CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. STRIBILD is fixed-dose combination of antiviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir DF [see Microbiology (12.4)].. 12.2 Pharmacodynamics. Effects on ElectrocardiogramThorough QT studies have been conducted for elvitegravir and cobicistat. The effect of the other two components, tenofovir and emtricitabine, or the combination regimen STRIBILD on the QT interval is not known.The effect of multiple doses of elvitegravir 125 and 250 mg (0.83 and 1.67 times the dose in STRIBILD) (coadministered with 100 mg RTV to boost the blood levels of elvitegravir) on QTc interval was evaluated in randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects. In study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericias correction method (QTcF) was below 10 msec. In this study, there was no clinically relevant prolongation of the QTc interval.The effect of single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in STRIBILD) on QTc interval was evaluated in randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 48 healthy subjects. In study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTc) was below 10 msec, the threshold for regulatory concern. Prolongation of the PR interval was noted in subjects receiving cobicistat in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg dose and 20.2 (22.8) for 400 mg dose cobicistat. Because the 150 mg cobicistat dose used in the STRIBILD fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with STRIBILD will result in clinically relevant PR prolongation.. 12.3 Pharmacokinetics. Absorption and Bioavailability STRIBILD: Following oral administration of STRIBILD with food in HIV-1 infected subjects, peak plasma concentrations were observed hours post-dose for elvitegravir, hours post-dose for cobicistat, hours post-dose for emtricitabine, and hours for tenofovir following the conversion of tenofovir DF (see Table for additional pharmacokinetic parameters). Table Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected SubjectsParameterMean +- SD[range: min:max]ElvitegravirFrom Population Pharmacokinetic analysis, N=419. CobicistatFrom Intensive Pharmacokinetic analysis, N=61-62, except cobicistat Ctrough N=53. Emtricitabine Tenofovir SD Standard DeviationCmax (microgram per mL)1.7 +- 0.4[0.4:3.7]1.1 +- 0.4[0.1:2.1]1.9 +- 0.5[0.6:3.6]0.45 +- 0.2[0.2:1.2]AUCtau (microgramhour per mL)23.0 +- 7.5[4.4:69.8]8.3 +- 3.8[0.5:18.3]12.7 +- 4.5[5.2:34.1]4.4 +- 2.2[2.1:18.2]Ctrough (microgram per mL)0.45 +- 0.26[0.05:2.34]0.05 +- 0.13[0.01:0.92]0.14 +- 0.25[0.04:1.94]0.10 +- 0.08[0.04:0.58] Effect of Food on Oral Absorption Relative to fasting conditions, the administration of single dose STRIBILD with light meal (~373 kcal, 20% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 34% and 24%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant. Relative to fasting conditions, the administration of single dose STRIBILD with high fat meal (~ 800 kcal, 50% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 87% and 23%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant. STRIBILD should be taken with food. Distribution Elvitegravir: Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drug concentration over the range of ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio was 0.73. Cobicistat: Cobicistat is 97-98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5. Emtricitabine: In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of drug concentration over the range of 0.02-200 micrograms per mL. Tenofovir Disoproxil Fumarate: In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01-25 micrograms per mL. Metabolism Elvitegravir: The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3 enzymes. Cobicistat: Cobicistat is metabolized by CYP3A and to minor extent by CYP2D6 enzymes and does not undergo glucuronidation. Emtricitabine and tenofovir are not significantly metabolized. Elimination Elvitegravir: The median terminal plasma half-life of elvitegravir following administration of STRIBILD is approximately 12.9 hours. After single dose administration of [14C] elvitegravir (coadministered with 100 mg RTV), 94.8% and 6.7% of the administered dose was excreted in feces and urine, respectively. Cobicistat: The median terminal plasma half-life of cobicistat following administration of STRIBILD is approximately 3.5 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, 86.2% and 8.2% of the administered dose was excreted in feces and urine, respectively. Emtricitabine and tenofovir are primarily excreted in the urine by combination of glomerular filtration and active tubular secretion.Special Populations Patients with Renal Impairment Elvitegravir and cobicistat: study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment. Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per min or with end stage renal disease requiring dialysis [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Patients with Hepatic Impairment Elvitegravir and cobicistat: study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dosage adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied [see Use in Specific Populations (8.7)]. Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following 300 mg dose of VIREAD has been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects. Hepatitis and/or Hepatitis Virus Co-infection Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis and/or virus infection had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir. Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis and/or virus infection on the pharmacokinetics of cobicistat. Emtricitabine and Tenofovir: Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in subjects coinfected with hepatitis and/or virus. Race Elvitegravir: Population pharmacokinetic analysis of elvitegravir in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir. Cobicistat: Population pharmacokinetics analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of COBI. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA. Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD. Gender No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat-boosted elvitegravir, emtricitabine and tenofovir DF. Pediatric Patients Emtricitabine has been studied in pediatric subjects from months to 17 years of age. Tenofovir DF has been studied in pediatric subjects from years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects have not been established [see Use in Specific Populations (8.4)]. Geriatric Patients Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [see Use in Specific Populations (8.5)]. Absorption and Bioavailability. STRIBILD: Following oral administration of STRIBILD with food in HIV-1 infected subjects, peak plasma concentrations were observed hours post-dose for elvitegravir, hours post-dose for cobicistat, hours post-dose for emtricitabine, and hours for tenofovir following the conversion of tenofovir DF (see Table for additional pharmacokinetic parameters).. Table Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected SubjectsParameterMean +- SD[range: min:max]ElvitegravirFrom Population Pharmacokinetic analysis, N=419. CobicistatFrom Intensive Pharmacokinetic analysis, N=61-62, except cobicistat Ctrough N=53. Emtricitabine Tenofovir SD Standard DeviationCmax (microgram per mL)1.7 +- 0.4[0.4:3.7]1.1 +- 0.4[0.1:2.1]1.9 +- 0.5[0.6:3.6]0.45 +- 0.2[0.2:1.2]AUCtau (microgramhour per mL)23.0 +- 7.5[4.4:69.8]8.3 +- 3.8[0.5:18.3]12.7 +- 4.5[5.2:34.1]4.4 +- 2.2[2.1:18.2]Ctrough (microgram per mL)0.45 +- 0.26[0.05:2.34]0.05 +- 0.13[0.01:0.92]0.14 +- 0.25[0.04:1.94]0.10 +- 0.08[0.04:0.58]. Effect of Food on Oral Absorption. Relative to fasting conditions, the administration of single dose STRIBILD with light meal (~373 kcal, 20% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 34% and 24%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.. Relative to fasting conditions, the administration of single dose STRIBILD with high fat meal (~ 800 kcal, 50% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 87% and 23%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.. STRIBILD should be taken with food.. Distribution. Elvitegravir: Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drug concentration over the range of ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio was 0.73. Cobicistat: Cobicistat is 97-98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5. Emtricitabine: In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of drug concentration over the range of 0.02-200 micrograms per mL. Tenofovir Disoproxil Fumarate: In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01-25 micrograms per mL.. Metabolism. Elvitegravir: The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3 enzymes.. Cobicistat: Cobicistat is metabolized by CYP3A and to minor extent by CYP2D6 enzymes and does not undergo glucuronidation.. Emtricitabine and tenofovir are not significantly metabolized.. Elimination. Elvitegravir: The median terminal plasma half-life of elvitegravir following administration of STRIBILD is approximately 12.9 hours. After single dose administration of [14C] elvitegravir (coadministered with 100 mg RTV), 94.8% and 6.7% of the administered dose was excreted in feces and urine, respectively.. Cobicistat: The median terminal plasma half-life of cobicistat following administration of STRIBILD is approximately 3.5 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, 86.2% and 8.2% of the administered dose was excreted in feces and urine, respectively.. Emtricitabine and tenofovir are primarily excreted in the urine by combination of glomerular filtration and active tubular secretion.. Patients with Renal Impairment. Elvitegravir and cobicistat: study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.. Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per min or with end stage renal disease requiring dialysis [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Patients with Hepatic Impairment. Elvitegravir and cobicistat: study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dosage adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied [see Use in Specific Populations (8.7)]. Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.. Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following 300 mg dose of VIREAD has been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.. Hepatitis and/or Hepatitis Virus Co-infection. Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis and/or virus infection had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.. Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis and/or virus infection on the pharmacokinetics of cobicistat.. Emtricitabine and Tenofovir: Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in subjects coinfected with hepatitis and/or virus.. Race. Elvitegravir: Population pharmacokinetic analysis of elvitegravir in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.. Cobicistat: Population pharmacokinetics analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of COBI.. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.. Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.. Gender. No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat-boosted elvitegravir, emtricitabine and tenofovir DF.. Pediatric Patients. Emtricitabine has been studied in pediatric subjects from months to 17 years of age. Tenofovir DF has been studied in pediatric subjects from years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects have not been established [see Use in Specific Populations (8.4)]. Geriatric Patients Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [see Use in Specific Populations (8.5)]. . Assessment of Drug Interactions[see also Contraindications (4) and Drug Interactions (7)]The drug-drug interaction studies described in Tables and were conducted with STRIBILD, elvitegravir (coadministered with cobicistat or RTV), or cobicistat administered alone.As STRIBILD is indicated for use as complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided [see Warnings and Precautions (5.4)]. The effects of coadministered drugs on the exposure of elvitegravir are shown in Table 8. The effects of elvitegravir or cobicistat on the exposure of coadministered drugs are shown in Table 9. For information regarding clinical recommendations, see Drug Interactions (7).Table Drug Interactions: Changes in Pharmacokinetic Parameters for Elvitegravir in the Presence of the Coadministered DrugAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of Coadministered Drug (mg)Elvitegravir Dose (mg)Cobicistat or RTV Booster Dose (mg)NMean Ratio of Elvitegravir PharmacokineticParameters (90% CI); No effect 1.00Cmax AUCCmin Antacids20 mL single dose given hours before elvitegravir50 single doseRTV100 single dose80.95(0.84,1.07)0.96(0.88,1.04)1.04(0.93,1.17)20 mL single dose given hours after elvitegravir100.98(0.88,1.10)0.98(0.91,1.06)1.00(0.90,1.11)20 mL single dose given hours before elvitegravir110.82(0.74,0.91)0.85(0.79,0.91)0.90(0.82,0.99)20 mL single dose given hours after elvitegravir100.79(0.71,0.88)0.80(0.75,0.86)0.80(0.73,0.89)Famotidine40 once daily given 12 hours after elvitegravir150 once dailyCobicistat150 once daily10 1.02(0.89,1.17)1.03(0.95,1.13)1.18(1.05,1.32)40 once daily given simultaneously with elvitegravir161.00(0.92,1.10)1.03(0.98,1.08)1.07(0.98,1.17)Ketoconazole200 twice daily150 once dailyRTV100 once daily181.17(1.04,1.33)1.48(1.36,1.62)1.67(1.48,1.88)Omeprazole40 once daily given hours before elvitegravir50 once daily RTV100 once daily90.93(0.83,1.04) 0.99(0.91,1.07) 0.94(0.85,1.04) 20 once daily given hours before elvitegravir150 once dailyCobicistat150 once daily111.16(1.04,1.30) 1.10(1.02,1.19) 1.13(0.96,1.34) 20 once daily given 12 hours after elvitegravir111.03(0.92,1.15)1.05(0.93,1.18)1.10(0.92,1.32)Rifabutin150 once every other day150 once dailyCobicistat150 once daily120.91(0.84,0.99) 0.79(0.74,0.85)0.33(0.27,0.40)Rosuvastatin10 single dose150 once dailyCobicistat150 once daily100.94(0.83,1.07)1.02(0.91,1.14)0.98(0.83,1.16)Table Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Elvitegravir plus Cobicistat, Cobicistat, or STRIBILDAll interaction studies conducted in healthy volunteers. Coadministered DrugDose of CoadministeredDrug (mg)Elvitegravir DoseN/A Not Applicable (mg)Cobicistat Booster Dose (mg)NMean Ratio of CoadministeredDrug PharmacokineticParametersNC Not Calculated (90% CI); No effect 1.00Cmax AUCCmin Buprenorphine16 24 once daily150 once daily150 once daily171.12(0.98 to 1.27)1.35(1.18 to 1.55)1.66(1.43 to 1.93)Norbuprenorphine1.24(1.03 to 1.49)1.42(1.22 to 1.67)1.57(1.31 to 1.88)Desipramine50 single doseN/A150 once daily81.24(1.08,1.44) 1.65(1.36,2.02)NCDigoxin0.5 single doseN/A150 once daily221.41(1.29,1.55)1.08 (1.00,1.17)NCNaloxone4 6 once daily150 once daily150 once daily170.72(0.61, 0.85)0.72(0.59, 0.87)N/ANorgestimate/ ethinyl estradiol0.180/0.215/ 0.250 norgestimate once daily150 once dailyStudy conducted with STRIBILD. 150 once daily 132.08(2.00,2.17)2.26(2.15,2.37)2.67(2.43,2.92)0.025 ethinyl estradiol once daily0.94(0.86,1.04)0.75(0.69,0.81)0.56(0.52,0.61)R-Methadone80-120 daily150 once daily150 once daily111.01(0.91, 1.13)1.07(0.96, 1.191.10(0.95, 1.28)S-Methadone0.96(0.87, 1.06)1.00(0.89, 1.12)1.02(0.89, 1.17)Rifabutin150 once every other day150 once daily150 once daily121.09(0.98,1.20)Comparison based on rifabutin 300 mg once daily. 0.92(0.83,1.03) 0.94(0.85,1.04) 25-O-desacetyl-rifabutin124.84(4.09,5.74) 6.25(5.08,7.69) 4.94(4.04,6.04) Rosuvastatin10 single dose150 single dose150 single dose101.89(1.48,2.42)1.38(1.14,1.67)NC. 12.4 Microbiology. Mechanism of Action Elvitegravir: Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases or II. Cobicistat: Cobicistat is selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism. Emtricitabine: Emtricitabine, synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5-triphosphate. Emtricitabine 5-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5-triphosphate is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase Tenofovir DF: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. Elvitegravir: Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases or II.. Cobicistat: Cobicistat is selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.. Emtricitabine: Emtricitabine, synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5-triphosphate. Emtricitabine 5-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5-triphosphate is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase . Tenofovir DF: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. Antiviral Activity in Cell Culture Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir DF: The triple combination of elvitegravir, emtricitabine, and tenofovir was not antagonistic in cell culture combination antiviral activity assays and was not affected by the addition of cobicistat. Elvitegravir: The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, monocyte/macrophage cells, and primary peripheral blood lymphocytes. The 50% effective concentrations (EC50) ranged from 0.02 to 1.7 nM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 value of 0.53 nM). Elvitegravir did not show inhibition of replication of HBV or HCV in cell culture. Cobicistat: Cobicistat has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV and does not antagonize the antiviral activity of elvitegravir, emtricitabine, or tenofovir. Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary peripheral blood mononuclear cells. The EC50 values for emtricitabine were in the range of 0.0013-0.64 micromolar. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC50 values ranged from 0.007-0.075 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007-1.5 micromolar). Tenofovir DF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04-8.5 micromolar. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and (EC50 values ranged from 0.5-2.2 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6-5.5 micromolar).. Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir DF: The triple combination of elvitegravir, emtricitabine, and tenofovir was not antagonistic in cell culture combination antiviral activity assays and was not affected by the addition of cobicistat.. Elvitegravir: The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, monocyte/macrophage cells, and primary peripheral blood lymphocytes. The 50% effective concentrations (EC50) ranged from 0.02 to 1.7 nM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 value of 0.53 nM). Elvitegravir did not show inhibition of replication of HBV or HCV in cell culture. Cobicistat: Cobicistat has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV and does not antagonize the antiviral activity of elvitegravir, emtricitabine, or tenofovir.. Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary peripheral blood mononuclear cells. The EC50 values for emtricitabine were in the range of 0.0013-0.64 micromolar. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC50 values ranged from 0.007-0.075 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007-1.5 micromolar). Tenofovir DF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04-8.5 micromolar. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and (EC50 values ranged from 0.5-2.2 micromolar) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6-5.5 micromolar).. Resistance In Cell Culture:Elvitegravir: HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was associated with the primary integrase substitutions T66A/I, E92G/Q, S147G, and Q148R. Additional integrase substitutions observed in cell culture selection included D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K, and V281M. Emtricitabine and Tenofovir DF: HIV-1 isolates with reduced susceptibility to emtricitabine or tenofovir have been selected in cell culture. Reduced susceptibility to emtricitabine was associated with M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir expressed K65R substitution in HIV-1 RT and showed 2-4 fold reduction in susceptibility to tenofovir. In Clinical Studies:In Treatment-Naive HIV-1-Infected Adult Subjects: In Studies 102 and 103 [see Clinical Studies (14)], the development of one or more primary substitutions associated with resistance to elvitegravir (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), emtricitabine, and/or tenofovir was observed in 53% (16/30) of the STRIBILD-treatment failure subjects with evaluable genotypic resistance data who received at least weeks of STRIBILD and had HIV-1 RNA greater than 400 copies per mL at Week 96 or at the time of early study drug discontinuation. The most common substitutions that emerged were M184V/I (N=15) in HIV-1 RT and the primary elvitegravir resistance-associated substitutions, E92Q (N=9), N155H (N=5), Q148R (N=3), and T66I (N=2) in integrase; K65R in RT was also detected (N=5). In virus isolates harboring the observed primary elvitegravir resistance substitutions, additional substitutions in integrase were detected including H51Y, L68I/V, G70R, I73V, G140C, S153A and E157Q. All subjects with evaluable data for RT and IN and who developed integrase substitutions associated with elvitegravir resistance (N=13) also developed the M184I/V RT substitutions, conferring reduced susceptibility to both elvitegravir and emtricitabine. In phenotypic analyses, HIV-1 isolates expressing M184V/I RT substitutions showed reduced susceptibility to emtricitabine (42- to greater than 152-fold); those expressing the primary elvitegravir resistance-associated integrase substitutions showed reduced susceptibility to elvitegravir (6- to greater than 198-fold); and those expressing the K65R RT substitution showed reduced susceptibility to tenofovir (0.8- to 1.6-fold), compared to wild-type reference HIV-1.. In Cell Culture:Elvitegravir: HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was associated with the primary integrase substitutions T66A/I, E92G/Q, S147G, and Q148R. Additional integrase substitutions observed in cell culture selection included D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K, and V281M. Emtricitabine and Tenofovir DF: HIV-1 isolates with reduced susceptibility to emtricitabine or tenofovir have been selected in cell culture. Reduced susceptibility to emtricitabine was associated with M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir expressed K65R substitution in HIV-1 RT and showed 2-4 fold reduction in susceptibility to tenofovir. In Clinical Studies:In Treatment-Naive HIV-1-Infected Adult Subjects: In Studies 102 and 103 [see Clinical Studies (14)], the development of one or more primary substitutions associated with resistance to elvitegravir (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), emtricitabine, and/or tenofovir was observed in 53% (16/30) of the STRIBILD-treatment failure subjects with evaluable genotypic resistance data who received at least weeks of STRIBILD and had HIV-1 RNA greater than 400 copies per mL at Week 96 or at the time of early study drug discontinuation. The most common substitutions that emerged were M184V/I (N=15) in HIV-1 RT and the primary elvitegravir resistance-associated substitutions, E92Q (N=9), N155H (N=5), Q148R (N=3), and T66I (N=2) in integrase; K65R in RT was also detected (N=5). In virus isolates harboring the observed primary elvitegravir resistance substitutions, additional substitutions in integrase were detected including H51Y, L68I/V, G70R, I73V, G140C, S153A and E157Q. All subjects with evaluable data for RT and IN and who developed integrase substitutions associated with elvitegravir resistance (N=13) also developed the M184I/V RT substitutions, conferring reduced susceptibility to both elvitegravir and emtricitabine. In phenotypic analyses, HIV-1 isolates expressing M184V/I RT substitutions showed reduced susceptibility to emtricitabine (42- to greater than 152-fold); those expressing the primary elvitegravir resistance-associated integrase substitutions showed reduced susceptibility to elvitegravir (6- to greater than 198-fold); and those expressing the K65R RT substitution showed reduced susceptibility to tenofovir (0.8- to 1.6-fold), compared to wild-type reference HIV-1.. Cross Resistance STRIBILD-treatment failure subject isolates exhibited varying degrees of cross resistance within the INSTI and NRTI drug classes depending on the specific substitutions observed. These isolates remained susceptible to all NNRTIs and protease inhibitors. Elvitegravir: Cross-resistance has been observed among INSTIs. Elvitegravir-resistant viruses showed varying degrees of cross-resistance in cell culture to raltegravir depending on the type and number of substitutions in HIV-1 integrase. Of the primary elvitegravir resistance-associated substitutions tested (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), all but three (T66I, E92G, and S147G) conferred greater than 1.5-fold reduced susceptibility to raltegravir (above the biological cutoff for raltegravir) when introduced individually into wild-type virus by site-directed mutagenesis. Of the primary raltegravir resistance-associated substitutions (Y143C/H/R, Q148H/K/R, and N155H), all but Y143C/H conferred greater than 2.5-fold reductions in susceptibility to elvitegravir (above the biological cutoff for elvitegravir). Emtricitabine: Cross-resistance has been observed among NRTIs. Emtricitabine-resistant isolates harboring an M184V/I substitution in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine. Tenofovir DF: Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed mean of zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V RT substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4) in HIV-1 RT, all of whom had reduced response in clinical trials.. STRIBILD-treatment failure subject isolates exhibited varying degrees of cross resistance within the INSTI and NRTI drug classes depending on the specific substitutions observed. These isolates remained susceptible to all NNRTIs and protease inhibitors.. Elvitegravir: Cross-resistance has been observed among INSTIs. Elvitegravir-resistant viruses showed varying degrees of cross-resistance in cell culture to raltegravir depending on the type and number of substitutions in HIV-1 integrase. Of the primary elvitegravir resistance-associated substitutions tested (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), all but three (T66I, E92G, and S147G) conferred greater than 1.5-fold reduced susceptibility to raltegravir (above the biological cutoff for raltegravir) when introduced individually into wild-type virus by site-directed mutagenesis. Of the primary raltegravir resistance-associated substitutions (Y143C/H/R, Q148H/K/R, and N155H), all but Y143C/H conferred greater than 2.5-fold reductions in susceptibility to elvitegravir (above the biological cutoff for elvitegravir).. Emtricitabine: Cross-resistance has been observed among NRTIs. Emtricitabine-resistant isolates harboring an M184V/I substitution in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine. Tenofovir DF: Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed mean of zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V RT substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4) in HIV-1 RT, all of whom had reduced response in clinical trials.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse drug reactions are discussed in other sections of the labeling:Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Boxed Warning, Warnings and Precautions (5.1)].Severe Acute Exacerbations of Hepatitis [see Boxed Warning, Warnings and Precautions (5.2)].New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3)].Bone Effects of Tenofovir DF [see Warnings and Precautions (5.5)].Immune Reconstitution Syndrome [see Warnings and Precautions (5.7)].. Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Boxed Warning, Warnings and Precautions (5.1)].. Severe Acute Exacerbations of Hepatitis [see Boxed Warning, Warnings and Precautions (5.2)].. New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3)].. Bone Effects of Tenofovir DF [see Warnings and Precautions (5.5)].. Immune Reconstitution Syndrome [see Warnings and Precautions (5.7)].. 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 Adverse Reactions from Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety assessment of STRIBILD is based on the Week 96 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-naive HIV-1 infected adult subjects [see Clinical Studies (14)]. total of 701 subjects received STRIBILD once daily for at least 96 weeks.The proportion of subjects who discontinued treatment with STRIBILD (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir DF 300 mg); ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg); or atazanavir (ATV) ritonavir (RTV) TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) due to adverse events, regardless of severity, was 4.6%, 6.8% and 5.9%, respectively. Table displays the frequency of adverse drug reactions greater than or equal to 5% of subjects in any treatment arm.Table Adverse Drug ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, attributed to study drugs. (all grades) Reported in >= 5% of Subjects in Any Treatment Arm in Studies 102 and 103 (Week 96 analysis).STRIBILDN=701ATRIPLAN=352ATV RTV TRUVADAN=355EYE DISORDERS Ocular icterus<1%0%13%GASTROINTESTINAL DISORDERS Diarrhea12%11%17% Flatulence2%<1%8% Nausea16%9%14%GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue4%8%6%HEPATOBILIARY DISORDERS Jaundice0%<1%9%NERVOUS SYSTEM DISORDERS Somnolence1%7%1% Headache7%4%6% Dizziness3%21%4%PSYCHIATRIC DISORDERS Insomnia3%8%1% Abnormal dreams9%26%4%SKIN AND SUBCUTANEOUS TISSUE DISORDERS RashRash 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. 3%15%6%See Warnings and Precautions (5.3), for discussion of renal adverse reactions from clinical trials experience with STRIBILD.. Adverse Reactions from Clinical Trials of the Components of STRIBILD. Emtricitabine and Tenofovir Disoproxil Fumarate: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF 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 AbnormalitiesThe 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 3.Table Laboratory Abnormalities (Grades 3-4) Reported in >= 2% of Subjects Receiving STRIBILD in Studies 102 and 103 (Week 96 analysis)STRIBILDATRIPLAATV RTV TRUVADALaboratory Parameter AbnormalityFrequencies are based on treatment-emergent laboratory abnormalities.,For subjects with serum amylase 1.5 upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in STRIBILD (N=61), ATRIPLA (N=36), and ATV +RTV TRUVADA (N=36) was 15%, 17%, and 25%, respectively.N=701N=352N=355AST (>5.0 ULN)2%6%6%Amylase (>2.0 ULN)3%2%4%Creatine Kinase (>= 10.0 ULN)7%14%10%Urine RBC (Hematuria) (> 75 RBC/HPF)3%2%4%In Study 103, BMD was assessed by DEXA in non-random subset of 120 subjects. Mean percentage decreases in BMD from baseline to Week 96 in the STRIBILD group (N 47) were comparable to the ATV RTV TRUVADA group (N 53) at the lumbar spine (-2.0% versus -3.5%, respectively) and at the hip (-3.2% versus -4.2%, respectively). In Studies 102 and 103, bone fractures occurred in 14 subjects (2.0%) in the STRIBILD group, subjects (2.3%) in the ATRIPLA group, and 14 subjects (3.9%) in the ATV RTV TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-naive subjects receiving tenofovir DF lamivudine efavirenz. Proteinuria (all grades) occurred in 46% of subjects receiving STRIBILD, 38% of subjects receiving ATRIPLA, and 37% 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 they stabilized. Table displays the mean changes in serum creatinine and eGFR levels at Week 96 and the percentage of subjects with elevations in serum creatinine (All Grades).Table Change from Baseline in Serum Creatinine and eGFR and Incidence of Elevated Serum Creatinine (All Grades) at Week 96STRIBILD(N=701)ATRIPLA(N=352)ATV RTV TRUVADA(N=355)Serum Creatinine (mg/dL)Mean change +-SD 0.13 (+-0.13)0.01 (+-0.13)0.08 (+-0.14)eGFR by Cockcroft-Gault (mL/min) -13.2 (+-15.7)-0.9 (+-16.1)-8.6 (+-17.8)Subjects with Elevations in Serum Creatinine (All Grades)(%)1015. Emtricitabine or Tenofovir DF: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grade or laboratory abnormalities of ALT (M: greater than 215 per L; F: greater than 170 per L), alkaline phosphatase (greater than 550 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 mm3), 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, similar percentage of subjects receiving STRIBILD, ATRIPLA, and ATV RTV TRUVADA were on lipid lowering agents at baseline (11%, 11%, and 12%, respectively). While receiving study drug through Week 96, an additional 8% of STRIBILD subjects were started on lipid lowering agents, compared to 9% of ATRIPLA and 8% of ATV RTV TRUVADA subjects.Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5.Table Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving STRIBILD or Comparator in Studies 102 and 103STRIBILDN=701ATRIPLAN=352ATV RTV TRUVADAN=355BaselineWeek 96BaselineWeek 96BaselineWeek 96mg/dLChangeThe change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values. mg/dLChange mg/dLChange Total Cholesterol (fasted)166[N=675]+12[N=571]161[N=343]+20[N=288]168[N=337]+11[N=279]HDL-cholesterol (fasted)43[N=675]+7[N=571]43[N=343]+9[N=288]42[N=335]+6[N=278]LDL-cholesterol (fasted)100[N=675]+12[N=572]97[N=343]+17[N=287]101[N=337]+13[N=280]Triglycerides (fasted)122[N=675]+8[N=571]121[N=343]+17[N=288]132[N=337]+25[N=279]. 6.2 Postmarketing Experience. Because postmarketing reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of tenofovir DF. No additional postmarketing adverse reactions specific for emtricitabine have been identified.Immune System Disordersallergic reaction, including angioedemaMetabolism and Nutrition Disorderslactic acidosis, hypokalemia, hypophosphatemiaRespiratory, Thoracic, and Mediastinal DisordersdyspneaGastrointestinal Disorderspancreatitis, increased amylase, abdominal painHepatobiliary Disordershepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)Skin and Subcutaneous Tissue DisordersrashMusculoskeletal and Connective Tissue Disordersrhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathyRenal and Urinary Disordersacute 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, polyuriaGeneral Disorders and Administration Site ConditionsastheniaThe following adverse reactions, listed under the body system headings above, may occur as consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

BOXED WARNING SECTION.

WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, component of STRIBILD, in combination with other antiretrovirals [see Warnings and Precautions (5.1)].STRIBILD is not approved for the treatment of chronic hepatitis virus (HBV) infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and human immunodeficiency virus-1 (HIV-1) and have discontinued EMTRIVA or VIREAD, which are components of STRIBILD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue STRIBILD. If appropriate, initiation of anti-hepatitis therapy may be warranted [see Warnings and Precautions (5.2)].. WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS BSee full prescribing information for complete boxed warning.Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (DF), component of STRIBILD. (5.1) STRIBILD is not approved for the treatment of chronic hepatitis virus (HBV) infection. Severe acute exacerbations of hepatitis have been reported in patients coinfected with HIV-1 and HBV who have discontinued EMTRIVA or VIREAD, two of the components of STRIBILD. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis therapy may be warranted. (5.2). Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (DF), component of STRIBILD. (5.1) STRIBILD is not approved for the treatment of chronic hepatitis virus (HBV) infection. Severe acute exacerbations of hepatitis have been reported in patients coinfected with HIV-1 and HBV who have discontinued EMTRIVA or VIREAD, two of the components of STRIBILD. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis therapy may be warranted. (5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of STRIBILD is based on the analyses of 96-week data from two randomized, double-blind, active-controlled trials, Study 102 and Study 103, in treatment-naive, HIV-1 infected subjects (N=1408, randomized and dosed) with baseline estimated creatinine clearance above 70 mL per min.In Study 102, subjects were randomized in 1:1 ratio to receive either STRIBILD (N=348) once daily or ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg; N=352) once daily. The mean age was 38 years (range 18-67), 89% were male, 63% were White, 28% were Black, and 2% were Asian. Twenty-four percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies per mL (range 2.6-6.5). The mean baseline CD4+ cell count was 386 cells per mm3 (range 3-1348) and 13% had CD4+ cell counts less than 200 cells per mm3. Thirty-three percent of subjects had baseline viral loads greater than 100,000 copies per mL.In Study 103, subjects were randomized in 1:1 ratio to receive either STRIBILD (N=353) once daily or ATV 300 mg RTV 100 mg TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) (N=355) once daily. The mean age was 38 years (range 19-72), 90% were male, 74% were White, 17% were Black, and 5% were Asian. Sixteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies per mL (range 1.7-6.6). The mean baseline CD4+ cell count was 370 cells per mm3 (range 5-1132) and 13% had CD4+ cell count less than 200 cells per mm3. Forty-one percent of subjects had baseline viral loads greater than 100,000 copies per mL.In both studies, subjects were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies per mL or greater than 100,000 copies per mL).Treatment outcomes of Study 102 and Study 103 through 96 weeks are presented in Table 10.Table 10 Virologic Outcome of Randomized Treatment of Study 102 and Study 103 at Week 96Week 96 window is between Day 631 and 714 (inclusive). Study 102Study 103STRIBILD(N=348)ATRIPLA(N=352)STRIBILD(N=353)ATV RTV TRUVADA(N=355)Virologic SuccessHIV-1 RNA 50 copies/mL84%82%83%82% Treatment Difference2.7% (95% CI -2.9%, 8.3%)1.1% (95% CI -4.5%, 6.7%)Virologic FailureIncludes subjects who had >=50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had viral value of >=50 copies/mL.6%8%7%7%No Virologic Data at Week 96 Window Discontinued Study Drug Due to AE or DeathIncludes patients who discontinued due to adverse event or death at any time point from Day through the time window if this resulted in no virologic data on treatment during the specified window. 5%6%4%6% Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA 50 copies/mLIncludes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. 5%4%5%5% Missing Data During Window but on Study Drug0%1%1%0 %In Study 102, the mean increase from baseline in CD4+ cell count at Week 96 was 278 cells per mm3 in the STRIBILD-treated subjects and 247 cells per mm3 in the ATRIPLA -treated subjects. In Study 103, the mean increase from baseline in CD4+ cell count at Week 96 was 242 cells per mm3 in the STRIBILD-treated subjects and 240 cells per mm3 in the ATV RTV TRUVADA-treated subjects.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. 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 in Table [see Drug Interactions (7.5), Clinical Pharmacology (12.3)]. Table Drugs that are Contraindicated with STRIBILDDrug ClassDrugs within class that are contraindicated with STRIBILDClinical CommentAlpha 1-Adrenoreceptor AntagonistAlfuzosinPotential for increased alfuzosin concentrations, which can result in hypotension.AntimycobacterialRifampinRifampin is potent inducer of CYP450 metabolism and may cause significant decrease in the plasma concentration of elvitegravir and cobicistat. This may result in loss of therapeutic effect to STRIBILD.Ergot DerivativesDihydroergotamineErgotamineMethylergonovinePotential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.GI Motility AgentCisapridePotential for serious and/or life-threatening events such as cardiac arrhythmias.Herbal ProductsSt. Johns wort (Hypericum perforatum)Coadministration of products containing St. Johns wort and STRIBILD may result in reduced plasma concentrations of elvitegravir and cobicistat. This may result in loss of therapeutic effect and development of resistance.HMG-CoA Reductase InhibitorsLovastatinSimvastatinPotential for serious reactions such as myopathy, including rhabdomyolysis.NeurolepticPimozidePotential for serious and/or life-threatening events such as cardiac arrhythmias.Phosphodiesterase-5 (PDE5) InhibitorSildenafilSee Drug Interactions (7), Table for sildenafil when dosed as VIAGRA for erectile dysfunction. when dosed as REVATIO for the treatment of pulmonary arterial hypertensionThere is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).Sedative/hypnoticsTriazolamOrally administered midazolamSee Drug Interactions (7), Table for parenterally administered midazolam. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with STRIBILD may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression.. 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). 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).

DESCRIPTION SECTION.

11 DESCRIPTION. STRIBILD is fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir DF for oral administration.Elvitegravir is an HIV-1 integrase strand transfer inhibitor.Cobicistat is mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.Emtricitabine is 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 tenofovir DF.Each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir DF (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 coating material containing indigo carmine (FD&C Blue 2) aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.. Elvitegravir is an HIV-1 integrase strand transfer inhibitor.. Cobicistat is mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.. Emtricitabine is 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 tenofovir DF.. Elvitegravir: The chemical name of elvitegravir is 6-(3-Chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.It has molecular formula of C23H23ClFNO5 and molecular weight of 447.9. It has the following structural formula:Elvitegravir is white to pale yellow powder with 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 [(2R,5R)-5-[(2S)-2-[(methyl[2-(propan-2-yl)-1,3-thiazol-4-yl]methylcarbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino-1,6-diphenylhexan-2-yl]carbamate.It has molecular formula of C40H53N7O5S2 and molecular weight of 776.0. It has the following structural formula:Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is white to pale yellow solid with solubility of 0.1 mg per mL in water at 20 C.. Chemical Structure. Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-)enantiomer of thio analog of cytidine, which differs from other cytidine analogs in that it has fluorine in the 5-position.It has molecular formula of C8H10FN3O3S and molecular weight of 247.25. It has the following structural formula:Emtricitabine is white to off-white crystalline powder with solubility of approximately 112 mg per mL in water at 25 C.. Chemical Structure. Tenofovir Disoproxil Fumarate: Tenofovir DF is fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir DF is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has molecular formula of C19H30N5O10P C4H4O4 and molecular weight of 635.51. It has the following structural formula:Tenofovir DF is white to off-white crystalline powder with solubility of 13.4 mg per mL in water at 25 C. All dosages are expressed in terms of tenofovir DF except where otherwise noted.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

Recommended dosage: One tablet taken once daily with food. (2.1)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. (2.2). Recommended dosage: One tablet taken once daily with food. (2.1). 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. (2.2). 2.1 Dosage Information. The recommended dosage of STRIBILD is one tablet taken orally once daily with food [see Clinical Pharmacology (12.3)].. 2.2 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 fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per min during treatment with STRIBILD as dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (DF) cannot be achieved [see Warnings and Precautions (5.3), Adverse Reactions (6.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Clinical Studies (14)]. 2.3 Dosage in Patients with Hepatic Impairment. No dosage adjustment of STRIBILD is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of STRIBILD in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, STRIBILD is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 2.4 Testing Prior to Initiation of STRIBILD. Prior to initiation of STRIBILD, patients should be tested for hepatitis infection [see Warnings and Precautions (5.2)] and estimated creatinine clearance, urine glucose and urine protein should be documented in all patients [see Warnings and Precautions (5.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Each STRIBILD tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate (tenofovir DF, equivalent to 245 mg of tenofovir disoproxil).The tablets are green, capsule-shaped, film-coated, debossed with GSI on one side and the number 1 surrounded by square box ) on the other side of the tablet.. Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate. (3). figure.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. See also Contraindications (4) and Clinical Pharmacology (12.3). STRIBILD is 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. (5.4, 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). STRIBILD is 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. (5.4, 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 Other Antiretroviral Medications. STRIBILD is 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. 7.2 Potential for STRIBILD to Affect Other Drugs. Cobicistat, 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. Elvitegravir is 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 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 (see Table 6).Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (see Table 6).. 7.4 Drugs Affecting Renal Function. Because emtricitabine and tenofovir, components of STRIBILD are primarily excreted by the kidneys by 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 (5.3)]. 7.5 Established and Other Potentially Significant Interactions Table provides listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either STRIBILD, the components of STRIBILD, (elvitegravir, cobicistat, emtricitabine, and tenofovir DF) 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.Table Established and Other Potentially SignificantThis 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 NameEffect on Concentration Increase, Decrease, <=> No Effect Clinical CommentAcid Reducing Agents:AntacidsIndicates that drug-drug interaction trial was conducted. (for example aluminum and magnesium hydroxide) elvitegravirElvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least hours.Antiarrhythmics:e.g.amiodaronebepridildigoxindisopyramideflecainidesystemic lidocaine mexiletinepropafenonequinidine antiarrhythmics digoxinConcentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.Antibacterials:clarithromycintelithromycin clarithromycin telithromycin cobicistatConcentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD. Patients with CLcr greater than or equal to 60 mL/min: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 mL/min and 60 mL/min: The dose of clarithromycin should be reduced by 50%.Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD.Anticoagulants:warfarinEffect on warfarin unknownConcentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD.Anticonvulsants:carbamazepineoxcarbazepine phenobarbitalphenytoin carbamazepine elvitegravir cobicistatCoadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered.clonazepamethosuximide clonazepam ethosuximideConcentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD.Antidepressants:Selective Serotonin Reuptake Inhibitors (SSRIs)e.g.paroxetineTricyclicAntidepressants (TCAs)e.g.amitriptylinedesipramineimipraminenortriptylinebupropriontrazodone SSRIs TCAs trazodoneConcentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended.Antifungals:itraconazole ketoconazolevoriconazole elvitegravir cobicistat itraconazole ketoconazolevoriconazoleConcentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering 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 colchicineSTRIBILD 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) hour later. Treatment course to be repeated no earlier than days. Prophylaxis of gout-flares coadministration of colchicine in patients receiving STRIBILD: If the original regimen was 0.6 mg twice day, the regimen should be adjusted to 0.3 mg once day. If the original regimen was 0.6 mg once 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 day).Antimycobacterial:rifabutinrifapentine elvitegravir cobicistatCoadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.Beta-Blockers:e.g.metoprololtimolol beta-blockersConcentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD.Calcium Channel Blockers:e.g. amlodipinediltiazemfelodipinenicardipinenifedipineverapamil calcium channel blockersConcentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD.Corticosteroid:Systemic:dexamethasone elvitegravir cobicistatSystemic dexamethasone, CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.Corticosteroid:Inhaled/Nasal:fluticasone fluticasoneConcomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.Endothelin Receptor Antagonists:bosentan bosentanCoadministration 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.HMG-CoA Reductase Inhibitors:atorvastatin atorvastatinInitiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.Hormonal Contraceptives:norgestimate/ethinyl estradiol norgestimate ethinyl estradiolThe 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 norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered.Immuno-suppressants:e.g.cyclosporinesirolimustacrolimus immuno-suppressantsConcentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.Narcotic Analgesics: buprenorphine/naloxone buprenorphine norbuprenorphine naloxoneConcentrations of buprenorphine and norbuprenorphine are increased when coadministered with STRIBILD. No dose adjustment of buprenorphine/naloxone is required upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects.Inhaled Beta Agonist:salmeterol salmeterolCoadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.Neuroleptics:e.g.perphenazinerisperidonethioridazine neurolepticsA decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD.Phosphodiesterase-5 (PDE5) Inhibitors: sildenafiltadalafilvardenafil PDE5 inhibitorsCoadministration with STRIBILD 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): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH).The following dose adjustments are recommended for the use of tadalafil with STRIBILD: Coadministration of tadalafil in patients on STRIBILD: In patients receiving STRIBILD for at least 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: Sildenafil at single dose not exceeding 25 mg in 48 hours, vardenafil at single dose not exceeding 2.5 mg in 72 hours, or tadalafil at single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events.Sedative/hypnotics:Benzodiazepines:e.g.Parenterally administered midazolamclorazepatediazepamestazolamflurazepambuspironezolpidem sedatives/hypnoticsConcomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in 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 single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated.With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.. Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH).. The following dose adjustments are recommended for the use of tadalafil with STRIBILD: Coadministration of tadalafil in patients on STRIBILD: In patients receiving STRIBILD for at least 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. In patients receiving STRIBILD for at least week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.. 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.. 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 either observed or are expected when STRIBILD is combined with the following drugs: entecavir, famciclovir, H2 receptor antagonists, methadone, proton pump inhibitors and ribavirin.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of STRIBILD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of STRIBILD in elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. STRIBILD tablets are green, capsule-shaped, film-coated, debossed with GSI on one side and the number 1 surrounded by square box ) on the other side. They are supplied by State of Florida DOH Central Pharmacy as follows:NDCStrengthQuantity/FormColorSource Prod. Code53808-0887-1150 MG 150 MG 200 MG 300 MG30 Tablets in Blister PackGREEN61958-1201. Store at 25 (77 F), excursions permitted to 15-30 (59-86 F) (see USP Controlled Room Temperature).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. STRIBILD(R) is indicated as complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naive.. STRIBILD is four-drug combination of elvitegravir, an HIV integrase strand transfer inhibitor (HIV-1 INSTI), cobicistat, CYP3A inhibitor, and emtricitabine and tenofovir DF, both HIV nucleoside analog reverse transcriptase inhibitors (HIV NRTI) and is indicated as complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naive. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling (Patient Information) statement to patients and healthcare providers is included on the products bottle label: ALERT: Find out about medicines that should NOT be taken with STRIBILD. Patients should be advised that:STRIBILD may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. Johns wort.Patients should remain under the care of healthcare provider when using STRIBILD.Patients should be informed that STRIBILD is not cure for HIV-1 infection. Patients should stay on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illnesses. Patients should be told that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.Patients should avoid doing things that can spread HIV-1 infection to others. Do not share needles or other injection equipment. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.Do not breastfeed. At least two of the drugs contained in STRIBILD can be passed to the baby in breast milk. It is not known whether this could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.It is important to take STRIBILD on regular dosing schedule with food and to avoid missing doses.Do not miss dose of STRIBILD. If patient misses dose of STRIBILD, the patient should take the missed dose as soon as they remember. If it is almost time for the next dose of STRIBILD, the patient should not take the missed dose, but resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of STRIBILD at any one time. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Advise patients that treatment with STRIBILD should be suspended if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [see Warnings and Precautions (5.1)].Instruct the patient that hepatitis testing is recommended prior to initiating antiretroviral therapy. Severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA or VIREAD [see Warnings and Precautions (5.2)]. STRIBILD should not be discontinued without first informing their healthcare provider.Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of STRIBILD. STRIBILD should be avoided with concurrent or recent use of nephrotoxic agent (e.g., high dose or multiple NSAIDs) [see Warnings and Precautions (5.3)].STRIBILD should not be coadministered with other antiretroviral products because it provides complete treatment regimen and because of potential drug interactions [see Warnings and Precautions (5.4) and Drug Interactions (7)].STRIBILD should not be administered in combination with ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, or VIREAD; with drugs containing lamivudine, including COMBIVIR, EPIVIR or EPIVIR-HBV, EPZICOM, or TRIZIVIR; with drugs containing RTV or regimens containing RTV; or with HEPSERA [see Warnings and Precautions (5.4)].Decreases in bone mineral density have been observed with the use of STRIBILD. Assessment of bone mineral density (BMD) should be considered in patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.5)].Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known [see Warnings and Precautions (5.6)].In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the bodys immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Patients should be advised to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.7)]. STRIBILD may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. Johns wort.. Patients should remain under the care of healthcare provider when using STRIBILD.. Patients should be informed that STRIBILD is not cure for HIV-1 infection. Patients should stay on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illnesses. Patients should be told that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.. Patients should avoid doing things that can spread HIV-1 infection to others. Do not share needles or other injection equipment. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.Do not breastfeed. At least two of the drugs contained in STRIBILD can be passed to the baby in breast milk. It is not known whether this could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.It is important to take STRIBILD on regular dosing schedule with food and to avoid missing doses.Do not miss dose of STRIBILD. If patient misses dose of STRIBILD, the patient should take the missed dose as soon as they remember. If it is almost time for the next dose of STRIBILD, the patient should not take the missed dose, but resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of STRIBILD at any one time. Do not share needles or other injection equipment. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.. Do not breastfeed. At least two of the drugs contained in STRIBILD can be passed to the baby in breast milk. It is not known whether this could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.. It is important to take STRIBILD on regular dosing schedule with food and to avoid missing doses.. Do not miss dose of STRIBILD. If patient misses dose of STRIBILD, the patient should take the missed dose as soon as they remember. If it is almost time for the next dose of STRIBILD, the patient should not take the missed dose, but resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of STRIBILD at any one time.. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Advise patients that treatment with STRIBILD should be suspended if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [see Warnings and Precautions (5.1)].. Instruct the patient that hepatitis testing is recommended prior to initiating antiretroviral therapy. Severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA or VIREAD [see Warnings and Precautions (5.2)]. STRIBILD should not be discontinued without first informing their healthcare provider.. Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of STRIBILD. STRIBILD should be avoided with concurrent or recent use of nephrotoxic agent (e.g., high dose or multiple NSAIDs) [see Warnings and Precautions (5.3)].. STRIBILD should not be coadministered with other antiretroviral products because it provides complete treatment regimen and because of potential drug interactions [see Warnings and Precautions (5.4) and Drug Interactions (7)].. STRIBILD should not be administered in combination with ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, or VIREAD; with drugs containing lamivudine, including COMBIVIR, EPIVIR or EPIVIR-HBV, EPZICOM, or TRIZIVIR; with drugs containing RTV or regimens containing RTV; or with HEPSERA [see Warnings and Precautions (5.4)].. Decreases in bone mineral density have been observed with the use of STRIBILD. Assessment of bone mineral density (BMD) should be considered in patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.5)].. Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known [see Warnings and Precautions (5.6)].. In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the bodys immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Patients should be advised to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.7)].

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. STRIBILD is fixed-dose combination of antiviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir DF [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Elvitegravir: Long-term carcinogenicity studies of elvitegravir were carried out in mice (104 weeks) and in rats for up to 88 weeks (males) and 90 weeks (females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day RTV at exposures 3- and 14-fold, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27-fold, respectively in male and female, the human systemic exposure.Elvitegravir was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation.Elvitegravir did not affect fertility in male and female rats at approximately 16- and 30-fold higher exposures (AUC), respectively, than in humans at the therapeutic 150 mg daily dose.Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18-fold higher than human exposures at the recommended 150 mg daily dose.. Cobicistat: In long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately times the human systemic exposure at the therapeutic daily dose.Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 4-fold higher than human exposures at the recommended 150 mg daily dose.Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2-fold higher than human exposures at the recommended 150 mg daily dose.. Emtricitabine: In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (23 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the therapeutic dose).Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.Tenofovir Disoproxil Fumarate: Long-term oral carcinogenicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 10 times (mice) and times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 10 times of that in humans. In rats, the study was negative for carcinogenic findings at exposures up to times that observed in humans at the therapeutic dose.Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir DF was negative when administered to male mice.There were no effects on fertility, mating performance or early embryonic development when tenofovir DF was administered to male rats at dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir, cobicistat, and tenofovir are secreted in milk. It is not known whether elvitegravir or cobicistat is excreted in human milk.In humans, samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.Samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk. Tenofovir-associated risks, including the risk of viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir disoproxil fumarate are unknown.Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving STRIBILD.

OVERDOSAGE SECTION.

10 OVERDOSAGE. No data are available on overdose of STRIBILD in patients. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with STRIBILD consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.. Elvitegravir: Limited clinical experience is available at doses higher than the therapeutic dose of elvitegravir. In one study, boosted elvitegravir equivalent to times the therapeutic dose of 150 mg once daily for 10 days was administered to 42 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.. Cobicistat: Limited clinical experience is available at doses higher than the therapeutic dose of cobicistat. In two studies, single dose of cobicistat 400 mg (2.7 times the dose in STRIBILD) was administered to total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.. Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study, single doses of emtricitabine 1200 mg (6 times the dose in STRIBILD) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.Hemodialysis treatment removes approximately 30% of the emtricitabine dose over 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per minute and dialysate flow rate of 600 mL per minute). It is not known whether emtricitabine can be removed by peritoneal dialysis.. Tenofovir DF: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one study, 600 mg tenofovir DF (2 times the dosage in STRIBILD) was administered to subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following single 300 mg dose of VIREAD, 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL. Label Image for 53808-0887150mg 150mg 200mg 300mg Label Image for 150mg 150mg 200mg 300mg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of STRIBILD in pediatric patients less than 18 years of age have not been established [see Clinical Pharmacology (12.3)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption and Bioavailability STRIBILD: Following oral administration of STRIBILD with food in HIV-1 infected subjects, peak plasma concentrations were observed hours post-dose for elvitegravir, hours post-dose for cobicistat, hours post-dose for emtricitabine, and hours for tenofovir following the conversion of tenofovir DF (see Table for additional pharmacokinetic parameters). Table Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected SubjectsParameterMean +- SD[range: min:max]ElvitegravirFrom Population Pharmacokinetic analysis, N=419. CobicistatFrom Intensive Pharmacokinetic analysis, N=61-62, except cobicistat Ctrough N=53. Emtricitabine Tenofovir SD Standard DeviationCmax (microgram per mL)1.7 +- 0.4[0.4:3.7]1.1 +- 0.4[0.1:2.1]1.9 +- 0.5[0.6:3.6]0.45 +- 0.2[0.2:1.2]AUCtau (microgramhour per mL)23.0 +- 7.5[4.4:69.8]8.3 +- 3.8[0.5:18.3]12.7 +- 4.5[5.2:34.1]4.4 +- 2.2[2.1:18.2]Ctrough (microgram per mL)0.45 +- 0.26[0.05:2.34]0.05 +- 0.13[0.01:0.92]0.14 +- 0.25[0.04:1.94]0.10 +- 0.08[0.04:0.58] Effect of Food on Oral Absorption Relative to fasting conditions, the administration of single dose STRIBILD with light meal (~373 kcal, 20% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 34% and 24%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant. Relative to fasting conditions, the administration of single dose STRIBILD with high fat meal (~ 800 kcal, 50% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 87% and 23%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant. STRIBILD should be taken with food. Distribution Elvitegravir: Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drug concentration over the range of ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio was 0.73. Cobicistat: Cobicistat is 97-98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5. Emtricitabine: In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of drug concentration over the range of 0.02-200 micrograms per mL. Tenofovir Disoproxil Fumarate: In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01-25 micrograms per mL. Metabolism Elvitegravir: The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3 enzymes. Cobicistat: Cobicistat is metabolized by CYP3A and to minor extent by CYP2D6 enzymes and does not undergo glucuronidation. Emtricitabine and tenofovir are not significantly metabolized. Elimination Elvitegravir: The median terminal plasma half-life of elvitegravir following administration of STRIBILD is approximately 12.9 hours. After single dose administration of [14C] elvitegravir (coadministered with 100 mg RTV), 94.8% and 6.7% of the administered dose was excreted in feces and urine, respectively. Cobicistat: The median terminal plasma half-life of cobicistat following administration of STRIBILD is approximately 3.5 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, 86.2% and 8.2% of the administered dose was excreted in feces and urine, respectively. Emtricitabine and tenofovir are primarily excreted in the urine by combination of glomerular filtration and active tubular secretion.Special Populations Patients with Renal Impairment Elvitegravir and cobicistat: study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment. Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per min or with end stage renal disease requiring dialysis [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Patients with Hepatic Impairment Elvitegravir and cobicistat: study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dosage adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied [see Use in Specific Populations (8.7)]. Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following 300 mg dose of VIREAD has been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects. Hepatitis and/or Hepatitis Virus Co-infection Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis and/or virus infection had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir. Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis and/or virus infection on the pharmacokinetics of cobicistat. Emtricitabine and Tenofovir: Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in subjects coinfected with hepatitis and/or virus. Race Elvitegravir: Population pharmacokinetic analysis of elvitegravir in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir. Cobicistat: Population pharmacokinetics analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of COBI. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA. Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD. Gender No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat-boosted elvitegravir, emtricitabine and tenofovir DF. Pediatric Patients Emtricitabine has been studied in pediatric subjects from months to 17 years of age. Tenofovir DF has been studied in pediatric subjects from years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects have not been established [see Use in Specific Populations (8.4)]. Geriatric Patients Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [see Use in Specific Populations (8.5)]. Absorption and Bioavailability. STRIBILD: Following oral administration of STRIBILD with food in HIV-1 infected subjects, peak plasma concentrations were observed hours post-dose for elvitegravir, hours post-dose for cobicistat, hours post-dose for emtricitabine, and hours for tenofovir following the conversion of tenofovir DF (see Table for additional pharmacokinetic parameters).. Table Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected SubjectsParameterMean +- SD[range: min:max]ElvitegravirFrom Population Pharmacokinetic analysis, N=419. CobicistatFrom Intensive Pharmacokinetic analysis, N=61-62, except cobicistat Ctrough N=53. Emtricitabine Tenofovir SD Standard DeviationCmax (microgram per mL)1.7 +- 0.4[0.4:3.7]1.1 +- 0.4[0.1:2.1]1.9 +- 0.5[0.6:3.6]0.45 +- 0.2[0.2:1.2]AUCtau (microgramhour per mL)23.0 +- 7.5[4.4:69.8]8.3 +- 3.8[0.5:18.3]12.7 +- 4.5[5.2:34.1]4.4 +- 2.2[2.1:18.2]Ctrough (microgram per mL)0.45 +- 0.26[0.05:2.34]0.05 +- 0.13[0.01:0.92]0.14 +- 0.25[0.04:1.94]0.10 +- 0.08[0.04:0.58]. Effect of Food on Oral Absorption. Relative to fasting conditions, the administration of single dose STRIBILD with light meal (~373 kcal, 20% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 34% and 24%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.. Relative to fasting conditions, the administration of single dose STRIBILD with high fat meal (~ 800 kcal, 50% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 87% and 23%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.. STRIBILD should be taken with food.. Distribution. Elvitegravir: Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drug concentration over the range of ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio was 0.73. Cobicistat: Cobicistat is 97-98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5. Emtricitabine: In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of drug concentration over the range of 0.02-200 micrograms per mL. Tenofovir Disoproxil Fumarate: In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01-25 micrograms per mL.. Metabolism. Elvitegravir: The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3 enzymes.. Cobicistat: Cobicistat is metabolized by CYP3A and to minor extent by CYP2D6 enzymes and does not undergo glucuronidation.. Emtricitabine and tenofovir are not significantly metabolized.. Elimination. Elvitegravir: The median terminal plasma half-life of elvitegravir following administration of STRIBILD is approximately 12.9 hours. After single dose administration of [14C] elvitegravir (coadministered with 100 mg RTV), 94.8% and 6.7% of the administered dose was excreted in feces and urine, respectively.. Cobicistat: The median terminal plasma half-life of cobicistat following administration of STRIBILD is approximately 3.5 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, 86.2% and 8.2% of the administered dose was excreted in feces and urine, respectively.. Emtricitabine and tenofovir are primarily excreted in the urine by combination of glomerular filtration and active tubular secretion.. Patients with Renal Impairment. Elvitegravir and cobicistat: study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.. Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per min or with end stage renal disease requiring dialysis [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Patients with Hepatic Impairment. Elvitegravir and cobicistat: study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dosage adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied [see Use in Specific Populations (8.7)]. Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.. Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following 300 mg dose of VIREAD has been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.. Hepatitis and/or Hepatitis Virus Co-infection. Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis and/or virus infection had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.. Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis and/or virus infection on the pharmacokinetics of cobicistat.. Emtricitabine and Tenofovir: Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in subjects coinfected with hepatitis and/or virus.. Race. Elvitegravir: Population pharmacokinetic analysis of elvitegravir in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.. Cobicistat: Population pharmacokinetics analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of COBI.. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.. Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.. Gender. No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat-boosted elvitegravir, emtricitabine and tenofovir DF.. Pediatric Patients. Emtricitabine has been studied in pediatric subjects from months to 17 years of age. Tenofovir DF has been studied in pediatric subjects from years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects have not been established [see Use in Specific Populations (8.4)]. Geriatric Patients Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [see Use in Specific Populations (8.5)].

PREGNANCY SECTION.

8.1 Pregnancy.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.1, 2.2, 2.3, 2.4)10/2013Warnings and PrecautionsNew Onset or Worsening Renal Impairment (5.3)10/2013Bone Effects of Tenofovir DF (5.5)10/2013.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationSTRIBILD(R) (STRY-bild)(elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate)TabletsImportant: Ask your healthcare provider or pharmacist about medicines that should not be taken with STRIBILD. For more information, see the section What should tell my healthcare provider before taking STRIBILDRead this Patient Information before you start taking STRIBILD and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.What is the most important information should know about STRIBILDSTRIBILD can cause serious side effects, including: 1.Build-up of lactic acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take STRIBILD or similar (nucleoside analogs) medicines. Lactic acidosis is serious medical emergency that can lead to death.Lactic acidosis can be hard to identify early, because the symptoms could seem like symptoms of other health problems. Call your healthcare provider right away if you get any of the following symptoms which could be signs of lactic acidosis:feel very weak or tiredhave unusual (not normal) muscle painhave trouble breathinghave stomach pain withnauseavomiting feel cold, especially in your arms and legsfeel dizzy or lightheadedhave fast or irregular heartbeat2.Severe liver problems. Severe liver problems can happen in people who take STRIBILD. In some cases, these liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis).Call your healthcare provider right away if you get any of the following symptoms of liver problems:your skin or the white part of your eyes turns yellow (jaundice)dark tea-colored urinelight-colored bowel movements (stools)loss of appetite for several days or longernauseastomach painYou may be more likely to get lactic acidosis or severe liver problems if you are female, very overweight (obese), or have been taking STRIBILD for long time. 3. Worsening of Hepatitis infection. If you have hepatitis virus (HBV) infection and take STRIBILD, your HBV may get worse (flare-up) if you stop taking STRIBILD. flare-up is when your HBV infection suddenly returns in worse way than before.Do not run out of STRIBILD. Refill your prescription or talk to your healthcare provider before your STRIBILD is all gone.Do not stop taking STRIBILD without first talking to your healthcare provider.If you stop taking STRIBILD, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking STRIBILD.For more information about side effects, see the section What are the possible side effects of STRIBILD What is STRIBILD STRIBILD is prescription medicine that is used without other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) in adults who have never taken HIV-1 medicines before. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).STRIBILD contains the prescription medicines elvitegravir, cobicistat, emtricitabine (EMTRIVA(R)) and tenofovir disoproxil fumarate (VIREAD(R)).It is not known if STRIBILD is safe and effective in children under 18 years of age.When used to treat HIV-1 infection, STRIBILD may:Reduce the amount of HIV-1 in your blood. This is called viral load.Increase the number of CD4+ (T) cells in your blood that help fight off other infections.Reduce the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).STRIBILD does not cure HIV-1 infections or AIDS. You must stay on continuous HIV-1 therapy to control HIV-1 infection and decrease HIV-related illnesses.Avoid doing things that can spread HIV-1 infection to others. Do not share or re-use needles or other injection equipment.Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades.Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.Ask your healthcare provider if you have any questions about how to prevent passing HIV-1 to other people.Who should not take STRIBILDDo not take STRIBILD if you also take medicine that contains: alfuzosin hydrochloride (UROXATRAL(R))cisapride (PROPULSID(R), PROPULSID QUICKSOLV(R))ergot-containing medicines, including:dihydroergotamine mesylate (D.H.E. 45(R), MIGRANAL(R))ergotamine tartrate (CAFERGOT(R), MIGERGOT(R),ERGOSTAT(R), MEDIHALER ERGOTAMINE(R), WIGRAINE(R), WIGRETTES(R))methylergonovine maleate (ERGOTRATE(R), METHERGINE(R)) lovastatin (ADVICOR(R), ALTOPREV(R), MEVACOR(R))oral midazolampimozide (ORAP(R))rifampin (RIFADIN(R), RIFAMATE(R), RIFATER(R), RIMACTANE(R))sildenafil (REVATIO(R)), when used for treating the lung problem, pulmonary arterial hypertension (PAH)simvastatin (SIMCOR(R), VYTORIN(R), ZOCOR(R))triazolam (HALCION(R))St. Johns wort (Hypericum perforatum) or product that contains St. Johns wortWhat should tell my healthcare provider before taking STRIBILDBefore taking STRIBILD, tell your healthcare provider if you: have liver problems including hepatitis infectionhave kidney problemshave bone problemshave any other medical conditionsare pregnant or plan to become pregnant. It is not known if STRIBILD can harm your unborn baby. Tell your healthcare provider if you become pregnant while taking STRIBILD. Pregnancy Registry. There is pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.are breastfeeding or plan to breastfeed. Do not breastfeed if you take STRIBILD. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.At least two of the medicines in STRIBILD can pass to your baby in your breast milk. It is not known if the other medicines in STRIBILD can pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby.Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. STRIBILD may affect the way other medicines work, and other medicines may affect how STRIBILD works.You should not take STRIBILD if you also take:any other medicines to treat HIV-1 infectionother medicines that contain tenofovir (ATRIPLA(R), COMPLERA(R), VIREAD(R), TRUVADA(R))other medicines that contain emtricitabine or lamivudine (ATRIPLA(R), COMPLERA(R), TRUVADA(R), COMBIVIR(R), EMTRIVA(R), EPIVIR(R) or EPIVIR-HBV(R), EPZICOM(R), TRIZIVIR(R))adefovir (HEPSERA(R))ritonavir (NORVIR(R), KALETRA(R))Especially tell your healthcare provider if you take:hormone-based contraceptives (birth control pills and patches)an antacid medicine that contains aluminum, magnesium hydroxide, or calcium carbonate. Take antacids at least hours before or after you take STRIBILD.medicines to treat depressionmedicines to prevent organ transplant rejectionmedicines to treat high blood pressureany of the following medicines: amiodarone (CORDARONE(R), PACERONE(R)) atorvastatin (LIPITOR(R), CADUET(R))bepridil hydrochloride (VASCOR(R), BEPADIN(R))bosentan (TRACLEER(R))buspironecarbamazepine (CARBATROL(R), EPITOL(R), EQUETRO(R), TEGRETOL(R))clarithromycin (BIAXIN(R), PREVPAC(R))clonazepam (KLONOPIN(R))clorazepate (GEN-XENE(R), TRANXENE(R))colchicine (COLCRYS(R))medicines that contain dexamethasonediazepam (VALIUM(R))digoxin (LANOXIN(R))disopyramide (NORPACE(R))estazolamethosuximide (ZARONTIN(R))flecainide (TAMBOCOR(R))flurazepamfluticasone (FLOVENT(R), FLONASE(R), FLOVENT(R) DISKUS(R), FLOVENT(R) HFA, VERAMYST(R))itraconazole (SPORANOX(R))ketoconazole (NIZORAL(R))lidocaine (XYLOCAINE(R))mexiletineoxcarbazepine (TRILEPTAL(R))perphenazinephenobarbital (LUMINAL(R))phenytoin (DILANTIN(R), PHENYTEK(R))propafenone (RYTHMOL(R))quinidine (NEUDEXTA(R))rifabutin (MYCOBUTIN(R))rifapentine (PRIFTIN(R))risperidone (RISPERDAL(R), RISPERDAL CONSTA(R))salmeterol (SEREVENT(R)) or salmeterol when taken in combination with fluticasone (ADVAIR DISKUS(R), ADVAIR HFA(R))sildenafil (VIAGRA(R)), tadalafil (CIALIS(R)) or vardenafil (LEVITRA(R), STAXYN(R)), for the treatment of erectile dysfunction (ED). If you get dizzy or faint (low blood pressure), have vision changes or have an erection that last longer than hours, call your healthcare provider or get medical help right away.tadalafil (ADCIRCA(R)), for the treatment of pulmonary arterial hypertensiontelithromycin (KETEK(R))thioridazinevoriconazole (VFEND(R))warfarin (COUMADIN(R), JANTOVEN(R))zolpidem (AMBIEN(R), EDLULAR(R), INTERMEZZO(R), ZOLPIMIST(R)) Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. Do not start any new medicines while you are taking STRIBILD without first talking with your healthcare provider or pharmacist.Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.How should take STRIBILD Take STRIBILD exactly as your healthcare provider tells you to take it. STRIBILD is taken by itself (not with other antiretroviral medicines) to treat HIV-1 infection. STRIBILD is usually taken time each day.Take STRIBILD with food.Do not change your dose or stop taking STRIBILD without first talking with your healthcare provider. Stay under healthcare providers care when taking STRIBILD.Do not miss dose of STRIBILD. If you miss dose of STRIBILD, take the missed dose as soon as you remember. If it is almost time for your next dose of STRIBILD, do not take the missed dose. Take the next dose of STRIBILD at your regular time. Do not take doses at the same time to make up for missed dose.If you take too much STRIBILD, call your healthcare provider or go to the nearest hospital emergency room right away.When your STRIBILD supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even short time. The virus may develop resistance to STRIBILD and become harder to treat.What are the possible side effects of STRIBILDSTRIBILD may cause the following serious side effects, including:See What is the most important information should know about STRIBILDNew or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and while you are taking STRIBILD. Your healthcare provider may tell you to stop taking STRIBILD if you develop new or worse kidney problems.Bone problems can happen in some people who take STRIBILD. Bone problems include bone pain, softening or thinning (which may lead to fractures). Your healthcare provider may need to do tests to check your bones.Changes in body fat can happen in people who take HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known.Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine.The most common side effects of STRIBILD include:nauseadiarrheaTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of STRIBILD. For more information, ask your healthcare provider or pharmacist.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store STRIBILDStore STRIBILD at room temperature between 68 to 77 (20 to 25 C).Keep STRIBILD in its original container.Keep the container tightly closed.Do not use STRIBILD if the seal over the bottle opening is broken or missing.Keep STRIBILD and all medicines out of reach of children.General information about STRIBILD.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use STRIBILD for condition for which it was not prescribed. Do not give STRIBILD to other people, even if they have the same symptoms you have. It may harm them.This leaflet summarizes the most important information about STRIBILD. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about STRIBILD that is written for health professionals.For more information, call 1-800-445-3235 or go to www.STRIBILD.com.What are the ingredients in STRIBILDActive ingredients: elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarateInactive ingredients: lactose monohydrate, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate. The tablets are film-coated with coating material containing indigo carmine (FD&C blue 2) aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.This Patient Information has been approved by the U.S. Food and Drug Administration.Manufactured and distributed by:Gilead Sciences, Inc.Foster City, CA 94404Issued: October 2013COMPLERA, EMTRIVA, HEPSERA, STRIBILD, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is trademark of Bristol-Myers Squibb Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners.This Product was Repackaged By:State of Florida DOH Central Pharmacy104-2 Hamilton Park DriveTallahassee, FL 32304USA 1.Build-up of lactic acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take STRIBILD or similar (nucleoside analogs) medicines. Lactic acidosis is serious medical emergency that can lead to death.Lactic acidosis can be hard to identify early, because the symptoms could seem like symptoms of other health problems. Call your healthcare provider right away if you get any of the following symptoms which could be signs of lactic acidosis:feel very weak or tiredhave unusual (not normal) muscle painhave trouble breathinghave stomach pain withnauseavomiting feel cold, especially in your arms and legsfeel dizzy or lightheadedhave fast or irregular heartbeat. feel very weak or tired. have unusual (not normal) muscle pain. have trouble breathing. have stomach pain withnauseavomiting nausea. vomiting. feel cold, especially in your arms and legs. feel dizzy or lightheaded. have fast or irregular heartbeat. 2.Severe liver problems. Severe liver problems can happen in people who take STRIBILD. In some cases, these liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis).Call your healthcare provider right away if you get any of the following symptoms of liver problems:your skin or the white part of your eyes turns yellow (jaundice)dark tea-colored urinelight-colored bowel movements (stools)loss of appetite for several days or longernauseastomach painYou may be more likely to get lactic acidosis or severe liver problems if you are female, very overweight (obese), or have been taking STRIBILD for long time. your skin or the white part of your eyes turns yellow (jaundice). dark tea-colored urine. light-colored bowel movements (stools). loss of appetite for several days or longer. nausea. stomach pain. 3. Worsening of Hepatitis infection. If you have hepatitis virus (HBV) infection and take STRIBILD, your HBV may get worse (flare-up) if you stop taking STRIBILD. flare-up is when your HBV infection suddenly returns in worse way than before.Do not run out of STRIBILD. Refill your prescription or talk to your healthcare provider before your STRIBILD is all gone.Do not stop taking STRIBILD without first talking to your healthcare provider.If you stop taking STRIBILD, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking STRIBILD.. Do not run out of STRIBILD. Refill your prescription or talk to your healthcare provider before your STRIBILD is all gone.. Do not stop taking STRIBILD without first talking to your healthcare provider.. If you stop taking STRIBILD, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking STRIBILD.. Reduce the amount of HIV-1 in your blood. This is called viral load.. Increase the number of CD4+ (T) cells in your blood that help fight off other infections.. Reduce the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).. Do not share or re-use needles or other injection equipment.. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades.. Do not have any kind of sex without protection. Always practice safer sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.. alfuzosin hydrochloride (UROXATRAL(R)). cisapride (PROPULSID(R), PROPULSID QUICKSOLV(R)). ergot-containing medicines, including:dihydroergotamine mesylate (D.H.E. 45(R), MIGRANAL(R))ergotamine tartrate (CAFERGOT(R), MIGERGOT(R),ERGOSTAT(R), MEDIHALER ERGOTAMINE(R), WIGRAINE(R), WIGRETTES(R))methylergonovine maleate (ERGOTRATE(R), METHERGINE(R)) dihydroergotamine mesylate (D.H.E. 45(R), MIGRANAL(R)). ergotamine tartrate (CAFERGOT(R), MIGERGOT(R),ERGOSTAT(R), MEDIHALER ERGOTAMINE(R), WIGRAINE(R), WIGRETTES(R)). methylergonovine maleate (ERGOTRATE(R), METHERGINE(R)). lovastatin (ADVICOR(R), ALTOPREV(R), MEVACOR(R)). oral midazolam. pimozide (ORAP(R)). rifampin (RIFADIN(R), RIFAMATE(R), RIFATER(R), RIMACTANE(R)). sildenafil (REVATIO(R)), when used for treating the lung problem, pulmonary arterial hypertension (PAH). simvastatin (SIMCOR(R), VYTORIN(R), ZOCOR(R)). triazolam (HALCION(R)). St. Johns wort (Hypericum perforatum) or product that contains St. Johns wort. have liver problems including hepatitis infection. have kidney problems. have bone problems. have any other medical conditions. are pregnant or plan to become pregnant. It is not known if STRIBILD can harm your unborn baby. Tell your healthcare provider if you become pregnant while taking STRIBILD. Pregnancy Registry. There is pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.. are breastfeeding or plan to breastfeed. Do not breastfeed if you take STRIBILD. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.At least two of the medicines in STRIBILD can pass to your baby in your breast milk. It is not known if the other medicines in STRIBILD can pass into your breast milk. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. At least two of the medicines in STRIBILD can pass to your baby in your breast milk. It is not known if the other medicines in STRIBILD can pass into your breast milk.. any other medicines to treat HIV-1 infection. other medicines that contain tenofovir (ATRIPLA(R), COMPLERA(R), VIREAD(R), TRUVADA(R)). other medicines that contain emtricitabine or lamivudine (ATRIPLA(R), COMPLERA(R), TRUVADA(R), COMBIVIR(R), EMTRIVA(R), EPIVIR(R) or EPIVIR-HBV(R), EPZICOM(R), TRIZIVIR(R)). adefovir (HEPSERA(R)). ritonavir (NORVIR(R), KALETRA(R)). hormone-based contraceptives (birth control pills and patches). an antacid medicine that contains aluminum, magnesium hydroxide, or calcium carbonate. Take antacids at least hours before or after you take STRIBILD.. medicines to treat depression. medicines to prevent organ transplant rejection. medicines to treat high blood pressure. any of the following medicines: amiodarone (CORDARONE(R), PACERONE(R)) atorvastatin (LIPITOR(R), CADUET(R))bepridil hydrochloride (VASCOR(R), BEPADIN(R))bosentan (TRACLEER(R))buspironecarbamazepine (CARBATROL(R), EPITOL(R), EQUETRO(R), TEGRETOL(R))clarithromycin (BIAXIN(R), PREVPAC(R))clonazepam (KLONOPIN(R))clorazepate (GEN-XENE(R), TRANXENE(R))colchicine (COLCRYS(R))medicines that contain dexamethasonediazepam (VALIUM(R))digoxin (LANOXIN(R))disopyramide (NORPACE(R))estazolamethosuximide (ZARONTIN(R))flecainide (TAMBOCOR(R))flurazepamfluticasone (FLOVENT(R), FLONASE(R), FLOVENT(R) DISKUS(R), FLOVENT(R) HFA, VERAMYST(R))itraconazole (SPORANOX(R))ketoconazole (NIZORAL(R))lidocaine (XYLOCAINE(R))mexiletineoxcarbazepine (TRILEPTAL(R))perphenazinephenobarbital (LUMINAL(R))phenytoin (DILANTIN(R), PHENYTEK(R))propafenone (RYTHMOL(R))quinidine (NEUDEXTA(R))rifabutin (MYCOBUTIN(R))rifapentine (PRIFTIN(R))risperidone (RISPERDAL(R), RISPERDAL CONSTA(R))salmeterol (SEREVENT(R)) or salmeterol when taken in combination with fluticasone (ADVAIR DISKUS(R), ADVAIR HFA(R))sildenafil (VIAGRA(R)), tadalafil (CIALIS(R)) or vardenafil (LEVITRA(R), STAXYN(R)), for the treatment of erectile dysfunction (ED). If you get dizzy or faint (low blood pressure), have vision changes or have an erection that last longer than hours, call your healthcare provider or get medical help right away.tadalafil (ADCIRCA(R)), for the treatment of pulmonary arterial hypertensiontelithromycin (KETEK(R))thioridazinevoriconazole (VFEND(R))warfarin (COUMADIN(R), JANTOVEN(R))zolpidem (AMBIEN(R), EDLULAR(R), INTERMEZZO(R), ZOLPIMIST(R)) amiodarone (CORDARONE(R), PACERONE(R)) atorvastatin (LIPITOR(R), CADUET(R)). bepridil hydrochloride (VASCOR(R), BEPADIN(R)). bosentan (TRACLEER(R)). buspirone. carbamazepine (CARBATROL(R), EPITOL(R), EQUETRO(R), TEGRETOL(R)). clarithromycin (BIAXIN(R), PREVPAC(R)). clonazepam (KLONOPIN(R)). clorazepate (GEN-XENE(R), TRANXENE(R)). colchicine (COLCRYS(R)). medicines that contain dexamethasone. diazepam (VALIUM(R)). digoxin (LANOXIN(R)). disopyramide (NORPACE(R)). estazolam. ethosuximide (ZARONTIN(R)). flecainide (TAMBOCOR(R)). flurazepam. fluticasone (FLOVENT(R), FLONASE(R), FLOVENT(R) DISKUS(R), FLOVENT(R) HFA, VERAMYST(R)). itraconazole (SPORANOX(R)). ketoconazole (NIZORAL(R)). lidocaine (XYLOCAINE(R)). mexiletine. oxcarbazepine (TRILEPTAL(R)). perphenazine. phenobarbital (LUMINAL(R)). phenytoin (DILANTIN(R), PHENYTEK(R)). propafenone (RYTHMOL(R)). quinidine (NEUDEXTA(R)). rifabutin (MYCOBUTIN(R)). rifapentine (PRIFTIN(R)). risperidone (RISPERDAL(R), RISPERDAL CONSTA(R)). salmeterol (SEREVENT(R)) or salmeterol when taken in combination with fluticasone (ADVAIR DISKUS(R), ADVAIR HFA(R)). sildenafil (VIAGRA(R)), tadalafil (CIALIS(R)) or vardenafil (LEVITRA(R), STAXYN(R)), for the treatment of erectile dysfunction (ED). If you get dizzy or faint (low blood pressure), have vision changes or have an erection that last longer than hours, call your healthcare provider or get medical help right away.. tadalafil (ADCIRCA(R)), for the treatment of pulmonary arterial hypertension. telithromycin (KETEK(R)). thioridazine. voriconazole (VFEND(R)). warfarin (COUMADIN(R), JANTOVEN(R)). zolpidem (AMBIEN(R), EDLULAR(R), INTERMEZZO(R), ZOLPIMIST(R)). Take STRIBILD exactly as your healthcare provider tells you to take it. STRIBILD is taken by itself (not with other antiretroviral medicines) to treat HIV-1 infection. STRIBILD is usually taken time each day.. Take STRIBILD with food.. Do not change your dose or stop taking STRIBILD without first talking with your healthcare provider. Stay under healthcare providers care when taking STRIBILD.. Do not miss dose of STRIBILD. If you miss dose of STRIBILD, take the missed dose as soon as you remember. If it is almost time for your next dose of STRIBILD, do not take the missed dose. Take the next dose of STRIBILD at your regular time. Do not take doses at the same time to make up for missed dose.. If you take too much STRIBILD, call your healthcare provider or go to the nearest hospital emergency room right away.. When your STRIBILD supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even short time. The virus may develop resistance to STRIBILD and become harder to treat.. See What is the most important information should know about STRIBILD. New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and while you are taking STRIBILD. Your healthcare provider may tell you to stop taking STRIBILD if you develop new or worse kidney problems.. Bone problems can happen in some people who take STRIBILD. Bone problems include bone pain, softening or thinning (which may lead to fractures). Your healthcare provider may need to do tests to check your bones.. Changes in body fat can happen in people who take HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known.. Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine.. nausea. diarrhea. Store STRIBILD at room temperature between 68 to 77 (20 to 25 C).. Keep STRIBILD in its original container.. Keep the container tightly closed.. Do not use STRIBILD if the seal over the bottle opening is broken or missing.

SPL UNCLASSIFIED SECTION.

2.1 Dosage Information. The recommended dosage of STRIBILD is one tablet taken orally once daily with food [see Clinical Pharmacology (12.3)].

STORAGE AND HANDLING SECTION.

Store at 25 (77 F), excursions permitted to 15-30 (59-86 F) (see USP Controlled Room Temperature).

USE IN SPECIFIC POPULATIONS SECTION.

Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk. (8.1)Nursing mothers: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.3). Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk. (8.1). Nursing mothers: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.3). 8.1 Pregnancy. Pregnancy Category BThere are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, STRIBILD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to STRIBILD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.. Animal Data. Elvitegravir: Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with elvitegravir during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans at the recommended daily dose of 150 mg.. Cobicistat: Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with cobicistat during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal NOAELs in rats and rabbits were respectively 1.8 and 4.3 times higher than the exposure in humans at the recommended daily dose of 150 mg.. Emtricitabine: The incidence of fetal variations and malformations was not increased in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose.. Tenofovir DF: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.. 8.3 Nursing Mothers. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir, cobicistat, and tenofovir are secreted in milk. It is not known whether elvitegravir or cobicistat is excreted in human milk.In humans, samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.Samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk. Tenofovir-associated risks, including the risk of viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir disoproxil fumarate are unknown.Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving STRIBILD. 8.4 Pediatric Use. Safety and effectiveness of STRIBILD in pediatric patients less than 18 years of age have not been established [see Clinical Pharmacology (12.3)].. 8.5 Geriatric Use. Clinical studies of STRIBILD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of STRIBILD in elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].. 8.6 Renal Impairment. Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per min is not recommended. Because STRIBILD is fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per min during treatment with STRIBILD as dose interval adjustment required for emtricitabine and tenofovir DF cannot be achieved [see Warnings and Precautions (5.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. 8.7 Hepatic Impairment. No dose adjustment of STRIBILD is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of STRIBILD in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, STRIBILD is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CLcr), urine glucose and urine protein before initiating treatment with STRIBILD. Monitor CLcr, urine glucose, and urine protein in all patients. Monitor serum phosphorus in patients at risk for renal impairment. Avoid administering STRIBILD with concurrent or recent use of nephrotoxic drugs. (5.3)Avoid coadministration with other anti-retroviral products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, or VIREAD; with drugs containing lamivudine; or with drugs or regimens containing ritonavir. Do not administer in combination with HEPSERA. (5.4)Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.5)Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.6)Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.7). New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CLcr), urine glucose and urine protein before initiating treatment with STRIBILD. Monitor CLcr, urine glucose, and urine protein in all patients. Monitor serum phosphorus in patients at risk for renal impairment. Avoid administering STRIBILD with concurrent or recent use of nephrotoxic drugs. (5.3). Avoid coadministration with other anti-retroviral products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, or VIREAD; with drugs containing lamivudine; or with drugs or regimens containing ritonavir. Do not administer in combination with HEPSERA. (5.4). Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.5). Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.6). Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.7). 5.1 Lactic 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 tenofovir DF, component of STRIBILD, in combination with other antiretrovirals. majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with STRIBILD 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).. 5.2 Patients Coinfected with HIV-1 and HBV. It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis virus (HBV) before initiating antiretroviral therapy. STRIBILD is not approved for the treatment of chronic HBV infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of STRIBILD. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD. If appropriate, initiation of anti-hepatitis therapy may be warranted.. 5.3 New Onset or Worsening Renal Impairment. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF, component of STRIBILD, and with the use of STRIBILD [see Adverse Reactions (6.2)].In the clinical trials of STRIBILD over 96 weeks, 10 (1.4%) subjects in the STRIBILD group (N=701) and (0.3%) subjects in the combined comparator groups (N 707) discontinued study drug due to renal adverse reaction. Of these discontinuations, in the STRIBILD group and in the combined comparator groups occurred during the first 48 week. Four (0.6%) of the subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of STRIBILD compared to none in the comparator groups. Two of these four subjects had renal impairment (i.e. estimated creatinine clearance less than 70 mL per minute) at baseline. The laboratory findings in these subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of STRIBILD. Renal replacement therapy was not required for these subjects.Estimated creatinine clearance, urine glucose and urine protein should be documented in all patients prior to initiating therapy. Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended.STRIBILD should be avoided with concurrent or recent use of nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [see Drug Interactions (7.4)]. Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.Routine monitoring of estimated creatinine clearance, urine glucose, and urine protein should be performed during STRIBILD therapy in all patients. Additionally, serum phosphorus should be measured in patients at risk for renal impairment. Although cobicistat (a component of STRIBILD) may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function [see Adverse Reactions (6.1)], patients who experience confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety.The emtricitabine and tenofovir DF components of STRIBILD are primarily excreted by the kidney. STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute as dose interval adjustment required for emtricitabine and tenofovir DF cannot be achieved with the fixed-dose combination tablet.. 5.4 Avoid Use with Other Antiretroviral Products. STRIBILD is indicated for use as complete regimen for the treatment of HIV-1 infection and coadministration with other antiretroviral products is not recommended.STRIBILD is not recommended for coadministration with the following:emtricitabine or tenofovir DF (ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, VIREAD);products containing lamivudine (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIZIVIR) or adefovir dipivoxil (HEPSERA);ritonavir (NORVIR, KALETRA).. emtricitabine or tenofovir DF (ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, VIREAD);. products containing lamivudine (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIZIVIR) or adefovir dipivoxil (HEPSERA);. ritonavir (NORVIR, KALETRA).. 5.5 Bone Effects of Tenofovir DF. Bone Mineral Density:In clinical trials in HIV-1 infected adults, tenofovir DF (a component of STRIBILD) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1.25 Vitamin levels were also higher in subjects receiving tenofovir DF. For additional information, see Adverse Reactions (6.1) and consult the VIREAD prescribing information.The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for HIV-1 infected patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.. Mineralization Defects:Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF [see Adverse Reactions (6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF [see Warnings and Precautions (5.3)].. 5.6 Fat 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. causal relationship has not been established.. 5.7 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including STRIBILD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.