Prezcobix

1 INDICATIONS AND USAGE PREZCOBIX and PREZCOBIX PED are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) in treatment-naïve and treatment-experienced adults and pediatric patients 3 years of age and older weighing at least 15 kg with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) . PREZCOBIX and PREZCOBIX PED are a two-drug combination of darunavir, a human immunodeficiency virus (HIV-1) protease inhibitor, and cobicistat, a CYP3A inhibitor, and are indicated for the treatment of HIV-1 in treatment-naïve and treatment-experienced adults and pediatric patients 3 years of age and older weighing at least 15 kg with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).

Recommended dosage: Adults and pediatric patients weighing at least 40 kg: One 800 mg/150 mg tablet taken once daily with food. ( 2.1 , 2.2 ) Pediatric patients weighing at least 25 kg to less than 40 kg: One 675 mg/150 mg tablet taken once daily with food. ( 2.1 , 2.2 ) Pediatric patients 3 years of age and older weighing at least 15 kg to less than 25 kg: One 600 mg/90 mg tablet for oral suspension taken once daily with food. PREZCOBIX PED must be dispersed in drinking water and taken immediately with food. ( 2.2 , 2.3 ) 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 or PREZCOBIX PED. When used with tenofovir disoproxil fumarate (TDF): 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.

2.1Overview of Different Dosage Forms Two

different dosage forms are available: PREZCOBIX Tablets: 800 mg/150 mg film-coated tablets for adults and pediatric patients weighing at least 40 kg. 675 mg/150 mg film-coated tablets for pediatric patients weighing at least 25 kg to less than 40 kg. PREZCOBIX PED Tablets for Oral Suspension: 600 mg/90 mg film-coated tablet for oral suspension for pediatric patients aged 3 years and older weighing at least 15 kg to less than 25 kg .

2.2Recommended Dosage in Adults and Pediatrics

3 Years of Age and Older Weighing at Least 15 kg The recommended dosages for adults and pediatric patients weighing at least 15 kg are shown in Table 1. The pediatric dose is based on weight. PREZCOBIX and PREZCOBIX PED are taken orally with food once daily in conjunction with other antiretroviral agents.

Table 1: Recommended Dosages of PREZCOBIX and PREZCOBIX PED in Adults and Pediatric Patients Weighing at Least 15 kg, who are Treatment-Naïve or Treatment-Experienced Without DRV RAMs DRV-resistance-associated mutations (RAMs): V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V. Patient Population Total Daily Dose Adults and pediatric patients weighing at least 40 kg One PREZCOBIX 800 mg darunavir/150 mg cobicistat tablet Pediatric Patients weighing at least 25 kg to less than 40 kg One PREZCOBIX 675 mg darunavir/150 mg cobicistat tablet Pediatric Patients aged 3 years and older weighing at least 15 kg to less than 25 kg One PREZCOBIX PED 600 mg darunavir/90 mg cobicistat tablet for oral suspension Before prescribing PREZCOBIX 675 mg/150 mg tablets, children should be assessed for the ability to swallow tablets. For patients unable to swallow the 675 mg/150 mg tablet whole, the scored tablet may be split by hand into two pieces. Each piece should be consumed immediately after splitting to ensure the entire dose is administered.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

2.3Preparation and Administration Instructions for

PREZCOBIX PED Advise patients or caregivers of patients taking PREZCOBIX PED to refer to the Instructions for Use to properly prepare and take the medication. PREZCOBIX PED must be dispersed in drinking water and taken immediately as described below. If not taken immediately, then the oral suspension should be discarded, and a new dose of medicine should be prepared.

The patient should not crush, chew or swallow the PREZCOBIX PED tablet for oral suspension. The following instructions should be followed: Place the tablet for oral suspension in a cup, add 30 mL (2 tablespoons) of non-carbonated room temperature drinking water. Stir well with a spoon until the tablet is completely dispersed.

The prepared medicine will appear reddish purple. Take all the prepared medicine immediately or to aid in administration, the prepared medicine can be further diluted with 10 mL (2 teaspoons) of water, orange juice, or 1 teaspoon of applesauce or yogurt. Mix and take the entire mixture immediately.

Add another 5 mL (1 teaspoon) of non-carbonated drinking water to the cup, swirl and drink completely. This step may be repeated as needed to ensure the entire dose is consumed.

2.4Testing Prior to Initiation of

PREZCOBIX or PREZCOBIX PED HIV Genotypic Testing HIV genotypic testing is recommended for antiretroviral treatment-experienced patients. However, when HIV genotypic testing is not feasible, PREZCOBIX or PREZCOBIX PED can be used in protease inhibitor-naïve patients, but is not recommended in protease inhibitor-experienced patients. Creatinine Clearance Prior to starting PREZCOBIX or PREZCOBIX PED, assess estimated creatinine clearance because cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function . When co-administering PREZCOBIX or PREZCOBIX PED with tenofovir disoproxil fumarate (tenofovir DF) assess estimated creatinine clearance, urine glucose, and urine protein at baseline .

2.5Not Recommended in Severe Renal Impairment

PREZCOBIX or PREZCOBIX PED co-administered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL per minute .

2.6Not Recommended in Severe Hepatic Impairment

PREZCOBIX or PREZCOBIX PED is not recommended for use in patients with severe hepatic impairment .

2.7Not Recommended During Pregnancy

PREZCOBIX or PREZCOBIX PED is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters . PREZCOBIX or PREZCOBIX PED should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with PREZCOBIX or PREZCOBIX PED.

Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis), liver injury, including some fatalities can occur with PREZCOBIX or PREZCOBIX PED. 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. 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 or PREZCOBIX PED. Discontinue treatment if severe reaction develops. When PREZCOBIX or PREZCOBIX PED is used in combination with a TDF containing regimen, cases of acute renal failure and Fanconi syndrome have been reported. PREZCOBIX or PREZCOBIX PED is not recommended in combination with other antiretroviral drugs that require pharmacokinetic boosting. Monitor in patients with a known sulfonamide allergy. Patients receiving PREZCOBIX or PREZCOBIX PED may develop new onset or exacerbations of diabetes mellitus/hyperglycemia, redistribution/accumulation of body fat, and immune reconstitution syndrome. Patients with hemophilia may develop increased bleeding events.

5.1Hepatotoxicity 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 participants. 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 or PREZCOBIX PED 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 or PREZCOBIX PED 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 or PREZCOBIX PED should prompt consideration of interruption or discontinuation of treatment.

5.2Severe 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 participants. 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 or PREZCOBIX PED 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.

5.3Effects 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 or PREZCOBIX PED, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. Prior to initiating therapy with PREZCOBIX or PREZCOBIX PED, assess estimated creatinine clearance . Dosage recommendations are not available for drugs that require dosage adjustments in PREZCOBIX or PREZCOBIX PED treated patients with renal impairment . 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.

5.4New 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 or PREZCOBIX PED, was used in an antiretroviral regimen that contained tenofovir DF. Co-administration of PREZCOBIX or PREZCOBIX PED and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min . Document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when PREZCOBIX or PREZCOBIX PED 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 or PREZCOBIX PED 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.

5.5Risk of Serious Adverse Reactions or Loss

of Virologic Response Due to Drug Interactions Initiation of PREZCOBIX or PREZCOBIX PED, which inhibits CYP3A, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving PREZCOBIX or PREZCOBIX PED 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 or PREZCOBIX PED. 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 or PREZCOBIX PED. loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s). loss of therapeutic effect of PREZCOBIX or PREZCOBIX PED and possible development of resistance from lower exposures of PREZCOBIX or PREZCOBIX PED. 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 or PREZCOBIX PED therapy; review concomitant medications during PREZCOBIX or PREZCOBIX PED therapy; and monitor for the adverse reactions associated with concomitant medications . When used with concomitant medications, PREZCOBIX or PREZCOBIX PED 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 or PREZCOBIX PED interactions .

5.6Antiretrovirals Not Recommended

PREZCOBIX or PREZCOBIX PED 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 or PREZCOBIX PED is not recommended in combination with products containing the individual components of PREZCOBIX or PREZCOBIX PED (darunavir and cobicistat) or with ritonavir. For additional recommendations on use of PREZCOBIX or PREZCOBIX PED with other antiretroviral agents, .

5.7Sulfa Allergy Darunavir

contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating PREZCOBIX or PREZCOBIX PED. In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in participants with or without a history of sulfonamide allergy.

5.8Diabetes 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 receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred.

In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established.

5.9Fat 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.

5.10Immune 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.

5.11Hemophilia 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.

Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. PREZCOBIX should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Darunavir and cobicistat are both substrates of the cytochrome P450 3A (CYP3A) isoform.

Co-administration of PREZCOBIX or PREZCOBIX PED with CYP3A inducers may lead to lower exposures of darunavir and cobicistat and potential loss of efficacy of darunavir and possible resistance. Examples of drugs that are contraindicated for co-administration with PREZCOBIX or PREZCOBIX PED are listed below. 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 PREZCOBIX or PREZCOBIX PED 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 )

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PREZCOBIX or PREZCOBIX PED during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary PREZCOBIX or PREZCOBIX PED is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters . A study evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of darunavir and cobicistat in the second and third trimesters compared to the post-partum period and . Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage.

However, available data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir and cobicistat 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) . 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 . 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 Not Recommended During Pregnancy PREZCOBIX or PREZCOBIX PED is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy and . PREZCOBIX or PREZCOBIX PED should not be initiated in pregnant individuals.

An alternative regimen is recommended for individuals who become pregnant during therapy with PREZCOBIX or PREZCOBIX PED. Data Human Data PREZCOBIX in combination with a background regimen was evaluated in a clinical trial of 7 pregnant participants taking PREZCOBIX (800 mg/150 mg) prior to enrollment and who were willing to remain on PREZCOBIX throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant participants completed the trial.

Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum . One out of 6 pregnant participants who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five pregnant participants had sustained virologic response (HIV-1 RNA <50 copies/mL) throughout the study period. There are no clinical data on the virologic response when PREZCOBIX is initiated during pregnancy.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of PREZCOBIX are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.

There were no new clinically relevant safety findings compared with the known safety profile of PREZCOBIX in adults with HIV-1. Darunavir : Based on prospective reports to the APR of over 980 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% CI: 2.3% to 5.3%) with first trimester exposure to darunavir-containing regimens and 2.5% (95% CI: 1.1% to 4.8%) with second/third trimester exposure to darunavir-containing regimens. Cobicistat : Based on prospective reports to the APR of over 570 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including over 480 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.7% (95% CI: 2.2% to 5.7%) and 1.1% (95% CI: 0.0% to 6.2%) with first and second/third trimester, respectively, to cobicistat-containing regimens.

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.

The following adverse reactions are discussed in other sections of the labeling: Hepatotoxicity Severe skin reactions Effects on serum creatinine New onset or worsening renal impairment when used with tenofovir DF Immune Reconstitution Syndrome The most common adverse reactions to darunavir, a component of PREZCOBIX or PREZCOBIX PED (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. 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 .

6.1Clinical 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. 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 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 participants with HIV-1. 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 Pediatrics No clinical trials with PREZCOBIX and PREZCOBIX PED were performed in pediatric participants. However, the safety of the components of PREZCOBIX, darunavir and cobicistat, co-administered with two nucleoside reverse transcriptase inhibitors, was evaluated through clinical trial GS-US-216-0128 in virologically-suppressed pediatric participants of 12 to less than 18 years of age with weight ≥40 kg (Cohort 1, N=7), pediatric participants 6 to less than 12 years of age with weight ≥25 kg to <40 kg (Cohort 2, N=8) and pediatric participants aged ≥3 years with weight ≥15 kg to <25 kg (Cohort 3, N=11) through Week 48. Safety analyses of this trial in these pediatric participants did not identify new safety concerns compared to the known safety profile of PREZCOBIX in adult participants .

6.2Postmarketing Experience The

following adverse reactions have been identified during post-approval use of darunavir. Because these reactions 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) Renal and Urinary Disorders Crystal nephropathy, crystalluria Skin and Subcutaneous Tissue Disorders Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms .