Symtuza

1. INDICATIONS AND USAGE SYMTUZA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 40 kg: who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. SYMTUZA is a four-drug combination of darunavir (DRV), a human immunodeficiency virus (HIV-1) protease inhibitor, cobicistat (COBI), a CYP3A inhibitor, and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg: who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

2. DOSAGE AND ADMINISTRATION Testing : Prior to or when initiating SYMTUZA, test patients for HBV infection. Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Recommended dosage : One tablet taken once daily with food in adults and pediatric patients, weighing at least 40 kg. Renal Impairment: SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL/min. Hepatic Impairment : SYMTUZA is not recommended in patients with severe hepatic impairment.

2.1Testing Prior to Initiation of

SYMTUZA Prior to or when initiating SYMTUZA, test patients for hepatitis B (HBV) virus infection . Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus .

2.2Recommended Dosage

SYMTUZA is a four-drug fixed-dose combination product containing 800 mg of darunavir (DRV), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of SYMTUZA is one tablet taken orally once daily with food in adults and pediatric patients weighing at least 40 kg. For patients who are unable to swallow the whole tablet, SYMTUZA may be split into two pieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting .

2.3Not Recommended in Patients with Severe Renal

Impairment SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute .

2.4Not Recommended in Patients with Severe Hepatic

Impairment SYMTUZA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) .

2.5Not Recommended During Pregnancy

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

5. WARNINGS AND PRECAUTIONS Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) including some fatalities can occur with SYMTUZA. 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. Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis may occur with SYMTUZA. Discontinue treatment if severe skin reaction develops. Patients receiving SYMTUZA may develop new onset or exacerbations of immune reconstitution syndrome. Monitor in patients with a known sulfonamide allergy. Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. Patients receiving SYMTUZA may develop new onset or exacerbation of diabetes mellitus/hyperglycemia and redistribution/accumulation of body fat. ( 5.9 , 5.10 ) Patients with hemophilia may develop increase bleeding events.

5.1Severe Acute Exacerbation of Hepatitis B

in Patients Coinfected with HIV-1 and HBV Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy . Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA. Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2Hepatotoxicity Drug-induced

hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir, a component of SYMTUZA. 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 been reported with darunavir. 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 therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with SYMTUZA and patients should be monitored during treatment as clinically appropriate. 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 SYMTUZA 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) should prompt consideration of interruption or discontinuation of SYMTUZA.

5.3Severe Skin Reactions In

patients receiving darunavir, a component of SYMTUZA, severe skin reactions may occur. These include conditions accompanied by fever and/or elevations of transaminases. Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%. During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported.

Discontinue SYMTUZA 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. Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with SYMTUZA in the AMBER trial . Rash events were mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing.

The discontinuation rate due to rash in subjects using SYMTUZA was 2%.

5.4Risk of Serious Adverse Reactions or Loss

of Virologic Response Due to Drug Interactions The concomitant use of SYMTUZA and other drugs may result in known or potentially significant drug interactions which may lead to : Clinically significant adverse reactions from greater exposures of concomitant drugs. Clinically significant adverse reactions from greater exposures of SYMTUZA. Loss of therapeutic effect of the concomitant drugs from lower exposures of active metabolite(s). Loss of therapeutic effect of SYMTUZA and possible development of resistance from lower exposures of SYMTUZA. See Table 4 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 SYMTUZA therapy; review concomitant medications during SYMTUZA therapy; and monitor for the adverse reactions associated with concomitant medications . When used with concomitant medications, SYMTUZA, which contains darunavir boosted with cobicistat, 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 SYMTUZA interactions .

5.5Immune Reconstitution Syndrome Immune

reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. 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.

5.6New Onset or Worsening Renal Impairment

Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events . SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions. Prior to or when initiating SYMTUZA and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients.

In patients with chronic kidney disease, also assess serum phosphorus. Discontinue SYMTUZA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Cobicistat, a component of SYMTUZA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration.

This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating SYMTUZA, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

5.7Sulfa Allergy Darunavir

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

5.8Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic

acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with SYMTUZA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.9Diabetes Mellitus/Hyperglycemia New

onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred.

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

5.10Fat 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.

5.11Hemophilia There

have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors (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.

4. CONTRAINDICATIONS Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. SYMTUZA 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 SYMTUZA with CYP3A inducers is expected to lower plasma concentrations of darunavir and cobicistat which may lead to loss of efficacy of darunavir and development of resistance. Examples of drugs that are contraindicated for co-administration with SYMTUZA due to the potential for serious and/or life-threatening events or loss of therapeutic effect 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 SYMTUZA is contraindicated to be co-administered with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or which may lead to loss of therapeutic effect of SYMTUZA and development of resistance.

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SYMTUZA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary SYMTUZA 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, cobicistat, emtricitabine, or tenofovir alafenamide (TAF) 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 SYMTUZA were administered separately at darunavir exposures less than 1- (mice and rabbits) and 2.6-times (rats) higher, at cobicistat exposures 1.7- and 4.1-times higher (rats and rabbits respectively), at emtricitabine exposures 88- and 7.3- times higher (mice and rabbits, respectively), and tenofovir alafenamide exposures equal to or 85- times higher (rats and rabbits, respectively) than human exposures at the recommended daily dose of these components in SYMTUZA . No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.1 times the human exposure at the recommended therapeutic dose. Clinical Considerations Not Recommended During Pregnancy SYMTUZA is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy and . SYMTUZA should not be initiated in pregnant individuals.

An alternative regimen is recommended for individuals who become pregnant during therapy with SYMTUZA. Data Human Data Darunavir and cobicistat in combination with a background regimen was evaluated in a clinical trial of 7 pregnant individuals taking darunavir and cobicistat prior to enrollment and who were willing to remain on darunavir and cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals 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 individuals 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 individuals had sustained virologic response (HIV RNA <50 copies/mL) throughout the study period. There are no clinical data on the virologic response when darunavir and cobicistat are initiated during pregnancy.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of SYMTUZA 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.

Darunavir : Based on prospective reports to the APR of over 960 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 640 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.7% (95% CI: 2.4% to 5.5%) with first trimester exposure to darunavir containing-regimens and 2.5% (95% CI: 1.1% to 4.9%) with second/third trimester exposure to darunavir-containing regimens. Cobicistat : Based on prospective reports to the APR of over 560 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including over 470 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% CI: 2.1% to 5.7%) and 1.1% (95% CI: 0.0% to 6.2%) with first and second/third trimester, respectively, to cobicistat-containing regimens. Emtricitabine : Based on prospective reports to the APR of over 5400 exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including over 3900 exposed in the first trimester and over 1500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) with first trimester exposure to emtricitabine-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) with the second/third trimester exposure to emtricitabine-containing regimens.

Tenofovir alafenamide (TAF) : Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) with first and second/third trimester exposure, respectively, to TAF-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 (2.6-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended daily dose of darunavir in SYMTUZA. 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 1.7 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. 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 4.1 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. 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 1.1 times the human exposures at the recommended daily dose of cobicistat in SYMTUZA. Emtricitabine : Emtricitabine was administered orally to pregnant mice and rabbits (up to 1000 mg/kg/day) through organogenesis (on GD 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 88 times higher and in rabbits approximately 7.3 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA. In a pre/postnatal development study, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth ( in utero ) through sexual maturity at daily exposures of approximately 88 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA. Tenofovir Alafenamide (TAF) : TAF was administered orally to pregnant rats (up to 250 mg/kg/day) and rabbits (up to 100 mg/kg/day) through organogenesis (on GD 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures approximately similar to (rats) and 85 times higher (rabbits) than the exposure in humans at the recommended daily dose.

TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 51 (rats) and 80 (rabbits) times higher than human tenofovir exposures at the recommended daily dose of TAF in SYMTUZA. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF (another prodrug of tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on GD 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposure in humans at the recommended daily dose of TDF.

6. ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe acute exacerbations of hepatitis B Hepatotoxicity Severe skin reactions Immune reconstitution syndrome New onset or worsening renal impairment Lactic acidosis/severe hepatomegaly with steatosis The most common adverse reactions (all grades, incidence greater than or equal to 2%) were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence. 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 practice. Clinical Trials in Adults Adverse Reactions in Adults with No Prior Antiretroviral Treatment History The safety profile of SYMTUZA in HIV-1 infected adults with no prior antiretroviral treatment history is based on Week 48 data from the AMBER trial, a randomized, double-blind, active-controlled trial where a total of 362 subjects received SYMTUZA once daily and 363 subjects received a combination of PREZCOBIX ® (fixed-dose combination of darunavir and cobicistat) and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). The proportion of subjects who discontinued treatment with SYMTUZA or PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4% respectively.

An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX + FTC/TDF are presented in Table 3.

Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade 3 adverse reaction was reported and no grade 4 adverse reactions were reported during treatment with SYMTUZA. Table 1: Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA (N=362) PREZCOBIX+FTC/TDF (N=363) All Grades At least Grade 2 All Grades At least Grade 2 Diarrhea 9% 2% 11% 2% Rash Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria 8% 4% 7% 5% Nausea 6% 1% 10% 3% Fatigue 4% 1% 4% 1% Headache 3% 1% 2% 1% Abdominal discomfort 2% - 4% <1% Flatulence 2% <1% 1% - Adverse Reactions in Virologically-Suppressed Adults The safety profile of SYMTUZA in virologically-suppressed HIV-1 infected adults is based on Week 48 data from 1,141 subjects in the EMERALD trial, a randomized, open-label, active-controlled trial where 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor (bPI) [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with FTC/TDF switched to SYMTUZA, and 378 subjects who continued their treatment regimen of a bPI with FTC/TDF. Overall, the safety profile of SYMTUZA in subjects in this study was similar to that in subjects with no prior antiretroviral treatment history. The proportion of subjects who discontinued treatment with SYMTUZA due to adverse events, regardless of severity, was 1%. Less Frequent Adverse Reactions The following adverse reactions occurred in less than 2% of adults with no antiretroviral treatment history or virologically suppressed subjects receiving SYMTUZA, or are from studies described in the prescribing information of the individual component PREZISTA (darunavir).

Gastrointestinal Disorders: dyspepsia, pancreatitis (acute), vomiting Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson syndrome Metabolism and Nutrition Disorders: anorexia, diabetes mellitus, lipodystrophy Reproductive System and Breast Disorders: gynecomastia Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis Psychiatric Disorders: abnormal dreams Immune System Disorders: (drug) hypersensitivity, immune reconstitution inflammatory syndrome Hepatobiliary Disorders: acute hepatitis Laboratory Abnormalities Table 2: Laboratory Abnormalities (Grade 2–4) Reported in ≥2% of Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) Laboratory Parameter Grade Limit SYMTUZA N=362 PREZCOBIX+FTC/TDF N=363 Creatinine Grade 2 >1.3 to 1.8 × ULN 4% 14% Grade 4 ≥3.5× ULN <1% 0 Triglycerides Grade 2 301–500 mg/dL 7% 4% Grade 3 501–1,000 mg/dL 1% 1% Grade 4 >1,000 mg/dL <1% <1% Total Cholesterol Grade 2 240–<300 mg/dL 17% 4% Grade 3 ≥ 300 mg/dL 2% 1% Low-Density Lipoprotein Cholesterol Grade 2 160–189 mg/dL 9% 4% Grade 3 ≥190 mg/dL 5% 1% Elevated Glucose Levels Grade 2 126–250 mg/dL 6% 6% Grade 3 251–500 mg/dL <1% 0 ALT and/or AST elevations (Grade 2–4 combined) occurred in 2% of adult subjects receiving SYMTUZA with no antiretroviral treatment history in AMBER (Week 48 Analysis). Results were consistent in subjects receiving PREZCOBIX+FTC/TDF. Table 3: Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA N=362 PREZCOBIX+FTC/TDF N=363 Baseline Week 48 Baseline Week 48 Mean The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the last value carried forward prior to initiating lipid-lowering agent post-baseline. mg/dL Change mg/dL Change N N corresponds to the number of subjects with paired values and not on a lipid-lowering agent at screening/baseline. Subjects on lipid-lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on PREZCOBIX+FTC/TDF).

Subjects initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF). N=304 One subject did not have a Week 48 result for LDL cholesterol (n=303). N=290 Total cholesterol 168 +30 164 +11 HDL cholesterol 45 +6 44 +2 LDL cholesterol 100 +19 98 +5 Triglycerides 117 +34 112 +21 Total cholesterol to HDL ratio 4.1 0.2 4.0

0.1The

percentage of subjects starting any lipid lowering drug during treatment in the SYMTUZA and PREZCOBIX + FTC/TDF arm were 1.7% (n=6) and 0.6% (n=2), respectively. Renal Laboratory Tests In the AMBER trial, which enrolled 725 adults with no prior antiretroviral treatment history, subjects had a median baseline eGFR (estimated glomerular filtration rate) of 119 mL/min (SYMTUZA) and 118 mL/min (PREZCOBIX + FTC/TDF). From baseline to Week 48, mean (SD) serum creatinine increased by 0.05 mg/dL in the SYMTUZA group and by 0.09 mg/dL in the PREZCOBIX + FTC/TDF group.

Median serum creatinine was 0.90 mg/dL (SYMTUZA) and 0.89 mg/dL (PREZCOBIX + FTC/TDF) at baseline and 0.95 mg/dL (SYMTUZA) and 0.97 mg/dL (PREZCOBIX +FTC/TDF) at Week 48. Increases in serum creatinine occurred by Week 2 of treatment and remained stable. Median urine protein-to-creatinine ratio (UPCR) was 47 mg/g (SYMTUZA) and 51 mg/g (PREZCOBIX + FTC/TDF) at baseline and 30 mg/g (SYMTUZA) and 34 mg/g (PREZCOBIX + FTC/TDF) at Week 48.

In the EMERALD trial which had 1,141 virologically-suppressed adults treated with an HIV protease inhibitor and TDF containing regimen with a median baseline eGFR of 104 mL/min (SYMTUZA) and 103 mL/min (bPI+FTC/TDF) who were randomized to continue their treatment regimen or switch to SYMTUZA, at Week 48, mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to SYMTUZA. Mean (SD) serum creatinine was 0.98 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at baseline and 0.99 mg/dL (SYMTUZA) and 0.99 mg/dL (bPI+FTC/TDF) at Week 48. Median serum creatinine was 0.97 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at baseline and 1.0 mg/dL (SYMTUZA) and 0.97 mg/dL (bPI+FTC/TDF) at Week 48. Median UPCR was 62 mg/g (SYMTUZA) and 63 mg/g (bPI+FTC/TDF) at baseline and 37 mg/g (SYMTUZA) and 53 mg/g (bPI+FTC/TDF) at Week 48.

Bone Mineral Density AMBER The effects of SYMTUZA compared to PREZCOBIX + FTC/TDF on bone mineral density (BMD) change from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 48 was −0.7% with SYMTUZA compared to −2.4% with PREZCOBIX + FTC/TDF at the lumbar spine and 0.2% compared to −2.7% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 16% of SYMTUZA subjects and 22% of PREZCOBIX + FTC/TDF subjects.

BMD declines of 7% or greater at the femoral neck were experienced by 2% of SYMTUZA subjects and 15% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known. EMERALD In EMERALD, bPI and TDF-treated subjects were randomized to continue their TDF-based regimen or switch to SYMTUZA; changes in BMD from baseline to Week 48 were assessed by DXA. The mean percentage change in BMD from baseline to Week 48 was 1.5% with SYMTUZA compared to −0.6% with bPI + FTC/TDF at the lumbar spine and 1.4% compared to -0.3% at the total hip.

BMD declines of 5% or greater at the lumbar spine were experienced by 2% of SYMTUZA subjects and 9% of bPI + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by no SYMTUZA subjects and 2% of bPI + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.

Clinical Trials in Pediatric Patients Adverse Reactions in Pediatric Patients Weighing At Least 40 kg No clinical trials with SYMTUZA were performed in pediatric patients. However, the safety of the components of SYMTUZA was evaluated in pediatric subjects of 12 to less than 18 years of age through clinical trials GS-US-216-0128 (virologically-suppressed, N=7 with weight ≥40 kg) for darunavir co-administered with cobicistat and other antiretroviral agents, and GS-US-292-0106 (treatment-naïve, N=50 with weight ≥35 kg) for a fixed-dose combination regimen containing cobicistat, emtricitabine, and tenofovir alafenamide together with elvitegravir. Safety analyses of the trials in these pediatric subjects did not identify new safety concerns compared to the known safety profile of SYMTUZA in adult subjects .

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) Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms Renal and Urinary Disorders: Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, Fanconi syndrome , crystal nephropathy, and crystalluria