`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205395Orig1s000
`LABELING
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`PREZCOBIX safely and effectively. See full prescribing information for
`PREZCOBIX.
`PREZCOBIX (darunavir and cobicistat) tablets, for oral use.
`Initial U.S. Approval: 2015
`----------------------------INDICATIONS AND USAGE----------------------------
`PREZCOBIX is a two drug combination of darunavir, a human
`immunodeficiency virus (HIV-1) protease inhibitor and cobicistat, a CYP3A
`inhibitor and is indicated for the treatment of HIV-1 infection in adult
`patients. (1)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`Recommended dosage: One tablet taken once daily with food. (2)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets: 800 mg of darunavir and 150 mg of cobicistat. (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`Coadministration with certain drugs for which altered plasma concentrations
`are associated with serious and/or life-threatening events or loss of therapeutic
`effect. (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`(cid:120) Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis), liver
`injury, including some fatalities can occcur with PREZCOBIX. Monitor
`liver function before and during therapy, especially in patients with
`underlying chronic hepatitis, cirrhosis, or in patients who have pre-
`treatment elevations of transaminases. (5.1, 6)
`(cid:120) Skin reactions ranging from mild to severe, including Stevens-Johnson
`Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and
`systemic symptoms and acute generalized exanthematous pustulosis, can
`occur with PREZCOBIX. Discontinue treatment if severe reaction
`develops. (5.2, 6)
`(cid:120) Assess creatinine clearance (CLcr) before initiating treatment. (5.3)
`(cid:120) When PREZCOBIX is used in combination with a tenofovir disoproxil
`fumarate (tenofovir DF) containing regimen, cases of acute renal failure
`and Fanconi syndrome have been reported. (5.4)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Testing Prior to Initiation of PREZCOBIX
`2.3 Patients with Renal Impairment
`2.4 Patients with Hepatic Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hepatotoxicity
`5.2 Severe Skin Reactions
`5.3 Effects on Serum Creatinine
`5.4 New Onset or Worsening Renal Impairment
`When Used with Tenofovir Disoproxil Fumarate
`5.5 Risk of Serious Adverse Reactions or Loss of
`Virologic Response Due to Drug Interactions
`5.6 Antiretrovirals Not Recommended
`5.7 Sulfa Allergy
`5.8 Diabetes Mellitus/Hyperglycemia
`5.9 Fat Redistribution
`5.10 Immune Reconstitution Syndrome
`5.11 Hemophilia
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`
`(cid:120) When used with tenofovir DF: Assess urine glucose and urine protein at
`baseline and monitor CLcr, urine glucose, and urine protein. Monitor serum
`phosphorus in patients with or at risk for renal impairment. (5.4)
`(cid:120) PREZCOBIX is not recommended in combination with other antiretroviral
`drugs that require pharmacokinetic boosting. (5.6)
`(cid:120) Monitor in patients with a known sulfonamide allergy. (5.7)
`(cid:120) Patients receiving PREZCOBIX may develop new onset or exacerbations
`of diabetes mellitus/hyperglycemia (5.8), redistribution/accumulation of
`body fat (5.7), and immune reconstitution syndrome(5.9).
`(cid:120) Patients with hemophilia may develop increased bleeding events. (5.11)
`------------------------------ADVERSE REACTIONS-------------------------------
`(cid:120) The most common adverse reactions to darunavir, a component of
`PREZCOBIX (incidence greater than or equal to 5%) of at least moderate
`severity (greater than or equal to Grade 2) were diarrhea, nausea, rash,
`headache, abdominal pain, and vomiting. (6)
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1 800 FDA
`1088 or www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS-------------------------------
`(cid:120) Coadministration of PREZCOBIX with other drugs can alter the
`concentration of other drugs and other drugs may alter the concentrations
`of darunavir or cobicistat. Consult the full prescribing information prior to
`and during treatment for potential drug interactions. (4, 5.6, 7, 12.3).
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`(cid:120) Pregnancy: Use during pregnancy only if the potential benefit justifies the
`potential risk. (8.1)
`(cid:120) Nursing Mothers: Women infected with HIV-1 should be instructed not to
`breastfeed due to the potential for HIV transmission and the potential for
`serious adverse reactions in nursing infants. (8.3)
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`approved patient labeling.
`
`Revised: 01/2015
`
`7 DRUG INTERACTIONS
`7.1 Potential for PREZCOBIX to Affect Other Drugs
`7.2 Potential for Other Drugs to Affect PREZCOBIX
`7.3 Potentially Significant Drug Interactions
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 Microbiology
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
`
`Reference ID: 3694997
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`1
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`
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`PREZCOBIX is indicated in combination with other antiretroviral agents for the treatment of
`human immunodeficiency virus (HIV-1) infection in treatment-naïve and treatment-experienced
`adults with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V,
`I54L, I54M, T74P, L76V, I84V, L89V).
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`PREZCOBIX is a fixed-dose combination product containing 800 mg of darunavir and 150 mg
`of cobicistat. In treatment-naïve and treatment-experienced adults with no darunavir resistance-
`associated substitutions, the recommended dosage of PREZCOBIX is one tablet taken once daily
`orally with food. Administer PREZCOBIX in conjunction with other antiretroviral agents.
`
`2.2 Testing Prior to Initiation of PREZCOBIX
`HIV Genotypic Testing:
`
`HIV genotypic testing is recommended for antiretroviral treatment-experienced patients.
`However, when HIV genotypic testing is not feasible, PREZCOBIX can be used in protease
`inhibitor-naïve patients, but is not recommended in protease inhibitor-experienced patients.
`
`Creatinine Clearance:
`
`Prior to starting PREZCOBIX, assess estimated creatinine clearance because cobicistat decreases
`estimated creatinine clearance due to inhibition of tubular secretion of creatinine without
`affecting actual renal glomerular function [see Warnings and Precautions (5.1)]. When
`coadministering PREZCOBIX with tenofovir disoproxil fumarate (tenofovir DF) assess
`estimated creatinine clearance, urine glucose, and urine protein at baseline [see Warnings and
`Precautions (5.3)].
`
`2.3 Patients with Renal Impairment
`PREZCOBIX coadministered with tenofovir DF is not recommended in patients who have an
`estimated creatinine clearance below 70 mL/min [see Warnings and Precautions (5.3) and
`Adverse Reactions (6.1)].
`
`2.4 Patients with Hepatic Impairment
`PREZCOBIX is not recommended for use in patients with severe hepatic impairment [see Use in
`Specific Populations (8.6) and Clinical Pharmacology (12.3)].
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`Reference ID: 3694997
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`3 DOSAGE FORMS AND STRENGTHS
`PREZCOBIX is supplied as pink, oval-shaped, film-coated tablets containing darunavir
`ethanolate equivalent to 800 mg of darunavir and 150 mg cobicistat. Each tablet is debossed with
`“800” on one side and “TG” on the other side.
`
`4 CONTRAINDICATIONS
`The concomitant use of PREZCOBIX and the following drugs (see Table 1) is contraindicated
`due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see
`Drug Interactions (7.3), Table 2].
`
`Drugs That Are Contraindicated With PREZCOBIX
`Drugs Within Class That Are
`Contraindicated With
`PREZCOBIX
`Alfuzosin
`
`Table 1:
`Drug Class
`
`Alpha 1-adrenoreceptor
`antagonist
`Antianginal
`Antiarrhythmic
`
`Anti-gout
`
`Ranolazine
`Dronedarone
`
`Colchicine
`
`Clinical Comment
`
`Potential for serious and/or life-threatening reactions
`such as hypotension.
`Potential for serious and/or life threatening reactions.
`Potential for serious and/or life-threatening reactions
`such as cardiac arrhythmias.
`Contraindicated in patients with renal and/or hepatic
`impairment due to potential for serious and/or
`life-threatening reactions.
`Potential for reduced plasma concentrations of
`darunavir, which may result in loss of therapeutic
`effect and development of resistance.
`Potential for serious and/or life-threatening reactions.
`Potential for serious and/or life-threatening reactions
`such as cardiac arrhythmias.
`Potential for serious and/or life-threatening reactions
`such as acute ergot toxicity characterized by
`peripheral vasospasm and ischemia of the extremities
`and other tissues.
`Potential for serious and/or life-threatening reactions
`such as cardiac arrhythmias.
`Potential for reduced plasma concentrations of
`darunavir, which may result in loss of therapeutic
`effect and development of resistance.
`Potential for serious reactions such as myopathy
`including rhabdomyolysis (see Table 2 for dosing
`recommendations for certain other HMG-CoA
`reductase inhibitors).
`Potential for sildenafil-associated adverse reactions
`(which include visual disturbances, hypotension,
`prolonged erection, and syncope).
`Potential for serious and/or life-threatening reactions
`such as prolonged or increased sedation or respiratory
`depression. Triazolam and orally administered
`midazolam are extensively metabolized by CYP3A.
`Coadministration of triazolam or orally administered
`midazolam with PREZCOBIX may cause large
`increases in the concentrations of these
`benzodiazepines.
`
`Antimycobacterial
`
`Rifampin
`
`Antipsychotic
`
`Ergot Derivative
`
`Lurasidone
`Pimozide
`
`Dihydroergotamine,
`Ergotamine, Methylergonovine
`
`GI Motility Agent
`
`Cisapride
`
`Herbal Product
`
`HMG-CoA Reductase
`Inhibitor
`
`St. John’s Wort (Hypericum
`perforatum)
`
`Lovastatin, Simvastatin
`
`PDE-5 inhibitor
`
`Sedative/Hypnotic
`
`Sildenafil for treatment of
`pulmonary arterial hypertension
`
`Orally administered Midazolam,
`Triazolam
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`Reference ID: 3694997
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`5 WARNINGS AND PRECAUTIONS
`5.1 Hepatotoxicity
`During
`the darunavir clinical development program (N=3063), where darunavir was
`coadministered with ritonavir 100 mg once or twice daily, drug-induced hepatitis (e.g., acute
`hepatitis, cytolytic hepatitis) was reported in 0.5% of subjects. Patients with pre-existing liver
`dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function
`abnormalities including severe hepatic adverse reactions.
`
`Post-marketing cases of liver injury, including some fatalities, have also been reported with
`darunavir coadministered with ritonavir. These have generally occurred in patients with
`advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities
`including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A
`causal relationship with darunavir coadministered with ritonavir has not been established.
`
`Appropriate laboratory testing should be conducted prior to initiating therapy with PREZCOBIX
`and patients should be monitored during treatment. Increased AST/ALT monitoring should be
`considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have
`pre-treatment elevations of transaminases, especially during the first several months of
`PREZCOBIX treatment.
`
`Evidence of new or worsening liver dysfunction (including clinically significant elevation of
`liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver
`tenderness, hepatomegaly) in patients on PREZCOBIX should prompt consideration of
`interruption or discontinuation of treatment.
`
`5.2 Severe Skin Reactions
`During
`the darunavir clinical development program (n=3063), where darunavir was
`coadministered with ritonavir 100 mg once or twice daily, severe skin reactions, accompanied by
`fever and/or elevations of transaminases in some cases, was reported in 0.4% of subjects.
`Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development
`program. During post-marketing experience toxic epidermal necrolysis, drug rash with
`eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been
`reported. Discontinue PREZCOBIX immediately if signs or symptoms of severe skin reactions
`develop. These can include but are not limited to severe rash or rash accompanied with fever,
`general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis
`and/or eosinophilia.
`
`Mild-to-moderate rash was also reported and often occurred within the first four weeks of
`treatment and resolved with continued dosing.
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`Reference ID: 3694997
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`5.3 Effects on Serum Creatinine
`Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of
`creatinine without affecting actual renal glomerular function. This effect should be considered
`when interpreting changes in estimated creatinine clearance in patients initiating PREZCOBIX,
`particularly in patients with medical conditions or receiving drugs needing monitoring with
`estimated creatinine clearance.
`
`Prior to initiating therapy with PREZCOBIX, assess estimated creatinine clearance [see Dosage
`and Administration (2.4)]. Dosage recommendations are not available for drugs that require
`dosage adjustments in PREZCOBIX-treated patients with renal impairment [see Drug
`Interactions (7.3), Clinical Pharmacology (12.2)]. Consider alternative medications that do not
`require dosage adjustments in patients with renal impairment.
`
`Although cobicistat may cause modest increases in serum creatinine and modest declines in
`estimated creatinine clearance without affecting renal glomerular function, patients who
`experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline
`should be closely monitored for renal safety.
`
`5.4 New Onset or Worsening Renal Impairment When Used with Tenofovir
`Disoproxil Fumarate
`Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been
`reported when cobicistat, a component of PREZCOBIX, was used in an antiretroviral regimen
`that contained tenofovir DF. Coadministration of PREZCOBIX and tenofovir DF is not
`recommended in patients who have an estimated creatinine clearance below 70 mL/min [see
`Dosage and Administration (2.3)].
`
`(cid:120) Document urine glucose and urine protein at baseline [see Dosage and Administration
`(2.2)] and perform routine monitoring of estimated creatinine clearance, urine glucose,
`and urine protein during treatment when PREZCOBIX is used with tenofovir DF.
`Measure serum phosphorus in patients with or at risk for renal impairment when used
`with tenofovir DF.
`
`(cid:120) Coadministration of PREZCOBIX and tenofovir DF in combination with concomitant or
`recent use of a nephrotoxic agent is not recommended.
`
`See cobicistat full prescribing information for additional information regarding cobicistat.
`
`5.5 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to
`Drug Interactions
`Initiation of PREZCOBIX, which inhibits CYP3A, in patients receiving medications metabolized
`by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving
`PREZCOBIX may increase plasma concentrations of these medications, which may increase the
`risk of clinically significant adverse reactions (including life-threatening or fatal reactions)
`
`5
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`Reference ID: 3694997
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`associated with the concomitant medications. Coadministration of PREZCOBIX with CYP3A
`inducers may lead to lower exposures of darunavir and cobicistat and loss of efficacy of
`darunavir and possible resistance. Therefore, consider the potential for drug interactions prior to
`and during PREZCOBIX therapy; review concomitant medications during PREZCOBIX
`therapy; and monitor for the adverse reactions associated with the concomitant drugs [see
`Contraindications (4), Drug Interactions (7)].
`
`When used with concomitant medications, PREZCOBIX may result in different drug interactions
`than those observed or expected with darunavir coadministered with ritonavir. Complex or
`unknown mechanisms of drug interactions preclude extrapolation of drug interactions with
`darunavir coadministered with ritonavir to certain PREZCOBIX interactions [see Drug
`Interactions (7) and Clinical Pharmacology (12.3)].
`
`5.6 Antiretrovirals Not Recommended
`PREZCOBIX is not recommended in combination with other antiretroviral drugs that require
`pharmacokinetic boosting (i.e., another protease inhibitor or elvitegravir) because dosing
`recommendations for such combinations have not been established and coadministration may
`result in decreased plasma concentrations of the antiretroviral agents, leading to loss of
`therapeutic effect and development of resistance.
`
`PREZCOBIX is not recommended in combination with products containing the individual
`components of PREZCOBIX (darunavir and cobicistat) or with ritonavir. For additional
`recommendations on use of PREZCOBIX with other antiretroviral agents, see Drug Interactions
`(7).
`
`5.7 Sulfa Allergy
`Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy
`after initiating PREZCOBIX. In clinical studies with darunavir coadministered with ritonavir, the
`incidence and severity of rash were similar in subjects with or without a history of sulfonamide
`allergy.
`
`5.8 Diabetes Mellitus/Hyperglycemia
`New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia
`have been reported during postmarketing surveillance in HIV infected patients receiving HIV
`protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of
`insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic
`ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia
`persisted in some cases. Because these events have been reported voluntarily during clinical
`practice, estimates of frequency cannot be made and causal relationships between HIV PI
`therapy and these events have not been established.
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`Reference ID: 3694997
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`5.9 Fat Redistribution
`Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement
`(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid
`appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and
`long-term consequences of these events are currently unknown. A causal relationship has not
`been established.
`
`5.10 Immune Reconstitution Syndrome
`Immune reconstitution syndrome has been reported in patients treated with combination
`antiretroviral therapy, including PREZCOBIX. During the initial phase of combination
`antiretroviral treatment, patients whose immune systems respond may develop an inflammatory
`response to indolent or residual opportunistic infections (such as Mycobacterium avium
`infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which
`may necessitate further evaluation and treatment.
`
`Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome)
`have also been reported to occur in the setting of immune reconstitution; however, the time to
`onset is more variable, and can occur many months after initiation of antiretroviral treatment.
`
`5.11 Hemophilia
`There have been reports of increased bleeding, including spontaneous skin hematomas and
`hemarthrosis in patients with hemophilia type A and B treated with HIV PIs. In some patients,
`additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs
`was continued or reintroduced if treatment had been discontinued. A causal relationship between
`PI therapy and these episodes has not been established.
`
`6 ADVERSE REACTIONS
`The following adverse reactions are discussed in other sections of the labeling:
`(cid:120) Hepatotoxicity [see Warnings and Precautions (5.1)]
`(cid:120) Severe skin reactions [see Warnings and Precautions (5.2)]
`(cid:120) Effects on serum creatinine [see Warnings and Precautions (5.3)]
`(cid:120) New onset or worsening renal impairment when used with tenofovir disoproxil fumarate
`[see Warnings and Precautions (5.4)]
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`of another drug and may not reflect the rates observed in clinical practice.
`
`During the darunavir clinical development program, where darunavir was coadministered with
`ritonavir 100 mg once or twice daily, the most common clinical adverse reactions (incidence
`greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were
`
`7
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`Reference ID: 3694997
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`
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`diarrhea, nausea, rash, headache, abdominal pain, and vomiting. See the darunavir full
`prescribing information for additional information on adverse reactions reported with darunavir
`coadministered with ritonavir. See cobicistat full prescribing information for clinical trial
`information on adverse reactions reported with cobicistat.
`
`One single arm clinical trial was conducted with darunavir and cobicistat administered as single
`entities in 313 HIV-infected subjects. Adverse reactions evaluated through Week 24 did not
`differ substantially from those reported in clinical trials with darunavir coadministered with
`ritonavir.
`
`6.2 Postmarketing Experience
`See the darunavir full prescribing information for postmarketing information.
`
`7 DRUG INTERACTIONS
`No drug interaction trials have been performed with PREZCOBIX or with darunavir
`coadministered with cobicistat as single entities. Drug interaction trials have been conducted
`with darunavir coadministered with ritonavir and with cobicistat alone.
`7.1 Potential for PREZCOBIX 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, coadministration of PREZCOBIX 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 2). Based
`on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo
`data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant
`extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is
`expected to be low based on CYP3A in vitro induction data.
`
`7.2 Potential for Other Drugs to Affect PREZCOBIX
`Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A, and to a minor
`extent, by CYP2D6. Drugs that induce CYP3A activity are expected to increase the clearance of
`darunavir and cobicistat, resulting in lowered plasma concentrations of darunavir and cobicistat
`which may lead to loss of therapeutic effect and development of resistance. Coadministration of
`PREZCOBIX and other drugs that inhibit CYP3A may result in increased plasma concentrations
`of darunavir and cobicistat (see Table 2).
`
`7.3 Potentially Significant Drug Interactions
`Table 2 provides dosing recommendations for expected clinically relevant interactions with
`PREZCOBIX. These recommendations are based on either drug interaction trials or predicted
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`Reference ID: 3694997
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`interactions due to the expected magnitude of interaction and potential for serious adverse events
`or loss of efficacy.
`
`Concomitant Drug
`Class:
`Drug Name
`
`Table 2: Potentially Significant Drug Interactions:
`Alterations in Dose or Regimen May Be Recommended
`Based on Drug Interaction Trials or Predicted Interaction
`Clinical Comment
`Effect on
`Concentration of
`Darunavir,
`Cobicistat, or
`Concomitant Drug
`HIV-1 Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
`didanosine
`(cid:108) darunavir
`(cid:108) cobicistat
`(cid:108) didanosine
`HIV-1 Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
`efavirenz,
`Coadministration with efavirenz is not recommended
`(cid:112) cobicistat
`because it may result in loss of therapeutic effect and
`(cid:112) darunavir
`development of resistance to darunavir.
`
`Didanosine should be administered one hour before or two
`hours after PREZCOBIX (administered with food).
`
`etravirine,
`
`(cid:112) cobicistat
`darunavir: effect
`unknown
`
`Coadministration with etravirine is not recommended
`because it may result in loss of therapeutic effect and
`development of resistance to darunavir.
`
`neviraprine
`
`Coadministration with nevirapine is not recommended
`(cid:112) cobicistat
`because it may result in loss of therapeutic effect and
`darunavir: effect
`development of resistance to darunavir.
`unknown
`HIV-1 Antiviral Agents: CCR5 co-receptor antagonists
`maraviroc
`Maraviroc is a substrate of CYP3A. When coadministered
`(cid:110) maraviroc
`with PREZCOBIX, patients should receive maraviroc 150
`mg twice daily.
`
`Other Agents
`Antiarrhythmics:
`e.g.
`amiodarone,
`disopyramide,
`flecainide,
`lidocaine (systemic),
`mexiletine,
`propafenone,
`quinidine,
`
`digoxin
`
`Antibacterial Agents
`clarithromycin,
`erythromycin,
`telithromycin
`Anticancer Agents:
`
`Reference ID: 3694997
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`(cid:110) antiarrhythmics
`
`Clinical monitoring is recommended upon coadministration
`with antiarrhythmics.
`
`(cid:110) digoxin
`
`(cid:110) darunavir
`(cid:110) cobicistat
`(cid:110) antibacterial
`
`When coadministering with digoxin, titrate the digoxin
`dose and monitor digoxin concentrations.
`Consider alternative antibiotics with concomitant use of
`PREZCOBIX.
`
`(cid:110) anticancer agent A decrease in the dosage or an adjustment of the dosing
`
`9
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`interval of dasatinib or nilotinib may be necessary when
`coadministered with PREZCOBIX. Consult the dasatinib
`and nilotinib prescribing information for dosing
`instructions.
`
`For vincristine and vinblastine, consider temporarily
`withholding the cobicistat-containing antiretroviral regimen
`in patients who develop significant hematologic or
`gastrointestinal side effects when PREZCOBIX is
`administered concurrently with vincristine or vinblastine. If
`the antiretroviral regimen must be withheld for a prolonged
`period, consider initiating a revised regimen that does not
`include a CYP3A or P-gp inhibitor.
`
`Concomitant use of apixaban is not recommended.
`
`Concomitant use with dabigatran etexilate is not
`recommended in specific renal impairment groups
`(depending on the indication). Please see the dabigatran US
`prescribing information for specific recommendations.
`
`Coadministration with rivaroxaban is not recommended.
`
`(cid:110) anticoagulant
`
`warfarin: effect
`unknown
`(cid:315) (cid:70)(cid:82)(cid:69)(cid:76)(cid:70)(cid:76)(cid:86)(cid:87)(cid:68)(cid:87)
`darunavir effect
`unknown
`
`Monitor the international normalized ratio (INR) when
`coadministering with warfarin.
`Consider alternative anticonvulsant or antiretroviral therapy
`to avoid potential changes in exposures. If coadministration
`is necessary, monitor for lack or loss of virologic response.
`
`phenobarbital:
`effect unknown
`phenytoin: effect
`unknown
`
`(cid:110) carbamazepine
`(cid:110) clonazepam
`
`SSRIs: effects
`unknown
`(cid:110) TCAs
`
`Monitor phenobarbital or phenytoin concentrations.
`
`Clinical monitoring is recommended.
`
`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.
`
`dasatinib,
`nilotinib,
`
`vinblastine,
`vincristine
`
`Anticoagulants:
`apixaban,
`
`dabigatran etexilate,
`
`rivaroxaban,
`
`warfarin
`
`Anticonvulsants that induce
`CYP3A:
`e.g. carbamazepine,
`oxcarbazepine, phenobarbital,
`phenytoin
`
`phenobarbital,
`phenytoin
`
`Anticonvulsants that are
`metabolized by CYP3A:
`e.g. clonazepam, carbamazepine
`Antidepressants:
`Selective Serotonin Reuptake
`Inhibitors (SSRIs):
`e.g.
`paroxetine,
`sertraline,
`
`Tricyclic
`Antidepressants (TCAs):
`e.g.
`amitriptyline,
`desipramine,
`imipramine,
`nortriptyline
`
`Reference ID: 3694997
`
`10
`
`
`
`Other antidepressants:
`trazodone
`Antifungals:
`itraconazole,
`ketoconazole,
`posaconazole,
`
`voriconazole
`
`Anti-gout:
`colchicine
`
`(cid:110) trazodone
`
`(cid:110) darunavir
`(cid:110) cobicistat
`
`(cid:110) itraconazole
`(cid:110) ketoconazole
`(cid:108) posaconazole
`(not studied)
`
`Voriconazole:
`effects unknown
`
`(cid:110) colchicine
`
`artemether: effect
`unknown
`lumefantrine: effect
`unknown
`(cid:110) rifabutin
`cobicistat: effects
`unknown
`darunavir: effects
`unknown
`
`Antimalarial:
`artemether/lumefantrine
`
`Antimycobacterials:
`rifabutin
`
`rifapentine
`(cid:533)-Blockers:
`e.g.
`carvedilol,
`metoprolol,
`timolol
`Calcium Channel
`Blockers:
`e.g.
`amlodipine,
`
`Monitor for increased darunavir or cobicistat adverse
`reactions.
`
`Specific dosing recommendations are not available for
`coadministration with itraconazole or ketoconazole.
`Monitor for increased itraconazole or ketoconazole adverse
`reactions.
`
`Coadministration with voriconazole is not recommended
`unless benefit/risk assessment justifies the use of
`voriconazole.
`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 with colchicine is contraindicated in
`patients with renal or hepatic impairment [see
`Contraindications (4)].
`Monitor for a potential decrease of antimalarial efficacy or
`potential QT prolongation.
`
`When used in combination with PREZCOBIX, the
`recommended dose of rifabutin is 150 mg every other day.
`Monitor for rifabutin-associated adverse reactions including
`neutropenia and uveitis.
`
`(cid:112) darunavir
`(cid:110) beta-blockers
`
`Coadministration with rifapentine is not recommended.
`Clinical monitoring is recommended for coadministration
`with beta-blockers that are metabolized by CYP2D6.
`
`(cid:110) calcium channel
`blockers
`
`Clinical monitoring is recommended for coadministration
`with calcium channel blockers metabolized by CYP3A.
`
`Reference ID: 3694997
`
`11
`
`
`
`diltiazem,
`felodipine,
`
`nifedipine,
`verapamil
`Corticosteroids
`(inhaled/nasal)
`metabolized by CYP3A:
`e.g.
`budesonide,
`fluticasone
`Corticosteroid
`systemic:
`e.g.
`dexamethasone
`
`Corticosteroids
`(systemic)
`metabolized by CYP3A:
`e.g.
`budesonide,
`prednisolone
`Endothelin receptor
`antagonists:
`bosentan
`
`Hepatitis C Virus (HCV)
`NS3-4A protease inhibitors:
`boceprevir,
`telaprevir,
`simeprevir
`
`HMG-CoA
`Reductase Inhibitors:
`e.g.
`atorvastatin,
`fluvastatin,
`pitavastatin,
`pravastatin,
`rosuvastatin
`Hormonal Contraceptives:
`
`(cid:110) corticosteroid
`
`(cid:112) darunavir
`(cid:112) cobicistat
`(cid:110) corticosteroids
`
`(cid:110) corticosteroid
`
`(cid:112) darunavir
`(cid:112) cobicistat
`(cid:110) bosentan
`
`darunavir: effects
`unknown
`boceprevir: effects
`unknown
`telaprevir: effects
`unknown
`(cid:110) simeprevir
`(cid:110) atorvastatin
`(cid:110) fluvastatin
`(cid:110) pravastatin
`(cid:110) rosuvastatin
`pitavastatin: effect
`unknown
`
`Coadministration with inhaled or nasal fluticasone or other
`corticosteroids that