Epclusa

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.

3 DOSAGE FORMS AND STRENGTHS 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. ( 3 ) Oral Pellets: 200 mg of sofosbuvir and 50 mg of velpatasvir; 150 mg of sofosbuvir and 37.5 mg of velpatasvir. ( 3 )

4 CONTRAINDICATIONS EPCLUSA and ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin [see Dosage and Administration (2.2 , 2.3 , 2.4) ]. EPCLUSA and ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated. ( 4 )

5 WARNINGS AND PRECAUTIONS 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. ( 5.1 ) 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. ( 5.2 , 7.3 ) 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. 5.2 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 [see Adverse Reactions (6.2) and Drug Interactions (7.3) ] . 5.3 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 [see Drug Interactions (7.3) ] . 5.4 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 [see Dosage and Administration (2.2) ].

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

16 HOW SUPPLIED/STORAGE AND HANDLING Tablets EPCLUSA tablets, 400 mg/100 mg, are pink, diamond-shaped, film-coated, debossed with "GSI" on one side and "7916" on the other. Each bottle contains 28 tablets (NDC 61958-2201-1), polyester coil, and is closed with a child-resistant closure. EPCLUSA tablets, 200 mg/50 mg, are pink, oval-shaped, film-coated, debossed with "GSI" on one side and "S/V" on the other. Each bottle contains 28 tablets (NDC 61958-2203-1), polyester coil, and is closed with a child-resistant closure. Store below 30 °C (86 ºF). Dispense only in original container. Oral Pellets EPCLUSA oral pellets, 200 mg/50 mg, are white to off-white, film-coated pellets supplied as unit-dose packets in cartons. Each carton contains 28 packets (NDC 61958-2204-1). EPCLUSA oral pellets, 150 mg/37.5 mg, are white to off-white, film-coated pellets supplied as unit-dose packets in cartons. Each carton contains 28 packets (NDC 61958-2205-1). Store below 30 °C (86 ºF). Do not use if carton tamper-evident seal or packet has been opened or damaged.