The following Structured Product Label (SPL) was submitted to the FDA by Janssen Products, Lp for the product Prezcobix Ped (NDC 59676-577). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 recommended dosage, other, 2.3 renal impairment, 2.4 hepatic impairment, 3 dosage forms and strengths, 4 contraindications, 5.1 hepatotoxicity, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
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).
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.
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)].
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PREZCOBIX during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.
Risk Summary
There are insufficient data with PREZCOBIX in pregnant women from the APR to inform a drug-associated risk of pregnancy outcomes. Available data from the APR show no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation.
The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15–20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.
In animal reproduction studies, no adverse developmental effects were observed when the components of PREZCOBIX were administered separately at darunavir exposures less than 1 (mice and rabbits) and 3-times (rats), and at cobicistat exposures 1.6 (rats) and 3.8 (rabbits) times human exposures at the recommended daily dose of these components in PREZCOBIX [see Data]. No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.2 times the human exposure at the recommended therapeutic dose.
Clinical Considerations
Dose Adjustment During Pregnancy and the Postpartum Period
Dosing recommendations cannot be made because the pharmacokinetics, safety, and efficacy of PREZCOBIX cannot be predicted from studies of other darunavir-containing regimens in pregnant women.
Data
Human Data
Darunavir: Based on prospective reports to the APR of 615 live births following exposure to darunavir-containing regimens during pregnancy (including 385 exposed in the first trimester and 230 exposed in the second/third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S. reference population of the MACDP.
The prevalence of birth defects in live births was 2.6% (95% CI: 1.2% to 4.7%) with first trimester exposure to darunavir-containing regimens and 1.7% (95% CI: 0.5% to 4.4%) with second/third trimester exposure to darunavir-containing regimens.
Cobicistat: Insufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects.
Animal Data
Darunavir: Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6–15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7–19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8–20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir co-administered with ritonavir.
Cobicistat: Cobicistat was administered orally to pregnant rats at doses up to 125 mg/kg/day on GD 6–17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.6 times higher than human exposures at the recommended daily dose of cobicistat.
In pregnant rabbits, cobicistat was administered orally at doses up to 100 mg/kg/day during GD 7–20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.8 times higher than human exposures at the recommended daily dose of cobicistat.
In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses up to 75 mg/kg from GD 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.2 times the human exposures at the recommended daily dose of cobicistat.
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV.
There are no data on the presence of darunavir or cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir and cobicistat are secreted into the milk of lactating rats [see Data]. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infants, instruct mothers not to breastfeed if they are receiving PREZCOBIX.
Data
Animal Data
Darunavir: Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose of darunavir with ritonavir.
Cobicistat: During the pre/postnatal developmental toxicology study at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10.
Juvenile Animal Toxicity Data
Darunavir: In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.
Darunavir: Darunavir, in the form of darunavir ethanolate, has the following chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. Its molecular formula is C27H37N3O7S ∙ C2H5OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:
Chemical Structure (Prezcobix 01)
Cobicistat: Cobicistat is adsorbed onto silicon dioxide. The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl[(2R,5R)-5-{[(2S)2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:
Chemical Structure (Prezcobix 02)
Cardiac Electrophysiology
Separate thorough QT trials have been conducted for darunavir co-administered with ritonavir and for cobicistat. The effect of darunavir co-administered with cobicistat on the QT interval has not been evaluated.
Darunavir: In a thorough QT/QTc study in 40 healthy subjects, darunavir doses (co-administered with 100 mg ritonavir) of approximately 2 times the recommended darunavir dose did not affect the QT/QTc interval.
Cobicistat: The effect of a single dose of cobicistat 250 mg and 400 mg (approximately 1.7 and 2.7 times the recommended dose) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT trial in 48 healthy subjects. In this trial, no significant QTc prolongation effect of cobicistat was detected. The dose of 400 mg cobicistat is expected to provide information on a high exposure clinical scenario. Prolongation of the PR interval was noted in subjects receiving cobicistat in the same trial. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg and 20.2 (22.8) msec for 400 mg of cobicistat.
Effects on Serum Creatinine
Cobicistat: The effect of cobicistat on serum creatinine was investigated in a trial in subjects with normal renal function (eGFR ≥ 80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50–79 mL/min, N=18). A statistically significant decrease in the estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFRCG) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (-9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (-11.9 ± 7.0 mL/min). No statistically significant changes in eGFRCG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate.
Absorption and Bioavailability
In healthy subjects, under fed conditions, when single doses of the darunavir and cobicistat fixed dose combination tablet were administered, the maximum plasma concentration was achieved within approximately 4 to 4.5 hours for darunavir and approximately 4 to 5 hours for cobicistat.
Effects of Food on Oral Absorption
When compared to fasted conditions, administration of PREZCOBIX to healthy adult subjects with a high-fat meal (965 total kcal: 129 kcal from protein, 236 kcal from carbohydrates and 600 kcal from fat) resulted in a 70% increase in AUC(0–inf) and a 127% increase in Cmax for darunavir. Cobicistat exposures were not affected by food. PREZCOBIX should be taken with food.
Distribution
Darunavir: Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).
Cobicistat: Cobicistat is 97–98% bound to human plasma proteins and the mean blood–to-plasma ratio was approximately 0.5.
Metabolism
Darunavir: In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance trial in healthy subjects showed that after single dose administration of 400 mg 14C-darunavir co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV-1.
Cobicistat: Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.
Elimination
Darunavir: A mass balance trial in healthy subjects showed that after single dose administration of 400 mg 14C-darunavir co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively.
When single doses of the darunavir and cobicistat fixed dose combination tablet were administered, the terminal elimination half-life of darunavir was approximately 7 hours under fed conditions.
Cobicistat: When single doses of the darunavir and cobicistat fixed dose combination tablet were administered, the terminal elimination half-life of cobicistat was approximately 4 hours under fed conditions. With single dose administration of 14C-cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.
Specific Populations
Hepatic Impairment
Darunavir: Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of darunavir 600 mg co-administered with ritonavir 100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [see Use in Specific Populations (8.6)].
Cobicistat: Cobicistat is primarily metabolized by the liver. A trial evaluating the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment on the pharmacokinetics of cobicistat has not been evaluated [see Use in Specific Populations (8.6)].
Hepatitis B or Hepatitis C Virus Co-Infection
Darunavir: In HIV-infected subjects taking darunavir co-administered with ritonavir, the 48 week analysis of the data from clinical studies in HIV-1 infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.
The effect of hepatitis B and/or C virus infection on the pharmacokinetics of PREZCOBIX have not been evaluated.
Renal Impairment
Darunavir: Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1 infected subjects with moderate renal impairment taking darunavir co-administered with ritonavir (creatinine clearance between 30–60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end stage renal disease taking darunavir co-adminstered with either ritonavir or cobicistat [see Use in Specific Populations (8.7)].
Cobicistat: A trial of the pharmacokinetics of cobicistat was performed in non-HIV infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects [see Use in Special Populations (8.7)].
Gender
Darunavir: In HIV-infected subjects taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1 infected females compared to males. This difference is not clinically relevant.
Cobicistat: No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat.
Race
Darunavir: Population pharmacokinetic analysis of darunavir in HIV-1 infected subjects taking darunavir co-administered with ritonavir indicated that race had no apparent effect on the exposure to darunavir.
Cobicistat: Population pharmacokinetic analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat.
Geriatric Patients
Darunavir: In HIV-infected subjects taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed no considerable differences in darunavir pharmacokinetics for ages 18 to 75 years compared to ages greater than or equal to 65 years (n=12) [see Use in Specific Populations (8.5)].
Cobicistat: Insufficient data are available to determine whether potential differences exist in the pharmacokinetics of cobicistat in geriatric (65 years of age and older) subjects compared to younger subjects.
Pediatric Patients
The pharmacokinetics of PREZCOBIX in pediatric subjects have not been established.
Drug Interactions
Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-gp, BCRP, MATE1, OATP1B1 and OATP1B3. 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.
Mechanism of Action
Darunavir: Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.
Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates.
Antiviral Activity
Darunavir: Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells, and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M (A, B, C, D, E, F, G), and group O primary isolates with EC50 values ranging from less than 0.1 to 4.3 nM. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. Darunavir did not show antagonism when studied in combination with the HIV protease inhibitors (PIs) amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, efavirenz, etravirine, rilpivirine, or nevirapine, and the fusion inhibitor enfuvirtide.
Cobicistat: Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1. The antiviral activity in cell culture of approved HIV-1 antiretroviral drugs was not antagonized by cobicistat.
Resistance
Cell Culture
Darunavir: HIV-1 isolates with a decreased susceptibility to darunavir have been selected in cell culture and obtained from subjects treated with darunavir co-administered with ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated substitutions resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.
Clinical Studies
The resistance profile of PREZCOBIX is driven by darunavir. Cobicistat does not select any HIV resistance substitutions, due to its lack of antiviral activity. For the clinical resistance profile of darunavir, refer to the darunavir full prescribing information.
Cross-resistance
Cross-resistance among PIs has been observed. Darunavir has a less than 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir. A less than 10-fold decreased susceptibility was observed for the other PIs in 26% to 96% of these PI resistant clinical isolates [nelfinavir (26%), ritonavir (34%), lopinavir (46%), indinavir (57%), atazanavir (59%), saquinavir (64%), amprenavir (70%), and tipranavir (96%)].
Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, or integrase strand transfer inhibitors is unlikely because the viral targets are different.
Baseline Genotype/Phenotype and Virologic Outcome Analyses
Baseline International AIDS Society (IAS)-defined PI resistance substitutions confer reduced virologic response to darunavir. Please refer to the "Baseline Genotype/Phenotype and Virologic Outcome Analyses" section in the darunavir full prescribing information.
Carcinogenesis and Mutagenesis
Darunavir: Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas was observed in males and females of both species and an increase in thyroid follicular cell adenomas was observed in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats) of exposures observed in humans at the recommended therapeutic doses (darunavir 600 mg co-administered with ritonavir 100 mg twice daily or darunavir 800 mg co-administered with ritonavir 100 mg once daily).
Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes, and in vivo micronucleus test in mice.
Cobicistat: In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day in males and females, respectively. Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.
Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
Impairment of Fertility
Darunavir: No effects on fertility or early embryonic development were observed with darunavir in rats.
Cobicistat: Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 4-fold higher than human exposures at the recommended 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2-fold higher than human exposures at the recommended 150 mg daily dose.
Instructions for Use
Advise patients to take PREZCOBIX with food every day on a regular dosing schedule, as missed doses can result in development of resistance. Inform patients not to alter the dose of PREZCOBIX or discontinue therapy with PREZCOBIX without consulting their physician [see Dosage and Administration (2.2)].
Hepatotoxicity
Inform patients that drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and liver injury, including some fatalities, could potentially occur with PREZCOBIX. Advise patients to contact their healthcare provider immediately if signs and symptoms of liver problems develop [see Warnings and Precautions (5.1)].
Severe Skin Reactions
Inform patients that skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, could potentially occur with PREZCOBIX. Advise patients to contact their healthcare provider immediately if signs or symptoms of severe skin reactions develop, including but not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, and/or conjunctivitis [see Warnings and Precautions (5.2)].
Renal Impairment
Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat is used in combination with a tenofovir DF-containing regimen [see Warnings and Precautions (5.4)].
Drug Interactions
PREZCOBIX may interact with many drugs; therefore, inform patients of the potential serious drug interactions with PREZCOBIX, and that some drugs are contraindicated with PREZCOBIX and other drugs may require dosage adjustment. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.
Instruct patients receiving hormonal contraceptives to use additional or alternative contraceptive (non-hormonal) measures during therapy with PREZCOBIX [see Drug Interactions (7)].
Immune Reconstitution Syndrome
Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.10)].
Fat Redistribution
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including PREZCOBIX and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.9)].
Pregnancy Registry
Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to PREZCOBIX [see Use in Specific Populations (8.1)].
Lactation
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].
Manufactured by:
Janssen Ortho LLC, Gurabo, PR 00778
Manufactured for:
Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560
© 2015 Janssen Pharmaceutical Companies
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)].
PREZCOBIX is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
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.
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].
| Drug Class | Drugs Within Class That Are Contraindicated With PREZCOBIX | Clinical Comment |
|---|---|---|
| Alpha 1-adrenoreceptor antagonist | alfuzosin | Potential for serious and/or life-threatening reactions such as hypotension. |
| Antianginal | ranolazine | Potential for serious and/or life threatening reactions. |
| Antiarrhythmic | dronedarone | Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Anticonvulsants | carbamazepine, phenobarbital, phenytoin | Potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance. |
| Anti-gout | colchicine | Contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. |
| Antimycobacterial | rifampin | Potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance. |
| Antipsychotics | lurasidone | Potential for serious and/or life-threatening reactions. |
| pimozide | Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. | |
| Ergot derivatives | dihydroergotamine, ergotamine, methylergonovine | 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. |
| GI motility agent | cisapride | Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Herbal product | St. John's wort (Hypericum perforatum) | Potential for reduced plasma concentrations of darunavir, which may result in loss of therapeutic effect and development of resistance. |
| Hepatitis C direct-acting antiviral | elbasvir/grazoprevir | Potential for the increased risk of alanine transaminase (ALT) elevations. |
| HMG-CoA reductase inhibitors | lovastatin, simvastatin | Potential for serious reactions such as myopathy including rhabdomyolysis (see Table 2 for dosing recommendations for certain other HMG-CoA reductase inhibitors). |
| PDE-5 inhibitor | sildenafil for treatment of pulmonary arterial hypertension | Potential for sildenafil-associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). |
| 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. |
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.
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.
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.
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)].
See cobicistat full prescribing information for additional information regarding cobicistat.
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. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of PREZCOBIX.
Increased concentrations may lead to:
Decreased antiretroviral concentrations may lead to:
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)].
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)].
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.
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.
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.
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.
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.
The following adverse reactions are discussed in other sections of the labeling:
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.
See the darunavir full prescribing information for postmarketing information.
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).
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).
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 therapeutic effect.
| Concomitant Drug Class: Drug Name | Effect on Concentration of Darunavir, Cobicistat, or Concomitant Drug | Clinical Comment |
|---|---|---|
| HIV-1 antiviral agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | ||
| didanosine | ↔ darunavir ↔ cobicistat ↔ didanosine | Didanosine should be administered one hour before or two hours after PREZCOBIX (administered with food). |
| HIV-1 antiviral agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||
| efavirenz | ↓ cobicistat ↓ darunavir | Co-administration with efavirenz is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir. |
| etravirine | ↓ cobicistat darunavir: effect unknown | Co-administration with etravirine is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir. |
| nevirapine | ↓ cobicistat darunavir: effect unknown | Co-administration with nevirapine is not 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. |
| Other agents | ||
| Antiarrhythmics: | For contraindicated antiarrhythmics, [see Contraindications (4)]. | |
| e.g. amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine | ↑ antiarrhythmics | Clinical monitoring is recommended upon co-administration with antiarrhythmics. |
| digoxin | ↑ digoxin | When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations. |
| Antibacterials: clarithromycin, erythromycin, telithromycin | ↑ darunavir ↑ cobicistat ↑ antibacterial | Consider alternative antibiotics with concomitant use of PREZCOBIX. |
| Anticancer agents: dasatinib, nilotinib | ↑ anticancer agent | 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. |
| vinblastine, vincristine | 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. | |
| Anticoagulants: apixaban | ↑ anticoagulant | Concomitant use of apixaban is not recommended. |
| dabigatran etexilate | 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. | |
| rivaroxaban | Co-administration with rivaroxaban is not recommended. | |
| warfarin | warfarin: effect unknown | Monitor the international normalized ratio (INR) when co-administering with warfarin. |
| Anticonvulsants: | For contraindicated anticonvulsants, [see Contraindications (4)]. | |
| Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g. eslicarbazepine, oxcarbazepine | ↓ cobicistat darunavir: effect unknown | 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. |
| Anticonvulsants that are metabolized by CYP3A: e.g. clonazepam | ↑ clonazepam | Clinical monitoring of anticonvulsants is recommended. |
| Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): e.g. paroxetine, sertraline | SSRIs: effects unknown | 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. |
| Tricyclic Antidepressants (TCAs): e.g. amitriptyline, desipramine, imipramine, nortriptyline | ↑ TCAs | |
| Other antidepressants: trazodone | ↑ trazodone | |
| Antifungals: itraconazole, ketoconazole, posaconazole | ↑ darunavir ↑ cobicistat | Monitor for increased darunavir or cobicistat adverse reactions. |
| ↑ itraconazole ↑ ketoconazole ↔ posaconazole | Specific dosing recommendations are not available for co-administration with itraconazole or ketoconazole. Monitor for increased itraconazole or ketoconazole adverse reactions. | |
| voriconazole | voriconazole: effects unknown | Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole. |
| Anti-gout: colchicine | ↑ colchicine | Co-administration with colchicine is contraindicated in patients with renal or hepatic impairment [see Contraindications (4)]. For patients without renal or hepatic impairment:
|
| Antimalarial: artemether/lumefantrine | artemether: effect unknown lumefantrine: effect unknown | Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation. |
| Antimycobacterials: | For contraindicated antimycobacterials, [see Contraindications (4)]. | |
| rifabutin | ↑ rifabutin cobicistat: effects unknown darunavir: effects unknown | When used in combination with PREZCOBIX, the recommended dose of rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis. |
| rifapentine | ↓ darunavir | Co-administration with rifapentine is not recommended. |
| Antipsychotics: | For contraindicated antipsychotics, [see Contraindications (4)]. | |
| e.g. perphenazine, risperidone, thioridazine | ↑ antipsychotic | A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with PREZCOBIX. |
| quetiapine | ↑ quetiapine | Initiation of PREZCOBIX in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine- associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking PREZCOBIX: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| β-Blockers: e.g. carvedilol, metoprolol, timolol | ↑ beta-blockers | Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized by CYP2D6. |
| Calcium channel blockers: e.g. amlodipine, diltiazem, felodipine, nifedipine, verapamil | ↑ calcium channel blockers | Clinical monitoring is recommended for co-administration with calcium channel blockers metabolized by CYP3A. |
| Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g. betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone | ↓ darunavir ↓ cobicistat ↑ corticosteroids | Co-administration with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to PREZCOBIX. Consider alternative corticosteroids. Co-administration with corticosteroids of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use. |
| Endothelin receptor antagonists: bosentan | ↓ darunavir ↓ cobicistat ↑ bosentan | Initiation of bosentan in patients taking PREZCOBIX: In patients who have been receiving PREZCOBIX for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Initiation of PREZCOBIX in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZCOBIX. After at least 10 days following the initiation of PREZCOBIX, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Switching from darunavir co-administered with ritonavir to PREZCOBIX in patients on bosentan: Maintain bosentan dose. |
| Hepatitis C virus (HCV): Direct-Acting Antivirals: simeprevir | darunavir: effects unknown ↑ simeprevir | For contraindicated HCV Direct-Acting Antivirals, [see Contraindications (4)]. No drug interaction data are available. Co-administration with simeprevir is not recommended. |
| HMG-CoA reductase inhibitors: | For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4)]. | |
| e.g. atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin | ↑ atorvastatin ↑ fluvastatin ↑ pravastatin ↑ rosuvastatin pitavastatin: effect unknown | For atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin, start with the lowest recommended dose and titrate while monitoring for safety (e.g. myopathy). Dosage recommendations with atorvastatin or rosuvastatin are as follows:
|
| Hormonal contraceptives: drospirenone/ethinylestradiol | ↑ drospirenone ↓ ethinylestradiol | For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. |
| other progestin/estrogen contraceptives | progestin: effects unknown estrogen: effects unknown | No data are available to make recommendations on co-administration with other hormonal contraceptives. Additional or alternative (non-hormonal) forms of contraception should be considered. |
| Immunosuppressants: cyclosporine, sirolimus, tacrolimus | ↑ immunosuppressants | These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended with concomitant use. |
| Immunosuppressant /neoplastic: everolimus | Co-administration of everolimus and PREZCOBIX is not recommended. | |
| Inhaled beta agonist: salmeterol | ↑ salmeterol | Co-administration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
| Narcotic analgesics metabolized by CYP3A: e.g. fentanyl, oxycodone | ↑ fentanyl ↑ oxycodone | Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. |
| tramadol | ↑ tramadol | A dose decrease may be needed for tramadol with concomitant use. |
| Narcotic analgesic for treatment of opioid dependence: buprenorphine, buprenorphine/naloxone, methadone | buprenorphine or buprenorphine/ naloxone: effects unknown methadone: effects unknown | Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking PREZCOBIX: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of PREZCOBIX in patients taking buprenorphine, buprenorphine/naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms. |
| Phosphodiesterase PDE-5 inhibitors: e.g. avanafil, sildenafil, tadalafil, vardenafil | ↑ PDE-5 inhibitors | Co-administration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established. Co-administration with PDE-5 inhibitors may result in an increase in PDE-5 inhibitor-associated adverse reactions including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil is contraindicated [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil with PREZCOBIX:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse reactions. |
| Platelet aggregation inhibitor: ticagrelor | ↑ ticagrelor | Co-administration of PREZCOBIX and ticagrelor is not recommended. |
| Sedatives/hypnotics: | For contraindicated sedatives/hypnotics, [see Contraindications (4)]. | |
| metabolized by CYP3A: e.g. buspirone, diazepam, estazolam, zolpidem | ↑ sedatives/hypnotics | With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions. |
| parenterally administered midazolam | Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered. | |
Clinically relevant drug-drug interactions have not been observed or are not anticipated with concomitant use of darunavir and cobicistat with rilpivirine, dolutegravir, raltegravir, abacavir, emtricitabine, emtricitabine/tenofovir alafenamide, tenofovir DF, lamivudine, stavudine, zidovudine, or acid modifying medications (antacids, H2-receptor antagonists, proton pump inhibitors).
Safety, effectiveness, and pharmacokinetics of PREZCOBIX in pediatric patients less than 18 years of age have not been established. Darunavir, a component of PREZCOBIX is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.
Clinical trials of PREZCOBIX did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of PREZCOBIX in elderly patients, reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].
No clinical trials were conducted with darunavir co-administered with cobicistat in hepatically impaired subjects and the effect of hepatic impairment on darunavir exposure when co-administered with cobicistat has not been evaluated. Based on the recommendations for darunavir co-administered with ritonavir, a dose adjustment for patients with mild or moderate hepatic impairment is not necessary. No pharmacokinetic or safety data are available regarding the use of darunavir in subjects with severe hepatic impairment. Therefore, PREZCOBIX is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].
A renal impairment trial was not conducted for darunavir co-administered with cobicistat [see Clinical Pharmacology (12.3)]. Cobicistat has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosage adjustment for renal impairment when used in combination with PREZCOBIX [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)].
Human experience of acute overdose with PREZCOBIX is limited. No specific antidote is available for overdose with PREZCOBIX. Treatment of overdose with PREZCOBIX consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since both darunavir and cobicistat are highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
PREZCOBIX is a fixed-dose combination tablet containing darunavir and cobicistat. Darunavir is an inhibitor of the human immunodeficiency virus (HIV-1) protease. Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
PREZCOBIX tablets are for oral administration. Each tablet contains darunavir ethanolate equivalent to 800 mg of darunavir and 150 mg of cobicistat. The tablets include the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, and silicified microcrystalline cellulose. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, polyethylene glycol, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.
PREZCOBIX is a fixed-dose combination of an HIV-1 antiviral drug, darunavir and a CYP3A inhibitor, cobicistat [see Microbiology (12.4)].
The pharmacokinetics of darunavir co-administered with cobicistat (150 mg) have been evaluated in healthy adult subjects and in HIV-1 infected subjects.
Darunavir is primarily metabolized by CYP3A. Cobicistat inhibits CYP3A, thereby increasing the plasma concentrations of darunavir.
Under fed (535 total kcal, 171 kcal from fat, 268 kcal from carbohydrates, 96 kcal from protein) and fasted conditions in healthy subjects, the 90% confidence intervals when comparing darunavir exposure between PREZCOBIX and darunavir 800 mg co-administered with cobicistat 150 mg as single entities were within 80–125%.
Darunavir exposure when comparing darunavir co-administered with cobicistat (as single entities) to darunavir co-administered with ritonavir was evaluated in a relative bioavailability trial [see cobicistat full prescribing information]. Table 3 displays the population pharmacokinetic estimates of darunavir after oral administration of darunavir 800 mg co-administered with ritonavir 100 mg once daily (based on sparse sampling in 335 subjects in Trial TMC114-C211 and 280 subjects in Trial TMC114-C229) and darunavir 800 mg co-administered with cobicistat 150 mg once daily administered as single entities (based on sparse sampling in 298 subjects in Trial GS-US-216-0130) to HIV-1 infected subjects.
| Trial TMC114-C211 (treatment-naïve) Darunavir 800 mg co-administered with ritonavir 100 mg once daily | Trial TMC114-C229 (treatment-experienced) Darunavir 800 mg co-administered with ritonavir 100 mg once daily | Trial GS-US-216-0130 (treatment-naïve and experienced) Darunavir 800 mg co-administered with cobicistat 150 mg once daily | |
|---|---|---|---|
| Parameter | N=335 | N=280 | N=298 |
| N=number of subjects with data | |||
| AUC24h (ng∙h/mL) | |||
| Mean ± Standard Deviation | 93026 ± 27050 | 93334 ± 28626 | 100152 ± 32042 |
| Median (Range) | 87854 (45000–219240) | 87788 (45456–236920) | 96900 (34500–224000) |
| C0h (ng/mL) | |||
| Mean ± Standard Deviation | 2282 ± 1168 | 2160 ± 1201 | 2043 ± 1257 |
| Median (Range) | 2041 (368–7242) | 1896 (184–7881) | 1875 (70–6890) |
The efficacy of PREZCOBIX is based on efficacy demonstrated in clinical trials of darunavir co-administered with ritonavir [see darunavir full prescribing information].
PREZCOBIX (darunavir and cobicistat) tablets, 800/150 mg, are supplied as pink, oval-shaped, film-coated tablets debossed with "800" on one side and "TG" on the other side.
PREZCOBIX is packaged in bottles of 30 tablets (NDC 59676-575-30).
Storage: Store at 20–25°C (between 68–77°F); with excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].
Advise the patient to read the FDA-approved patient labeling (Patient Information).
| This Patient Information has been approved by the U.S. Food and Drug Administration. | Revised: January 2018 | |
| PATIENT INFORMATION PREZCOBIX® (prez-koe-bix) (darunavir and cobicistat) tablets | ||
| Please read this information before you start taking PREZCOBIX and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. | ||
What is the most important information I should know about PREZCOBIX?
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| What is PREZCOBIX? PREZCOBIX is a prescription HIV-1 (Human Immunodeficiency Virus 1) medicine used with other antiretroviral medicines to treat HIV-1 infection in adults. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). PREZCOBIX contains the prescription medicines PREZISTA (darunavir) and TYBOST (cobicistat). It is not known if PREZCOBIX is safe and effective in children under 18 years of age. | ||
| Who should not take PREZCOBIX? Do not take PREZCOBIX with any of the following medicines:
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| What should I tell my healthcare provider before taking PREZCOBIX? Before taking PREZCOBIX, tell your healthcare provider if you:
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How should I take PREZCOBIX?
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| What are the possible side effects of PREZCOBIX? PREZCOBIX may cause serious side effects, including:
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| Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of PREZCOBIX. For more information, ask your healthcare provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | ||
How should I store PREZCOBIX?
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| General information about PREZCOBIX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PREZCOBIX for a condition for which it was not prescribed. Do not give PREZCOBIX to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about PREZCOBIX that is written for health professionals. For more information call 1-800-526-7736. | ||
| What are the ingredients in PREZCOBIX? Active ingredients: darunavir and cobicistat Inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, and silicified microcrystalline cellulose. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, polyethylene glycol, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide. Manufactured by: Janssen Ortho LLC, Gurabo, PR 00778 Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560 © 2015 Janssen Pharmaceutical Companies | ||
NDC 59676-575-30
PREZCOBIX®
(darunavir and cobicistat)
Tablets
800 mg/150 mg
Each tablet contains darunavir
ethanolate (equivalent to
800 mg of darunavir) and
150 mg cobicistat.
Keep out of reach of children
Rx only
30 Tablets
Principal Display Panel (800 mg/150 mg Tablet Bottle Label)
* Please review the disclaimer below.
