CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205395Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Cross Discipline Team Leader Review
`Mary Singer. MD.. Ph.D.. Medical Team Leader. DAVP
`
`Cross-Discipline Team Leader Review
`
`
`
`Ma Sin er, MD PhD
`From
`m__
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Prezcobix (Damnavir/cobicistat)
`
`Dosage forms / Strength
`
`Fixed dose combination tablet/ 800 mg damnavir and 150
`m - cobicistat
`
`
`
`Proposed Indication(s)
`
`Recommended:
`
`Treatment of HIV—1 infection in adults in combination with
`other antiretroviral agents
`Approval
`
`Page 1 of 12
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`Reference ID: 3681714
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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`1. Introduction
`
`Darunavir, an HIV protease inhibitor, coadministered with ritonavir, was initially approved for
`treatment of HIV-1 in combination with other antiretroviral agents in June, 2006. Darunavir
`(Prezista) is currently available as film coated tablets (75, 150, 600, and 800 mg) and as an oral
`suspension for use in pediatric patients 3 years and older. In treatment-naïve and treatment-
`experienced adults with no darunavir resistance- associated substitutions, darunavir is dosed as
`800 mg with 100 mg ritonavir once daily. In treatment-experienced adults with at least one
`darunavir resistance-associated substitution, the darunavir dosage is 600 mg coadministered
`with 100 mg ritonavir twice daily. Pediatric dosing of darunavir with ritonavir is based on
`weight in patients 3 years of age and older. Darunavir (Prezista) was developed by Janssen
`Pharmaceuticals, Inc.
`
`Cobicistat was developed by Gilead Sciences as an alternative pharmacokinetic “booster” to
`ritonavir, and was approved as a single entity on September, 2014 for the indication of
`increasing systemic exposure of atazanavir or darunavir (once daily dosing regimen) in
`combination with other antiretroviral agent in treatment of HIV-1 infection. Cobicistat, like
`ritonavir is a strong CYP3A inhibitor, but is has no antiretroviral activity. Cobicistat was
`initially approved in 2012 as part of the fixed dose combination tablet, Stribild, which contains
`cobicistat, elvitegravir, emtricitabine, and tenofovir disoproxil fumarate for treatment of HIV-
`1.
`
`2. Background
`Janssen, in collaboration with Gilead, developed a fixed dose combination tablet containing
`darunavir 800 mg and cobicistat150 mg. The proposed indication for this fixed dose tablet is
`treatment of HIV-1 infection in
`-naïve and
`-experienced adults with
`no darunavir resistance associated substitutions.
`
`The safety and efficacy of the darunavir/cobicistat fixed dose combination tablet was based on
`that of the individual approved products, darunavir (in combination with low dose ritonavir
`used to increase darunavir exposure by virtue of its CYP3A inhibitory activity) and safety and
`activity of cobicistat. The safety and efficacy of darunavir in combination with ritonavir was
`based on randomized controlled trials of darunavir/ritonavir in treatment-naïve and treatment-
`experienced HIV-infected adults and pediatric patients, as reviewed for NDAs 21976 and
`202895. The safety and activity of cobicistat was based on a trial comparing safety and
`efficacy of atazanavir/cobicistat (300 mg/100 mg) to atazanavir/ritonavir (300 mg/100 mg) in
`treatment-naïve adults, as well as on pharmacokinetic bridging data which showed atazanavir
`exposures similar to that when atazanavir was coadministered with ritonavir. Cobicistat is also
`approved for use with darunavir (administered as single entities), based on pharmacokinetic
`bridging data, as reviewed for NDA 203094. For this NDA submission, the following trials
`were submitted as a bridge to the individual components of the FDC:
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`Page 2 of 12
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`Reference ID: 3681714
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`(b) (4)
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`(b) (4)
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`

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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`1. TMC114IFD1001: a phase one oral bioavailability study which evaluated two
`FDCs of DRV/Cobi (G003 and G004) compared to darunavir/ritonavir 800
`mg/100 mg daily;
`2. TMC114IFD1003: a phase one bioequivalence study of the selected FDC
`formulation compared to DRV and Cobi administered as single agents; and
`3. GS-US-216-0130: a phase 3 open-label, single arm study of DRV and Cobi
`administered as single agents in ART-naïve or experienced HIV-infected
`adults.
`
`Note that the first bioavailability trial, TMC114IFD1001, was not considered essential for this
`submission and was not reviewed; while TMC114IFD1003 was considered the pivotal trial for
`this submission. Trial TMC114IFD1003 demonstrated that the darunavir exposures achieved
`with darunavir/cobicistat FDC tablet were similar to those observed with darunavir
`coadministered with cobicistat as single entities. The single-arm, open-label GS-US-216-0130
`trial was considered supportive to provide 24 week safety information for DRV 800 mg
`coadministered with cobicistat 150 mg.
`
`3. CMC/Device
`
`The drug product, Prezcobix, is an immediate release film-coated tablet consisting of a fixed
`dose combination (FDC) of 800 mg equivalent of darunavir
` and 150 mg equivalent
`of cobicistat
`The tablets are oval shaped, debossed and film-coated with a pink
`color. The darunavir/cobicistat 800 mg/150 mg tablets are packaged in 120 mL, white, high
`density polyethylene (HDPE) bottles. Each bottle contains 30 tablets and is capped
`. A shelf life of 24 months is
`granted for all climatic zones for drug product packaged in the proposed commercial container
`closure system.
`
`The Drug Master Files (DMFs) for the darunavir and cobicistat drug substances are adequate.
`The Drug Master Files (DMF 25188 and DMF 18825) for the cobicistat on silicon dioxide and
`darunavir ethanolate drug substances supporting this NDA are adequate. Information on
`characterization of impurities for darunavir and cobicistat drug substances is included in the
`respective DMFs, and no new impurities were observed in the 800/150 mg darunavir/cobicistat
`film-coated tablets. Information provided for NDA 205395 regarding drug product
`manufacturing, raw materials controls and specifications, analytical methods, and drug product
`stability is adequate to support the quality of the drug product through its shelf-life of 24
`months.
`
`All requested inspections of manufacturing sites for drug product and drug substance have
`been completed and the overall recommendation from the Office of Compliance is
`“Acceptable” for establishment evaluation. The Product Quality Microbiology Review by Dr.
`Erika Pfeiler recommends approval; and from a CMC perspective, the NDA has provided
`adequate information to assure the identity, strength, purity and quality of the drug product,
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`and is recommended for approval. For full details, see CMC review by Fuqiang Liu, Ph.D. and
`Stephen Miller, Ph.D.
`
`4. Nonclinical Pharmacology/Toxicology
`No new pharmacology/toxicology studies were submitted to the NDA and there have been no
`new safety concerns based on non-clinical studies identified with darunavir or cobicistat.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Because the efficacy and safety of darunavir has been established as a single entity in
`combination with ritonavir for treatment of HIV-1 (see NDAs 21976 for 202895 for
`Prezista tablet and oral suspension, respectively), a clinical trial to evaluate the efficacy
`and safety of FDC darunavir/cobicistat tablet was not required; and the efficacy and safety
`of this new combination product relies on that previously established for darunavir, and on
`the safety and activity of cobicistat along with the pharmacokinetic bridging data discussed
`above. Cobicistat, a CYP3A inhibitor with no intrinsic antiviral activity was approved as a
`single entity as a pharmaco-enhancer for the HIV protease inhibitors, atazanavir and
`darunavir (NDA 203094, approved September 2014) and as part of the FDC Stribild
`(elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (NDA 203100,
`approved 2012).
`
`The pivotal trial for this NDA, TMC114IFD1003 (1003), compared the relative
`bioavailability of darunavir and cobicistat administered as part of the FDC tablet to single
`entity formulations of daruanvir (two 400 mg tablets) and cobicistat (150 mg tablets). This
`trial also evaluated the food effect data for the darunavir/cobicistat FDC tablet. The
`Clinical Pharmacology review evaluated the food effect data; while the Biopharmaceutics
`review evaluated the relative bioavailability data, the inspections findings by the Office of
`Scientific Investigations (OSI), as well as the relevant bioanalytical information. The
`Biopharmaceutics review also evaluated drug product dissolution method development and
`acceptance criteria as well as drug product formulation development and dissolution
`quality risks. For full details, please see Clinical Pharmacology review by Drs. Stanley Au
`and Kellie Reynolds, in the Office of Clinical Pharmacology; and the Biopharmaceutics
`review by Drs. Minerva Hughes and Angelica Dorantes, in the Office of New Drug
`Quality Assessment.
`
`In brief, the 90% confidence intervals for darunavir exposure were within 80-125% for the
`FDC tablet compared to the single entity tablets of darunavir and cobicistat in trial 1003, as
`noted in the Biopharmaceutics review. The dissolution methods and acceptance criteria
`were considered acceptable by the Biopharmaceutics reviewers for product quality control.
`The Office of Scientific Investigation (OSI) was consulted to inspect the clinical and
`bioanalytical sites used for trial 1003 and found all clinical and analytical study data
`acceptable. The Biopharmaceutics reviewers have recommended approval of this NDA for
`the darunavir/cobicistat FDC tablet.
`
`Page 4 of 12
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`Reference ID: 3681714
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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`In trial 1003, a food effect was observed for darunavir when administered with cobicistat
`as a fixed dose combination tablet, as noted in the Clinical Pharmacology review. An
`increase in darunavir AUC and Cmax (70% and 127%, respectively) was demonstrated
`when the darunavir/cobicistat FDC tablet was administered with a high fat meal in
`comparison to fasting. This increase in exposure was somewhat higher than that observed
`in previous studies in which darunavir was administered with ritonavir as single entities
`(48% increase in darunavir AUC and 59% increase in Cmax) under high fat compared to
`fasted conditions. No food effect was observed for cobicistat administered as part of the
`darunavir/cobicistat FDC product in trial 1003. The darunavir (Prezista) full prescribing
`information includes a recommendation that darunavir in combination with ritonavir be
`administered with food; and because no specific exposure-related safety issues have been
`identified for darunavir at the recommended darunavir/ritonavir dosage regimens, the
`Applicant’s recommendation to administer darunavir/cobicistat FDC tablet with food was
`considered acceptable; and the Clinical pharmacology reviewers have recommended
`approval for this NDA.
`
`6. Clinical Microbiology
`
`Please see Clinical Microbiology Review by Drs. Takashi Komatsu and Jules O’Rear for
`full details. In brief, the single arm, open-label trial, GS-US-216-0130, in which treatment-
`naïve and treatment-experienced HIV-1 infected subjects who had no darunavir resistance-
`associated substitutions were treated for 24 weeks with darunavir 800 mg plus cobicistat
`150 mg as single entities in combination with 2 fully active NRTIs was reviewed to
`evaluate development of resistance-associated substitutions in subjects who experienced
`virologic failure. None of the subjects had primary resistance substitutions for darunavir at
`screening. A total of 36 subjects with evaluable resistance data (30/277, 11% treatment
`naïve and 6/17, 35% treatment-experienced subjects) were identified as having virologic
`failure. Among virologic failure subjects with available genotypic data, a total of 10 amino
`acid substitutions in the HIV protease developed on treatment. Five of these were
`identified in 5 treatment-naïve subjects and 5 were identified in 5 treatment-experienced
`subjects with virologic failure. One subject developed the DRV resistance-associated
`substitution, PI I84I/V; however the susceptibility to DRV was not reduced in the isolate
`from this subject possibly due to a mixture of wild type (I) and mutant (V) viruses. No new
`darunavir resistance-associated substitutions were identified; and none of the subjects with
`available genotypic data developed primary resistance-associated substitutions to any of
`the reverse transcriptase inhibitors.
`7. Clinical/Statistical- Efficacy
`
`The Applicant conducted an open-label, single arm, multicenter trial, GS-US-216-0130, to
`evaluate safety and efficacy of darunavir/cobicistat as single entities coadministered with 2
`fully active NRTIs in HIV-1 infected, antiretroviral treatment-naïve (n=295) and treatment-
`experienced (n=18) adults with no DRV resistance-associated substitutions. As efficacy for the
`darunavir/cobicistat fixed dose combination tablet is extrapolated from that of
`darunavir/ritonavir, this trial was considered supportive for efficacy and safety. At baseline,
`
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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`the median age of subjects was 35 years, 11% were female, 40% were non-white, 42% had
`HIV-1 RNA >100,000 copies/mL, and 19% had CD4+ cell count <200 cells/mm3. At 24
`weeks, 82% of subjects treated with darunavir coadministered with cobicistat plus two
`nucleoside reverse transcriptase inhibitors achieved HIV RNA <50 copies/mL. At 24 weeks,
`247/295 (84%) treatment-naïve subjects and 11/18 (61%) treatment-experienced subjects
`achieved an HIV RNA < 50 copies/mL. In a cross-study comparison, at 48 weeks, HIV RNA
`< 50 copies/mL at 48 weeks was achieved in 84% treatment-naïve subjects treated with
`darunavir/ritonavir 800 mg/100 mg once daily and in 78% subjects treated with
`lopinavir/ritonavir 800 mg/200 mg once daily both in combination with tenofovir disoproxil
`fumarate and emtricitabine (Trial TMC114-C211, as reviewed for NDA 21976). In treatment-
`experienced patients with no darunavir associated resistance substitutions, 69% subjects who
`received darunavir/ritonavir 800 mg/100 mg once daily, and 69% subjects who received
`darunavir/ritonavir 600 mg/100 mg twice daily plus an optimized background regimen
`achieved HIV RNA < 50 copies/mL at week 48 in Study TMC114-C214 (NDA 21976).
`Acknowledging the limitations of cross-study comparisons and of interpreting data from a
`single arm, noncomparative trial, the results of GS-US-216-0130 provide support that DRV
`coadministered with cobicistat has adequate antiviral activity. See Dr. Sarita Boyd’s clinical
`review for further details. A statistical review was not considered necessary for this
`application, as trial GS-US-216-0130 is not considered an adequate well-controlled trial and is
`considered solely as supportive information for this NDA.
`
`8. Safety
`
`The safety of darunavir/cobicistat FDC tablet is extrapolated from the safety of
`darunavir/ritonavir reviewed under NDA 21976. The ongoing open-label, single arm,
`multicenter trial, GS-US-216-0130 submitted with this application was considered supportive
`for safety. The 24 week safety data was reviewed by Dr. Sarita Boyd, and no new safety
`concerns were identified. The following table summarizes safety findings at the 24 week cut
`point for trial GS-US-216-0130. No deaths were reported in the trial, and overall, 88%
`subjects experienced at least one adverse event, 5% had a serious AE, 5% discontinued due to
`AE, and 6% experienced a Grade 3 or 4 AE.
`
`Table 1. Safety Summary for GS-US-216-0130 (24 week timepoint)
`Darunavir 800 mg plus cobicistat 150 mg
`daily
`N= 313
`n (%)
`275 (88)
`15 (5)
`15 (5)
`0
`18 (6)
`
`Any adverse event
`Serious adverse event
`Discontinuation due to adverse event
`Death
`Severe (grade 3 or 4 AE)
`N= number of subjects
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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`The most common SAEs in this trial were fever and rash, reported in 2 subjects each.
`Investigators considered 3 SAEs related or possibly related to study drugs: immune
`reconstitution syndrome, rash, and maculopapular rash. No cases of Stevens Johnson
`syndrome, DRESS, or TEN were reported in this trial. Darunavir and cobicistat have each
`been associated with rash (see full prescribing information for each), so rash is not unexpected
`with the darunavir/cobicistat FDC tablet. Immune reconstitution syndrome has been associated
`with antiretroviral therapy, and is found as a Warning in the prescribing information for HIV
`protease inhibitors.
`
`The most common adverse events resulting in study drug discontinuation were rash in 9
`subjects (3%), hypersensitivity in 2(0.6%) subjects (described as rash in one subject and rash
`with angioedema in one subject), and nausea in 2 subjects (0.6%). Overall, the most common
`AEs regardless of causality were rash (7%), diarrhea (5%), upper respiratory tract infection
`(4%), and nausea (3%). The most common AEs considered related to study drugs by
`investigators were rash (5%), nausea (2%) and diarrhea (2%). These adverse events have all
`been described in prescribing information for darunavir and/or cobicistat. Darunavir has been
`associated with rashes ranging from mild to severe, and the full prescribing information
`includes a Warning for severe skin reactions.
`
`Grade 3 or 4 laboratory abnormalities were reported for ALT in 7 subjects (2%), and AST in 6
`subjects (2%). ALT and AST elevation was not associated with bilirubin elevation fitting Hy’s
`law criteria in any of these subjects. One subject with Gilbert’s syndrome at baseline
`experienced a grade 3 bilirubin elevation with no concomitant ALT, AST or alkaline
`phosphatase elevation. No grade 3 or 4 creatinine elevation was reported, although 23 subjects
`(7%) had grade 1 or 2 creatinine elevation, as expected with cobicistat. Grade 3 or 4 amylase
`and lipase elevations were reported in 6 (2%) and 5 (2%) subjects, respectively; however
`amylase and/or lipase elevations were not associated with pancreatitis or symptoms of
`pancreatitis. Grade 3 or 4 hematologic abnormalities were reported in 4 subjects with
`neutropenia, 1 with thrombocytopenia, and 1 with anemia (hemoglobin 6.5- < 7.5). All 4
`subjects with neutropenia received tenofovir/emtricitabine (TDF/FTC) in addition to darunavir
`and cobicistat. Neutropenia in these subjects was not associated with any reports of infection
`or other adverse events, and was not considered clinically significant. The single report of
`Grade 4 thrombocytopenia was associated with an SAE of idiopathic thrombocytopenic
`purpura (ITP), which is associated with HIV infection; and the Grade 3 hemoglobin decrease
`was reported in a patient with severe pelvic inflammatory disease.
`
`Review of the 120-day safety update, which included additional safety information from the
`ongoing trial, GS-US-216-0130, and from the renal impairment trial, GS-US-236-0118, did
`not reveal any new or unexpected adverse reactions.
`9. Advisory Committee Meeting
`An Advisory Committee meeting was not held for this application.
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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader. DAVP
`
`10.
`
`Pediatrics
`
`Efficacy of antiretroviral therapy can be extrapolated from adults to pediatric patients with
`HIV, because the pathophysiology of HIV infection is similar in both, and because suppression
`of HIV RNA is associated with decreased morbidity (i.e. AIDS or non-AIDS related
`morbidity) and mortality in both adult and pediatric patients. The cobicistat commercial
`sponsor has a PREA requirement to evaluate darunavir coadministered with cobicistat as
`single entities in pediatric patients to assess safety, antiviral activity and pharmacokinetics in
`order to determine appropriate dosing regimens.
`
`This applicant will have a PREA requirement for each pediatric age group noted below to
`evaluate the pharmacokinetics, safety, and antiviral activity of darunavir/cobicistat fixed dose
`combination (FDC) age-appropriate formulation in HIV-infected pediatric subjects ages 3
`year to < 6 years weighing at least 15 kg, ages 6 years to < 12 years; and ages 12 to (”years of
`age). A pediatric clinical trial may not be required if the dosing recommendation for the FDC
`age-appropriate fonnulation can be supported by pediatric trials already conducted with the
`individual drug products and if the age-appropriate FDC formulation produces similar
`exposures as the individual components. The Applicant will also evaluate the relative oral
`bioavailability of the darimavir/cobicistat age-appropriate fixed dose formulation in
`comparison to the individual components in healthy adults once pediatric doses are established
`for darunavir and cobicistat.
`mm)
`
`0)“)
`
`The bioequivalence of the fixed dose combination product, darunavir/cobicistat 800 mg/150
`mg has already been established in healthy adults in comparison to the single agents, and may
`be appropriate for some pediatric patients (e.g. adolescents).
`
`The Applicant requested a waiver for a pediatric assessment in patients < 3 years old because
`of safety concerns with darunavir in this age group. Darunavir has been approved in pediatric
`patients 2 3 years of age, but not in younger patients because of increased mortality observed
`in a juvenile animal toxicity study. A waiver for pediatric assessments in pediatric patients 2 3
`years of age weighing < 15 kg was also requested for the fixed dose combination because the
`product fails to represent a meaningful therapeutic benefit over existing therapies (i.e.
`danmavir and ritonavir are currently available as separate entities for this age group,
`and is unlikely to
`be used in a substantial number of pediatric patients. A deferral was requested for pediatric
`patients 2 3 years to < 18 years of age weighing 2 15 kg because adult studies are completed
`and ready for approval, and because the different darlmavir/cobicistat FDC age-appropriate
`formulations necessary for weight based dosing cannot be developed until dosing
`recommendations are available for darunavir and cobicistat as single agents. The cobicistat
`sponsor is currently evaluating safety, antiviral activity and pharmacokinetics of darlmavir and
`cobicistat as single agents in pediatric patients. The Division and the pediatric review
`committee (PeRC) agreed with the Applicant’s proposed waiver and deferral.
`
`(h) (4)
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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`Other Relevant Regulatory Issues
`11.
`Financial disclosures were not required for investigators of the single arm, open-label trial of
`darunavir and cobicistat administered as single entities, GS-US-216-0130, because the trial
`was considered supportive. Financial disclosures were obtained for the pivotal bioequivalence
`trial, TMC114IFD1003, for 4 of the 5 clinical investigators. The Applicant was unable to
`obtained financial disclosure for one clinical investigator who participated in the trial despite
`numerous attempts. However, ORA inspection of the clinical site did not result in any
`citations, and there was no evidence to suggest any deficiencies, irregularities or biases. Thus,
`the lack of financial disclosure information from a single investigator should not preclude
`approval this supplement.
`12.
`Labeling
`
`The proposed proprietary name for darunavir/cobicistat fixed dose combination tablet,
`Prezcobix, was considered acceptable by DMEPA and DAVP. One issue raised by DMEPA
`concerned the Applicant’s proposal to
`
`
`
`Additional issues for the FPI included including lurasidone, an atypical antipsychotic, as a
`contraindicated medication due to a drug interaction
`
`if coadministered with darunavir/cobicistat FDC tablet. The
`Division of Psychiatry Products was consulted and recommended the contraindication because
`of safety concerns with coadministration
`Alternative
`antipsychotic agents are available which could potentially be substituted for lurasidone. The
`applicant agreed with this change.
`
`For Section 8, Use in Specific Populations, 8.1 Pregnancy, the final Pregnancy Labeling Rule
`was published this month in the Federal Register, and will require removal of pregnancy
`category as well as reorganization of this section within a risk summary. Because these
`changes are not yet mandatory, they will not be made with this submission, pending revision
`of this section in the darunavir and cobicistat labeling.
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`Other content and formatting changes have been made in consultation with the acting associate
`director for labeling in DAVP, Dr. Katie Schumann. The Applicant has accepted these
`changes.
`
`13.
`
`Recommendations/Risk Benefit Assessment
`
`! Recommended Regulatory Action: Approval
`
`! Risk Benefit Assessment
`
`The review team found the risk-benefit profile of the darunavir/cobicistat FDC
`tablet acceptable. The risks and benefits are similar to those outlined for the
`individual entities as reviewed in the respective NDAs for darunavir and cobicistat.
`In addition, because cobicistat is used in combination with darunavir to increase
`darunavir exposures similar to the use of ritonavir in combination with darunavir or
`other HIV protease inhibitors, the risk-benefit considerations are similar to those
`assessed for darunavir/ritonavir. Efficacy and safety of the darunavir/cobicistat
`FDC tablets were extrapolated from clinical trials of darunavir/ritonavir in
`treatment-naïve and treatment experienced subjects with HIV-1, based on
`bioequivalence data between darunavir/cobicistat FDC tablet and the single entities
`and between darunavir and cobicistat administered as single entities and darunavir
`ritonavir administered as single entities. The single arm, open-label trial which
`evaluated darunavir and cobicistat as single entities was considered supportive for
`both efficacy and safety of the darunavir/cobicistat FDC tablet.
`
`! Recommendation for Postmarketing Risk Evaluation and Management
`Strategies: A REMS is not recommended for this application.
`
`! Recommendation for other Postmarketing Requirements and Commitments:
`
`Other than the pediatric postmarketing requirements (PMRs) required under PREA,
`no other postmarketing commitments or requirements are recommended. The
`PREA PMRs and proposed timelines for completion agreed to by the Applicant
`include:
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`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`1. Evaluate the pharmacokinetics, safety, and antiviral activity (efficacy) of
`darunavir/cobicistat fixed dose combination (FDC) age-appropriate formulation
`in HIV-infected pediatric subjects 3 years to less than 6 years of age and
`weighing at least 15 kg. The safety and antiviral activity (efficacy) of
`darunavir/cobicistat FDC age-appropriate formulation in pediatric subjects
`should be evaluated for a minimum of 24 weeks. A clinical trial in children
`ages 3 to less than 6 years may not be required if the dosing recommendation
`for the FDC age-appropriate formulation can be supported by pediatric trials
`already conducted with the individual drug products and if the age-appropriate
`FDC produces similar exposures as the individual components.
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`
`03/31/2020
`12/31/2020
`12/31/2021
`
`2. Evaluate the pharmacokinetics, safety, and antiviral activity (efficacy) of
`darunavir/cobicistat fixed dose combination (FDC) age-appropriate formulation
`in HIV-infected pediatric subjects 6 years to less than 12 years of age. The
`safety and antiviral activity (efficacy) of darunavir/cobicistat FDC age-
`appropriate in pediatric subjects should be evaluated for a minimum of 24
`weeks. A clinical trial in children ages 6 to less than 12 years may not be
`required if the dosing recommendation for the FDC age-appropriate
`formulation can be supported by pediatric trials already conducted with the
`individual drug products and if the age-appropriate FDC produces similar
`exposures as the individual components.
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`
`03/31/2020
`12/31/2020
`12/31/2021
`
`3. Evaluate the pharmacokinetics, safety, and antiviral activity (efficacy) of
`darunavir/cobicistat fixed-dose combination (FDC) tablets in HIV-infected
`pediatric subjects 12 years to less than 18 years of age
`. The safety and antiviral activity (efficacy) of darunavir/cobicistat FDC
`tablets in pediatric subjects should be evaluated for a minimum of 24 weeks. A
`clinical trial in children 12 years to less than 18 years of age
`
`may not be required if the dosing recommendation for the FDC
`tablets can be supported by pediatric trials already conducted with the
`individual drug products and if the FDC produces similar exposures as the
`individual components.
`
`
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`
`03/31/2020
`12/31/2020
`12/31/2021
`
`Page 11 of 12
`
`Reference ID: 3681714
`
`11
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`Mary Singer, MD., Ph.D., Medical Team Leader, DAVP
`
`As noted above, these PREA PMRs depend on development of age-appropriate
`formulations, and determination of appropriate dosing regimen for each of the proposed
`age groups in clinical trials of darunavir and cobicistat administered as single agents, as
`required by the cobicistat commercial sponsor with the cobicistat NDA.
`
`! Recommended Comments to Applicant
`No additional comments will be conveyed to the applicant.
`
`Page 12 of 12
`
`Reference ID: 3681714
`
`12
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`MARY E SINGER
`01/02/2015
`
`Reference ID: 3681714
`
`