Allergy Drug Products
`HFD-S70
`
`Review Completion Date:
`
`July 19, 2002
`
`Singulairl” 4 mg Granules
`Montelukast sodium
`
`
`
`L706,63l
`'
`Sodium I-(((1(R)-(3—(2-(7-chloro-2-quinolinyI)-(E)-
`ethyi)(3-(2-(1-hydroxy-1-methylethyl)propyl)thio)—
`methyl)cyc1opropane)acetate
`N/A
`C35H35ClNNa03 S; 608.2
`
`_
`
`’”
`
`/'
`-.._
`
`I
`
`g
`
`Inn
`
`0}!
`
`'
`
`Merck
`NDAs 20-829 and 20-330;
`INDS 39,568, 47,726 and 58,819;
`DMFs E.
`
`3
`
`Leukotriene D4/E4 receptor antagonist
`
`Asthma
`
`Montelukast Sodium Ora] Granule £4 mg[500 mg!
`Ingredient
`Amount (mg/packet)
` Montelukast sodium
`(free acid equivalent)
`Mannitol
`
`
`
`Hydroxypropyl cellulose
`Magnesium stearate
`
`Total packet weight
`\ 500.0
`
`
`
`Drug:
`Trade Name:
`Generic Name:
`
`Code Name:
`Chemical Name:
`
`CAS Registry Number:
`Molecular Formula/'Weight:
`Structure:
`
`Manufacturer for the Drug:
`Relevant INDsfNDAs/DMFs:
`
`Drug Class:
`
`Indication:
`
`'
`
`Clinical formulation:
`
`

`
`Route of Administration:
`Proposed use:
`
`
`_
`
`Oral
`E ‘
`
`APPEARS nus wmr
`on omcmm
`
`

`
`Executive Summary
`
`Recommendations
`
`A. Recommendation on Approvability
`The application is approvable from the preclinical viewpoint.
`
`B. Recommendation for Nonclinical Studies
`None.
`
`C. Recommendations on Labeling
`Revise the dose ratios in the carcinogenesis, and overdose sections of the labeling
`(See recommended labeling section for details).
`
`Summary of Nonclinical Findings
`
`A. Brief Overview of Nonclinical Findings
`
`Montelukast is non-genotoxic, non-carcinogenic and non-teratogenic in the preclinical
`toxicological evaluations. The gastrointestinal system is the primary target organ of
`montelukast toxicity in rats and monkeys. The secondary target organs of toxicity of
`the drug include the adrenals, lung, kidney, heart and lymphoid system. The No-
`Observed Adverse Effect Level (NOAEL) is 50 and 150 mg/kg/day for the adult rats
`and monkeys, respectively. The toxicity profile of montelukast in juvenile and adult
`monkeys is similar, but
`the juvenile monkey are more sensitive (NOAEL = 50
`mg/kg/day)-
`
`B. Pharrnacologic Activity
`
`leukotriene antagonist. It binds to the
`is an orally active cysteinyl
`Montelukast
`CysLT;
`receptor with high affinity ‘and blocks
`the physiologic actions of
`LTD4/LTDE4 at the receptor. The oral median effective dose of montelukast is 0.0]
`mg/kg in relieving allergen-induced bronchoeonstriction in squirrel monkeys. The
`approved clinical dose of the drug for the asthma indication is 10 mg once a day in
`adults and 4 mg once a day in children 2 years of age and older.
`
`.
`
`C. Nonclinical Safety Issues Relevant to Clinical Use
`None.
`
`Administrative
`
`/57
`
`A. Reviewer signature:
`
`B. Supervisor signature:
`
`7 3/
`
`Concunence —
`Non-Concurrence - / Z
`
`(see memo attached)
`
`7
`
`iii
`
`.: ..___ .._ ._.__..._‘
`
`

`
`TABLE OF CONTENTS - PHARMACOLOGY/7‘0.XICOLOGYREVIEW
`
`1.
`
`PHARMACOLOGY: ...................................
`
`....................................................................1
`
`II. SAFETY PHARMACOLOGY:1
`
`III. PHARMACoK1NET1CsrroxICo1<INET1Cs: ...........................................................,..1
`
`Iv. GENERAL TOXICOLOGY:..............................................................................................1
`
`v. GENETIC TOXICOLOGY: ..............................................................................................1
`
`VI. CARC1NoGEN1CITY:A...............,..........................................
`
`................................1
`
`vn. REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY:..................
`
`.........1
`
`vm. SPECIAL TOXICOLOGY STUDIES: .............................................................
`
`..........1
`
`IX. DETAILED CONCLUSIONS AND RECOMMENDATIONS: .....................................1
`
`x. APPENDIXIATTACHMENTS: ..........................................................................................5
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`iv
`
`

`
`Reviewer: u iPei Ph.D.
`
`NDA No.2 -409
`
`PHARMA COLOGY/TOXICOLOGY REVIEW
`
`Note: This document contains no review of preclinical data because no such data was submitted.
`The sponsor refers to relevant previous submissions for preclinical pharmacology and toxicology
`data of montelukast (see relevant INDS and NDAS on the cover page). Dr. Shannon Williams
`conducted a comprehensive review of the data and his review is attached for reference. The
`current review deals with the approvability and labeling review of the application only.
`
`I.
`
`PHARMACOLOGY:
`
`Not Applicable.
`
`II.
`
`SAFETY PHARMACOLOGY:
`
`Not Applicable.
`
`III.
`
`PHARMACOKINETICSFFOXICOKINETICS:
`
`Not Applicable.
`
`IV.
`
`GENERAL TOXICOLOGY:
`
`Not Applicable.
`
`'
`
`V.
`
`GENETIC TOXICOLOGY:
`
`Not Applicable.
`
`VI.
`
`CARCINOGENICITY:
`
`Not Applicable.
`
`VII. REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY:
`
`Not Applicable.
`
`VIII. SPECIAL TOXICOLOGY STUDIES:
`
`Not Applicable.
`
`'
`
`IX.
`
`DETAILED CONCLUSIONS AND RECOMMENDATIONS:
`
`Conclusions: The sponsor has provided sufficient evidence to support the preclinical safety of
`montelukast in asthmatic children -- to 23 months of age. Montelukast, a leukotriene receptor
`antagonist, is already approved and marketed for the asthma indication in adult and pediatric
`patients as young as two years of age (NDAs 20-829 and 20-830). Table. 1 summarizes the
`approved montelukast asthma applications in the Division. Notice that both dosage forms and
`doses differ between adult and pediatric asthmatic patients: 10-mg film-coated tablets for adults,
`5-mg chewable tablets for children of six to fourteen years old, and 4—mg chewable tablets for
`children of two to five years old. The current application uses oral granules (a new formulation,
`
`

`
`A
`
`1-‘.
`
`Reviewer: Lugi Pei, Ph.D.
`
`NDA No 21-409
`
`with the same ingredient as the chewable tablets)
`_____._
`
`--"-
`
`Table 1. Agrgroved Montelukast Applications
`
`NDA No.
`
`Dosage
`
`Strength
`
`Age
`
`Indication Approval Date
`
`20-829
`20-830
`/S-008
`
`Film-coated tablets
`Chewable tablets
`Chewable tablets
`
`10 mg
`5 mg
`4 mg
`
`Adults
`6 — 14 yr
`2 —- 5 E
`
`Asthma
`Asthma
`Asthma
`
`20-FEB-1998
`20-FEB-1998
`3-MAR—2000
`
`the sponsor has extensively characterized the
`In seeking approval of previous applications,
`toxicity of montelukast in adult animals.
`It has also evaluated the effect of the drug in juvenile
`animals. The Division has reviewed all previously submitted studies (See Table 2 for these
`reviews). Among them, Dr- Shannon Williams’ 01-DEC-1997 review of the original NDA
`submission is attached for reference as it provides a comprehensive summary and evaluation of
`all the preclinical data for montelukast.
`
`Table 2. Relevant Previous Pharmacology and Toxicology Reviews of Montelukast
`IND/NDA No.
`Reviewer Name
`Date of Review Completion
`NDAs 20-829/830
`Shannon Williams, Ph.D.
`December 1, 1997
`NDAS 20-829/830
`Executive CAC report
`June 1 1, 1997
`1ND 39,568
`Shannon Williams, Ph.D.
`June 2, 1997
`
`IND 39,568
`IND 39,568
`
`Shannon Williams, Ph.D.
`Young Sue Choi, Ph.D.
`
`October 24, I996
`July 13, 1992
`
`Briefly, tnontelukast is non-mutagenic, non-carcinogenic and non-teratogenic in the in vitro and
`in vivo laboratory testing. The gastrointestinal system is the primary target organ of montelukast
`toxicity. The secondary target organs of toxicity of the drug include the adrenals, lung, kidney,
`heart and lymphoid system. The No-Observed Adverse Effect Level (NOAEL) is 50 and 150
`mg/kg/day for adult rats and monkeys, respectively.
`
`The effect of montelukast on growth and development is evaluated in, juvenile mjonkeys. In Study
`94-9003 (reviewed by Dr. Shannon Williams on 24-Oct-1996 in IND 39,568), four-week-old
`monkeys (at
`the commencement of the exposure) were closed orally with 25, 50 and 150
`mg/kg/day of montelukast for 13 weeks. The gastrointestinal system was identified as a major
`target organ of montelukast toxicity. Treatment—related findings included epithelial vacuolation
`of glandular mucosa, chronic enteritis and colitis at the high dose group. The NOAEL was 50
`mg/kg/day.
`
`Available data have shown that the toxicity profile of rnontelukast between juveriile and adult
`monkeys is similar, but the juveniles are more sensitive to the drug than the adults. The higher
`NOAEL (150 mg/kg/day) in the adult monkeys than the juvenile monkeys (50 mg/kg/day)
`illustrates the point.
`
`

`
`eviewer: Lu iPei
`
`h.D
`
`ANO. 2l-409
`
`The current application proposes to extend the indicated pediatric population of montelukast
`
`from the age of two years down to 1
`The application does not contain any preclinical
`data as the Division concurred with the approach previously in a pre-NDA meeting dated April
`26, 2001. The sponsor’s states that “the available data in the reference NDAS are sufficient to
`support the preclinical safety of montelul-tastin pediatric asthmatic patients of "" _
`to two
`years old”. This statement is reasonable. Physiological and developmental stages between 4-
`week-old juvenile monkeys and 6-month-old infant babies are probably comparable although the
`exact comparability is not known. This comparability between juvenile monkeys and babies
`suggests no need for additional testing in juvenile animals. Thus, the approval of the application
`is recommended from the preclinical viewpoint.
`
`However, AUC ratios in sections of Carcinogenesis and’Overdose of the labeling need revision.
`(The sponsor proposes keeping them as they are.) The reason is that the pediatric and adult
`patients demonstrate different plasma rnontelukast levels: the younger the age, the higher the
`plasma AUCS. Table 3 summaries the plasma drug levels and corresponding AUC ratios
`between the animals and different age of human populations. This review finds that
`the
`difference of 18-35% in plasma drug levels between the adult and pediatric patients is sufficient
`to warrant revisions of the dose ratio. The remaining sections of the preclinical labeling should
`remain the same.
`
`Table 3. Human Plasma Montelukast Levels
`
`-
`Population (age)
`AUC (ng.hr/ml)
`Standard Error
`Ratio
`ediatric/Adult
`
`6yr-
`Adult
`2569
`166
`-
`
`2-
`< 6 yr
`' 272]
`N/A
`1.06
`
`l——
`< 2 yr
`3039
`213
`1.18
`
`6mo.—
`< 1 yr.
`3471
`499
`1.35
`
`6mo.—-
`< 2 yr
`3223
`250
`1.26
`
`I
`
`Source: Vol. 1, Clinical Summary, p. 36, Table 9.
`
`General Toxicology Issues: None.
`
`Recommendations:
`
`I. An approval of the application is recommended from the preclinical viewpoint.
`2. Revise the dose ratios in the Carcinogenesis and Overdose Sections
`
`APPEARS nus
`on omcuviiw
`
`

`
`Reviewer: Lugi Pei, Ph.D.
`
`EQA No. 21-409
`
`Labeling with basis for findings:
`
`This section addresses the revision of AUC ratios of the labeling for the 12-month and older
`patients only. The Division in an internal meeting of 24-JUN-2002 determined that
`the
`application demonstrated the safety and efficacy of rnontelukast in children 12 to 23 months of
`age, but not in the
`""—
`U
`New AUC ratios are calculated based on the mean
`plasma drug level (3.04 tight/ml) in children 12 -— 23 months of age. Table 4 shows the newly
`calculated and recommended AUC ratios for the labeling. The recommended ratios are those
`calculated numbers rounded to the nearest 10.
`
`Table 4. Parameters for Deriving AUC Ratios for Preclinical Labeling of Montelukast
`Labeling
`Species
`Dose
`AUC
`AUC Ratio (animal/human}
`Section
`(mg/kg/day)
`(Egh/ml! "
`Calculated
`Recommended
`Carcinogenesis
`100
`116.7
`38.4
`40
`200
`326.9‘
`107.5
`1 I0
`
`Mice
`Rat
`
`Overdosage
`
`200
`202
`616.5‘
`5000
`Mice
`300
`296.7
`901.7“
`5000
`Rat
`a. These montelukast AUC values in mice and rats were used to calculate AUC ratios for the
`
`approved labeling. (See Dr. Timothy McGovem’s review dated l2-JUN-1998 and Dr. Will1am‘s
`memorandum dated 27-FEB4998 in NDAS 20-829 and 20-830.)
`
`b. Average of the male and female AUCs in Study T93-034-0.
`9
`Average of the male (404.8 pg.h/ml) and female AUCS (248.9 p.g.h/ml) in Study T93—O54—0.
`d. AUC values at 800 mg/kg in both species, for AUC values plateaus in mice and rats following a
`single dose of 800 mg/kg.
`
`The new AUC ratios are recommended for both adult and pediatric populations because they
`provide more conservative estimates of the safety margins. Table 5 provides a comparison of
`the approved and the newly recommended AUC ratios. Note that the approved ratios were
`based on the mean plasma AUC of 2.67 ug.hr/ml in adults. (The current submission indicates
`that AUC in adults is 2.56 pg/ml). The recommended ratios are based on the plasma AUC of
`
`3.04 1.1g.hr/ml in children of 12 —- 23 months of age and are 10 — 20% smaller than the approved
`ones. The smaller AUC ratios provide more conservative estimates of the safetymargin. Also,
`the difference in AUC ratios between the two populations of interest is so small that the listing
`of both AUC ratios is not warranted.
`
`Table 5. Comparison of the Approved and Recommenced AUC Ratios for Montelukast Labeling '
`
`Labeling Section
`Approved 3
`Recommended d
`
`
`Carcinogenicity
`Rat (200 mg/kg/day)
`Mice (100 mgfkg/day)
`Overdose
`
`120
`45
`
`110
`40
`
`230
`Rat (5000 mg/kg)
`340
`Mice {S000 mgkgl
`a. The current approved labeling for patients aged 2 years and old.
`b. Newly calculated AUC ratios based on plasma montelukast levels in children 12-23 months of age.
`
`200
`300
`
`4
`
`

`
`fieviewer: Lugj Pei, Ph.D.
`
`'
`
`NDA No. 21-409
`
`Additional information about the labeling review of montelul-cast can be found in the following
`documents under either NDA 20-829 or NDA 20-830:
`
`Labeling Review by Timothy McGovern on January 27, 2000.
`Addendum to Labeling Review #2 by Timothy McGovern on December 12, 1998
`Labeling Review by Timothy McGovern on June 12, 1998
`Memorandum by Shannon Williams, February 27, 1998
`
`Suggested Sample Labeling (for patients 12 months of age and above):
`
`The Carcinogenesis, Mutagenesis and Impairment of Fertility Section:
`
`No evidence oftumorigenicity was seen in either a 2-year carcinogenicity study in Sprague-
`Dawley rats at oral gavage doses up to 200 mg/kg/day (estimated exposure was approximately
`-—-—..;.;.times the area under the plasma concentration versus time curve (AUC) for adults and
`children at the maximum recommended daily oral dose) or in a 92-week carcinogenicity study in
`
`mice at oral gavage doses up to 100 mg/kg/day (estimated exposure was approximately-
`times the AUC for adults and children at the maximum recommended daily oral dose).
`
`The Overdose Section:
`
`No mortality occurred following single oral doses of montelukast up to 5000 mg/kg in mice
`
`(estimated exposure was approximately _
`-times the AUC for adults and children at the
`maximum recommended daily oral dose) and rats (estimated exposure was approximately 1'-
`'--*times the AUC for adults and children at the maximum recommended daily oral dose).
`
`X.
`
`APPENDIXIATTACHMENTS:
`
`Addendum to review: None.
`
`Other relevant materials (Studies not reviewed, appended consults, etc.):
`Dr. Shannon Williams’ review dated 01-DEC-1997.
`
`Any compliance issues: None.
`
`

`
`
`
`I NDA NoReviewer: Lu iPei pm). 1409
`
`
`
`
`
`ATTACHMENT
`
`Pharmacology and Toxicology Review of Montelukast
`
`Shannon Williams, Ph.D.
`
`December 1, I99 7
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`BEST POSSIBLE COPY
`
`....-—...._...-_-__r__._.—.._.....—.—.—,..-.—————-r+-—.;-v—----—-v—~—.-3-'—--'—+:L*-
`
`.
`
`-
`
`< "
`
`,'
`
`' “"""' "
`
`

`
`DIVISION OF PULMONARY DRUG PRODUCTS
`
`REVIEW OF PHARMACOLOGY AND TOXICOLOGY DATA
`
`Original Review
`
`NDA No. 20-829 and 20,830
`
`Submission date: 21 FEB 97
`
`Information to be Conveyed to Sponsor: Yes (X ), No ( )
`
`Reviewer: Shannon P. Williams, Ph.D. Date Review Completed: 01 DEC 9?
`
`Sponsor:
`
`Merck & Co., lnc., West Point, PA
`
`Drug Names: Generic: montelukast sodium; Commercial: Singulairm;
`Code: MK—0476, MK-476 and I.-706,631
`
`[R-(E)]—l -[[[ l -[3 -[2-(7-chloro—2-quinolinyl)cthenyl]phenyl]-3-[2—(l ~hydroxy-l -
`Chemical Name:
`methylethyl)phenyl]propyl]thio]methyl]cyclopropaue acetic acid, monosodium salt.
`
`Structure:
`
`
`
`Empirical Formula: C35H35ClNNa03S (M.W. = 608.18)
`
`Dru Product Formulation: 10 m Tablet
`In redient
`Core Tablet m )
`Film Coatin m
`
`Montelul-cast sodium (free acid equivalent)
`Hydroxypropyl cellulose
`Microctystalline cellulose
`Lactose monohydrate
`Croscarmellose sodium
`7
`Magnesium stearate
`Hydroxypropyl‘methylcellulose
`Titanium Dioxide
`
`Red Iron Oxide
`
`Yellow Iron Oxide
`
`Carnauba Wax Powder
`
`Total Tablet Weight (mg)
`
`10.4 (10.0)
`
`-—
`
`\
`
`.
`
`--'--
`
`--
`
`i
`
`- --
`
`—-"‘—'
`
`Drug Product Formulation: 5 mg Chewable Tablet
`
`

`
`NDA 20,829 and 20,830
`Page 2
`
`Ingredient
`Montelukast sodium (free acid equivalent)
`Mannitol, USP
`
`Microcrystalline cellulose, NF
`
`mgffablet
`5.2 (5.0)
`~
`‘
`
`F
`
`"‘
`
`7
`
`Croscarmellose sodium, NF .
`I-Iydroxypropyl cellulose, NF(EXF)
`Artificial Cherry Falvor, NF
`Magnesium stearate,-NF
`Aspartame, NF
`
`Red Ferric Oxide, NF -
`
`Total Tablet Weight
`
`300.0 mg
`
`Excipients, Degradants and Impurities: The proposed levels of all excipients, in both the
`adult tablet and the children’s chewable tablet, occur at levels well within the ranges of those
`used in other currently approved drug products. Thus, there are no nonclinical issues with the
`proposed excipients in either the adult or pediatric formulation.
`
`Class: cysteinyl leukotriene CysLT. receptor antagonist
`
`Indication: prophylaxis and chronic treatment of asthma in adult and pediatric patients '
`
`Route: Oral
`
`Pediatric Dose 5 mg (tablet) once daily, In a 25 kg child this is 0.25 mg/kg, 6.2 mg/m’.
`
`Adult Dose:
`
`10 mg (tablet) once daily in adults, In a 50 kg adult this is 0.2 mg/kg, 7.4 mg/n1’.
`
`Related INDs/NDAs/DMFs:
`
`_
`2-:-
`
`_
`
`,
`
`"-
`
`- Previous Review(s), Date(s) and Reviewer(s): This NDA has not been reviewed previously.
`Relevant reviews of related INDS are listed below:
`
`'
`
`IND 39-568, L706,63 1, 13 JUL 92, Y.S. Choi, Ph.D.
`
`IND 39-568, L706,63 I, 29 OCT 92, Y.S. Choi, Ph.D.
`
`IND 39-568, L706,63 l, 25 JUL 93, Y.S. Choi, Ph.D.
`IND 39-568, L706,63l, 24 OCT 96, S. P. Williams Ph.D.
`IND 39-568, 1,706,631, 02 JUN 97, S. P. Williams Ph.D.
`,;
`'
`"
`'
`'
`'
`’ ‘ '
`'
`_
`_
`
`'
`
`_
`
`—
`
`.
`
`.1‘
`‘J
`
`V
`
`L
`
`

`
`NDA 20,829 and 20,330
`Page3
`
`Preclinical Studies Submitted and Reviewed in this NDA:
`
`Note: Unless otherwise sgecizzed, studies were submitted to IND 39, 568
`ACUTE TOXICITY STUDIES
`[Ref. No.]
`
`TT#92 -
`2820
`
`[G-2]
`
`[G-4]
`
`{G-5]
`
`[G-6]
`
`[G-7]
`[G-8]
`
`Vol.Ipp.
`
`1.30/H-6}
`
`29/G88
`
`29/G199
`
`29/G206
`
`29/G216 ‘
`'
`29/G216
`29/G239
`
`Acute Oral Toxicity Study In Mice
`
`PHARMACOKINETIC STUDIES
`
`Absorption and Disposition of MK—0476 in Mice, Rats &
`Monkeys‘
`{"C]MK-0476; Distribution in Blood and OctanollBuffer
`Partition‘
`Gastrointestinal Absorption Sites of [”C]MK-0476 in Maine
`Rats“
`
`Plasma Levels of MK-0476 After 14-Day Repeated Ora}
`Administration of MK—0476 in Male Rats"
`Plasma Protein Binding of ["C]-MK- 0475*
`Tissue Distribution of Radioactivity in Rats After Oral
`Administration of ["C]MK-0476*
`Vfhole Body Autoradiography in Rats”
`Comparison of Metabolic Profiles of MK-0476 in Human,
`Monkey, Rat and Mouse‘
`Hepatic Microsomal Metabolism of MK—0476 in Mouse, Rat,
`Monkey and Human‘
`LOCAL TOLERANCE
`
`Dermal Irritation Study in Rabbits TT #941-2649
`Bovine Cornea BCOP Assay TT #94-4268
`Ocular Irritation Study in Rabbits TI #94-4269
`Dermal Irritation Study In Rflabits TI" #92-2819
`Bovine Cornea BCOP Assay TT #92-4272
`Ocular Irritation Study In Rabbits TT #92-4269
`SPECIAL TOXICITY
`
`Oral/Subcutaneous Immunogenicity Study in Guinea pigs T1“
`#959805
`
`.C«
`
`J
`
`[G—9]
`[G~l2]
`
`29/G247
`29/G387
`
`[G-15]
`
`29/G456
`
`‘
`
`30/H-20
`30/H—30
`30/H—35
`30/I-I-72
`30/H-98
`' 30/H-126
`
`31/Q-87
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`BEST POSSIBLE copy
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`

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`NDA 20,829 and 20,830
`Page 4
`
`Previously Reviewed Preclinical Studies Submitted in this NDA:
`
`
`
`
` STUDY TYPEIREFERENCE NO. Vol./pp. Reviewer Date of Rev.
`
`
`
`PHARMACOLOGY STUDIES / Fl— F26
`
`28fl-‘22-P373
`
`ANCILLARY PHARMACOLOGY
`
`Behavior and other effects in BKTO mice [F-25]
`Cardiovascular and autonomic effects in anesthetized
`
`dogs [F-25]
`Renal effects in conscious dogs [F-25]
`Respiratory effects in conscious dogs [F25 and F-26]
`Gastric acid secretion in chronic gastric fistula dogs:
`[F-25]
`
`PHARMACOKINETIC STUDIES
`
`2 8 / F- 2 5
`
`Choi
`
`13 JUL 92
`
`28/F-25
`2 8 / F — 2 S
`23/ F-25
`2 8/ F26
`
`Choi
`Choi
`Choi
`Williams
`
`13 JUL 92
`13 JUL 92
`13 JUL 92
`02 JUN 97
`
`28/F25
`
`Choi
`
`l3JUL92
`
`Physiological Disgosition in Rats and Monkeys/[G-1 [
`SINGLE DOSE TOXICITY
`
`29/G-39
`
`Choi
`
`13 JUL 92
`
`PO Tox. Study in Mice TT #91-2787
`IVTox.StudyinMice TT #91-2788
`POTox- Study in Rats TT #91-2789
`IVTox. Study in Rats TT #91—2790
`PO TK Study in Mice. TT #92 - 113 - D
`PO TK Study in Rats.
`‘IT #92 - 03 1- 0
`MULTIPLE DOSE TOXICITY
`
`7/A—l7
`7/A-17
`71A-I7
`7/ A-17
`7/ A-33
`7/ A—98
`
`Choi
`Choi
`Choi
`Choi
`Williams
`Williams
`
`5—Wk PO Tox. Study In Monkeys TT #91-121-0
`14-VVl< PO Tox. Study In Monkeys TT #92-611-0
`53-‘Vic PO Tox. Study In Monkeys Tl" #92-650-0
`I4-Wk PO Tox. In Infant Monkeys TT #94-9003
`5- Wk PO Tox. Study In Rats TT #9]-120-0
`Range-Find (8-Day PO) Tox. in Rats TT #92-609-0
`14- Wk PO Tox Study In Rats TT #92-610-0
`14-W'k PO Tox./TK Study In Rats TT #92—098-0
`53-‘Wk PO Tox/TK Study In Rats TT #92-651-0
`16-Day PO TK Study In Rats TT #93-054-0
`Range-Find (8-Day PO)Tox. in Mice TT #92—0'70-0
`14-Wk PO Tox. Study in Mice TT #93-001-0
`5-Wk PO TK Study in Mice TT #93—034-0
`16-Day IV Tox. Study In Rats Tl" #93-144-0
`16-day IV Tox Study In Monkeys TT #93-145-0
`17 day IV Irritation Study In Monkeys TT #94-629-0
`Ch0i* Studies reviewed under "~—A———._.-
`
`Choi
`8/B-90
`Williams
`9/B-402
`9- 1 0/B-701 Williams
`11/B-1232 Williams
`ll-12/B-1362
`Choi
`12/B-1799 Williams
`12-13/B-1820 Williams
`15-I 6/B-3107 Williams
`13-15/B-2375 Williams
`16/B-3585 Williams
`16/B-3703 Williams
`17/B-3738 Williams
`17/B-3907 Williams
`17/B-401 3
`Choi‘
`17/B-4145
`Choi‘
`'17/B-4371
`Choi‘
`
`l3 JUL 92
`I3JUL92
`l3JUL92
`IBJUL92
`02 JUN 97
`02 JUN 97
`
`13 JUL 92
`24 OCT 96
`24 OCT 96
`24 OCT 96
`13 JUL 92
`02 JUN 97
`24 OCT 96
`24 OCT 96
`24 OCT 96
`02 JUN 97
`02 JUN 97
`02 JUN 97
`02 JUN 97
`27 JUL 95
`27 JUL 95
`27 JUL 95
`
`

`
`Previouslv Reviewed Preclinical Studies Submitted in this NDA: CONT...
`
`NDA 20,829 and 20,830
`Page 5
`
`
`REPRODUCTIVE TOXICITY
`
`PO Rng-find in (non-pregnant) Rabbits Tl‘ #923716-2
`PO Range-find in (pregnant) Rabbits TT #92-716-l
`PO Develop. Tox. Study in Rabbits TT #92-716-0
`MK-0476: PO TK in Pregnant Rabbits. 'I‘T#93-738-0
`MK-0476: PO TK Study in Pregnant Rats wl
`Secretion in Milk. T'l'#93—740-O
`
`PO Range-find Study in Rats Tl" #92-717-1
`PO Develop. Tox. Study in Rats TT #92-717-0
`PO Fertility In Female Rats TT #92-723-0
`PO Fertility In Male Rats Tl‘ #93-706-0
`PO Late Gestation & Lactation in Rats TT #93-728-0 21-22/C-1136
`
`20-2]/C-500
`
`21/C-990
`
`Vol./pp.
`
`l9/C-48
`
`19/086
`19/016!)
`
`l9/C-228
`
`22/C-I282
`l9/C-280
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`20/C-403
`
`23/D-31
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`23fD—3 l
`23/D—8S
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`23/D- l 4]
`23/D-141
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`23/D— l 94
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`23/D-240
`23/D-240
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`23fD-289
`23/D-349
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`23/D-349
`
`24/D-420
`24/D-487
`
`23/D—487
`
`
`Reviewer
`Date of Rev.
`
`Williams
`
`Williams
`Williams
`
`Williams
`Williams
`
`Williams
`Williams
`
`Williams
`Williams
`
`Williams
`Williams
`
`Williams
`Williams
`
`Williams
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`Williams
`Williams
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`Williams
`
`Williams
`Williams
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`Williams
`Williams
`Willi/ams
`Williams
`Williams
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`OZJUN97
`02JUN97
`
`OZJUN97
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`OZJUN9?‘
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`OZJUN97
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`OZJUN97
`02JUN97
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`OZJUN97
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`OZJUN97
`D2JUN97
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`02JUN97
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`24 OCT 96
`24 OCT 96
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`24 OCT 96
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`24 OCT 96
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`24 OCT 96
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`02 JUN 97
`24 OCT 96
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`Williams
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`_ 24 OCT 96
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`GENETIC /MUTAGENIC TOXICITY
`
`-
`
`‘Ames Assay Tl" #91-8031
`Ames Assay ‘IT #91-8046 ‘
`Ames Assay TT #93-8044 '
`V79 M. cell Range-Find Cytotox. study TT #93-8550
`V-79 M. Cell Mutagenesis Assay TT #93-8551 '
`. V-79 M. Cell Mutagenesis Assay ‘IT #93-8563 ‘
`Rat Hepatocyte Rng-Find Cytotoxicity TT #91-8375
`Alkaline Elution/Rat Hepatocyte Assay TT #9]-8376
`Alkaline ElutionfRat Hepatocyte Assay Tl‘ #93-8494
`CHO Rng-Find Cytotox. and Solubility TT #9]-888]
`In Vitro Chrorn. Aberrat. in CHO Cells TT #91-8882
`
`In Vitro Chrom. Aberrat. in CHO Cells ‘IT #94-8638
`
`Mouse Bone Marrow Chrom. Aberrat. TT #93-8681
`
`Mouse Bone Marrow Chrom. Aberrat. TT #93-8696
`
`ONCOGENICICARCINOGENIC POTENTIAL
`
`lO6~Week PO Care. Study In Rats TT #93-078-0
`92-Week PO Carc. Study In Mice Tl" #93-1 10-0,-l
`SPECIAL TOXICITY
`_
`
`25-26:’ E-19 Williams
`
`24 OCT 96
`
`26-27/E-557 Williams
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`24 OCT 96
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`3]/Q-20
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`Oral Phototoxicity Study in Mice "IT #9l—2722
`P0 Enzyme Induction Study in Mice [H-S0] TT #91-
`3llQ-28
`061-0,-4
`Oral Enzyme Induction Study In Rats TT #91-074-0 3]/Q-42
`In vitro Hemolytic Assay In RatfHumanfDog Whole
`Blood And Washed RBCs TT #92-4903
`In Vitro Hemolytic Assay Dog Whole Blood And
`Washed RBCS TT #92-4909
`.
`Oral Drug Interaction Study In Mice Tl" #92-2651
`
`Choi* Studies reviewed under IND’
`
`31/Q-60
`
`31/Q-60
`31/Q-67
`
`Choi
`
`13 JUL 97
`
`Choi
`Choi
`
`13 JUL 97
`13 JUL 97
`
`Choi*
`
`27 JUL 93
`
`Choi‘
`Choi
`
`27 JUL 95
`13 JUL 92
`
`

`
`NDA 20,829 and 20,330
`Page 6
`
`/.-wn..\‘
`
`Note: Portions ofthis review were excerpted directlyfrom the sponsor’: submission.
`
`PHARMACOLOGY
`
`Table 1 (below and succeeding page) presents a tabulated summary of the studies which
`investigated the pharmacodynamic activity of monteiukast.
`
`Table 1
`-—
`
`Biological Activities _of Montelukast
`
`

`
`- .. , ..- .....H...
`
`
`
`‘--.-..~ _....._L...¢.1_._'._..-._....‘'_._._;....._.‘'
`
`L.u—--—-I ..-..........-. -.:
`
`.‘..-_‘.‘_ .. _
`
`. _. .-'.
`
`.
`
`-
`
`NDA 20,829 and 20,830
`Page 7
`
`

`
`NDA 20,829 and 20,830
`Page 8
`.-_.-
`
`Summary of Pharmacodynamic Activity:
`included receptor
`Submitted studies on the pharmacodynaxnic activity of montelukast
`binding studies, effects on contraction of isolated tissues,
`effects on agonist—induced bronchoconstriction, effects on
`antigen-induced bronchoconstriction and other miscellaneous
`
`pharmacological_studies. Receptor binding studies using guinea-
`pig lung, sheep lung, and human differentiated U937 cell
`
`membranes, and studies on isolated guinea—pig trachea showed that
`monteluksast is a potent and selective competitive antagonist of
`the Cys LT1receptor; Potency and selectivity at the Cys LT;
`receptor was also demonstrated in in vivo studies wherein
`'
`montelukast, administered by
`i.v., aerosol or oral route
`inhibited leukotriene D4—induced bronchoconstriction in guinea
`
`in conscious sheep
`pigs, squirrel monkeys, and to a lesser extent
`following aerosol administration. Montelukast was devoid of such
`inhibitory activity against-a variety of other
`bronchoconstrictors
`including: histamine, arachidonic acid,
`
`serotonin, and acetylcholine in anesthetized guinea pigs.
`
`A role for the Cys LT: receptor in antigen or ascaris-induced
`bronchoconstriction was demonstrated in in vivo models including:
`
`ascaris~induced
`antigen-induced dyspnea in inbred rats,
`bronchoconstriction in conscious squirrel monkeys and ascaris—
`induced early and late phase bronchoconstriction in conscious
`sheep, wherein montelukast was shown to be a potent and selective _
`antagonist of the induced bronchoconstriction.
`
`Thus, collectively the available pharmacodynamic studies suggest
`that Montelukast may have therapeutic value in treating human
`diseases such as bronchial asthma.
`
`SAFETYPHARMACOLOGY
`
`Previously submitted ancillary pharmacological studies included
`effects of montelukast on cardiovascular, renal, gastric,
`respiratory or CNS and behavioral parameters, where no
`The said
`significant activities were noted at the doses tested.
`studies have been reviewed previously (See attached Pharmacology
`Reviews by Dr
`. Choi dated 7/13/92
`and by Drl Williams dated 02
`
`

`
`NDA 20,829 and 20,830
`Page9
`
`JUN 97) are more fully discussed in the Overall Summary and
`Evaluation Section of the Document.
`
`PHARMACOKINETICS AND TOXICOKINETICS
`
`Methods: The absorption, distribution, metabolism and excretion (ADME) of montelukast were
`studied in mice, rats, and rhesus monkeys following oral and iv dosing with Radio-labeled [“
`C]—montelukast (["C]MK-0476, Batch # L«706,63 1-0035009), and Unlabeled MK-0476 Batch #
`
`L-706,631-001M035). The concentration of montelukast in plasma was measured by.
`‘
`'
`'
`_
`“-“_‘-‘—*—"—-—--—. Radioactivity in tissues, urine, bfle and feces was determined
`The limit of detection was
`0.03] pg‘/ml. Initially conducted pharmacokinetic studies in rats and monkeys (Ref. [G-1]) were
`previously reviewed (See Pharmacology Review of-—--*f~—-‘by Dr. Choi dated 7/ 1 3f92).
`Although some variability between the two studies was observed, in general reported results were
`similar between the two studies. Thus, this review will focus on the more recent study submitted,
`unless indicated. Unless stated otherwise, male animals were used in the ADME studies. The
`animals were fasted overnight prior to oral absorption studies.
`
`‘
`
`Results:
`
`Absorption:
`Oral:
`
`.
`
`Table 2 below presents a tabulated summary of the pharmacokinetics of rnontelukast following
`oral administration in rats, mice, monkeys and humans.
`
`'
`
`Table 2 Pharmacokinetics of Montelukast in Laboratory Animals and Humans After
`Oral Administration (Mean i S.D.) (Sponsor’s Summary Table G-2, NDA 20-829
`Vol. 29 pp G-9)
`
`
`
`
`2.82 :1: 1.61
`
`4.35 :i: 1.68
`
`15.? 2t 16.5
`
`
`
`
`
`I
`
`
`AUCo_..
`( -min/ml
`100 3: 53.7
`
`5803235
`
`1106 32 325
`4795 3. 3628
`
`Species
`
`Rat
`
`(n=3—4)
`
`Mouse "
`
`Monkey
`(n=4)
`
`
`
`
`
`
`
`Dose
`
`(mg/kg)
`5
`
`25
`so
`
`200
`
`5
`
`50
`
`200
`
`5
`
`25
`50
`
`
`
`(min)
`80.2 312.8‘
`
`
`176 3122 °
`
`
`
`
`
`
`
`
`
`34.2 1 13.3
`32.6 3: 9.57
`
`35.3 +. 26.7
`
`A
`
`37.5 :1: 8.66
`675 :l: 26.0
`
`80.0 3 34.6
`
`30
`
`60
`
`120
`
`
`
`152 1 29.4 ‘
`36.2 i 9.42
`78.8 :t 48.0
`457 1 55.9‘
`52.8 :t 25.2
`67.5 :I: 35.7
`
`38.4 :L- 13.6
`10] :1: 37.5
`
`Cmax
`
`( : ml)
`1.27 :I: 1.36
`
`Tmax
`
`(min)
`22.5 :1: 8.66
`
`F
`
`(%)
`29.6 1 17.3
`
`
`
`
`
`736 :k 191
`4.54 :1: 2.08
`5360 i255?
`21.6 i 4.32
`7795 :l: 2751
`27.3 :t 11.6
`
`BEST POSSIBLE COPY
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`

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`
`
`NDA 20,829 and 20,830
`Page 10
`
`150
`
`35456 :1:
`12405
`
`60.4 a 15.9
`
`90.0 1 60.0
`
`(n=6
`
`'0.126
`
`146 :l: 26.5
`
`0.335 :1: 0.035
`
`220 at 49.0
`
`53.2 :l: 20.4
`
`
`57.3 :1: 12.9 -
`
`' Mean plasma concentrations from three animals at each sampling time were used in the estimation
`ofpharrnacokinetic parameters.
`“Clinical dose 10 mg (mean body weight = 79.3 kg)
`["C]MK-0476, Batch # L-706,63]-0038009; Unlabeled MK-0476 # L-706,631-001M035
`° Ref. G-l Reviewed b Y.S. Choi in harrnacolog review dated 7-13-92
`
`
`
`
`
`
`
`The Data in Table 2 above show that Montelukast was rapidly absorbed in rats and mice with
`increased Tmax indicative prolonged absorption seen with dose increases from 5 to 200 mg/kg in
`both species . Absorption was somewhat slower in monkeys and humans and in monkeys the
`rate of absorption appeared independent of the dose. Bioavailability (F°/a) although somewhat
`variable appeared to be independe_nt of dose at the doses tested being around 30-35% in rats, 36-
`60 % in mice and monkeys, with greatest bioavailability (67%) observed in humans.
`In rats and
`mice increases in doses produced roughly proportional increases in Cmax and AUC values over
`the doses of 5 to 200 mg/kg. In monkeys increasing doses produced roughly proportional
`increases in AUC values, with less than proportional increases in Cmax values over a dose range
`of 5 to 150 mg/kg. Comparisons between species showed that similar doses resulted in greatest
`exposure (Cmax and AUC) in monkeys, relative to rats and mice, where exposure was
`comparable. Elimination half-life values following oral dosing were not provided in the study
`from which the nonclinical data in Table 2 was derived [Ref G-2]. However, previously
`conducted pharmacokinetic studies in rats and monkeys (Reviewed by Y.S. Choi in
`pharmacology review dated 7—l3-92) reported elimination half-life values of 80.2 1 12.8 and
`176 1 122 min in rats and 152 1 29.4 and 457 1 55.9 min in monkeys following oral
`administration of montelukast at doses of 5 and 25 mg/kg, respectively [Ref. G-1].
`
`, Additional repeat dose pharrnacokinetic testing in rats [Ref. G—6] showed similar
`pharmacokinetic parameters: Cmax [0.563 to 0.875 pg/ml], Tmax [40-55min], AUC [80-I17
`pg-min/ml], and 11/2 [87-105 min] on days I, 8, and 14 of dosing, indicating that repeated oral
`administration of MK-0476 (5 mg/kg) for 2 weeks had no significant effects on its
`I
`pharrnacokinetic handling in rats [Ref. G-6].
`
`Other studies conducted in rats investigated the mechanism behind the low bioavailability (33%)
`in rats in relation to potential intestinal metabolism and/or first pass metabolism.
`In vitro studies using an isolated rat intestinal loop preparation showed that introduction of a 1
`mg (3-4 mgfkg ) dose of [”C]-montelukast directly into the jejunum underwent negligible
`intestinal metabolism [Ref. G-2]. In contrast, studies which compared the steady-state drug
`concentrations in systemic plasma during portal or femoral vein infusion (4 mg/min estimated the
`first pass metabolism to be 27% [Ref. G-2]. Th