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

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA: 205395
`Brand Name
`Generic Name
`Reviewer
`Pharmacometrics Reviewer
`Clinical Pharmacology Team
`Leader
`OCP Division
`OND Division
`Applicant
`Formulation; strength(s)
`
`Indication
`Review Type
`
`Table of Contents
`
`Original Submission Date: March 31, 2014
`Prezcobix
`Darunavir/cobicistat
`Stanley Au, Pharm.D., BCPS
`Jeffry Florian, Ph.D.
`
`Kellie Reynolds, Pharm.D. (acting)
`Division of Clinical Pharmacology 4
`Division of Antiviral Products (DAVP)
`Janssen Research and Development
`Fixed dose combination tablet: Darunavir 800
`mg/cobicistat 150 mg
`Treatment of HIV-1 infection
`505 (b)(1) New Drug Application, standard review
`
`1 Executive Summary................................................................................................... 2
`1.1 Recommendation................................................................................................ 2
`1.2
`Postmarketing Commitments or Requirements.............................................. 3
`1.3
`Summary of Important Clinical Pharmacology and Biopharmaceutics
`Findings .......................................................................................................................... 3
`2 Labeling Recommendations...................................................................................... 5
`3
`Individual Trial Reviews......................................................................................... 59
`4 Pharmacometrics Review........................................................................................ 64
`
`Reference ID: 3676386
`
`1
`
`

`

`1 Executive Summary
`
`The applicant, Janssen Research and Development, submitted a New Drug Application
`(NDA) for a fixed dose combination tablet consisting of darunavir 800 mg and cobicistat
`150 mg (formulation G006). Another applicant, Gilead Sciences, submitted the cobicistat
`NDA (203094) and cobicistat in combination with darunavir as single entities was
`evaluated as part of the cobicistat NDA. Cobicistat was approved for U.S. marketing in
`September 2014. The pivotal trial for the current NDA compared the relative
`bioavailability for darunavir and cobicistat as part of a fixed dose combination tablet
`compared to single entity formulations. The TMC114IFD1003 trial evaluated the relative
`bioavailability of the fixed dose combination tablet consisting of darunavir 800 mg and
`cobicistat 150 mg that is proposed for U.S. marketing (formulation G006) compared to
`single entity formulations of darunavir (two 400 mg tablets, formulation F030) and
`cobicistat (150 mg tablets). The food effect of the darunavir and cobicistat fixed dose
`combination tablets (formulation G006) was also evaluated as part of the
`TMC114IFD1003 trial.
`
`The Clinical Pharmacology review evaluated the food effect data for the fixed dose
`combination tablet consisting of darunavir and cobicistat (formulation G006).
`Additional pertinent review issues for the TMC114IFD1003 trial include evaluating the
`relative bioavailability data and reviewing the inspection findings from the Office of
`Scientific Investigations, as well as the relevant bioanalytical information. The
`biopharmaceutics reviewers within the Office of New Drug Quality Assessment
`(ONDQA) will assess these regulatory issues. Additionally, the Division of
`Pharmacometrics evaluated the darunavir population pharmacokinetic data from the GS-
`US-216-130 trial (with darunavir and cobicistat administered as single entities) that the
`applicant proposes to include in the U.S. prescribing information for the
`darunavir/cobicistat fixed dose combination tablets (see section 4 for the
`Pharmacometrics review and the clinical pharmacology review for NDA 203094 for
`further information regarding the GS-US-216-130 trial).
`
`The TMC114IFD1001 trial that was also included as part of NDA 205395 was not
`reviewed by the Office of Clinical Pharmacology. The TMC114IFD1001 trial was not
`conducted with the G006 formulation and instead compared two formulations of a fixed
`dose combination tablet consisting of darunavir 800 mg and cobicistat 150 mg
`(formulation G003 and formulation G004) to darunavir 800 mg and ritonavir 100 mg as
`single entities. The review of this trial was not necessary since cobicistat in combination
`with darunavir as single entities is an approved regimen in the United States for the
`treatment of HIV-1 infection.
`
`1.1 Recommendation
`
`The clinical pharmacology information submitted in the NDA supports the approval of
`the application.
`
`Reference ID: 3676386
`
`2
`
`

`

`1.2 Postmarketing Commitments or Requirements
`
`There are no postmarketing commitments or requirements for this NDA.
`
`1.3
`
`Summary of Important Clinical Pharmacology and Biopharmaceutics
`Findings
`
`A) Evaluation of the food effect data from the TMC114IFD1003 trial
`
`A food effect was observed for darunavir when administered as a fixed dose combination
`tablet in combination with cobicistat. When compared to fasted conditions, with high fat
`meals, a 70% increase in AUC[0-inf] and a 127% increase in Cmax were observed when
`darunavir is administered as part of a fixed dose combination tablet with cobicistat The
`changes in darunavir exposure when administered with cobicistat as part of a fixed dose
`combination tablet exceeds the magnitude of the increase in Cmax and AUC(0-inf) for
`darunavir when coadministered with ritonavir as single entity formulations with a high fat
`meal when compared to fasted conditions (48% increase in AUC[0-inf] and 59% increase
`in Cmax). There was no food effect trial that was conducted for darunavir when
`coadministered with cobicistat as single entities.
`
`The single entity darunavir U.S. prescribing information recommends that darunavir in
`combination with ritonavir should be administered with food. The same recommendation
`also applies for darunavir and cobicistat when coadministered as single entities. No
`specific darunavir exposure-safety issues have been identified for the range of darunavir
`exposures associated with the dosage regimens that are included in the darunavir U.S.
`prescribing information. A food effect was not observed for cobicistat when
`administered as part of a fixed dose combination tablet with darunavir. Therefore, for
`darunavir and cobicistat, the applicant’s recommendation to administer the
`darunavir/cobicistat fixed dose combination tablet with food is acceptable.
`
`B) Clinical Pharmacology revisions to the proposed U.S prescribing information for the
`darunavir/cobicistat fixed dose combination tablets
`
`The Clinical Pharmacology revisions to the proposed U.S prescribing information for the
`darunavir/cobicistat fixed dose combination tablets that are outlined in section 2
`(Labeling Recommendations) were primarily based on the information in the cobicistat
`U.S. prescribing information that is relevant to administration with darunavir. Please see
`the Clinical Pharmacology review for NDA 203094 for further information regarding the
`extrapolation of drug-drug interaction information for darunavir coadminstered with
`ritonavir to darunavir coadminstered with cobicistat. For drug-drug interactions that are
`not currently included in the darunavir or cobicistat U.S. prescribing information, the
`proposed recommendations in section 7 were based on a determination regarding the
`most appropriate recommendation in the absence of drug-drug interaction data for
`concomitant use with darunavir coadministered with cobicistat.
`
`Reference ID: 3676386
`
`3
`
`

`

`C) Review of the bioanalytical data for the GS-US-216-130 trial
`
`The bioanalytical information to support the darunavir concentration data for the GS-US-
`216-130 trial was reviewed as part of the Clinical Pharmacology review for NDA
`209094. At the time the review was finalized, the long term stability data for darunavir
`that was necessary for the darunavir plasma samples from the GS-US-216-130 trial was
`not available. The information was requested from Janssen. Based on the information
`that was provided, stability for darunavir was demonstrated for up to 588 days at both
`-20°C and -70°C in K2EDTA anticoagulated plasma.
`
`D) Evaluation of the relative bioavailability data from the TMC114IFD1003 trial (based
`on the ONDQA Biopharmaceutics review)
`
`The applicant demonstrated that the 90% confidence were within 80-125% for the
`darunavir/cobicistat fixed dose combination tablets compared with the single entity
`darunavir and cobicistat tablets under both fed (non high fat) and fasting conditions in the
`TMC114IFD1003 trial.
`
`Reference ID: 3676386
`
`4
`
`

`

`Labeling Recommendations
`
`The applicant’s proposed revisions and the clinical pharmacology reviewer’s proposed modifications for the darunavir and cobicistat
`fixed dose combination tablets U.S. prescribing information are displayed below. Changes are highlighted in yellow where
`applicable. The proposed changes below are supported by the review, where applicable. The darunavir and cobicistat fixed dose
`combination tablets U.S. prescribing information was not finalized at the time the review was completed.
`
`Highlights
`
`Applicant proposed language
`
`Proposed reviewer changes
`
`Contraindications
`
`Contraindications
`
`Coadministration with
`
`o Coadministration with certain drugs for which altered plasma
`concentrations are associated with serious and/or life-threatening events
`or loss of therapeutic effect. (4)
`
`7, 12.3).
`
`A licant I-roosed lano . e
`
`Proosed reviewer chan es
`
`Drug Interactions
`
`Drug Interactions
`
`Co-administration of TRADENAME with other drugs can alter the
`concentration of other drugs and other drugs mav alter the
`(m4)
`concentrations of darunavir or cobicistat.
`
`out;
`
`Co-administration of TRADENAME with other drugs can alter the
`concentration of other drugs and other drugs mav alter the concentragigns
`of danmavir or cobicistat.
`(51(4)
`
`(4,
`
`(4.
`
`

`

`Section 4-Contraindications
`
`Applicant proposed language
`
`Tabl
`Drug
`
`ss
`
`Drugs That Are Contraindicated With darunavir/ritonavir
`Drugs Within Class
`Clinical Comment
`That Are
`Contraindicated With
`TRADENAME
`Pimozide
`
`Potential for serious and/or
`life-threatening reactions such as
`cardiac arrhythmias.
`
`Applicant proposed language
`
`None
`
`Proposed reviewer changes
`
`Table
`Drug Class
`
`Antipsychotic
`
`Drugs That Are Contraindicated With TRADENAME
`Drugs Within Class
`Clinical Comment
`That Are
`Contraindicated With
`TRADENAME
`Pimozide
`
`Potential for serious and/or
`life-threatening reactions such as cardiac
`arrhythmias.
`
`Proposed reviewer changes
`
`Reference ID: 3676386
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`Section 5-Warnings and Precautions
`
`Applicant proposed language
`
`Proposed reviewer changes
`
`Reference ID: 3676386
`
`7
`
`(b) (4)
`
`

`

`Section 7-Drug Interactions
`
`Applicant proposed language
`
`Proposed reviewer changes
`
`No drug interaction trials have been performed using TRADENAME and
`drug interaction trials have
` been conducted with darunavir
`
`with ritonavir.
`
`Reference ID: 3676386
`
`8
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`7.1 Potential for TRADENAME to Affect Other Drugs
`
`7.1 Potential for TRADENAME to Affect Other Drugs
`
`When evaluated separately, darunavir and cobicistat both inhibited CYP3A
`and CYP2D6. Cobicistat inhibits the following transporters: p-
`glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Therefore,
`co-administration of TRADENAME with drugs that are primarily
`metabolized by CYP3A and/or CYP2D6 or are substrates of P-gp, BCRP,
`OATP1B1 or OATP1B3 may result in increased plasma concentrations of
`such drugs, which could increase or prolong their therapeutic effect and
`can be associated with adverse events (see Table
`.
`
`Reference ID: 3676386
`
`9
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical pharmacology reviewer note:
`
`
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`HIV-1 Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
`
`Reference ID: 3676386
`
`10
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Potentially Significant Drug Interactions: Alterations in
`Table
`Dose or Regimen May Be Recommended Based on Drug Interaction
`Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`HIV-1 Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
`efavirenz
`Coadministration with efavirenz is not
`(cid:112) cobicistat
`recommended because it may result in the loss of
`(cid:112) darunavir
`therapeutic effect and development of resistance to
`darunavir.
`
`etravirine
`
`neviraprine
`
`(cid:112) cobicistat
`darunavir: effect
`unknown
`
`Coadministration with etravirine is not
`recommended because it may result in the loss of
`therapeutic effect and development of resistance to
`darunavir.
`
`(cid:112) cobicistat
`darunavir: effect
`unknown
`
`Coadministration with nevirapine is not
`recommended because it may result in the loss of
`therapeutic effect and development of resistance to
`darunavir.
`
`Reference ID: 3676386
`
`11
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
` Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`HIV-1 Antiviral Agents: CCR5 co-receptor antagonists
`maraviroc
`(cid:110) maraviroc
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`HIV-1 Antiviral Agents: CCR5 co-receptor antagonists
`maraviroc
`Maraviroc is a substrate of CYP3A. When
`(cid:110) maraviroc
`coadministered with TRADENAME, patients
`should receive maraviroc 150 mg twice daily.
`
`Reference ID: 3676386
`
`12
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Table : Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`(cid:110) antiarrhythmics
`
`Clinical monitoring is recommended upon
`coadministration with antiarrhythmics.
`
`Other Agents
`Antiarrhythmics:
`e.g.
`amiodarone,
`disopyramide,
`flecainide,
`lidocaine (systemic),
`mexiletine,
`propafenone,
`quinidine
`
`digoxin
`
`(cid:110) digoxin
`
`When coadministering with digoxin, titrate the
`digoxin dose and monitor digoxin concentrations.
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`(cid:110)a
`
`ntiarrhythmics
`
`Concomitant Drug
`Class:
`Drug Name
`
`Other Agents
`Antiarrhythmics:
`e.g.
`amiodarone,
`
`disopyramide,
`flecainide,
`lidocaine
`(systemic),
`mexiletine,
`propafenone,
`quinidine,
`
`digoxin
`
`(cid:110) digoxin
`
`Reference ID: 3676386
`
`13
`
`(b
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Antibacterial
`clarithromycin,
`erythromycin,
`telithromycin
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`(cid:110) darunavir
`(cid:110) cobicistat
`(cid:110) antibacterial
`
`Concomitant Drug
`Class:
`Drug Name
`
`Antibacterial
`clarithromycin,
`erythromycin,
`telithromycin
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`(cid:110) darunavir
`(cid:110) cobicistat
`(cid:110) antibacterial
`
`Clinical Comment
`
`Consider alternative antibiotics with concomitant
`use of TRADENAME.
`
`Reference ID: 3676386
`
`14
`
`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`
`
`Pro osed reviewer Chan
`
`Table 8 Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Table 8 Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Concomitant Drug Effect on
`Concentration
`
`Clinical Comment
`
`'
`
`linical Comment
`
`‘bitor.
`
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`
`Drug
`Anticancer AgentszT anticancer A decrease in the dosage or an adjustment of the
`agent
`dosing interval of dasatinib and nilotinib may be
`necefisw for patients when apgdministered
`a.)(Sonsult the
`(dasatinib) and
`(nilotinib) prescribing information for
`dosing instructions.
`
`-
`
`.
`'
`'
`'
`
`'
`
`'
`
`'
`
`'
`
`'
`
`'
`
`.
`
`_
`
`'
`
`'
`
`.
`
`~
`
`'
`
`:
`
`.
`
`‘ decrease in the dosage or an adjustment of the
`c osing interval of dasatinib or nilotinib may be
`u ecessary for patients when coadministered with
`‘
`‘ D ENAME. Consult the dasatinib and
`u ' otinib prescribing information for dosing
`'
`tructions.
`
`I or vincn'stine and vinblastine. consider
`
`emporarily withholding the cobicistat—containing
`. tiretroviral regimen in patients who develop
`igniticant hematologic or gastrointestinal side
`- ffects when TRADENAIVIE is administered
`
`oncurrently with vincristine or vinblastine. If the
`. Itiretroviral regimen must be withheld for a
`prolonged period. consider initiating a rew'sed
`. egimen that does not include a CYP3A or P—gp
`'
`
`

`

`Clinical Comment
`
`Concomitant Drug Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`
`-
`
`- ‘ 1.} Comment
`
`Table-Potentially Significant Drug Interactions: Alterations in Dose or Regimen Table. Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`on the indication). Please see the
`
`‘ ticoagnlants:
`A
`.; I 0 mm
`
`'
`
`.
`
`: igatran etexilate,
`
`.
`
`.
`
`. n 'tant use of apixaban is not moo-oaded.
`
`oncomimnt use with dabigatran etexilate is not
`-' in specific renal impailment groups
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
` Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`(cid:315) (cid:70)(cid:82)(cid:69)(cid:76)(cid:70)(cid:76)(cid:86)(cid:87)(cid:68)(cid:87)
`Anticonvulsants:
`Anticonvulsants that
`darunavir:effect
`induce CYP3A
`unknown
`(e.g., carbamazepine
`oxcarbazepine,
`phenytoin,
`phenobarbital)
`
`phenobarbital
`phenytoin
`
`phenobarbital:
`effect unknown
`phenytoin: effect
`unknown
`
`Anticonvulsants that
`(cid:110) carbamazepine
`are metabolized by
`(cid:110)clonazepam
`CYP3A (e.g.
`clonazepam,
`carbamazepine)
`
`Clinical Comment
`
`Consider alternative anticonvulsant or
`antiretroviral therapy to avoid potential changes in
`exposures. If coadministration is necessary,
`monitor for lack or loss of virologic response.
`
`Monitor phenobarbital or phenytoin concentrations
`
`Clinical monitoring of anticonvulsants is
`recommended.
`
`Reference ID: 3676386
`
`17
`
`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`Clinical Comment
`
`When coadministering with SSRIs, TCAs, or
`trazodone, careful dose titration of the
`antidepressant to the desired effect, including
`using the lowest feasible initial or maintenance
`dose, and monitoring for antidepressant response
`are recommended.
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`SSRIs: effects
`unknown
`(cid:110) TCAs
`(cid:110) trazodone
`
`Concomitant Drug
`Class:
`Drug Name
`
`Antidepressants:
`Selective Serotonin
`Reuptake Inhibitors
`(SSRIs):
`e.g.
`paroxetine,
`sertraline
`
`Tricyclic
`Antidepressants
`(TCAs):
`e.g.
`amitriptyline
`desipramine,
`imipramine
`nortriptyline
`
`Other
`antidepressants:
`trazodone
`
`Reference ID: 3676386
`
`18
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
` Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Concomitant Drug
`Class:
`Drug Name
`
`Antifungals:
`itraconazole,
`ketoconazole,
`posaconazole
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`(cid:110) darunavir
`(cid:110) cobicistat
`
`(cid:110) itraconazole
`(cid:110) ketoconazole
`(cid:108) posaconazole
`(not studied
`
`Clinical Comment
`
`Monitor for increased darunavir or cobicistat
`adverse events.
`
`Specific dosing recommendations are not available
`for coadministration with itraconazole or
`ketoconazole. Monitor for increased itraconazole or
`ketoconazole adverse reactions.
`
`voriconazole
`
`Voriconazole:
`effects unknown
`
`Coadministration with voriconazole is not
`recommended unless the benefit/risk assessment
`justifies the use of voriconazole.
`
`Reference ID: 3676386
`
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`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
` Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Anti-gout:
`colchicine
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`(cid:110) colchicine
`
`Concomitant Drug
`Class:
`Drug Name
`
`Anti-gout:
`colchicine
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`(cid:110) colchicine
`
`Clinical Comment
`
`Treatment of gout flares-coadministration of
`colchicine:
`0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg
`(half tablet) 1 hour later. Treatment course to be
`repeated no earlier than 3 days.
`Prophylaxis of gout flares-coadministration of
`colchicine:
`If the original regimen was 0.6 mg twice a
`day, the regimen should be adjusted to 0.3 mg
`once a day. If the original regimen was 0.6 mg
`once a day, the regimen should be adjusted to 0.3
`mg once every other day.
`Treatment of familial Mediterranean fever -
`coadministration of colchicine:
`Maximum daily dose of 0.6 mg (may be given as
`0.3 mg twice a day).
`
`Coadministration of TRADENAME with
`colchicine is CONTRAINDICATED in patients
`with renal or hepatic impairment.
`
`Reference ID: 3676386
`
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`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
` Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`
`Concomitant Drug
`Class:
`Drug Name
`
`Antimalarial:
`artemether/
`lumefantrine
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`artemether:effect
`unknown
`lumefantrine:
`effect unknown
`
`Clinical Comment
`
`Monitor for a potential decrease of antimalarial
`efficacy or potential QT prolongation.
`
`Reference ID: 3676386
`
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`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`Antimycobacterial:
`rifabutin
`
`(cid:110)rifabutin
`cobicistat: effects
`unknown
`darunavir: effects
`unknown
`
`When used in combination with TRADENAME,
`the recommended dose of rifabutin is 150 mg
`every other day. Monitor for rifabutin associated
`adverse reactions including neutropenia and
`uveitis.
`
`rifapentine
`
`(cid:112) darunavir
`
`Co-administration of TRADENAME with
`rifapentine is not recommended.
`
`Reference ID: 3676386
`
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`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`(cid:110) beta-blockers
`
`Concomitant Drug
`Class:
`Drug Name
`
`(cid:533)-Blockers:
`e.g.
`carvedilol,
`metoprolol,
`timolol
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`(cid:533)-Blockers:
`e.g.
`carvedilol,
`metoprolol,
`timolol
`
`(cid:110) beta-blockers Clinical monitoring is recommended for
`coadministration with beta-blockers that are
`metabolized by CYP2D6.
`
`Reference ID: 3676386
`
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`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
` Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`(cid:110) calcium
`channel blockers
`
`Clinical monitoring is recommended for
`coadministration with calcium channel blockers
`metabolized by CYP3A.
`
`Calcium Channel
`Blockers:
`e.g.
`amlodipine,
`diltiazem,
`felodipine,
`nifedipine,
`verapamil
`
`Reference ID: 3676386
`
`24
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`(b)
`(4)
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`(b) (4)
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`(b) (4)
`
`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`(cid:110) corticosteroid
`
`Concomitant Drug
`Class:
`Drug Name
`
`Corticosteroids
`(inhaled/nasal)
`metabolized by
`CYP3A:
`e.g.
`budesonide,
`fluticasone
`
`Clinical Comment
`
`Coadministration with inhaled or nasal fluticasone
`or other corticosteroids that are metabolized by
`CYP3A may result in reduced serum cortisol
`concentrations. Alternative corticosteroids should
`be considered, particularly for long term use.
`
`Reference ID: 3676386
`
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`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Corticosteroids
`(systemic):
`e.g.
`dexamethasone
`
`(cid:112) darunavir
`(cid:112) cobicistat
`(cid:110) corticosteroid
`
`Coadministration with dexamethasone or other
`corticosteroids that induce CYP3A may result in
`loss of therapeutic effect and development of
`resistance to darunavir.
`Consider alternative corticosteroids.
`
`Corticosteroid
`(systemic)
`metabolized by
`CYP3A:
`e.g.
`budesonide
`prednisolone
`
`(cid:110) corticosteroid
`
`Coadministration with corticosteroids that are
`metabolized by CYP3A, particularly for long-term
`use, may increase the risk for development of
`systemic corticosteroid effects including Cushing’s
`syndrome and adrenal suppression. Consider the
`potential benefit of treatment versus the risk of
`systemic corticosteroid effects.
`
`Reference ID: 3676386
`
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`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Endothelin
`receptor
`antagonists:
`bosentan
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`(cid:112) darunavir
`(cid:112) cobicistat
`(cid:110) bosentan
`
`Concomitant Drug
`Class:
`Drug Name
`
`Endothelin
`receptor
`antagonists:
`bosentan
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`(cid:112) darunavir
`(cid:112) cobicistat
`(cid:110) bosentan
`
`Clinical Comment
`
`Initiation of bosentan in patients taking
`TRADENAME:
`In patients who have been receiving
`TRADENAME for at least 10 days, start bosentan
`at 62.5 mg once daily or every other day based
`upon individual tolerability.
`Initiation of TRADENAME in patients on
`bosentan:
`Discontinue use of bosentan at least 36 hours prior
`to initiation of TRADENAME. After at least
`10 days following the initiation of TRADENAME,
`resume bosentan at 62.5 mg once daily or every
`other day based upon individual tolerability
`
`Switching from darunavir/ritonavir to
`TRADENAME in patients on bosentan:
`Maintain bosentan dose.
`
`Reference ID: 3676386
`
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`

`

`Applicant proposed language
`
`Proposed reviewer changes
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Potentially Significant Drug Interactions: Alterations in Dose or Regimen
`Table
`May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
`
`Clinical Comment
`
`Concomitant Drug
`Class:
`Drug Name
`
`Effect on
`Concentration
`of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`
`Clinical Comment
`
`No drug interaction data are available.
`Coadministration with boceprevir, simeprevir, or
`telaprevir is not recommended.
`
`Concomitant Drug
`Class:
`Drug Name
`
`Hepatitis C Virus
`(HCV)
`NS3-4A Protease
`Inhibitors:
`boceprevir,
`telaprevir
`
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant
`Drug
`darunav