CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205395Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`
`205-395
`Supporting
`Document
`1
`
`Sponsor
`Submission Date
`3/31/14
`
`CDER Received
`Date
`3/31/14
`
`Product:
`
`Indication:
`Applicant:
`Review Division:
`Reviewer(s):
`
`Darunavir/Cobicistat Fixed Dose Combination
`(DRV-COBI FDC)
`Treatment of HIV infection
`Janssen Products LP
`Division of Antiviral Products
`Peyton Myers, PhD
`
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`Disclaimer
`
`Hanan Ghantous, Ph.D., DABT
`Debra B. Birnkrant, M.D.
`Nina Mani, Ph.D.
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 205-395 are owned by Janssen Products or are data for
`which Janssen Products has obtained a written right of reference. Any information or
`data necessary for approval of NDA 205-395 that Janssen Products does not own or
`have a written right to reference constitutes one of the following: (1) published literature,
`or (2) a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the
`drug’s approved labeling. Any data or information described or referenced below from
`reviews or publicly available summaries of a previously approved application is for
`descriptive purposes only and is not relied upon for approval of NDA 205-395.
`
`Reference ID: 3677960
`
`1
`
`

`

`NDA# 205-395
`
`Reviewer: L. Peyton Myers, PhD
`
`TABLE OF CONTENTS
`
`1 EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3 RECOMMENDATIONS............................................................................................ 3
`2 DRUG INFORMATION ............................................................................................ 6
`2.1 DRUG................................................................................................................. 6
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 6
`2.3 DRUG FORMULATION ........................................................................................... 7
`2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 7
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 7
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 7
`2.7 REGULATORY BACKGROUND ................................................................................ 7
`3 STUDIES SUBMITTED............................................................................................ 7
`3.1
`STUDIES REVIEWED............................................................................................. 7
`3.2
`STUDIES NOT REVIEWED ..................................................................................... 7
`3.3
`PREVIOUS REVIEWS REFERENCED........................................................................ 7
`
`Reference ID: 3677960
`
`2
`
`

`

`NDA# 205-395
`
`Reviewer: L. Peyton Myers, PhD
`
`Executive Summary
`1
`Introduction
`1.1
`Janssen Products has submitted an NDA to support the fixed dose combination (FDA)
`therapy of darunavir (DRV, prezista®, TMC114; HIV-1 protease inhibitor) and cobicistat
`(COBI or GS-9350; CYP450 3A enzyme inhibitor) for the treatment of HIV infection. The
`proposed clinical dose regimen includes 800 mg/day DRV + 150 mg/day COBI.
`
`There are approved NDAs for DRV which indicate that DRV must be co-administered
`with ritonavir (also a CYP3A inhibitor). This will be the first FDC for DRV and COBI.
`1.2 Brief Discussion of Nonclinical Findings
`No new studies were submitted. All nonclinical studies were included in the individual
`drug product NDAs.
`1.3 Recommendations
`1.3.1 Approvability
`There are no nonclinical pharmacology and toxicology issues which would preclude the
`approval of the FDC of DRV(800 mg/day)+COBI(150 mg/day)
`1.3.2 Additional Non Clinical Recommendations
`None.
`Labeling
`1.3.3
`The label for the FDC of DRV+COBI is merged from the single drug product NDA
`labels. The merged label is acceptable.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`Pregnancy Category C: PREZCOBIX should be used during pregnancy only if
`the potential benefit justifies the potential risk.
`
`No adequate and well controlled studies have been conducted in pregnant
`women using darunavir, cobicistat, or PREZCOBIX.
`
`Antiretroviral Pregnancy Registry: To monitor maternal fetal outcomes of
`pregnant women exposed to PREZCOBIX, an Antiretroviral Pregnancy Registry
`has been established. Physicians are encouraged to register patients by calling 1
`800 258 4263.
`
`Reference ID: 3677960
`
`3
`
`

`

`NDA# 205-395
`
`Reviewer: L. Peyton Myers, PhD
`
`Animal Data:
`
`Cobicistat: Studies in animals have shown no evidence of teratogenicity or an
`effect on reproductive function. In offspring from rat and rabbit dams treated with
`cobicistat during pregnancy, there were no toxicologically significant effects on
`developmental endpoints. The exposures at the embryo fetal No Observed
`Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 1.4 and
`3.3 times higher than the exposure in humans at the recommended daily dose of
`150 mg.
`
`Darunavir: Reproduction studies conducted with darunavir showed no
`embryotoxicity or teratogenicity in mice and rats in the presence or absence of
`ritonavir as well as in rabbits with darunavir alone. In these studies, darunavir
`exposures (based on AUC) were higher in rats (3 fold), whereas in mice and
`rabbits, exposures were lower (less than 1 fold) compared to those obtained in
`humans at the recommended clinical dose of darunavir
` with ritonavir.
`In the rat pre and postnatal development study, a reduction in pup body weight
`gain was observed with darunavir alone or
` with ritonavir during
`lactation. This was due to exposure of pups to drug substances via the milk.
`Sexual development, fertility and mating performance of offspring were not
`affected by maternal treatment with darunavir alone or
` with
`ritonavir. The maximal plasma exposures achieved in rats were approximately
`50% of those obtained in humans at the recommended clinical dose boosted with
`ritonavir.
`
`In the juvenile toxicity study where rats were directly dosed with darunavir,
`deaths occurred from post natal day 5 through 11 at plasma exposure levels
`ranging from 0.1 to 1.0 of the human exposure levels. In a 4 week rat toxicology
`study, when dosing was initiated on post natal day 23 (the human equivalent of 2
`to 3 years of age), no deaths were observed with a plasma exposure (in
`combination with ritonavir) of 0.1 of the human plasma exposure levels.
`
`8.3
`
`Nursing Mothers
`
`The Centers for Disease Control and Prevention recommend that HIV infected
`mothers in the United States not breastfeed their infants to avoid risking
`postnatal transmission of HIV. Although it is not known whether darunavir or
`cobicistat are secreted in human milk, darunavir and cobicistat are secreted into
`the milk of lactating rats. Because of both the potential for HIV transmission and
`the potential for serious adverse reactions in nursing infants, instruct mothers not
`to breastfeed.
`
`8.4
`
`Pediatric Use
`
`Safety, effectiveness, and pharmacokinetics of PREZCOBIX in pediatric patients
`less than 18 years of age have not been established. Darunavir, and thus
`
`Reference ID: 3677960
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA# 205-395
`
`Reviewer: L. Peyton Myers, PhD
`
`PREZCOBIX is not recommended in pediatric patients below 3 years of age in
`view of toxicity and mortality observed in juvenile rats dosed with darunavir [see
`Nonclinical Toxicology (13.2)].
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis and Mutagenesis
`
`Darunavir: Darunavir was evaluated for carcinogenic potential by oral gavage
`administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and
`1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg
`administered to rats. A dose related increase in the incidence of hepatocellular
`adenomas and carcinomas m" observed in males and females of both species
`“m an increase in thyroid follicular cell adenomas in male rats. The
`observed hepatocellular findings in rodents are considered to be of limited
`relevance to humans. Repeated administration of darunavir to rats caused
`hepatic microsomal enzyme induction and increased thyroid hormone
`elimination, which predispose rats, but not humans, to thyroid neoplasms. At the
`highest tested doses, the systemic exposures to darunavir (based on AUC) were
`between 0.4 and 0.7 fold (mice) and 0.7 and 1 fold (rats),
`“m
`observed in humans at the recommended therapeutic doses
`
`lb) (4)
`
`(b) (4)
`
`Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo
`assays including bacterial reserve mutation (Ames), chromosomal aberration in
`human lymphocytes and in vivo micronucleus test in mice.
`Cobicistat: In a long term carcinogenicity study in mice, no drug related increases
`in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males
`and females, respectively). Cobicistat exposures at these doses were
`approximately 7 (male) and 16 (females) times, respectively, the human systemic
`exposure at the therapeutic daily dose. In a long term carcinogenicity study of
`cobicistat in rats, an increased incidence of follicular cell adenomas and/or
`carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day
`in males, and at 30 mg/kg/day in females. The follicular cell findings are
`considered to be rat specific, secondary to hepatic microsomal enzyme induction
`and thyroid hormone imbalance, and are not relevant for humans. At the highest
`doses tested in the rat carcinogenicity study, systemic exposures were
`approximately 2 times the human systemic exposure at the therapeutic daily
`dose.
`
`Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test),
`mouse lymphoma or rat micronucleus assays.
`
`Reference ID: 3677960
`
`

`

`NDA# 205-395
`
`Reviewer: L. Peyton Myers, PhD
`
`Impairment of Fertility
`
`Darunavir: No effects on fertility or early embryonic development were observed
`with darunavir in rats and darunavir has shown no teratogenic potential in mice or
`rats (in the presence or absence of ritonavir),
` rabbits.
`
`Cobicistat: Cobicistat did not affect fertility in male or female rats at daily
`exposures (AUC) approximately 4 fold higher than human exposures at the
`recommended 150 mg daily dose.
`
`Fertility was normal in the offspring of rats exposed daily from before birth (in
`utero) through sexual maturity at daily exposures (AUC) of approximately 1.2 fold
`higher than human exposures at the recommended 150 mg daily dose.
`
`13.2 Animal Toxicology and/or Pharmacology
`
`Darunavir: In juvenile rats single doses of darunavir (20 mg/kg to 160 mg/kg at
`ages 5 11 days) or multiple doses of darunavir (40 mg/kg to 1000 mg/kg at age
`12 days) caused mortality. The mortalities were associated with convulsions in
`some of the animals. Within this age range exposures in plasma, liver and brain
`were dose and age dependent and were considerably greater than those
`observed in adult rats. These findings were attributed to the ontogeny of the
`CYP450 liver enzymes involved in the metabolism of darunavir and the
`immaturity of the blood brain barrier. No treatment related mortalities were noted
`in juvenile rats after a single dose of darunavir at 1000 mg/kg on day 26 of age or
`after repeat dosing at 500 mg/kg from day 23 to 50 of age. The exposures and
`toxicity profile in the older animals (day 23 or day 26) were comparable to those
`observed in adult rats. Due to uncertainties regarding the rate of development of
`the human blood brain barrier and liver enzymes, do not administer
` in pediatric patients below 3 years of age.
`
`Drug Information
`2
`2.1 Drug
`
`Generic Name
`Darunavir/cobicistat 800mg/150mg (DRV/COBI) Fixed-Dose Combination (FDC)
`tablets
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`NDA 203-100 -- COBI FDC
`NDA 203-094 -- COBI
`NDA 21976 -- DRV
`
`Reference ID: 3677960
`
`6
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA# 205-395
`
`Reviewer: L. Peyton Myers, PhD
`
`2.3 Drug Formulation
`Fixed Dose Tablets
`2.4 Comments on Novel Excipients
`None.
`2.5 Comments on Impurities/Degradants of Concern
`None.
`
`Proposed Clinical Population and Dosing Regimen
`2.6
`HIV treatment with 800mg/150mg (DRV/COBI) Fixed-Dose Combination (FDC) tablets
`2.7 Regulatory Background
`DRV and COBI are both approved under their respective NDAs. This is the FDC tablet
`combination with DRV and COBI. All data for COBI and DRV are in their respective
`NDAs.
`3
`3.1
`N/A
`3.2
`N/A
`3.3
`None.
`
`Studies Submitted
`Studies Reviewed
`
`Studies Not Reviewed
`
`Previous Reviews Referenced
`
`Reference ID: 3677960
`
`7
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`LAINE P MYERS
`12/23/2014
`
`HANAN N GHANTOUS
`12/24/2014
`
`Reference ID: 3677960
`
`

`

`PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR
`NDA/BLA or Supplement
`Stamp Date: March 31, 2014
`Applicant: Janssen Products LP
`NDA/BLA Number: 205395
`Drug Name: DRV/COBI FDC NDA/BLA Type: Standard (Not NME)
`
`On initial overview of the NDA/BLA application for filing:
`
`Content Parameter
`1 Is the pharmacology/toxicology section
`organized in accord with current regulations
`and guidelines for format and content in a
`manner to allow substantive review to
`begin?
`2 Is the pharmacology/toxicology section
`indexed and paginated in a manner allowing
`substantive review to begin?
`3 Is the pharmacology/toxicology section
`legible so that substantive review can
`begin?
`4 Are all required (*) and requested IND
`studies (in accord with 505 b1 and b2
`including referenced literature) completed
`and submitted (carcinogenicity,
`mutagenicity, teratogenicity, effects on
`fertility, juvenile studies, acute and repeat
`dose adult animal studies, animal ADME
`studies, safety pharmacology, etc)?
`5 If the formulation to be marketed is
`different from the formulation used in the
`toxicology studies, have studies by the
`appropriate route been conducted with
`appropriate formulations? (For other than
`the oral route, some studies may be by
`routes different from the clinical route
`intentionally and by desire of the FDA).
`6 Does the route of administration used in the
`animal studies appear to be the same as the
`intended human exposure route? If not, has
`the applicant submitted a rationale to justify
`the alternative route?
`7 Has the applicant submitted a statement(s)
`that all of the pivotal pharm/tox studies
`have been performed in accordance with the
`GLP regulations (21 CFR 58) or an
`explanation for any significant deviations?
`8 Has the applicant submitted all special
`studies/data requested by the Division
`during pre-submission discussions?
`
`Yes No
`
`N/A.
`
`Comment
`
`No module 4 – no data to review.
`The review will consist entirely of a label
`review.
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`File name: 5_Pharmacology_Toxicology Filing Checklist for NDA_BLA or Supplement
`010908
`Reference ID: 3501498
`
`

`

`PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR
`NDA/BLA or Supplement
`Content Parameter
`Yes No
`9 Are the proposed labeling sections relative
`to pharmacology/toxicology appropriate
`(including human dose multiples expressed
`in either mg/m2 or comparative
`serum/plasma levels) and in accordance
`with 201.57?
`10 Have any impurity – etc. issues been
`addressed? (New toxicity studies may not
`be needed.)
`11 Has the applicant addressed any abuse
`potential issues in the submission?
`
`Comment
`Will review this section to conform with the
`individual drug product(s) labels.
`
`X
`
`N/A
`
`N/A
`
`12 If this NDA/BLA is to support a Rx to OTC
`switch, have all relevant studies been
`submitted?
`
`N/A
`
`IS THE PHARMACOLOGY/TOXICOLOGY SECTION OF THE APPLICATION
`FILEABLE? ___Yes_____
`
`If the NDA/BLA is not fileable from the pharmacology/toxicology perspective, state the reasons
`and provide comments to be sent to the Applicant.
`
`None.
`
`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-
`day letter.
`
`None.
`
`Laine Peyton Myers, PhD
`Reviewing Pharmacologist
`
`Hanan Ghantous, PhD, DABT
`Team Leader/Supervisor
`
`April 30, 2014
`Date
`
`April 30, 2014
`Date
`
`File name: 5_Pharmacology_Toxicology Filing Checklist for NDA_BLA or Supplement
`010908
`Reference ID: 3501498
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`LAINE P MYERS
`05/06/2014
`
`HANAN N GHANTOUS
`05/06/2014
`
`Reference ID: 3501498
`
`