`
`
` 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
`
`
`
`
`
`
`
`
`
`---------------------------RECENT MAJOR CHANGES--------------------------
`
`
`Contraindications (4)
`09/2016
`
`
`Warnings and Precautions
`
`
`09/2016
`Risk of Serious Adverse Reactions due to Drug Interactions (5.5)
`
`
`
`----------------------------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 occur 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 before initiating treatment. (5.3)
`
`
`
`
`•
`
`
`•
`
`
`
`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 Renal Impairment
`
`
`2.4 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
`
`
`
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`• 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 creatinine clearance , 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 (5.9), and immune reconstitution
`
`
`
`
`
`syndrome. (5.10)
`
`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)
`
`
`Lactation: Women infected with HIV-1 should be instructed not to
`
`
`
`
`
`breastfeed due to the potential for HIV transmission. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`
`approved patient labeling.
`
`
`Revised: 06/2017
`
`
`
`
`
`
`7.2 Potential for Other Drugs to Affect PREZCOBIX
`
`
`
`
`7.3 Potentially Significant Drug Interactions
`
`7.4 Drugs without Clinically Significant Interactions
`
`
`
`
`with PREZCOBIX
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2
`Lactation
`
`
`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
`
`
`
`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: 4111060
`
`
`
` 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 (5.3)]. 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
`
`
`(5.4)].
`
`2.3 Renal Impairment
`
`
`
`PREZCOBIX co-administered with tenofovir DF is not recommended in patients who have an
`
`
`estimated creatinine clearance below 70 mL per minute [see Warnings and Precautions (5.4) and
`
`
`
`
`
`
`
`Adverse Reactions (6.1)].
`
`
`2.4 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: 4111060
`
`
`
` 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
`
`
`
`
`
`
`
` PREZCOBIX is contraindicated with the following drugs (see Table 1) 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
`
` alfuzosin
`
` Drug Class
`
`
` Alpha 1-adrenoreceptor
` antagonist
`
` Antianginal
`
` Antiarrhythmic
`
`
`
`
` ranolazine
`
` dronedarone
`
`
`
`
` Anticonvulsants
`
`
` carbamazepine, phenobarbital,
`
` phenytoin
`
`
`
`
`
` Anti-gout
`
`
`
` colchicine
`
`
`
` Antimycobacterial
`
`
`
` rifampin
`
`
`
` Antipsychotics
`
`
` lurasidone
`
` pimozide
`
`
`
` Ergot derivatives
`
`
`
`
`
` GI motility agent
`
`
`
`
`
`
`
` Herbal product
`
`
`
`
` Hepatitis C direct-acting
`
` antiviral
`HMG-CoA reductase
`
` inhibitors
`
`
`
` PDE-5 inhibitor
`
` dihydroergotamine,
`
`
` ergotamine, methylergonovine
`
`
`
`
`
` cisapride
`
`
` St. John’s wort (Hypericum
` perforatum)
`
`
`
`
`
`
` elbasvir/grazoprevir
`
`
`
` 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.
`
` Potential for reduced plasma concentrations of
` darunavir, which may result in loss of therapeutic
`
`
`
` effect and development of resistance.
` 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 the increased risk of alanine
`
`
`
` transaminase (ALT) elevations.
`
`
` 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).
`
`Reference ID: 4111060
`
`
`
` 3
`
`
`
`
` Sedatives/hypnotics
`
`
`
` orally administered
`
`
` midazolam, triazolam
`
`
`
` 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.
`
`Co-administration of triazolam or orally administered
`
`
`midazolam with PREZCOBIX may cause large
`increases in the concentrations of these
`
` benzodiazepines.
`
`
`
`
`
`
` 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.
`
`Reference ID: 4111060
`
`
`
` 4
`
`
`
`
`
`
`
`
`
` 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,
`
`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 (2.2)]. Dosage recommendations are not available for drugs that require
`
`dosage adjustments in PREZCOBIX-treated patients with renal impairment [see Drug
`
`
`
`Interactions (7.3) and 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 medications metabolized by CYP3A.
`
`
`
`
`
`Reference ID: 4111060
`
`
`
` 5
`
`
`
`
` Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease
`
` concentrations of PREZCOBIX.
`
`
`
`
`
`
`
` Increased concentrations may lead to:
`
`
`•
`
`
`
` clinically significant adverse reactions, potentially leading to severe, life threatening, or
` fatal events from higher exposures of concomitant medications.
`
`
`
`
`
`
`
`
`
` clinically significant adverse reactions from higher exposures of PREZCOBIX.
`
`
`
`
`•
` Decreased antiretroviral concentrations may lead to:
`
`
`
`
`
`
`
`
`
` loss of therapeutic effect of PREZCOBIX and possible development of resistance.
`
`
`
`
`
`
`•
` See Table 2 for steps to prevent or manage these possible and known significant drug
`
`
`
`
`
`
`
` interactions, including dosing recommendations. 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 concomitant medications [see
`
`
`
` Contraindications (4) and Drug Interactions (7)].
`
`
`
`
`
`
`
` 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
`
`
`
`
`
` 6
`
`Reference ID: 4111060
`
`
`
`
`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
`
`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)]
`
`
`
`Reference ID: 4111060
`
`
`
` 7
`
`
`
`
`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.
`
`6.2 Postmarketing Experience
`
`
`See the darunavir full prescribing information for postmarketing information.
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Potential for PREZCOBIX to Affect Other Drugs
`
`
`
`
`
`Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat
`
`
`
`inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, 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, MATE1, 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).
`
`
`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. Co-administration of PREZCOBIX and 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. No drug interaction trials have been performed with PREZCOBIX or with
`
`
`
`Reference ID: 4111060
`
`
`
` 8
`
`
`
`
`
` darunavir co-administered with cobicistat as single entities. Drug interaction trials have been
` conducted with darunavir co-administered with ritonavir or with cobicistat alone.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 2:
`
` Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be
`
`
`
` Recommended Based on Drug Interaction Trials or Predicted Interaction
` (see Contraindications (4) for a complete list of contraindicated drugs)
`
`
` Effect on Concentration of
` Clinical Comment
`
`
`
` Concomitant Drug Class:
` Darunavir, Cobicistat, or
`
`
` Drug Name
`
` Concomitant Drug
` HIV-1 antiviral agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
`
`
` didanosine
`
` Didanosine should be administered one hour before
`
`
` ↔ darunavir
`
` or two hours after PREZCOBIX (administered with
`
`
` ↔ cobicistat
`
`
` food).
`
` ↔ didanosine
`
`
` 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.
`
`
`
` Co-administration with etravirine is not
`
` recommended because it may result in loss of
`
`
` therapeutic effect and development of resistance to
`
`
` darunavir.
`
`
`
` Co-administration with nevirapine is not
`
` recommended because it may result in loss of
`
`
` therapeutic effect and development of resistance to
`
`
` darunavir.
`
`
`
`
` etravirine
`
`
`
` nevirapine
`
` ↓ cobicistat
`
`
` darunavir: effect unknown
`
`
`
` ↓ cobicistat
`
`
` darunavir: effect unknown
`
`
`
`
`
` HIV-1 antiviral agents: CCR5 co-receptor antagonists
`
` maraviroc
`
`
` ↑ maraviroc
`
` Other agents
`
` Antiarrhythmics:
`
`
`
`
`
` e.g. amiodarone,
`
`
`
` disopyramide, flecainide,
` lidocaine (systemic),
`
`
` mexiletine, propafenone,
`
` quinidine
`
` digoxin
`
`
`
`
`
`
`
`
`
` ↑ antiarrhythmics
`
`
`
`
`
` ↑ digoxin
`
`
`
`
` Antibacterials:
`
` clarithromycin,
` erythromycin, telithromycin
`
` Anticancer agents:
`
`
`
` dasatinib, nilotinib
`
`
`
`
`
` ↑ darunavir
`
`
` ↑ cobicistat
`
`
` ↑ antibacterial
`
` ↑ anticancer agent
`
`
`
`Reference ID: 4111060
`
` Maraviroc is a substrate of CYP3A. When co-
`
`
` administered with PREZCOBIX, patients should
` receive maraviroc 150 mg twice daily.
`
`
`
`
`
`
`
`
`
` For contraindicated antiarrhythmics, [see
`
` Contraindications (4)].
`
`
` 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
`
`
`
` 9
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` vinblastine, vincristine
`
`
`
`
` Anticoagulants:
`
` apixaban
`
` dabigatran etexilate
`
`
`
`
`
`
` rivaroxaban
`
`
`
`
` warfarin
`
`
`
` ↑ anticoagulant
`
`
`
`
`
`
`
`
`
` warfarin: effect unknown
`
`
`
` Anticonvulsants:
`
`
`
`
`
`
` ↓ cobicistat
` darunavir: effect unknown
`
`
`
`
`
`
`
` Anticonvulsants with
` CYP3A induction effects
`
`
`that are NOT
`
`contraindicated:
`
`e.g. eslicarbazepine,
`
`oxcarbazepine
`
`
` Anticonvulsants that are
`
` metabolized by CYP3A:
`
`
`e.g. clonazepam
`
` Antidepressants:
`
`
` Selective Serotonin
`
`Reuptake Inhibitors
`
`(SSRIs):
`
`
`
`e.g. paroxetine, sertraline
`
` Tricyclic Antidepressants
`
` (TCAs):
`
`e.g. amitriptyline,
`
`
`desipramine, imipramine,
`
` nortriptyline
`
`
`
` 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.
`
` For contraindicated anticonvulsants, [see
`
` Contraindications (4)].
`
` 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.
`
`
`
`
`
`
`
`
`
` ↑ clonazepam
`
`
`
`
`
` SSRIs: effects unknown
`
`
` ↑ TCAs
`
`
`
`
`
`
`
`
` Clinical monitoring of anticonvulsants 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.
`
`
`
`Reference ID: 4111060
`
`
`
` 10
`
`
`
`
`
`
`
` Other antidepressants:
`
` trazodone
`
`
` Antifungals:
`
` itraconazole, ketoconazole,
` posaconazole
`
`
`
`
`
`
` voriconazole
`
`
` Anti-gout:
`
` colchicine
`
` Antimalarial:
`
` artemether/lumefantrine
`
`
`
`
`
` Antimycobacterials:
`
`
`
`
` rifabutin
`
`
`
` rifapentine
`
`
`
`
`
` ↑ trazodone
`
`
`
`
`
` ↑ darunavir
`
`
` ↑ cobicistat
`
`
`
` ↑