` 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--------------------------­
`
`
`Warnings and Precautions,
`
`
`
`
`Risk of Serious Adverse Reactions or Loss of
`
`
`
`12/2020
`Virologic Response 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 treatment­
`
`
`
`
`naïve and treatment-experienced adults and pediatric patients weighing at
`
`
`
`
`least 40 kg with no darunavir resistance-associated substitutions (V11I, V32I,
`
`
`
`L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). (1)
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
`
`
`
`Recommended dosage: One tablet taken once daily with food in adults and
`pediatric patients weighing at least 40 kg. (2.1)
`
`
`
`
`Testing Prior to Initiation: HIV genotypic testing is recommended for
`
`
`
`
`
`antiretroviral treatment experienced patients. Assess estimated creatinine
`
`
`clearance in all patients prior to starting PREZCOBIX. 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. (2.2)
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`Tablets: 800 mg of darunavir and 150 mg of cobicistat. (3)
`
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------­
`PREZCOBIX is contraindicated in patients receiving certain co-administered
`
`
`
`
`drugs for which altered plasma concentrations are associated with serious
`
`
`
`and/or life-threatening events or loss of therapeutic effect. (4, 7.2)
`
`
`------------------------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)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`Testing Prior to Initiation of PREZCOBIX
`2.2
`
`
`
`2.3 Not Recommended in Severe Renal Impairment
`
`2.4 Not Recommended in Severe Hepatic
`
`
`
`Impairment
`
`
`
`2.5 Not Recommended During Pregnancy
`
`
`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
`
`Reference ID: 4830581
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`
`
`
`
`
`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)
`
`• 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)
`
`
`
`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. (6.1)
`
`
`
`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: PREZCOBIX is not recommended during pregnancy due to
`
`
`
`
`
`
`•
`substantially lower exposures of darunavir and cobicistat during
`
`
`
`pregnancy. (8.1, 12.3)
`
`
`Lactation: Breastfeeding is not recommended. (8.2)
`
`
`
`Pediatrics: Not recommended for pediatric patients weighing less than
`
`
`
`40 kg. (8.4)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`approved patient labeling.
`
`
`Revised: 07/2021
`
`
`
`
`
`7.2 Potential for Other Drugs to Affect PREZCOBIX
`
`
`
`7.3 Established and Other Potentially Significant
`
`
`
`
`Drug Interactions
`
`
`7.4 Drugs without Clinically Significant Interactions
`
`
`
`
`with PREZCOBIX
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2
`Lactation
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`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
`
`14.1 Clinical Trial Results in Adults with HIV-1
`
`
`
`
`Infection
`
`
`
`
`14.2 Clinical Trial Results in Pediatric Subjects with
`
`
`HIV-1 Infection
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
` 1
`
`

`

`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`
`listed.
`
`Reference ID: 4830581
`
`
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` 2
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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 and pediatric patients weighing at least 40 kg 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 and pediatric patients weighing at
`
`
`
`
`least 40 kg 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 Not Recommended in Severe 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 Not Recommended in Severe 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: 4830581
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`
`
` 3
`
`

`

`
` 2.5 Not Recommended During Pregnancy
`
`
`PREZCOBIX is not recommended during pregnancy because of substantially lower exposures of
`
`
`darunavir and cobicistat during the second and third trimesters [see Use in Specific Populations
`
`
`
`(8.1) and Clinical Pharmacology (12.3)].
`
`PREZCOBIX should not be initiated in pregnant individuals. An alternative regimen is
`
`recommended for those who become pregnant during therapy with PREZCOBIX.
`
`
`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 in patients receiving the following co-administered drugs [see
`
`
`
`Drug Interactions (7.3) and Clinical Pharmacology (12.3)].
`
`• Alpha 1-adrenoreceptor antagonist: alfuzosin
`
`
`
`
`• Anticonvulsants: carbamazepine, phenobarbital, phenytoin
`
`
`
`• Anti-gout: colchicine, in patients with renal and/or hepatic impairment
`
`
`
`
`• Antimycobacterial: rifampin
`
`
`
`• Antipsychotics: lurasidone, pimozide
`
`
`
`
`• Cardiac Disorders: dronedarone, ivabradine, ranolazine
`
`
`
`
`• Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine
`
`
`
`• Herbal product: St. John’s wort (Hypericum perforatum)
`
`
`
`• Hepatitis C direct acting antiviral: elbasvir/grazoprevir
`
`
`
`
`• Lipid modifying agents: lomitapide, lovastatin, simvastatin
`
`
`
`• Opioid Antagonist: naloxegol
`
`
`
`• PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension
`
`
`
`
`
`• Sedatives/hypnotics: orally administered midazolam, triazolam
`
`
`
`Reference ID: 4830581
`
`
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` 4
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`

`

`
`
`
`
` 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,
`
`
`
`
` 5
`
`Reference ID: 4830581
`
`

`

`
` 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 and
`
`
`
`
`
`reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications
`
`
`that inhibit or induce CYP3A may respectively increase or decrease concentrations of
`
`PREZCOBIX.
`
`These interactions 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.
`
`
`
`
`
` 6
`
`Reference ID: 4830581
`
`

`

`
`
`•
`
`
`
` loss of therapeutic effect of the concomitant medications from lower exposures of active
`metabolite(s).
`
`
`
`•
`
`loss of therapeutic effect of PREZCOBIX and possible development of resistance from lower
`
`
`
`
`exposures of PREZCOBIX.
`
`See Table 1 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 patients with HIV-1 infection 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.
`
`
`
`
` 7
`
`Reference ID: 4830581
`
`

`

`
`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, Guillain-Barré syndrome and
`
`
`autoimmune hepatitis) 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 DF [see Warnings and
`
`
`Precautions (5.4)]
`
`
`Immune Reconstitution Syndrome [see Warnings and Precautions (5.10)]
`
`
`
`
`•
`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.
`
`
`
`
`
` 8
`
`Reference ID: 4830581
`
`

`

`
`
` Clinical Trials in Adults
`
`
` 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 on adverse reactions reported with darunavir
`information for additional
`
` 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 subjects with HIV-1 infection. Adverse reactions evaluated through Week 24 did
`
`
`
` not differ substantially from those reported in clinical trials with darunavir co-administered with
`
`
`
`
` ritonavir.
` Clinical Trials in Pediatric Patients
`
`No clinical trials with PREZCOBIX were performed in pediatric patients. However, the safety of
`
`
`the components of PREZCOBIX, darunavir and cobicistat, co-administered with two nucleoside
`
`reverse transcriptase inhibitors, was evaluated in pediatric subjects of 12 to less than 18 years of
`
`
`
`
`age with HIV-1 infection through clinical trial GS-US-216-0128 (virologically-suppressed, N=7
`with weight ≥40 kg) through Week 48. Safety analyses of this trial in these pediatric subjects did
`
`
`
`
`
`not identify new safety concerns compared to the known safety profile of PREZCOBIX in adult
`
`
`
`
`subjects [see Clinical Studies (14.2)].
`
`
`6.2 Postmarketing Experience
`
`
`The following events have been identified during post-approval use of darunavir. Because these
`
`
`events are reported voluntarily from a population of uncertain size, it is not always possible to
`
`
`
`
`reliably estimate their frequency or establish a causal relationship to drug exposure.
`
`Metabolism and Nutrition Disorders
`
`
`Redistribution of body fat
`
`Musculoskeletal and Connective Tissue Disorders
`Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors)
`
`Skin and Subcutaneous Tissue Disorders
`
`Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with
`
`
`eosinophilia and systemic symptoms [see Warnings and Precautions (5.2)].
`
`
`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
`
`
`
`
`
` 9
`
`Reference ID: 4830581
`
`

`

`
`
`
`
`
` 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. Co-administration of
` PREZCOBIX with drugs that have active metabolite(s) formed by CYP3A may result in reduced
`
` plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic
`
`
`
`
`
` effect (see Table 1).
`
`
`
` 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 1).
`
`
`
`
`
`
` 7.3 Established and Other Potentially Significant Drug Interactions
`
`
`
`
`
`
` Table 1 provides dosing recommendations for expected clinically relevant interactions with
`
`
`
`
` PREZCOBIX (this table is not all inclusive). 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 therapeutic effect. The table includes potentially
`
`
`
`
` significant interactions but is not all inclusive. For the list of contraindicated drugs, [see
`
`
`
`
`
` Contraindications (4)].
` Established and Other Potentially Significant* Drug Interactions: Alterations in Dose or
` Table 1:
`
`
`Regimen May Be Recommended
`
` Effect on Concentration
`
` of Darunavir,
`
` Concomitant Drug Class:
`
` Cobicistat, or
` Clinical Comment
`Concomitant Drug
`
` Drug Name
`
`
` HIV-1 antiviral agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
` Didanosine should be administered one hour before
`
`
`
`
`
` ↔ darunavir
` didanosine
`
` or two hours after PREZCOBIX (administered with
`
` ↔ cobicistat
`
`↔ didanosine
`
` food).
`
`
`HIV-1 antiviral agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
`
`Co-administration with efavirenz is not
`
`
`
` ↓ cobicistat
` efavirenz
`↓ darunavir
`
`
`recommended because it may result in loss of
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`Reference ID: 4830581
`
`
`
` 10
`
`

`

`
`
`
`
` HIV-1 antiviral agents: CCR5 co-receptor antagonists
`
`
`maraviroc
`
`
` ↑ maraviroc
`
`Other agents
`
`Alpha 1-adrenoreceptor
`
` antagonist:
`
`alfuzosin
`
` Antibacterials:
`
` clarithromycin,
`
` erythromycin, telithromycin
`
` Anticancer agents:
`
`dasatinib, nilotinib
`
`
` ↑ alfuzosin
`
`
`
`
`
`
`
` ↑ darunavir
`
`
` ↑ cobicistat
`
`
` ↑ antibacterial
`
` ↑ anticancer agent
`
`
`
`
`vinblastine, vincristine
`
`
`
`
`
` Anticoagulants:
`
` Direct Oral Anticoagulants
`
`(DOACs)
`
`apixaban
`
`
`
` ↑ apixaban
`
`
`
`
`
` rivaroxaban
`
`
`
` betrixaban
`
` dabigatran
`
` edoxaban
`
` Other Anticoagulants:
`
` warfarin
`
`
`
`↑ rivaroxaban
`
`
`
`
`
`
` ↔ betrixaban
`
`
` ↔ dabigatran
`
` ↔ edoxaban
`
`
`
`
`
`warfarin: effect unknown
`
`
` Anticonvulsants:
`
` carbamazepine,
` phenobarbital, phenytoin
`
`
`
`
`
` ↓ darunavir
`
`
` ↓ cobicistat
`
`Anticonvulsants with CYP3A
`
` induction effects that are
`
`NOT contraindicated:
`
`e.g. eslicarbazepine,
`
` oxcarbazepine
`
`
`
` ↓ cobicistat
` darunavir: effect unknown
`
`
`
`
`Reference ID: 4830581
`
`Maraviroc is a substrate of CYP3A. When co-
`administered with PREZCOBIX, patients should
`
`
` receive maraviroc 150 mg twice daily.
`
`
` Co-administration is contraindicated due to
`
` potential for serious and/or life-threatening
`
` reactions such as hypotension.
`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.
`
` Due to potentially increased bleeding risk, dosing
`
`recommendations for co-administration of apixaban
`
`with PREZCOBIX depends on the apixaban dose.
`
`Refer to apixaban dosing instructions for
`co-administration with strong CYP3A and P-gp
`
`inhibitors in apixaban prescribing information.
`
` Co-administration of rivaroxaban with
`
` PREZCOBIX is not recommended because it may
`
` lead to an increased bleeding risk.
`
`
` No dose adjustment is needed when betrixaban,
`
` dabigatran, or edoxaban is co-administered with
`
` PREZCOBIX.
`
`
`
`
`
`
`Monitor the international normalized ratio (INR)
` when co-administering with warfarin.
`
`
`
` Co-administration is contraindicated due to
`
`
` potential for reduced plasma concentrations of
` darunavir, which may result in loss of therapeutic
`
`
`
` effect and development of resistance.
`Consider alternative anticonvulsant or antiretroviral
`
`
` therapy to av