Velpatasvir And Sofosbuvir

1 INDICATIONS AND USAGE EPCLUSA is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection [see Dosage and Administration (2.2 , 2.3 , 2.4) and Clinical Studies (14) ] : without cirrhosis or with compensated cirrhosis with decompensated cirrhosis for use in combination with ribavirin. EPCLUSA is a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, and velpatasvir, an HCV NS5A inhibitor, and is indicated for the treatment of adults and pediatric patients 3 years of age and older with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection ( 1 ): without cirrhosis or with compensated cirrhosis with decompensated cirrhosis for use in combination with ribavirin.

2 DOSAGE AND ADMINISTRATION Testing prior to the initiation of therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. ( 2.1 ) See recommended treatment regimen and duration in patients 3 years of age and older with genotypes 1, 2, 3, 4, 5, or 6 HCV in table below: ( 2.2 ) Patient Population Regimen and Duration Treatment-naïve and treatment-experienced In clinical trials, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir). , without cirrhosis and with compensated cirrhosis (Child-Pugh A) EPCLUSA 12 weeks Treatment-naïve and treatment-experienced , with decompensated cirrhosis (Child-Pugh B and C) EPCLUSA + ribavirin 12 weeks Recommended dosage in adults: One tablet (400 mg of sofosbuvir and 100 mg of velpatasvir) taken orally once daily with or without food. ( 2.3 ) Recommended dosage in pediatric patients 3 years and older: Recommended dosage is based on weight. Refer to Table 2 of the full prescribing information for specific dosing guidelines based on body weight. ( 2.4 ) For pediatric patients less than 6 years of age, administer EPCLUSA oral pellets with food. ( 2.4 ) Instructions for Use should be followed for preparation and administration of EPCLUSA oral pellets. ( 2.5 ) HCV/HIV-1 coinfection: For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the table above. ( 2.2 ) For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is EPCLUSA once daily for 12 weeks. ( 2.2 ) If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. ( 2.3 , 2.4 ) For patients with renal impairment including end stage renal disease on dialysis, follow the dosage recommendations in the table above. ( 2.6 ) 2.1 Testing Prior to the Initiation of Therapy Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with EPCLUSA [see Warnings and Precautions (5.1) ]. 2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older Table 1 shows the recommended treatment regimen and duration based on patient population . For patients with HCV/HIV-1 coinfection follow the dosage recommendations in Table 1. For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is EPCLUSA once daily for 12 weeks [see Clinical Studies (14.3 and 14.5) ]. Refer to Drug Interactions (7) for dosage recommendations for concomitant drugs. Table 1 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV Patient Population Treatment Regimen and Duration Treatment-naïve and treatment-experienced In clinical trials in adults, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir). , without cirrhosis and with compensated cirrhosis (Child-Pugh A) EPCLUSA 12 weeks Treatment-naïve and treatment-experienced , with decompensated cirrhosis (Child-Pugh B or C) EPCLUSA + ribavirin See Dosage and Administration 2.3 and 2.4 for ribavirin dosage recommendations . 12 weeks 2.3 Recommended Dosage in Adults The recommended dosage of EPCLUSA in adults is one tablet (400 mg sofosbuvir and 100 mg velpatasvir) taken orally once daily with or without food [see Clinical Pharmacology (12.3) ] . When administered with EPCLUSA, the recommended dosage of ribavirin is based on weight (administered with food): 1,000 mg per day for patients less than 75 kg and 1,200 mg for those weighing at least 75 kg, divided and administered twice daily. The starting dosage and on-treatment dosage of ribavirin can be decreased based on hemoglobin and creatinine clearance. For ribavirin dosage modifications refer to the ribavirin prescribing information [see Use in Specific Populations (8.6) and Clinical Studies (14.4) ]. 2.4 Recommended Dosage in Pediatric Patients 3 Years of Age and Older The recommended dosage of EPCLUSA in pediatric patients 3 years of age and older is based on weight and provided in Table 2. Table 3 provides the weight-based dosage of ribavirin when used in combination with EPCLUSA for pediatric patients. Take EPCLUSA oral pellets or tablets once daily with or without food. In pediatric patients less than 6 years of age, administer the oral pellets with food to increase tolerability related to palatability [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) , and Clinical Studies (14.8) ] . Table 2 Dosing for Pediatric Patients 3 Years and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV Using EPCLUSA Oral Pellets or Tablets Body Weight (kg) EPCLUSA Daily Dose Dosing of EPCLUSA Oral Pellets Dosing of EPCLUSA Tablet less than 17 150 mg/37.5 mg per day one 150 mg/37.5 mg packet of pellets once daily N/A 17 to less than 30 200 mg/50 mg per day one 200 mg/50 mg packet of pellets once daily one 200 mg/50 mg tablet once daily at least 30 400 mg/100 mg per day two 200 mg/50 mg packets of pellets once daily one 400 mg/100 mg tablet once daily Two 200 mg/50 mg tablets once daily can be used for patients who cannot swallow the 400 mg/100 mg tablet. Table 3 Recommended Dosing for Ribavirin in Combination Therapy with EPCLUSA for Pediatric Patients 3 Years and Older Body Weight (kg) Oral Ribavirin Daily Dosage The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food. less than 47 15 mg per kg per day (divided dose AM and PM) 47–49 600 mg per day (1 × 200 mg AM, 2 × 200 mg PM) 50–65 800 mg per day (2 × 200 mg AM, 2 × 200 mg PM) 66–80 1,000 mg per day (2 × 200 mg AM, 3 × 200 mg PM) greater than 80 1,200 mg per day (3 × 200 mg AM, 3 × 200 mg PM) 2.5 Preparation and Administration of Oral Pellets See the EPCLUSA oral pellets full Instructions for Use for details on the preparation and administration of EPCLUSA oral pellets. Do not chew EPCLUSA oral pellets to avoid a bitter aftertaste. EPCLUSA oral pellets can be taken directly in the mouth or with food (See Instructions for Use ). In pediatric patients less than 6 years of age, administer the oral pellets with food to increase tolerability related to palatability. Sprinkle the oral pellets on one or more spoonfuls of non-acidic soft food at or below room temperature. Examples of non-acidic foods include pudding, chocolate syrup, and ice cream. Take EPCLUSA oral pellets within 15 minutes of gently mixing with food and swallow the entire contents without chewing. 2.6 Renal Impairment No dosage adjustment of EPCLUSA is recommended in patients with any degree of renal impairment, including patients requiring dialysis. Administer EPCLUSA with or without ribavirin according to the recommendations in Table 1 [see Adverse Reactions (6.1) , Use in Specific Populations (8.6) , and Clinical Studies (14.6) ]. Refer to ribavirin tablet prescribing information for ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per minute.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Serious Symptomatic Bradycardia When Coadministered with Amiodarone [see Warnings and Precautions (5.2) ]. The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed in adults and pediatric subjects 6 years of age and older with treatment with EPCLUSA for 12 weeks are headache and fatigue. ( 6.1 ) The most common adverse reactions (incidence greater than or equal to 10%, grade 1 or 2) observed in pediatric subjects less than 6 years of age are vomiting and product use issue (spitting up the drug). ( 6.1 ) The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with EPCLUSA and ribavirin for 12 weeks in adult patients with decompensated cirrhosis are fatigue, anemia, nausea, headache, insomnia, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. If EPCLUSA is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects Adverse Reactions in Subjects without Cirrhosis or with Compensated Cirrhosis The adverse reactions data for EPCLUSA in patients without cirrhosis or with compensated cirrhosis were derived from three Phase 3 clinical trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3) which evaluated a total of 1035 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis, who received EPCLUSA for 12 weeks. EPCLUSA was studied in placebo- and active-controlled trials [see Clinical Studies (14.2) ] . The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received EPCLUSA for 12 weeks. The most common adverse reactions (adverse events assessed as causally related by the investigator and at least 10%) were headache and fatigue in subjects treated with EPCLUSA for 12 weeks. Adverse reactions, all grades, observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with EPCLUSA in ASTRAL-1 include headache (22%), fatigue (15%), nausea (9%), asthenia (5%), and insomnia (5%). Of subjects receiving EPCLUSA who experienced these adverse reactions, 79% had an adverse reaction of mild severity (Grade 1). With the exception of asthenia, each of these adverse reactions occurred at a similar frequency or more frequently in subjects treated with placebo compared to subjects treated with EPCLUSA (asthenia: 3% versus 5% for the placebo and EPCLUSA groups, respectively). The adverse reactions observed in subjects treated with EPCLUSA in ASTRAL-2 and ASTRAL-3 were consistent with those observed in ASTRAL-1. Irritability was also observed in greater than or equal to 5% of subjects treated with EPCLUSA in ASTRAL-3. Adverse Reactions in Subjects Coinfected with HCV and HIV-1 The safety assessment of EPCLUSA in subjects with HCV/HIV-1 coinfection was based on an open-label clinical trial (ASTRAL-5) in 106 subjects who were on stable antiretroviral therapy [see Clinical Studies (14.3) ] . The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. The most common adverse reactions occurring in at least 10% of subjects were fatigue (22%) and headache (10%). Adverse Reactions in Subjects with Decompensated Cirrhosis The safety assessment of EPCLUSA in subjects infected with genotype 1, 2, 3, 4, or 6 HCV with decompensated cirrhosis was based on one Phase 3 trial (ASTRAL-4) including 87 subjects who received EPCLUSA with ribavirin for 12 weeks. All 87 subjects had Child-Pugh B cirrhosis at screening. On the first day of treatment with EPCLUSA with ribavirin, 6 subjects and 4 subjects were assessed to have Child-Pugh A and Child-Pugh C cirrhosis, respectively [see Clinical Studies (14.4) ] . The most common adverse reactions (adverse events assessed as causally related by the investigator, all grades with frequency of 10% or greater) in the 87 subjects who received EPCLUSA with ribavirin for 12 weeks were fatigue (32%), anemia (26%), nausea (15%), headache (11%), insomnia (11%), and diarrhea (10%). Of subjects who experienced these adverse reactions, 98% had adverse reactions of mild to moderate severity. A total of 4 (5%) subjects permanently discontinued EPCLUSA with ribavirin due to an adverse event; there was no adverse event leading to discontinuation that occurred in more than 1 subject. Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 23% and 7% of subjects treated with EPCLUSA with ribavirin for 12 weeks, respectively. Ribavirin was permanently discontinued in 17% of subjects treated with EPCLUSA with ribavirin for 12 weeks, due to adverse reactions. Less Common Adverse Reactions Reported in Clinical Trials The following adverse reactions occurred in less than 5% of subjects without cirrhosis or with compensated cirrhosis treated with EPCLUSA for 12 weeks and are included because of a potential causal relationship. Rash: In the ASTRAL-1 study, rash occurred in 2% of subjects treated with EPCLUSA and in 1% of subjects treated with placebo. No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity. Depression: In the ASTRAL-1 study, depressed mood occurred in 1% of subjects treated with EPCLUSA and was not reported by any subject taking placebo. No serious adverse reactions of depressed mood occurred, and all events were mild or moderate in severity. The following adverse reactions occurred in less than 10% of subjects with decompensated cirrhosis (ASTRAL-4) treated with EPCLUSA with ribavirin for 12 weeks and are included because of a potential causal relationship. Rash: Rash occurred in 5% of subjects treated with EPCLUSA with ribavirin. No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity. Laboratory Abnormalities Lipase Elevations: In ASTRAL-1, isolated, asymptomatic lipase elevations of greater than 3×ULN were observed in 3% and 1% of subjects treated with EPCLUSA and placebo for 12 weeks, respectively; and in 6% and 3% of subjects treated with EPCLUSA in ASTRAL-2 and ASTRAL-3, respectively. In the Phase 3 trial of subjects with decompensated cirrhosis (ASTRAL-4), lipase was assessed when amylase values were greater than or equal to 1.5×ULN. Isolated, asymptomatic lipase elevations of greater than 3×ULN were observed in 2% of subjects treated with EPCLUSA with ribavirin for 12 weeks. Creatine Kinase: In ASTRAL-1, isolated, asymptomatic creatine kinase elevations greater than or equal to 10×ULN were reported in 1% and 0% of subjects treated with EPCLUSA and placebo for 12 weeks, respectively; and in 2% and 1% of subjects treated with EPCLUSA in ASTRAL-2 and ASTRAL-3, respectively. In the Phase 3 trial with decompensated cirrhosis (ASTRAL-4), isolated, asymptomatic creatine kinase elevations greater than or equal to 10×ULN were reported in 1% of subjects treated with EPCLUSA with ribavirin for 12 weeks. Indirect Bilirubin: Increases in indirect bilirubin up to 3 mg/dL above baseline were noted among HIV-1/HCV coinfected subjects treated with EPCLUSA and an atazanavir/ritonavir-based antiretroviral regimen. The elevated indirect bilirubin values were not associated with clinical adverse events, and all subjects completed 12 weeks of EPCLUSA without dose adjustment or treatment interruption of either EPCLUSA or HIV antiretroviral agents. Adverse Reactions in Adult Liver Transplant Recipients The safety assessment of EPCLUSA in liver transplant recipients was based on an open-label clinical trial (Trial 2104) in 79 adults without cirrhosis or with compensated cirrhosis who received EPCLUSA for 12 weeks [see Clinical Studies (14.5) ] . One subject discontinued treatment due to an adverse event on Day 7. The adverse reactions observed were consistent with the known safety profile of EPCLUSA. Adverse reactions occurring in at least 5% of subjects were headache (18%), fatigue (15%), nausea (8%), diarrhea (6%), and asthenia (5%). Adverse Reactions in Adults with Severe Renal Impairment Requiring Dialysis In an open-label trial (Trial 4062), in which a total of 59 adults with HCV with compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis received EPCLUSA for 12 weeks, the most common adverse reaction was nausea (7%) [see Clinical Studies (14.6) ]. Adverse Reactions in People Who Inject Drugs (PWID), Including Those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder The safety of EPCLUSA in PWID is based on an open-label Phase 2 trial (SIMPLIFY) that enrolled 103 adult subjects with chronic HCV genotype 1, 2, 3, and 4 infection. Subjects who self-reported injection drug use within the 6 months prior to starting treatment were eligible and were treated with EPCLUSA for 12 weeks. The trial included a subset of 58 subjects on MAT for opioid use disorder. The adverse reactions observed from SIMPLIFY both overall and in subjects on MAT were consistent with the known safety profile of EPCLUSA. The most common adverse reactions overall were fatigue (18%), nausea (13%), and headache (11%) [see Use in Specific Populations (8.8) and Clinical Studies (14.7) ]. Adverse reactions leading to permanent discontinuation of treatment were not observed in any subjects. Adverse Reactions in Pediatric Subjects 3 Years of Age and Older The safety assessment of EPCLUSA in pediatric subjects 3 years of age and older is based on data from a Phase 2, open-label clinical trial (Study 1143) that enrolled 216 subjects who were treated with EPCLUSA for 12 weeks [see Clinical Studies (14.8) ] . The adverse reactions observed in pediatric subjects 6 years of age and older were consistent with those observed in clinical trials of EPCLUSA in adults. Among the 41 pediatric subjects less than 6 years of age, gastrointestinal adverse reactions were reported more commonly compared to subjects 6 years of age and older. Vomiting and product use issue (spitting up the drug) were reported in 15% and 10% of subjects, respectively; these adverse reactions were mild (Grade 1 or 2) and led to treatment discontinuation in 5 (12%) subjects [see Use in Specific Populations (8.4) and Clinical Studies (14.8) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sofosbuvir. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with a sofosbuvir-containing regimen [see Warnings and Precautions (5.2) and Drug Interactions (7.3) ]. Skin and Subcutaneous Tissue Disorders Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema

12.3 Pharmacokinetics The pharmacokinetic properties of the components of EPCLUSA are provided in Table 5. The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite, GS-331007, and velpatasvir are provided in Table 6. Table 5 Pharmacokinetic Properties of the Components of EPCLUSA Sofosbuvir Velpatasvir CES1 = carboxylesterase 1; HINT1 = histidine triad nucleotide-binding protein 1. Absorption T max (hr) 0.5–1 3 Effect of moderate meal (relative to fasting) Values refer to mean systemic exposure. Moderate meal = ~600 kcal, 30% fat; high fat meal = ~800 kcal, 50% fat. EPCLUSA can be taken with or without food. ↑ 60% ↑ 34% Effect of high fat meal (relative to fasting) ↑ 78% ↑ 21% Distribution % Bound to human plasma proteins 61–65 >99.5 Blood-to-plasma ratio 0.7 0.52–0.67 Metabolism Metabolism Cathepsin A CES1 HINT1 CYP2B6 CYP2C8 CYP3A4 Elimination Major route of elimination SOF: metabolism GS-331007 GS-331007 is the primary circulating nucleoside metabolite of SOF. : glomerular filtration and active tubular secretion Biliary excretion as parent (77%) t 1/2 (hr) t 1/2 values refer to median terminal plasma half-life. SOF: 0.5 GS-331007 : 25 15 % Of dose excreted in urine Single dose administration of [ 14 C] SOF or [ 14 C] VEL in mass balance studies. 80 Predominantly as GS-331007. 0.4 % Of dose excreted in feces 14 94 Table 6 Multiple Dose Pharmacokinetic Parameters of Sofosbuvir and its Metabolite, GS-331007, and Velpatasvir Following Oral Administration of EPCLUSA in HCV-Infected Adults Parameter Mean (%CV) Sofosbuvir From Population PK analysis, N = 666 GS-331007 From Population PK analysis, N = 1029 Velpatasvir From Population PK analysis, N = 1025 CV = coefficient of variation; NA = not applicable. C max (ng/mL) 567 (30.7) 898 (26.7) 259 (54.3) AUC tau (ng∙hr/mL) 1268 (38.5) 14372 (28.0) 2980 (51.3) C trough (ng/mL) NA - 42 (67.3) Sofosbuvir and GS-331007 AUC 0–24 and C max were similar in healthy adult subjects and subjects with HCV infection. Relative to healthy subjects (N=331), velpatasvir AUC 0–24 and C max were 37% lower and 42% lower, respectively, in HCV-infected subjects. Velpatasvir AUC increases in a greater than proportional manner from 5 to 50 mg and in a less than proportional manner from 50 to 450 mg in healthy volunteers. However, velpatasvir exhibited more than or near dose-proportional increase in exposures 25 mg to 150 mg in HCV-infected patients when coadministered with sofosbuvir. Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 1200 mg. Specific Populations Pediatric Patients: The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were determined in HCV genotype 1, 2, 3, 4, or 6 infected pediatric subjects 3 years of age and older receiving a daily dose of EPCLUSA as described below in Table 7. Sofosbuvir AUC tau and C max and velpatasvir C max values were 67%, 69%, and 78% higher in pediatric subjects ≥30 kg, 68%, 70%, and 96% higher in pediatric subjects 17 to <30 kg, and 103%, 135%, and 92% higher in pediatric subjects <17 kg compared to those observed in adults. These differences were not considered clinically significant. GS-331007 exposures and velpatasvir AUC tau and C tau values in pediatric subjects were similar to those observed in adults. Table 7 Exposures of Sofosbuvir, GS-331007, and Velpatasvir at Steady-State in HCV-Infected Pediatric Subjects 3 Years of Age and Older Population PK derived parameters Weight Group Dose PK Parameter Mean (%CV) Sofosbuvir GS-331007 Velpatasvir CV = coefficient of variation; NA = not applicable. <17 kg Sofosbuvir N=11; GS-331007 N=11; Velpatasvir N=11 150/37.5 mg C max (ng/mL) 1550 (65.2) 1090 (17.0) 488 (46.6) AUC tau (ng∙hr/mL) 2830 (63.7) 11900 (19.7) 4480 (53.4) C trough (ng/mL) NA - 57.4 (82.7) 17 to <30 kg Sofosbuvir N=62; GS-331007 N=64; Velpatasvir N=64 200/50 mg C max (ng/mL) 1200 (73.8) 1070 (27.2) 483 (39.5) AUC tau (ng∙hr/mL) 2280 (55.6) 11400 (43.3) 4090 (38.5) C trough (ng/mL) NA - 43 (65.8) ≥30 kg Sofosbuvir N=90; GS-331007 N=101; Velpatasvir N=101 400/100 mg C max (ng/mL) 1310 (91.4) 1180 (24.6) 456 (56.4) AUC tau (ng∙hr/mL) 2570 (82.8) 13600 (27.6) 4240 (46.7) C trough (ng/mL) NA - 42.2 (66.4) The pharmacokinetics of sofosbuvir, GS-331007 and velpatasvir have not been established in pediatric subjects less than 3 years of age [see Use in Specific Populations (8.4) and Clinical Studies (14.7) ] . Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 82 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir, GS-331007, or velpatasvir [see Use in Specific Populations (8.5) ] . Patients with Renal Impairment: The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m 2 ), moderate (eGFR between 30 to less than 50 mL/min/1.73 m 2 ), severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m 2 ), the sofosbuvir AUC 0–inf was 61%, 107%, and 171% higher in subjects with mild, moderate, and severe renal impairment, while the GS-331007 AUC 0–inf was 55%, 88%, and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir and GS-331007 AUC 0–inf was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed approximately 18% of administered dose [see Dosage and Administration (2.6) and Use in Specific Populations (8.6) ]. The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in velpatasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment [see Use in Specific Populations (8.6) ]. The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected subjects with ESRD requiring dialysis treated with EPCLUSA for 12 weeks. The results were generally consistent with those in HCV negative subjects with ESRD requiring dialysis. Patients with Hepatic Impairment: The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C, respectively). Relative to subjects with normal hepatic function, the sofosbuvir AUC 0–24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC 0–24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of sofosbuvir and GS-331007 [see Use in Specific Populations (8.7) ]. The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV negative subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Velpatasvir plasma exposure (AUC inf ) was similar in subjects with moderate hepatic impairment, severe hepatic impairment, and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of velpatasvir [see Use in Specific Populations (8.7) ]. Race: Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of sofosbuvir, GS-331007, or velpatasvir. Gender: Population pharmacokinetics analysis in HCV-infected subjects indicated that gender had no clinically relevant effect on the exposure of sofosbuvir, GS-331007, or velpatasvir. Drug Interaction Studies After oral administration of EPCLUSA, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction (hydrolysis followed by sequential phosphorylation) to form the pharmacologically active triphosphate. In clinical pharmacology studies, both sofosbuvir and the primary circulating metabolite GS-331007 (dephosphorylated nucleotide metabolite) were monitored for purposes of pharmacokinetic analyses. Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Velpatasvir is also transported by OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John's wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of EPCLUSA [see Warnings and Precautions (5.3) and Drug Interactions (7.3) ] . Coadministration with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir and/or velpatasvir plasma concentrations without increasing GS-331007 plasma concentration. Drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. Velpatasvir is an inhibitor of drug transporter P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentration, velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3, or MATE1, or CYP or UGT1A1 enzymes. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 and GS-331007 is not an inhibitor of OAT1, OAT3, OCT2, and MATE1. Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes. The effects of coadministered drugs on the exposure of sofosbuvir, GS-331007, and velpatasvir are shown in Table 8. The effects of sofosbuvir, velpatasvir, or EPCLUSA on the exposure of coadministered drugs are shown in Table 9 [see Drug Interactions (7) ]. Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Sofosbuvir, GS-331007, and Velpatasvir in the Presence of the Coadministered Drug All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) SOF Dose (mg) VEL Dose (mg) N Mean Ratio (90% CI) of Sofosbuvir, GS-331007, and Velpatasvir PK With/Without Coadministered Drug No Effect=1.00 C max AUC C min NA = not available/not applicable, ND = not dosed, DF = disoproxil fumarate. Atazanavir/ ritonavir + emtricitabine/ tenofovir DF 300/100 + 200/300 once daily 400 once daily 100 once daily 24 sofosbuvir 1.12 (0.97, 1.29) 1.22 (1.12, 1.33) NA GS-331007 1.21 (1.12, 1.29) 1.32 (1.27, 1.36) 1.42 (1.37, 1.49) velpatasvir 1.55 (1.41, 1.71) 2.42 (2.23, 2.64) 4.01 (3.57, 4.50) Carbamazepine 300 twice daily 400 single dose ND 24 sofosbuvir 0.52 (0.43, 0.62) 0.52 (0.46, 0.59) NA GS-331007 1.04 (0.97, 1.11) 0.99 (0.94, 1.04) NA Cyclosporine 600 single dose 400 single dose ND 19 sofosbuvir 2.54 (1.87, 3.45) 4.53 (3.26, 6.30) NA GS-331007 0.60 (0.53, 0.69) 1.04 (0.90, 1.20) NA ND 100 single dose 12 velpatasvir 1.56 (1.22, 2.01) 2.03 (1.51, 2.71) NA Darunavir/ ritonavir + emtricitabine/ tenofovir DF 800/100 + 200/300 once daily 400 once daily 100 once daily 29 sofosbuvir 0.62 (0.54, 0.71) 0.72 (0.66, 0.80) NA GS-331007 1.04 (0.99, 1.08) 1.13 (1.08, 1.18) 1.13 (1.06, 1.19) velpatasvir 0.76 (0.65, 0.89) 0.84 (0.72, 0.98) 1.01 (0.87, 1.18) Efavirenz/ emtricitabine/ tenofovir DF Administered as ATRIPLA ® (efavirenz, emtricitabine, and tenofovir DF fixed-dose combination). 600/200/300 once daily 400 once daily 100 once daily 14 sofosbuvir 1.38 (1.14, 1.67) 0.97 (0.83, 1.14) NA GS-331007 0.86 (0.80, 0.93) 0.90 (0.85, 0.96) 1.01 (0.95, 1.07) velpatasvir 0.53 (0.43, 0.64) 0.47 (0.39, 0.57) 0.43 (0.36, 0.52) Elvitegravir/ cobicistat/emtricitabine/tenofovir alafenamide Administered as GENVOYA ® (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fixed-dose combination). 150/150/200/10 once daily 400 once daily 100 once daily 24 sofosbuvir 1.23 (1.07, 1.42) 1.37 (1.24, 1.52) NA GS-331007 1.29 (1.25, 1.33) 1.48 (1.43, 1.53) 1.58 (1.52, 1.65) velpatasvir 1.30 (1.17, 1.45) 1.50 (1.35, 1.66) 1.60 (1.44, 1.78) Elvitegravir/ cobicistat/emtricitabine/tenofovir DF Administered as STRIBILD ® (elvitegravir, cobicistat, emtricitabine, and tenofovir DF fixed-dose combination). 150/150/200/300 once daily 400 once daily 100 once daily 24 sofosbuvir 1.01 (0.85, 1.19) 1.24 (1.13, 1.37) NA GS-331007 1.13 (1.07, 1.18) 1.35 (1.30, 1.40) 1.45 (1.38, 1.52) velpatasvir 1.05 (0.93, 1.19) 1.19 (1.07, 1.34) 1.37 (1.22, 1.54) Famotidine 40 single dose simultaneously with EPCLUSA 400 single dose 100 single dose 60 sofosbuvir 0.92 (0.82, 1.05) 0.82 (0.74, 0.91) NA GS-331007 0.84 (0.78, 0.89) 0.94 (0.91, 0.98) NA velpatasvir 0.80 (0.70, 0.91) 0.81 (0.71, 0.91) NA 40 single dose 12 hours prior to EPCLUSA 60 sofosbuvir 0.77 (0.68, 0.87) 0.80 (0.73, 0.88) NA GS-331007 1.20 (1.13, 1.28) 1.04 (1.01, 1.08) NA velpatasvir 0.87 (0.76, 1.00) 0.85 (0.74, 0.97) NA Ketoconazole 200 twice daily ND 100 single dose 12 velpatasvir 1.29 (1.02, 1.64) 1.71 (1.35, 2.18) NA Lopinavir/ ritonavir + emtricitabine/ tenofovir DF 4×200/50 + 200/300 once daily 400 once daily 100 once daily 24 sofosbuvir 0.59 (0.49, 0.71) 0.71 (0.64, 0.78) NA GS-331007 1.01 (0.98, 1.05) 1.15 (1.09, 1.21) 1.15 (1.07, 1.25) velpatasvir 0.70 (0.59, 0.83) 1.02 (0.89, 1.17) 1.63 (1.43, 1.85) Methadone 30 to 130 daily 400 once daily ND 14 sofosbuvir 0.95 (0.68, 1.33) 1.30 (1.00, 1.69) NA GS-331007 0.73 (0.65, 0.83) 1.04 (0.89, 1.22) NA Omeprazole 20 once daily simultaneously with EPCLUSA 400 single dose fasted 100 single dose fasted 60 sofosbuvir 0.66 (0.55, 0.78) 0.71 (0.60, 0.83) NA GS-331007 1.18 (1.10, 1.26) 1.00 (0.95, 1.05) NA velpatasvir 0.63 (0.50, 0.78) 0.64 (0.52, 0.79) NA 20 once daily 12 hours prior to EPCLUSA 400 single dose fasted 100 single dose fasted 60 sofosbuvir 0.55 (0.47, 0.64) 0.56 (0.49, 0.65) NA GS-331007 1.26 (1.18, 1.34) 0.97 (0.94, 1.01) NA velpatasvir 0.43 (0.35, 0.54) 0.45 (0.37, 0.55) NA 20 once daily 2 hours prior to EPCLUSA 400 single dose fed EPCLUSA was administered under fasted conditions in the reference arms. 100 single dose fed 40 sofosbuvir 0.84 (0.68, 1.03) 1.08 (0.94, 1.25) NA GS-331007 0.94 (0.88, 1.02) 0.99 (0.96, 1.03) NA velpatasvir 0.52 (0.43, 0.64) 0.62 (0.51, 0.75) NA 20 once daily 4 hours after EPCLUSA 400 single dose fed 100 single dose fed 38 sofosbuvir 0.79 (0.68, 0.92) 1.05 (0.94, 1.16) NA GS-331007 0.91 (0.85, 0.98) 0.99 (0.95, 1.02) NA velpatasvir 0.67 (0.58, 0.78) 0.74 (0.63, 0.86) NA 40 once daily 4 hours after EPCLUSA 400 single dose fed 100 single dose fed 40 sofosbuvir 0.70 (0.57, 0.87) 0.91 (0.76, 1.08) NA GS-331007 1.01 (0.96, 1.07) 0.99 (0.94, 1.03) NA velpatasvir 0.44 (0.34, 0.57) 0.47 (0.37, 0.60) NA Rifabutin 300 once daily 400 single dose ND 20 sofosbuvir 0.64 (0.53, 0.77) 0.76 (0.63, 0.91) NA GS-331007 1.15 (1.03, 1.27) 1.03 (0.95, 1.12) NA Rifampin 600 once daily 400 single dose ND 17 sofosbuvir 0.23 (0.19, 0.29) 0.28 (0.24, 0.32) NA GS-331007 1.23 (1.14, 1.34) 0.95 (0.88, 1.03) NA ND 100 single dose 12 velpatasvir 0.29 (0.23, 0.37) 0.18 (0.15, 0.22) NA 600 single dose ND 100 single dose 12 velpatasvir 1.28 (1.05, 1.56) 1.46 (1.17, 1.83) NA Tacrolimus 5 single dose 400 single dose ND 16 sofosbuvir 0.97 (0.65, 1.43) 1.13 (0.81, 1.57) NA GS-331007 0.97 (0.83, 1.14) 1.00 (0.87, 1.13) NA No effect on the pharmacokinetic parameters of sofosbuvir, GS-331007, or velpatasvir was observed with dolutegravir; the combination of emtricitabine, rilpivirine, and tenofovir DF; emtricitabine; raltegravir; or tenofovir DF. Table 9 Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Sofosbuvir, Velpatasvir, or EPCLUSA All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) SOF Dose (mg) VEL Dose (mg) N Mean Ratio (90% CI) of Coadministered Drug PK With/Without Sofosbuvir, Velpatasvir, or EPCLUSA No Effect=1.00 C max AUC C min NA = not available/not applicable, ND = not dosed, DF = disoproxil fumarate. Atazanavir/ ritonavir + emtricitabine/ tenofovir DF Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir DF. atazanavir 300 once daily 400 once daily 100 once daily 24 1.09 (1.00, 1.19) 1.20 (1.10, 1.31) 1.39 (1.20, 1.61) ritonavir 100 once daily 0.89 (0.82, 0.97) 0.97 (0.89, 1.05) 1.29 (1.15, 1.44) emtricitabine 200 once daily 1.01 (0.96, 1.06) 1.02 (0.99, 1.04) 1.06 (1.02, 1.11) tenofovir DF 300 once daily 1.55 (1.43, 1.68) 1.30 (1.24, 1.36) 1.39 (1.31, 1.48) Atorvastatin 40 single dose 400 once daily 100 once daily 26 1.68 (1.49, 1.89) 1.54 (1.45, 1.64) NA Darunavir/ ritonavir + emtricitabine/ tenofovir DF Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir DF. darunavir 800 once daily 400 once daily 100 once daily 29 0.90 (0.86, 0.95) 0.92 (0.87, 0.98) 0.87 (0.79, 0.95) ritonavir 100 once daily 1.07 (0.97, 1.17) 1.12 (1.05, 1.19) 1.09 (1.02, 1.15) emtricitabine 200 once daily 1.05 (1.01, 1.08) 1.05 (1.02, 1.08) 1.04 (0.98, 1.09) tenofovir DF 300 once daily 1.55 (1.45, 1.66) 1.39 (1.33, 1.44) 1.52 (1.45, 1.59) Digoxin 0.25 single dose ND 100 21 1.88 (1.71, 2.08) 1.34 (1.13, 1.60) NA Efavirenz/ emtricitabine/ tenofovir DF Administered as ATRIPLA (efavirenz, emtricitabine, and tenofovir DF fixed-dose combination). efavirenz 600 once daily 400 once daily 100 once daily 15 0.81 (0.74, 0.89) 0.85 (0.80, 0.91) 0.90 (0.85, 0.95) emtricitabine 200 once daily 1.07 (0.98, 1.18) 1.07 (1.00, 1.14) 1.10 (0.97, 1.25) tenofovir DF 300 once daily 1.77 (1.53, 2.04) 1.81 (1.68, 1.94) 2.21 (2.00, 2.43) Elvitegravir/ cobicistat/emtricitabine/tenofovir alafenamide Administered as GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fixed-dose combination). elvitegravir 150 once daily 400 once daily 100 once daily 24 0.87 (0.80, 0.94) 0.94 (0.88, 1.00) 1.08 (0.97, 1.20) cobicistat 150 once daily 1.16 (1.09, 1.23) 1.30 (1.23, 1.38) 2.03 (1.67, 2.48) emtricitabine 200 once daily 1.02 (0.97, 1.06) 1.01 (0.98, 1.04) 1.02 (0.97, 1.07) tenofovir alafenamide 10 once daily 0.80 (0.68, 0.94) 0.87 (0.81, 0.94) NA Elvitegravir/ cobicistat/emtricitabine/tenofovir DF Administered as STRIBILD (elvitegravir, cobicistat, emtricitabine, and tenofovir DF fixed-dose combination). elvitegravir 150 once daily 400 once daily 100 once daily 24 0.93 (0.86, 1.00) 0.93 (0.87, 0.99) 0.97 (0.91, 1.04) cobicistat 150 once daily 1.11 (1.06, 1.17) 1.23 (1.17, 1.29) 1.71 (1.54, 1.90) emtricitabine 200 once daily 1.02 (0.97, 1.08) 1.01 (0.98, 1.04) 1.06 (1.01, 1.11) tenofovir DF 300 once daily 1.36 (1.25, 1.47) 1.35 (1.29, 1.42) 1.45 (1.39, 1.51) Emtricitabine/ rilpivirine/ tenofovir DF Administered as COMPLERA ® (emtricitabine, rilpivirine, and tenofovir DF fixed-dose combination). emtricitabine 200 once daily 400 once daily 100 once daily 24 0.95 (0.90, 1.00) 0.99 (0.97, 1.02) 1.05 (0.99, 1.11) rilpivirine 25 once daily 0.93 (0.88, 0.98) 0.95 (0.90, 1.00) 0.96 (0.90, 1.03) tenofovir DF 300 once daily 1.44 (1.33, 1.55) 1.40 (1.34, 1.46) 1.84 (1.76, 1.92) Norelgestromin norgestimate 0.180/0.215/0.25/ethinyl estradiol 0.025 once daily ND 100 once daily 13 0.97 (0.88, 1.07) 0.90 (0.82, 0.98) 0.92 (0.83, 1.03) 400 once daily ND 15 1.07 (0.94, 1.22) 1.06 (0.92, 1.21) 1.07 (0.89, 1.28) Norgestrel ND 100 once daily 13 0.96 (0.78, 1.19) 0.91 (0.73, 1.15) 0.92 (0.73, 1.18) 400 once daily ND 15 1.18 (0.99, 1.41) 1.19 (0.98, 1.45) 1.23 (1.00, 1.51) Ethinyl estradiol ND 100 once daily 12 1.39 (1.17, 1.66) 1.04 (0.87, 1.24) 0.83 (0.65, 1.06) 400 once daily ND 15 1.15 (0.97, 1.36) 1.09 (0.94, 1.26) 0.99 (0.80, 1.23) Pravastatin 40 single dose ND 100 once daily 18 1.28 (1.08, 1.52) 1.35 (1.18, 1.54) NA Rosuvastatin 10 single dose ND 100 once daily 18 2.61 (2.32, 2.92) 2.69 (2.46, 2.94) NA Raltegravir + emtricitabine/ tenofovir DF emtricitabine 200 once daily 400 once daily 100 once daily 30 1.08 (1.04, 1.12) 1.05 (1.03, 1.07) 1.02 (0.97, 1.08) tenofovir DF 300 once daily 1.46 (1.39, 1.54) 1.40 (1.34, 1.45) 1.70 (1.61, 1.79) raltegravir 400 twice daily 1.03 (0.74, 1.43) 0.97 (0.73, 1.28) 0.79 (0.42, 1.48) Tacrolimus 5 single dose 400 single dose ND 16 0.73 (0.59, 0.90) 1.09 (0.84, 1.40) NA No effect on the pharmacokinetic parameters of the following coadministered drugs was observed or is expected with EPCLUSA (buprenorphine/naloxone, dolutegravir, lopinavir/ritonavir, or methadone) or its components sofosbuvir (cyclosporine) or velpatasvir (cyclosporine).