Tablets EPCLUSA is a fixed-dose combination tablet containing sofosbuvir and velpatasvir for oral administration. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor and velpatasvir is an NS5A inhibitor. Each 400 mg/100 mg tablet contains 400 mg sofosbuvir and 100 mg velpatasvir, and each 200 mg/50 mg tablet contains 200 mg sofosbuvir and 50 mg velpatasvir. The tablets include the following inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Pellets EPCLUSA oral pellets are for oral administration, supplied as small, white to off-white pellets in unit-dose packets. Each unit-dose of EPCLUSA oral pellets contains either 200 mg sofosbuvir and 50 mg velpatasvir or 150 mg sofosbuvir and 37.5 mg velpatasvir and the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The oral pellets are film-coated with a coating material containing the following inactive ingredients: amino methacrylate copolymer, colloidal silicon dioxide, hypromellose, L-tartaric acid, polyethylene glycol, stearic acid, talc, and titanium dioxide. Sofosbuvir: The IUPAC name for sofosbuvir is ( S )-isopropyl 2-(( S )-(((2 R ,3 R ,4 R ,5 R )-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C 22 H 29 FN 3 O 9 P and a molecular weight of 529.45. It has the following structural formula: Sofosbuvir is a white to off-white crystalline solid with a solubility of at least 2 mg/mL across the pH range of 2–7.7 at 37 °C and is slightly soluble in water. Velpatasvir: The IUPAC name for velpatasvir is methyl {(1 R )-2-[(2 S ,4 S )-2-(5-{2-[(2 S ,5 S )-1-{(2 S )-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydro[2]benzopyrano[4',3':6,7]naphtho[1,2- d ]imidazol-9-yl}-1 H -imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate. It has a molecular formula of C 49 H 54 N 8 O 8 and a molecular weight of 883.0. It has the following structural formula: Velpatasvir is practically insoluble (less than 0.1 mg/mL) above pH 5, slightly soluble (3.6 mg/mL) at pH 2, and soluble (greater than 36 mg/mL) at pH 1.2. Chemical Structure Chemical Structure

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 : 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: without cirrhosis or with compensated cirrhosis with decompensated cirrhosis for use in combination with ribavirin.

EPCLUSA is available as tablets or pellets for oral use. Each dosage form is available in two dose strengths: 400 mg/100 mg Tablets: pink, diamond-shaped, film-coated tablet debossed with "GSI" on one side and "7916" on the other side. Each tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir. 200 mg/50 mg Tablets: pink, oval-shaped, film-coated tablet debossed with "GSI" on one side and "S/V" on the other side. Each tablet contains 200 mg of sofosbuvir and 50 mg of velpatasvir. 200 mg/50 mg Oral Pellets: white to off-white, film-coated pellets in unit-dose packets. Each packet contains 200 mg of sofosbuvir and 50 mg of velpatasvir. 150 mg/37.5 mg Oral Pellets: white to off-white, film-coated pellets in unit-dose packets. Each packet contains 150 mg of sofosbuvir and 37.5 mg of velpatasvir. Tablets: 400 mg of sofosbuvir and 100 mg of velpatasvir; 200 mg of sofosbuvir and 50 mg of velpatasvir. Oral Pellets: 200 mg of sofosbuvir and 50 mg of velpatasvir; 150 mg of sofosbuvir and 37.5 mg of velpatasvir.

Testing prior to the initiation of therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. 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: 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. 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. For pediatric patients less than 6 years of age, administer EPCLUSA oral pellets with food. Instructions for Use should be followed for preparation and administration of EPCLUSA oral pellets. HCV/HIV-1 coinfection: For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in the table above. 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. If used in combination with ribavirin, follow the recommendations for ribavirin dosing and dosage modifications. For patients with renal impairment including end stage renal disease on dialysis, follow the dosage recommendations in the table above

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

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 . Refer to Drug Interactions 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 . 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

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 . 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 . 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

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 . Refer to ribavirin tablet prescribing information for ribavirin dosage modification for patients with CrCl less than or equal to 50 mL per minute.

Risk of Hepatitis B Virus Reactivation: Test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. Monitor HCV/HBV coinfected patients for HBV reactivation and hepatitis flare during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. Bradycardia with amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with EPCLUSA is not recommended. In patients without alternative viable treatment options, cardiac monitoring is recommended. 5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur. Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with EPCLUSA. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with EPCLUSA and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated

Serious Symptomatic Bradycardia When Coadministered with Amiodarone Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen (HARVONI ® [ledipasvir/sofosbuvir]). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown. Coadministration of amiodarone with EPCLUSA is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered EPCLUSA: Counsel patients about the risk of symptomatic bradycardia. Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who are taking EPCLUSA who need to start amiodarone therapy due to no other alternative viable treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting EPCLUSA should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion, or memory problems

Risk of Reduced Therapeutic Effect Due to Concomitant Use of EPCLUSA with Inducers of P-gp and/or Moderate to Strong Inducers of CYP Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St. John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to potentially reduced therapeutic effect of EPCLUSA. The use of these agents with EPCLUSA is not recommended

Risks Associated with Ribavirin and EPCLUSA Combination Treatment If EPCLUSA is administered with ribavirin, the warnings and precautions for ribavirin apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin .

P-gp inducers and/or moderate to strong CYP inducers (e.g., rifampin, St. John's wort, carbamazepine): May decrease concentrations of sofosbuvir and/or velpatasvir. Use of EPCLUSA with P-gp inducers and/or moderate to strong CYP inducers is not recommended. ( 5.3 , 7 ) Consult the full prescribing information prior to use for potential drug interactions. ( 5.2 , 5.3 , 7 ) Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact safe and effective use of concomitant medications. Frequent monitoring of relevant laboratory parameters (INR or blood glucose) and dose adjustments of certain concomitant medications may be necessary

Potential for Other Drugs to Affect EPCLUSA Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Drugs that are 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. The use of these agents with EPCLUSA is not recommended . EPCLUSA may be coadministered with P-gp, BCRP, and CYP inhibitors

Potential for EPCLUSA to Affect Other Drugs Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, and OATP2B1. Coadministration of EPCLUSA with drugs that are substrates of these transporters may increase the exposure of such drugs

Established and Potentially Significant Drug Interactions Clearance of HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment. Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Table 4 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either EPCLUSA, the components of EPCLUSA (sofosbuvir and velpatasvir) as individual agents, or are predicted drug interactions that may occur with EPCLUSA . Table 4 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase. Clinical Effect/Recommendation DF = disoproxil fumarate. Acid Reducing Agents: ↓ velpatasvir Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of velpatasvir. Antacids (e.g., aluminum and magnesium hydroxide) Separate antacid and EPCLUSA administration by 4 hours. H 2 -receptor antagonists These interactions have been studied in healthy adults. (e.g., famotidine) H 2 -receptor antagonists may be administered simultaneously with or 12 hours apart from EPCLUSA at a dose that does not exceed doses comparable to famotidine 40 mg twice daily. Proton-pump inhibitors (e.g., omeprazole) Coadministration of omeprazole or other proton-pump inhibitors is not recommended. If it is considered medically necessary to coadminister, EPCLUSA should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton-pump inhibitors has not been studied. Antiarrhythmics: amiodarone Effect on amiodarone, sofosbuvir, and velpatasvir concentrations unknown Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with EPCLUSA is not recommended; if coadministration is required, cardiac monitoring is recommended . digoxin ↑ digoxin Therapeutic concentration monitoring of digoxin is recommended when coadministered with EPCLUSA. Refer to digoxin prescribing information for monitoring and dose modification recommendations for concentration increases of less than 50%. Anticancers: topotecan ↑ topotecan Coadministration is not recommended. Anticonvulsants: carbamazepine phenytoin phenobarbital ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended. Antimycobacterials: rifabutin rifampin rifapentine ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended. HIV Antiretrovirals: efavirenz ↓ velpatasvir Coadministration of EPCLUSA with efavirenz-containing regimens is not recommended. Regimens containing tenofovir DF ↑ tenofovir Monitor for tenofovir-associated adverse reactions in patients receiving EPCLUSA concomitantly with a regimen containing tenofovir DF. Refer to the prescribing information of the tenofovir DF-containing product for recommendations on renal monitoring. tipranavir/ritonavir ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended. Herbal Supplements: St. John's wort (Hypericum perforatum) ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended . HMG-CoA Reductase Inhibitors: rosuvastatin ↑ rosuvastatin Coadministration of EPCLUSA with rosuvastatin may significantly increase the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Rosuvastatin may be administered with EPCLUSA at a dose that does not exceed 10 mg. atorvastatin ↑ atorvastatin Coadministration of EPCLUSA with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis

Drugs without Clinically Significant Interactions with EPCLUSA Based on drug interaction studies conducted with the components of EPCLUSA (sofosbuvir or velpatasvir) or EPCLUSA, no clinically significant drug interactions have been observed or are expected with the following drugs : EPCLUSA: atazanavir/ritonavir, buprenorphine/naloxone, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, methadone, naltrexone, raltegravir, or rilpivirine. Sofosbuvir: ethinyl estradiol/norgestimate, or tacrolimus. Velpatasvir: ethinyl estradiol/norgestimate, ketoconazole, or pravastatin. See Table 4 for use of EPCLUSA with certain HIV antiretroviral regimens .