SYMTUZA

SYMTUZA ® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) is a fixed-dose combination tablet. Darunavir is an inhibitor of the HIV-1 protease. Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family. Emtricitabine, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). Tenofovir alafenamide, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. SYMTUZA tablets are for oral administration. Each tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 11.2 mg of tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing polyethylene glycol (macrogol), polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, and yellow ferric oxide. Darunavir : Darunavir, in the form of darunavir ethanolate, has the following chemical name: [(1 S ,2 R )-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3 R ,3a S ,6a R )-hexahydrofuro[2,3- b ]furan-3-yl ester monoethanolate. Its molecular formula is C 27 H 37 N 3 O 7 S ∙ C 2 H 5 OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula: Chemical Structure Cobicistat : Cobicistat is adsorbed onto silicon dioxide. The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl[(2 R ,5 R )-5-{[(2 S )-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 C 40 H 53 N 7 O 5 S 2 and a molecular weight of 776.02. It has the following structural formula: Chemical Structure Emtricitabine : The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2 R -hydroxymethyl-[1,3]-oxathiolan-5 S -yl)-(1H)-pyrimidin-2-one. Emtricitabine is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position. Emtricitabine has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24. It has the following structural formula: Chemical Structure Tenofovir alafenamide : The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N -[( S )-[[(1 R )-2-(6-amino-9 H -purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-,1-methylethyl ester, (2 E )-2-butenedioate (2:1). Tenofovir alafenamide fumarate has a molecular formula of C 21 H 29 O 5 N 6 P∙½(C 4 H 4 O 4 ) and a formula weight of 534.50. It has the following structural formula: Chemical Structure

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. ( 1 )

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. ( 2.1 ) Recommended dosage : One tablet taken once daily with food in adults and pediatric patients, weighing at least 40 kg. ( 2.2 ) Renal Impairment: SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL/min. ( 2.3 ) Hepatic Impairment : SYMTUZA is not recommended in patients with severe hepatic impairment. ( 2.4 ) 2.1 Testing Prior to Initiation of SYMTUZA Prior to or when initiating SYMTUZA, test patients for hepatitis B (HBV) virus infection [see Warnings and Precautions (5.1) ] . 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 [see Warnings and Precautions (5.6) ] . 2.2 Recommended 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 [see Clinical Pharmacology (12.3) ] . 2.3 Not Recommended in Patients with Severe Renal Impairment SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute [see Use in Specific Populations (8.6) ] . 2.4 Not Recommended in Patients with Severe Hepatic Impairment SYMTUZA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) ] . 2.5 Not Recommended During Pregnancy SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)] . SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with SYMTUZA.

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 [see Drug Interactions (7.5) ] 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. ( 4 )

The following adverse reactions are discussed in other sections of the labeling: Severe acute exacerbations of hepatitis B [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Severe skin reactions [see Warnings and Precautions (5.3) ] Immune reconstitution syndrome [see Warnings and Precautions (5.5) ] New onset or worsening renal impairment [see Warnings and Precautions (5.6) ] Lactic acidosis/severe hepatomegaly with steatosis [see Warnings and Precautions (5.8) ] The most common adverse reactions (all grades, incidence greater than or equal to 2%) were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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 0.1 The 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 (0.10) mg/dL in the SYMTUZA group and by 0.09 (0.11) 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 (0.18) mg/dL (SYMTUZA) and 0.98 (0.19) mg/dL (bPI+FTC/TDF) at baseline and 0.99 (0.18) mg/dL (SYMTUZA) and 0.99 (0.21) 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 [see Clinical Studies (14.3) ] . 6.2 Postmarketing 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 [see Warnings and Precautions (5.3) ] Renal and Urinary Disorders: Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, Fanconi syndrome [see Warnings and Precautions (5.6) ] , crystal nephropathy, and crystalluria

Co-administration of SYMTUZA with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of SYMTUZA components. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.4 , 7 , 12.3 ) 7.1 Not Recommended With Other Antiretroviral Medications SYMTUZA is a complete regimen for HIV-1 infection and co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. For this reason, information regarding potential drug-drug interactions with other antiretroviral medications is not provided. 7.2 Potential for SYMTUZA to Affect Other Drugs Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of SYMTUZA with drugs that are primarily metabolized by CYP3A and/or CYP2D6, or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events. Co-administration of SYMTUZA with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 4 ). 7.3 Potential for Other Drugs to Affect SYMTUZA Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Co-administration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 4 ). Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF, which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit P-gp may increase the absorption and plasma concentrations of TAF (see Table 4 ). 7.4 Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily excreted by the kidneys through glomerular filtration and active tubular secretion, co-administration of SYMTUZA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.6) ] . 7.5 Significant Drug Interactions Table 4 provides examples of established or potentially clinically significant drug interactions with SYMTUZA and recommended steps to prevent or manage these interactions. These recommendations are based on drug interaction trials conducted with the components of SYMTUZA, as individual agents or in combination, or are predicted interactions. No drug interaction trials have been performed with SYMTUZA or with all the components administered together. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs. The table includes potentially significant interactions but is not all inclusive , and therefore the label of each drug that is co- administered with SYMTUZA should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regard to co- administration. Table 4: Significant Drug Interactions Concomitant Drug Class: Drug Name Examples Effect on Concentration Clinical Comment This table is not all inclusive ↑ = increase, ↓ = decrease, ↔ = no effect Alpha 1-adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of SYMTUZA. 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 SYMTUZA. 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 SYMTUZA 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: Direct Oral Anticoagulants (DOACs) apixaban ↑ apixaban Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with SYMTUZA depend on the apixaban dose. Refer to apixaban dosing instructions for co-administration with P-gp and strong CYP3A inhibitors in apixaban prescribing information. rivaroxaban ↑ rivaroxaban Co-administration of rivaroxaban with SYMTUZA is not recommended because it may lead to an increased bleeding risk. dabigatran etexilate edoxaban ↑ dabigatran ↑ edoxaban Refer to the dabigatran etexilate or edoxaban prescribing information for recommendations regarding co-administration. The specific recommendations are based on indication, renal function, and effect of the co-administered P-gp inhibitors on the concentration of dabigatran or edoxaban. Clinical monitoring is recommended when a DOAC not affected by CYP3A4 but transported by P-gp, including dabigatran etexilate and edoxaban, is co-administered with SYMTUZA. Other Anticoagulants warfarin warfarin: effect unknown Monitor international normalized ratio (INR) upon co-administration of SYMTUZA with warfarin. Anticonvulsants: carbamazepine, phenobarbital, phenytoin ↓ cobicistat ↓ darunavir ↓ tenofovir alafenamide Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g., eslicarbazepine, oxcarbazepine ↓ cobicistat ↓ tenofovir alafenamide 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, isavuconazole, ketoconazole, posaconazole ↑ darunavir ↑ cobicistat Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole (not studied) Specific dosing recommendations are not available for co-administration with these antifungals. 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 is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. For patients without renal or hepatic impairment: Treatment of gout flares – co-administration of colchicine: 0.6 mg (1 tablet) ×1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout flares – co-administration of colchicine: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimalarial: artemether/lumefantrine artemether: effect unknown lumefantrine: effect unknown Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation. Antimycobacterials: rifampin ↓ cobicistat ↓ darunavir ↓ tenofovir alafenamide Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. rifabutin ↑ rifabutin ↓ TAF cobicistat: effects unknown darunavir: effects unknown Co-administration of SYMTUZA with rifabutin is not recommended. If the combination is needed, the recommended dose of rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis. rifapentine ↓ darunavir ↓ TAF Co-administration with rifapentine is not recommended. Antipsychotics: lurasidone ↑ lurasidone Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. pimozide ↑ pimozide Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. 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 SYMTUZA. quetiapine ↑ quetiapine Initiation of SYMTUZA 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 SYMTUZA: 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. Cardiac Disorders: ranolazine, ivabradine ↑ ranolazine Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. dronedarone ↑ dronedarone Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias Other antiarrhythmics 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. Corticosteroids: dexamethasone (systemic) ↓ darunavir ↓ cobicistat Co-administration with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to SYMTUZA. Consider alternative corticosteroids. Corticosteroids primarily metabolized by CYP3A: e.g., betamethasone budesonide ciclesonide fluticasone methylprednisolone mometasone triamcinolone ↑ corticosteroids Co-administration with corticosteroids (all routes of administration) 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 SYMTUZA : In patients who have been receiving SYMTUZA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Initiation of SYMTUZA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of SYMTUZA. After at least 10 days following the initiation of SYMTUZA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Switching from darunavir co-administered with ritonavir to SYMTUZA in patients on bosentan: Maintain bosentan dose. Ergot derivatives: e.g., dihydroergotamine, ergotamine, methylergonovine ↑ ergot derivatives Co-administration is contraindicated due to 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. Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir ↑ elbasvir/grazoprevir Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Co-administration of SYTMUZA with glecaprevir/pibrentasvir is not recommended. Herbal product: St. John's wort ( Hypericum perforatum ) ↓ cobicistat ↓ darunavir ↓ tenofovir alafenamide Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. Hormonal contraceptives: Additional or alternative (non-hormonal) forms of contraception should be considered when estrogen based contraceptives are co-administered with SYMTUZA. drosperinone/ethinylestradiol ↑ drosperinone ↓ 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 oral or other hormonal contraceptives. 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 SYMTUZA is not recommended. irinotecan Discontinue SYMTUZA at least 1 week prior to starting irinotecan therapy. Do not administer SYMTUZA with irinotecan unless there are no therapeutic alternatives. 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. Lipid modifying agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis. 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. Dosage recommendations with atorvastatin or rosuvastatin are as follows: atorvastatin dosage should not exceed 20 mg/day rosuvastatin dosage should not exceed 20 mg/day Other lipid modifying agents : lomitapide ↑ lomitapide Co-administration is contraindicated due to potential for markedly increased transaminases associated with increased plasma concentrations of lomitapide. 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 SYMTUZA: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of SYMTUZA 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. Opioid Antagonist naloxegol ↑ naloxegol Co-administration of SYMTUZA and naloxegol is contraindicated due to potential for precipitating opioid withdrawal symptoms. Phosphodiesterase PDE-5 inhibitors: ↑ PDE-5 inhibitors e.g., avanafil, sildenafil, tadalafil, vardenafil 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 used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). The following dose adjustments are recommended for use of tadalafil with SYMTUZA: Initiation of tadalafil in patients taking SYMTUZA: In patients receiving SYMTUZA for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Initiation of SYMTUZA in patients taking tadalafil: Avoid use of tadalafil during the initiation of SYMTUZA. Stop tadalafil at least 24 hours prior to starting SYMTUZA. After at least one week following the initiation of SYMTUZA, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Patients switching from darunavir co-administered with ritonavir to SYMTUZA: Maintain tadalafil dose. Use of PDE-5 inhibitors for erectile dysfunction: 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 SYMTUZA and ticagrelor is not recommended. clopidogrel ↓ clopidogrel active metabolite Co-administration of SYMTUZA and clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel. prasugrel ↔ prasugrel active metabolite No dose adjustment is needed when prasugrel is co-administered with SYMTUZA. Sedatives/hypnotics: orally administered midazolam, triazolam ↑ midazolam ↑ triazolam Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. 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. Urinary antispasmodics fesoterodine ↑ fesoterodine When fesoterodine is co-administered with SYMTUZA, do not exceed a fesoterodine dose of 4 mg once daily. solifenacin ↑ solifenacin When solifenacin is co-administered with SYMTUZA, do not exceed a solifenacin dose of 5 mg once daily.

Storage Store at 20°C–25°C (between 68°F–77°F); with excursions permitted to 15°C–30°C (59°F–86°F). Dispense only in the original container. Keep container tightly closed with desiccant inside to protect from moisture. Keep SYMTUZA out of reach of children.