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`
`
`
`
`
` 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------------------------------­
`Co-administration 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----------------------­
`
`
`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)
`
`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)
`
`Assess creatinine clearance (CLcr) before initiating treatment. (5.3)
`
`
`•
`• 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)
`
`
`
`•
`
`•
`
`
`•
`
`
`• 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)
`
`
`
`PREZCOBIX is not recommended in combination with other
`
`
`
`antiretroviral drugs that require pharmacokinetic boosting. (5.6)
`
`
`
`
`• Monitor in patients with a known sulfonamide allergy. (5.7)
`
`
`
`
`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).
`
`Patients with hemophilia may develop increased bleeding events. (5.11)
`•
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`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------------------------------­
`Co-administration 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-----------------------­
`
`Pregnancy: Use during pregnancy only if the potential benefit justifies
`•
`
`
`
`the potential risk. (8.1)
`
`
`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.
`
`
`
`
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`
`
`
`Revised: 03/2016
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`Testing prior to Initiation of PREZCOBIX
`2.2
`
`
`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
`
`
`
`
`
`
`
`
`
`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: 3910526
`
`
`
` 1
`
`

`

`
`
`
` FULL PRESCRIBING INFORMATION
`
` 1
` INDICATIONS AND USAGE
`
`
`
`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 co­
`
`
`
`
`administering 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 co-administered 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)].
`
`
`
`
`Reference ID: 3910526
`
`
`
` 2
`
`

`

`
` 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].
`
`
`
`
`
`
` Table 1:
`
`
`
`
`
` Drugs That Are Contraindicated With PREZCOBIX
`
` Drugs Within Class That Are
`Contraindicated With
`
` PREZCOBIX
` Drug Class
`
`
`
` Alpha 1-adrenoreceptor Alfuzosin
` antagonist
`
` Antianginal
`
` Antiarrhythmic
`
`
`
`
`
`
` Anti-gout
`
`
`
` Antimycobacterial
`
`
`
` Antipsychotic
`
`
`
` Ergot Derivative
`
`
`
` GI Motility Agent
`
`
`
`
`
` Herbal Product
`
`
`
` HMG-CoA Reductase
`
` Inhibitor
`
`
`
` PDE-5 inhibitor
`
`
`
` Sedative/Hypnotic
`
`
`
` Ranolazine
`
` Dronedarone
`
`
`
`
` Colchicine
`
`
`
` Rifampin
`
`
` Lurasidone
`
` Pimozide
`
` Dihydroergotamine,
`
` Ergotamine, Methylergonovine
`
`
`
`
`
`
`
`
`
` Cisapride
`
`
`
`
`
` St. John’s Wort (Hypericum
`
` perforatum)
`
`
`
` Lovastatin, Simvastatin
`
` Sildenafil for treatment of
`
` pulmonary arterial hypertension
`
`
`
`
`
` 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).
` Orally administered Midazolam, Potential for serious and/or life-threatening reactions
`
`
`
` Triazolam
`
` such as prolonged or increased sedation or respiratory
`
`
` depression. Triazolam and orally administered
` midazolam are extensively metabolized by CYP3A.
`
`
` Co-administration of triazolam or orally administered
`
`
`
` midazolam with PREZCOBIX may cause large
`increases in the concentrations of these
`
` benzodiazepines.
`
`Reference ID: 3910526
`
`
`
` 3
`
`

`

`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Hepatotoxicity
`
`
`During the darunavir clinical development program (N=3063), where darunavir was co­
`
`
`administered 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 co-administered 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 co-administered 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 co­
`
`
`administered 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.
`
`
`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,
`
`
`Reference ID: 3910526
`
`
`
` 4
`
`

`

`
`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. Co-administration 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)].
`
`
`
`•
`
`
`•
`
`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.
`
`
`Co-administration 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)
`
`associated with the concomitant medications. Co-administration 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)].
`
`
`
`
`
`Reference ID: 3910526
`
`
`
` 5
`
`

`

`
`When used with concomitant medications, PREZCOBIX may result in different drug interactions
`
`
`than those observed or expected with darunavir co-administered with ritonavir. Complex or
`
`
`unknown mechanisms of drug interactions preclude extrapolation of drug interactions with
`
`
`darunavir co-administered 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 co-administration 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 co-administered 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.
`
`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
`
`
`
`
` 6
`
`Reference ID: 3910526
`
`

`

`
`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:
`
`
`
`
`•
`
`
`•
`
`
`•
`
`Hepatotoxicity [see Warnings and Precautions (5.1)]
`
`
`
`
`Severe skin reactions [see Warnings and Precautions (5.2)]
`
`
`
`
`Effects on serum creatinine [see Warnings and Precautions (5.3)]
`
`
`
`
`
`•
`
`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 co-administered 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
`
`
`
`diarrhea, nausea, rash, headache, abdominal pain, and vomiting. See the darunavir full
`
`prescribing information for additional information on adverse reactions reported with darunavir
`
`co-administered 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 co-administered with
`
`
`
`ritonavir.
`
`
`Reference ID: 3910526
`
`
`
` 7
`
`

`

`
`
`
`
`
` 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 co­
`
`
`
`
`administered with cobicistat as single entities. Drug interaction trials have been conducted with
`darunavir co-administered 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, co-administration 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. Co-administration 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
`
`interactions due to the expected magnitude of interaction and potential for serious adverse events
`
`or loss of efficacy.
`
`
`
`
` Table 2:
`
`
`
`
`
`
`
` Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be
`
`
`
`
` Recommended Based on Drug Interaction Trials or Predicted Interaction
`
` Effect on Concentration
`
` of Darunavir,
` Concomitant Drug
`
` Cobicistat, or
`
` Class:
` Clinical Comment
` Concomitant Drug
` Drug Name
`
`
`
` HIV-1 Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
`
` didanosine
`
`
` ↔ darunavir
`
` Didanosine should be administered one hour before
`
` or two hours after PREZCOBIX (administered with
`
`
` ↔ cobicistat
`
`
` food).
`
` ↔ didanosine
`
`
`
`
`
`Reference ID: 3910526
`
`
`
` 8
`
`

`

`
` HIV-1 Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
`
`
`
`
`
` Co-administration with efavirenz is not
` efavirenz,
`
`
` ↓ cobicistat
`
` recommended because it may result in loss of
`
`
`
` ↓ darunavir
`
` therapeutic effect and development of resistance to
`
`
`
`
`
` darunavir.
`
`
`etravirine,
`
` ↓ cobicistat
`
`
`Co-administration with etravirine is not
`
`
`
`
` darunavir: effect
`recommended because it may result in loss of
`
`
`
`
` unknown
`therapeutic effect and development of resistance to
`
`
`
`
`darunavir.
`
`neviraprine
`
`↓ cobicistat
`
`
`
`darunavir: effect
`
`
`
` Co-administration with nevirapine is not
`unknown
`
`
` recommended because it may result in loss of
`
` therapeutic effect and development of resistance to
`
`
` darunavir.
`
`
`
`
`
` HIV-1 Antiviral Agents: CCR5 co-receptor antagonists
`
` maraviroc
`
`
` ↑ maraviroc
`
`
`
`
`
` Maraviroc is a substrate of CYP3A. When co­
`
`
` administered with PREZCOBIX, patients should
` receive maraviroc 150 mg twice daily.
`
`
`
`
`
`
`
` Clinical monitoring is recommended upon co­
` administration with antiarrhythmics.
`
`
`
`
`
`
`
`
`
`
`When co-administering with digoxin, titrate the
`
`
` digoxin dose and monitor digoxin concentrations.
`
`
` Consider alternative antibiotics with concomitant
`
` use of PREZCOBIX.
`
`
`A decrease in the dosage or an adjustment of the
` dosing interval of dasatinib or nilotinib may be
`
`
`
`
`
`
`
` necessary when co-administered 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.
`
`
`
`
`
`
`
` 9
`
`
`
`
` ↑ antiarrhythmics
`
`
`
`
`
`
`
`
`
`
`
`↑ digoxin
`
`
`
` ↑ darunavir
`
`
` ↑ cobicistat
`
` ↑ antibacterial
`
`
`
`
`
` ↑ anticancer agent
`
`
`
`
`
` Other Agents
`
` Antiarrhythmics:
`
`
` e.g.
` amiodarone,
`
`
` disopyramide,
`
` flecainide,
` lidocaine (systemic),
`
` mexiletine,
`
` propafenone,
`
` quinidine,
`
`digoxin
`
`
`
`
`
`
`
`
`
` Antibacterial Agents
` clarithromycin,
`
`
` erythromycin,
`
` telithromycin
` Anticancer Agents:
`
` dasatinib,
`
` nilotinib,
`
`
`
`
` vinblastine,
`
` vincristine
`
`
` Anticoagulants:
`
` apixaban,
`
`
` ↑ anticoagulant
`
`
`
`
`Reference ID: 3910526
`
`

`

`
`
`
`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
`
`
`
`Other antidepressants:
`
`trazodone
`
` Antifungals:
`
` itraconazole,
`
` ketoconazole,
`
` posaconazole,
`
`
`
`
`
`
`voriconazole
`
`
`
`
`
`
`
`
`
`warfarin: effect
`
`unknown
`
`
` ↓ cobicistat
`
`
`
`
` darunavir effect
`
` unknown
`
`
`
`
`phenobarbital:
`
`effect unknown
`
`phenytoin: effect
`unknown
`
`
`↑ carbamazepine
`
`
`↑ clonazepam
`
`
`
`
` SSRIs: effects
`
` unknown
`
`
` ↑ TCAs
`
`
`
`
`
`
`
`
`
`
`
`
`↑ trazodone
`
`
`
`
`
` ↑ darunavir
`
`
`↑ cobicistat
`
`
`
`↑ itraconazole
`
`
`↑ ketoconazole
`
`
`↔ posaconazole (not
`
`studied)
`
`
`Voriconazole:
`
`effects unknown
`
`Reference ID: 3910526
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
` Co-administration with rivaroxaban is not
`
` recommended.
`
` Monitor the international normalized ratio (INR)
`
`
` when co-administering with warfarin.
`Consider alternative anticonvulsant or antiretroviral
`
` therapy to avoid potential changes in exposures. If
`
` co-administration is necessary, monitor for lack or
`
` loss of virologic response.
`
`
`
`
`
`Monitor phenobarbital or phenytoin concentrations.
`
`
`
`
`
`
`Clinical monitoring is recommended.
`
`
`
` When co-administering 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.
`
`
`
`
`
`
`
`
`
`
`
`
` Monitor for increased darunavir or cobicistat
`
` adverse reactions.
`
`Specific dosing recommendations are not available
`
`
`
` for co-administration with itraconazole or
` ketoconazole. Monitor for increased itraconazole or
`
`
` ketoconazole adverse reactions.
`
`Co-administration with voriconazole is not
`recommended unless benefit/risk assessment
`
`
` justifies the use of voriconazole.
`
`
`
`
`
`
` 10
`
`

`

`
`
` Anti-gout:
`
` colchicine
`
`
`
` ↑ colchicine
`
`
`
`
`
` Antimalarial:
`
` artemether/lumefantrine
`
`
`
`
` Antimycobacterials:
`
` rifabutin
`
`
`
`
`
`rifapentine
`
`
`
`
` Antipsyc