STRIBILD

STRIBILD is a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and TDF for oral administration. Elvitegravir is an HIV-1 integrase strand transfer inhibitor. Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family. Emtricitabine is a synthetic nucleoside analog of cytidine. EMTRIVA is the brand name for emtricitabine. Tenofovir DF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. VIREAD is the brand name for TDF. Each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil). The tablets include the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate. The tablets are film coated with a coating material containing indigo carmine (FD&C Blue #2) aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. Elvitegravir: The chemical name of elvitegravir is 6-(3-Chloro-2-fluorobenzyl)-1-[(2 S )-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. It has a molecular formula of C 23 H 23 ClFNO 5 and a molecular weight of 447.9. It has the following structural formula: Elvitegravir is a white to pale-yellow powder with a solubility of less than 0.3 micrograms per mL in water at 20 °C. Chemical Structure Cobicistat: 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-4-yl)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 776.0. It has the following structural formula: Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale-yellow solid with a solubility of 0.1 mg per mL in water at 20 °C. Chemical Structure Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-[(2 R ,5 S )-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. 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. It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.25. It has the following structural formula: Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg per mL in water at 25 °C. Chemical Structure Tenofovir DF: Tenofovir DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF is 9-[( R )-2-[[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P ∙ C 4 H 4 O 4 and a molecular weight of 635.51. It has the following structural formula: Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg per mL in water at 25 °C. All dosages are expressed in terms of TDF except where otherwise noted. Chemical Structure

STRIBILD ® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older weighing at least 35 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of STRIBILD [see Clinical Studies (14) ] . STRIBILD is a four-drug combination of elvitegravir, an HIV integrase strand transfer inhibitor (HIV-1 INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir disoproxil fumarate (TDF), both HIV nucleoside analog reverse transcriptase inhibitors (HIV NRTI) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older weighing at least 35 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of STRIBILD. ( 1 , 14 )

Testing: Prior to initiation of STRIBILD, test patients for hepatitis B virus infection. Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, serum phosphorous, estimated serum 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. ( 2.2 ) Dosage in renal impairment: Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Discontinue in patients with estimated creatinine clearance below 50 mL per minute. ( 2.3 ) 2.1 Testing Prior to Initiation and During Treatment with STRIBILD Prior to initiation of STRIBILD, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . Prior to initiation and during use of STRIBILD, 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 (5.2) ] . 2.2 Recommended Dosage STRIBILD is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of TDF. The recommended dosage of STRIBILD is one tablet taken orally once daily with food in adults and pediatric patients 12 years of age and older with a body weight at least 35 kg and creatinine clearance greater than or equal to 70 mL per minute [see Clinical Pharmacology (12.3) ] . 2.3 Dosage Adjustment in Patients with Renal Impairment Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute during treatment with STRIBILD, as the dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (DF) cannot be achieved [see Warnings and Precautions (5.2) , Adverse Reactions (6.1) , Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . No data are available to make dose recommendations for pediatric patients with renal impairment. 2.4 Not Recommended in Patients with Severe Hepatic Impairment STRIBILD is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. 2.5 Not Recommended During Pregnancy STRIBILD is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters [see Use in Specific Populations (8.1) ] . STRIBILD should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with STRIBILD [see Use in Specific Populations (8.1) ] .

Coadministration of STRIBILD is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of STRIBILD and possible resistance) are listed below [see Drug Interactions (7.5) and Clinical Pharmacology (12.3) ]. Alpha 1-adrenoreceptor antagonist: alfuzosin Anticonvulsants: carbamazepine, phenobarbital, phenytoin Antimycobacterial: rifampin Antipsychotics: lurasidone, pimozide Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine Herbal Products: St. John's wort ( Hypericum perforatum ) Lipid-modifying Agents: lomitapide, lovastatin, simvastatin Phosphodiesterase-5 (PDE-5) Inhibitor: sildenafil when administered as Revatio ® for the treatment of pulmonary arterial hypertension Sedative/hypnotics: triazolam, orally administered midazolam Coadministration of STRIBILD is contraindicated with drugs that: Are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious adverse events. ( 4 ) Strongly induce CYP3A, which may lead to lower exposure of one or more components and loss of efficacy of STRIBILD and possible resistance. ( 4 )

The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.2) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.3) ] . Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.6) ] . Most common adverse drug reactions to STRIBILD (incidence greater than or equal to 10%, all grades) are nausea and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 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 HIV-1 Infected Adult Subjects with No Antiretroviral Treatment History The safety assessment of STRIBILD is based on the Week-144 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-naïve HIV-1 infected adult subjects [see Clinical Studies (14) ]. A total of 701 subjects received STRIBILD once daily in these two studies. The proportion of subjects who discontinued treatment with STRIBILD, ATRIPLA, or ATV+RTV+TRUVADA due to adverse events, regardless of severity, was 6.0%, 7.4%, and 8.5%, respectively. Table 1 displays the frequency of adverse reactions greater than or equal to 5% of subjects in any treatment arm. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drugs. (All Grades) Reported in ≥5% of Adult Subjects in Any Treatment Arm in Studies 102 and 103 (Week-144 Analysis) STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 EYE DISORDERS Ocular icterus <1% 0% 13% GASTROINTESTINAL DISORDERS Diarrhea 12% 11% 17% Flatulence 2% <1% 8% Nausea 16% 9% 14% GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 4% 8% 6% HEPATOBILIARY DISORDERS Jaundice 0% <1% 9% NERVOUS SYSTEM DISORDERS Somnolence 1% 7% 1% Headache 7% 4% 6% Dizziness 3% 21% 5% PSYCHIATRIC DISORDERS Insomnia 3% 9% 1% Abnormal dreams 9% 27% 4% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Rash event includes dermatitis, drug eruption, eczema, pruritus, pruritus generalized, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, and urticaria. 4% 15% 6% See Warnings and Precautions (5.2) for a discussion of renal adverse reactions from clinical trials experience with STRIBILD. Additional adverse reactions observed with STRIBILD included suicidal ideation and suicide attempt (0.3%), all in subjects with a preexisting history of depression or psychiatric illness. Clinical Trials in Virologically Suppressed HIV-1 Infected Adult Subjects No new adverse reactions to STRIBILD through Week 48 were identified in 584 virologically stably suppressed adult subjects switching to STRIBILD from a regimen containing a RTV-boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). In a combined analysis of studies 115 and 121, the frequency of adverse reactions (all grades) was 24% in subjects switching to STRIBILD compared to 6% of subjects in either group who stayed on their baseline antiretroviral regimen, RTV-boosted PI+TRUVADA or NNRTI+TRUVADA. Common adverse reactions that occurred in greater than or equal to 2% of subjects switching to STRIBILD were nausea (4%), flatulence (2%), and headache (2%). The proportion of subjects who discontinued treatment with STRIBILD, the RTV-boosted PI, or the NNRTI due to adverse events was 2%, 3%, and 1%, respectively. Clinical Trials of the Components of STRIBILD in Adult Subjects Emtricitabine and TDF: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or TDF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving STRIBILD in studies 102 and 103 are presented in Table 2. Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Adult Subjects Receiving STRIBILD in Studies 102 and 103 (Week-144 Analysis) Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. , For subjects with serum amylase >1.5 × upper limit of normal (ULN), lipase test was also performed. The frequency of increased lipase (Grades 3–4) occurring in STRIBILD (N=69), ATRIPLA (N=40), and ATV+RTV+TRUVADA (N=38) was 17%, 15%, and 24%, respectively. STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 AST (>5.0 × ULN) 3% 6% 6% ALT (>3.0 × ULN) 2% 5% 4% Amylase (>2.0 × ULN) 3% 3% 5% Creatine Kinase (≥10.0 × ULN) 8% 15% 11% Urine RBC (Hematuria) (>75 RBC/HPF) 4% 2% 4% In Study 103, BMD was assessed by DEXA in a nonrandom subset of 120 subjects (STRIBILD group, N=54; ATV+RTV+TRUVADA group, N=66). Mean percentage decreases in BMD from baseline to Week 144 in the STRIBILD group were comparable to that in the ATV+RTV+TRUVADA group at the lumbar spine (−1.43% versus −3.68%, respectively) and at the hip (−2.83% versus −3.77%, respectively). In studies 102 and 103, bone fractures occurred in 27 subjects (3.9%) in the STRIBILD group, 8 subjects (2.3%) in the ATRIPLA group, and 19 subjects (5.4%) in the ATV+RTV+TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-naïve subjects receiving TDF + lamivudine + efavirenz. Proteinuria (all grades) occurred in 52% of subjects receiving STRIBILD, 41% of subjects receiving ATRIPLA, and 42% of subjects receiving ATV+RTV+TRUVADA. The cobicistat component of STRIBILD has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with STRIBILD, after which levels stabilized. Table 3 displays the mean changes in serum creatinine and eGFR levels at Week 144 and the percentage of subjects with elevations in serum creatinine (all grades). Table 3 Change from Baseline in Serum Creatinine and eGFR and Incidence of Elevated Serum Creatinine (All Grades) in Studies 102 and 103 at Week 144 STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 Serum Creatinine (mg/dL) Mean change ± standard deviation 0.14 (±0.14) 0.01 (±0.12) 0.09 (±0.15) eGFR by Cockcroft-Gault (mL/minute) −14.0 (±16.6) −1.9 (±17.9) −9.8 (±19.4) Subjects with Elevations in Serum Creatinine (All Grades) (%) 12 2 6 Emtricitabine or TDF: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or TDF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of ALT (M: greater than 215 U per L; F: greater than 170 U per L), alkaline phosphatase (greater than 550 U per L), bilirubin (greater than 2.5 × ULN), serum glucose (less than 40 or greater than 250 mg per dL), glycosuria (greater than or equal to 3+), neutrophils (less than 750 per mm 3 ), fasting cholesterol (greater than 240 mg per dL), and fasting triglycerides (greater than 750 mg per dL). Serum Lipids: In the clinical trials of STRIBILD, a similar percentage of subjects receiving STRIBILD, ATRIPLA, and ATV+RTV+TRUVADA were on lipid-lowering agents at baseline (12%, 12%, and 13%, respectively). While receiving study drug through Week 144, an additional 11% of STRIBILD subjects were started on lipid-lowering agents, compared to 13% of ATRIPLA and 12% of ATV+RTV+TRUVADA subjects. Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4. Table 4 Lipid Values, Mean Change from Baseline at Week 144 in Adult Subjects Receiving STRIBILD or Comparator in Studies 102 and 103 STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 Baseline Week 144 Baseline Week 144 Baseline Week 144 mg/dL Change The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. mg/dL Change mg/dL Change Total Cholesterol (fasted) 166 [N=675] +17 [N=535] 161 [N=343] +22 [N=262] 168 [N=337] +16 [N=243] HDL-cholesterol (fasted) 43 [N=675] +7 [N=535] 43 [N=343] +9 [N=262] 42 [N=335] +7 [N=242] LDL-cholesterol (fasted) 100 [N=675] +15 [N=535] 97 [N=343] +19 [N=262] 101 [N=337] +18 [N=242] Triglycerides (fasted) 122 [N=675] +12 [N=535] 121 [N=343] +5 [N=262] 132 [N=337] +22 [N=242] Clinical Trials in Pediatric Subjects The safety of STRIBILD in 50 HIV-1 infected, treatment-naïve pediatric subjects aged 12 to less than 18 years and weighing at least 35 kg was evaluated through 48 weeks in an open-label clinical trial (Study 112) [see Clinical Studies (14.4) ]. In this study, the safety profile of STRIBILD was similar to that in adults. Twenty-two subjects (44%) had treatment-emergent proteinuria (Grades 1–2). One subject met laboratory criteria for proximal renal tubulopathy, evidenced by sustained proteinuria and normoglycemic glycosuria beginning at Week 32. The subject continued to receive STRIBILD and was ultimately lost to follow-up. Among the 50 pediatric subjects receiving STRIBILD for 48 weeks, mean BMD increased from baseline to Week 48, +0.68% at the lumbar spine and +0.77% for total body less head. Mean changes from baseline BMD Z-scores (height-age adjusted) to Week 48 were −0.09 for lumbar spine and −0.12 for total body less head. At Week 48, 7 STRIBILD subjects had significant (greater than or equal to 4%) lumbar spine BMD loss and 2 had significant total body less head BMD loss. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TDF. Because postmarketing 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. No additional postmarketing adverse reactions specific for emtricitabine have been identified. Immune System Disorders allergic reaction, including angioedema Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders dyspnea Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT) Skin and Subcutaneous Tissue Disorders rash Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. ( 7.1 ) STRIBILD can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of one or more components of STRIBILD. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions. ( 4 , 7.2 , 7.3 , 12.3 ) 7.1 Not Recommended with Other Antiretroviral Medications STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided [see Contraindications (4) , Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] . 7.2 Potential for STRIBILD to Affect Other Drugs Cobicistat, a component of STRIBILD, is an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: P-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3. Thus, coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3, may result in increased plasma concentrations of such drugs. Coadministration of STRIBILD with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentration of these active metabolite(s) (Table 5). Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates. 7.3 Potential for Other Drugs to Affect One or More Components of STRIBILD Elvitegravir and cobicistat, components of STRIBILD, are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance (Table 5). Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (Table 5). 7.4 Drugs Affecting Renal Function Because emtricitabine and tenofovir, components of STRIBILD, are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD 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 (5.2) ] . 7.5 Established and Other Potentially Significant Interactions Table 5 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either STRIBILD or the components of STRIBILD (elvitegravir, cobicistat, emtricitabine, and TDF) as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD [for magnitude of interaction see Clinical Pharmacology (12.3) ]. The table includes potentially significant interactions but is not all inclusive [see Contraindications (4) and Clinical Pharmacology (12.3) ]. Table 5 Established and Other Potentially Significant This table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect on Concentration ↑=Increase, ↓=Decrease Clinical Comment Alpha 1-adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Coadministration with alfuzosin is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. Antiarrhythmics: e.g., amiodarone bepridil digoxin Indicates that a drug-drug interaction trial was conducted. disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine ↑ antiarrhythmics ↑ digoxin Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD. Antibacterials: clarithromycin ↑ clarithromycin ↑ cobicistat Patients with CLcr greater than or equal to 60 mL/minute: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 mL/minute and 60 mL/minute: The dose of clarithromycin should be reduced by 50%. Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban rivaroxaban betrixaban dabigatran edoxaban ↑ apixaban Due to potentially increased bleeding risk, dosing recommendations for coadministration with STRIBILD depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. ↑ rivaroxaban Coadministration of rivaroxaban with STRIBILD is not recommended because it may lead to an increased bleeding risk. ↑ betrixaban ↑ dabigatran ↑ edoxaban Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as STRIBILD depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information. warfarin Effect on warfarin unknown Monitor international normalized ratio (INR) upon coadministration of warfarin with STRIBILD. Anticonvulsants: carbamazepine phenobarbital phenytoin ↓ elvitegravir ↓ cobicistat Coadministration with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of elvitegravir therapeutic effect and development of resistance. oxcarbazepine Alternative anticonvulsants should be considered when STRIBILD is coadministered with oxcarbazepine. clonazepam ethosuximide ↑ clonazepam ↑ ethosuximide Clinical monitoring is recommended upon coadministration of clonazepam or ethosuximide with STRIBILD. Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine ↑ SSRIs (except sertraline) ↑ TCAs ↑ trazodone Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended when coadministered with STRIBILD. Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline bupropion trazodone Antifungals: itraconazole ketoconazole voriconazole ↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑ voriconazole When coadministered with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD. Anti-gout: colchicine ↑ colchicine STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD: 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 – coadministration of colchicine in patients receiving STRIBILD: 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 – coadministration of colchicine in patients receiving STRIBILD: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterial: rifampin ↓ elvitegravir ↓ cobicistat Coadministration with rifampin is contraindicated due to potential for loss of elvitegravir therapeutic effect and development of resistance . rifabutin rifapentine Coadministration of STRIBILD with rifabutin or rifapentine is not recommended. Antiplatelets: ticagrelor clopidogrel ↑ ticagrelor ↓ clopidogrel active metabolite Coadministration with ticagrelor is not recommended. Coadministration with clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel. Antipsychotics: lurasidone ↑ lurasidone Coadministration with lurasidone is contraindicated due to potential for serious and/or life-threatening reactions. pimozide ↑ pimozide Coadministration with pimozide is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. quetiapine ↑ quetiapine Initiation of STRIBILD in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If coadministration 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 STRIBILD : Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Other antipsychotics e.g., perphenazine risperidone thioridazine ↑ antipsychotic A decrease in the dose of antipsychotics that are metabolized by CYP3A4 or CYP2D6 may be needed when coadministered with STRIBILD. Beta-Blockers: e.g., metoprolol timolol ↑ beta-blockers Clinical monitoring is recommended and a dose decrease of the beta-blocker may be necessary when these agents are coadministered with STRIBILD. Calcium Channel Blockers: e.g., amlodipine diltiazem felodipine nicardipine nifedipine verapamil ↑ calcium channel blockers Clinical monitoring is recommended upon coadministration of calcium channel blockers with STRIBILD. Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone ↓ elvitegravir ↓ cobicistat ↑ corticosteroids Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to elvitegravir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose 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 (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. Endothelin Receptor Antagonists: bosentan ↑ bosentan Coadministration of bosentan in patients on STRIBILD: In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of STRIBILD in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ↑ ergot derivatives Coadministration 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 Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/voxilaprevir ↑ tenofovir The safety of increased tenofovir concentrations in the setting of HARVONI ® (ledipasvir/sofosbuvir) and STRIBILD has not been established. Coadministration is not recommended. Patients receiving STRIBILD concomitantly with EPCLUSA ® (sofosbuvir/velpatasvir) or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with tenofovir disoproxil fumarate. Herbal Products: St. John's wort (Hypericum perforatum) ↓ elvitegravir ↓ cobicistat Coadministration is contraindicated due to potential for loss of elvitegravir therapeutic effect and development of resistance. Hormonal Contraceptives: drospirenone/ethinyl estradiol levonorgestrel norgestimate/ethinyl estradiol ↑ drospirenone ↑ levonorgestrel ↑ norgestimate ↓ ethinyl estradiol Additional or alternative non-hormonal forms of contraception should be considered when estrogen based contraceptives are coadministered with STRIBILD. Plasma concentrations of drospirenone may be increased when coadministered with cobicistat- containing products. Clinical monitoring is recommended due to the potential for hyperkalemia. The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events. Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than drospirenone, levonorgestrel, or norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered. Immuno-suppressants: e.g., cyclosporine sirolimus tacrolimus ↑ immuno-suppressants Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD. Lipid-modifying Agents: HMG-CoA Reductase Inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis. atorvastatin ↑ atorvastatin Initiate atorvastatin with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety (e.g., myopathy). Do not exceed a dosage of atorvastatin 20 mg daily. Other Lipid-modifying Agents: lomitapide ↑ lomitapide Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases. Narcotic Analgesics: buprenorphine/naloxone ↑ buprenorphine ↑ norbuprenorphine ↓ naloxone Patients should be closely monitored for sedation and cognitive effects. fentanyl ↑ fentanyl Careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended with coadministration. tramadol ↑ tramadol A dose decrease may be needed for tramadol with concomitant use. Inhaled Beta Agonist: salmeterol ↑ salmeterol Coadministration of salmeterol and STRIBILD is not recommended because it may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Medications or Oral Supplements Containing Polyvalent Cations (e.g., Mg, Al, Ca, Fe, Zn): calcium or iron supplements, including multivitamins cation-containing antacids or laxatives sucralfate buffered medications ↓ elvitegravir Separate STRIBILD and administration of medications, antacids, or oral supplements containing polyvalent cations by at least 2 hours. Phosphodiesterase-5 (PDE-5) Inhibitors: sildenafil tadalafil vardenafil ↑ PDE-5 inhibitors Coadministration of sildenafil with STRIBILD is contraindicated when used for treatment of pulmonary arterial hypertension (PAH), due to potential for PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of tadalafil for PAH: Coadministration of tadalafil in patients on STRIBILD: In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability. Coadministration of STRIBILD in patients on tadalafil: Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: The below PDE-5 inhibitors can be used along with increased monitoring for PDE-5-inhibitor associated adverse events: Sildenafil at a single dose not exceeding 25 mg in 48 hours, or Tadalafil at a single dose not exceeding 10 mg in 72 hours, or Vardenafil at a single dose not exceeding 2.5 mg in 72 hours Sedative/hypnotics: midazolam (oral), triazolam ↑ midazolam ↑ triazolam Coadministration with triazolam or orally administered midazolam is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with STRIBILD may cause large increases in the concentrations of these benzodiazepines. Other benzodiazepines: e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem ↑ sedatives/hypnotics Coadministration of parenteral midazolam with STRIBILD should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended. 7.6 Drugs without Clinically Significant Interactions with STRIBILD Based on drug interaction studies conducted with the components of STRIBILD, no clinically significant drug interactions have been observed or are expected when STRIBILD is combined with the following drugs: famciclovir, famotidine, methadone, omeprazole, prasugrel (active metabolite), and sertraline.

Store at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature). Keep container tightly closed. Dispense only in original container.