These Highlights Do Not Include All The Information Needed To Use Sofosbuvir And Velpatasvir Tablets Safely And Effectively. See Full Prescribing Information For Sofosbuvir And Velpatasvir Tablets.

Clinical Trials in Adult Subjects

Store below 30 °C (86 ºF).

No specific antidote is available for overdose with sofosbuvir and velpatasvir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with sofosbuvir and velpatasvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of velpatasvir since velpatasvir is highly bound to plasma protein.

Sofosbuvir and velpatasvir tablets (400 mg/100 mg) are fixed-dose combination tablets containing sofosbuvir and velpatasvir for oral administration. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor and velpatasvir is an NS5A inhibitor.

Each tablet contains 400 mg sofosbuvir and 100 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.

The pharmacokinetics, safety, and effectiveness of sofosbuvir and velpatasvir for treatment of HCV genotype 1, 2, 3, 4, or 6 infection in treatment-naïve and treatment-experienced pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1143, N=216; 190 treatment-naïve, 26 treatment-experienced). No clinically meaningful differences in pharmacokinetics were observed in comparison to those observed in adults.

The safety and effectiveness in pediatric subjects were comparable to those observed in adults. However, among the 41 pediatric subjects less than 6 years of age, vomiting and product use issue (spitting up the drug) were reported more frequently (15% and 10%, respectively; all Grade 1 or 2) compared to subjects 6 years of age and older. Five subjects (12%) discontinued treatment after vomiting or spitting up the drug [see Dosage and Administration (2.4, 2.5), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.8)].

The safety and effectiveness of sofosbuvir and velpatasvir for treatment of HCV genotype 5 in pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis are supported by sofosbuvir, GS-331007, and velpatasvir exposures in adults and pediatric patients [see Dosage and Administration (2.2 and 2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.8)]. Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection who have decompensated cirrhosis (Child-Pugh B or C).

In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased [see Clinical Pharmacology (12.3)]. No data are available regarding the safety of sofosbuvir and velpatasvir in pediatric patients with renal impairment [see Use in Specific Populations (8.6)].

The safety and effectiveness of sofosbuvir and velpatasvir have not been established in pediatric patients less than 3 years of age.

Clinical trials of sofosbuvir and velpatasvir included 156 subjects aged 65 and over (12% of total number of subjects in the Phase 3 clinical trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of sofosbuvir and velpatasvir is warranted in geriatric patients [see Clinical Pharmacology (12.3)].

Sofosbuvir and velpatasvir 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)].

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)].

• 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 sofosbuvir and velpatasvir 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. (7.3)

No dosage adjustment of sofosbuvir and velpatasvir tablets (400 mg/100 mg) is recommended in patients with any degree of renal impairment, including patients requiring dialysis. Administer sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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.

No dosage adjustment of sofosbuvir and velpatasvir is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration (2.6), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)]. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including ESRD requiring dialysis. Additionally, no safety data are available in pediatric patients with renal impairment [see Use in Specific Populations (8.4)]. Refer to ribavirin tablet prescribing information regarding use of ribavirin in patients with renal impairment.

The pharmacokinetic properties of sofosbuvir and velpatasvir are provided in Table 5. The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite, GS-331007, and velpatasvir are provided in Table 6.

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.

No dosage adjustment of sofosbuvir and velpatasvir is recommended for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Clinical and hepatic laboratory monitoring (including direct bilirubin), as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with sofosbuvir and velpatasvir and ribavirin [see Adverse Reactions (6.1)].

Sofosbuvir and velpatasvir 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.

Sofosbuvir and velpatasvir tablets (400 mg/100 mg) are a fixed-dose combination of sofosbuvir and velpatasvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].

• 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 sofosbuvir and velpatasvir is not recommended. In patients without alternative viable treatment options, cardiac monitoring is recommended. (5.2, 7.3)

• 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)

• 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 sofosbuvir and velpatasvir (EPCLUSA) oral pellets with food. (2.4)
• Instructions for Use should be followed for preparation and administration of sofosbuvir and velpatasvir (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 sofosbuvir and velpatasvir 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)

Each sofosbuvir and velpatasvir tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir. The tablets are pink, diamond-shaped, film-coated, and debossed with "ASE" on one side and "9761" on the other side.

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.

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 sofosbuvir and velpatasvir is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions.

The recommended dosage of sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir, 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)].

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Table 12 presents the clinical trial design including different treatment groups that were conducted with sofosbuvir and velpatasvir with and without ribavirin in subjects with chronic hepatitis C (HCV) genotype 1, 2, 3, 4, 5, and 6 infection. For detailed description of trial design and recommended regimen and duration [see Dosage and Administration (2.2, 2.3, and 2.4) and Clinical Studies (14.2, 14.3, 14.4, 14.5, 14.6, 14.7, and 14.8)].

The ribavirin dosage was weight-based (1000 mg daily administered in two divided doses for subjects less than 75 kg and 1200 mg for those greater than or equal to 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 trials or in combination with sofosbuvir and velpatasvir in the ASTRAL-4 trial. Ribavirin dosage adjustments were performed according to the ribavirin prescribing information. Serum HCV RNA values were measured during the clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. SVR12, defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in all the trials. Relapse is defined as HCV RNA greater than or equal to LLOQ during the post-treatment period after having achieved HCV RNA less than LLOQ at the end of treatment. On-treatment virologic failure is defined as breakthrough, rebound, or non-response.

Each sofosbuvir and velpatasvir tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir, is pink, diamond-shaped, film-coated, debossed with "ASE" on one side and "9761" on the other. Each carton contains 28 tablets (2 blister cards each containing 14 tablets) (NDC 72626-2701-1).

The efficacy of sofosbuvir and velpatasvir once daily for 12 weeks was evaluated in an open-label trial (Study 1143) in 214 genotype 1, 2, 3, 4, or 6 HCV treatment-naïve (N=188) or treatment-experienced (N=26) pediatric subjects 3 years of age and older without cirrhosis or with compensated cirrhosis.

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 sofosbuvir and velpatasvir [see Warnings and Precautions (5.1)].

If sofosbuvir and velpatasvir is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.

NDC 72626-2701-1

ASEGUA™

THERAPEUTICS

Sofosbuvir and Velpatasvir

400 mg/100 mg

tablets

Take 1 tablet once daily

Rx only

Note to pharmacist:

Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that should

NOT be taken with Sofosbuvir and Velpatasvir

Contents:

28 tablets: Two blister cards containing 14 tablets per blister card

Authorized generic of Epclusa^®

ASTRAL-5 was an open-label trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection who were coinfected with HIV-1. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, raltegravir or elvitegravir/cobicistat.

Of the 106 treated subjects, the median age was 57 years (range: 25 to 72); 86% of the subjects were male; 51% were White; 45% were Black; 22% had a baseline body mass index at least 30 kg/m²; the proportions of patients with genotype 1, 2, 3, or 4 HCV infection were 74%, 10%, 11%, and 5%, respectively; no subjects with genotype 5 or 6 HCV were treated with sofosbuvir and velpatasvir; 77% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels of at least 800,000 IU/mL; 18% had compensated cirrhosis; and 29% were treatment experienced. The overall mean CD4+ count was 598 cells/µL (range: 183−1513 cells/µL) and 57% of subjects had CD4+ counts > 500 cells/μL.

Table 17 presents the SVR12 for the ASTRAL-5 trial by HCV genotype.

No subject had HIV-1 rebound during treatment and CD4+ counts were stable during treatment.

ASTRAL-4 was a randomized, open-label trial in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection and Child-Pugh B cirrhosis at screening. Subjects were randomized in a 1:1:1 ratio to treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 12 weeks (N=90), sofosbuvir and velpatasvir tablets (400 mg/100 mg) with ribavirin for 12 weeks (N=87), or sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 24 weeks (N=90). Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate).

Demographics and baseline characteristics were balanced across the treatment groups. Of the 267 treated subjects, the median age was 59 years (range: 40 to 73); 70% of the subjects were male; 90% were White; 6% were Black; 42% had a baseline body mass index at least 30 kg/m². The proportions of subjects with genotype 1, 2, 3, 4, or 6 HCV were 78%, 4%, 15%, 3%, and less than 1% (1 subject), respectively. No subjects with genotype 5 HCV infection were enrolled. 76% had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels at least 800,000 IU/mL; 55% were treatment-experienced; and 95% of subjects had Model for End Stage Liver Disease (MELD) score less than or equal to 15 at baseline. Although all subjects had Child-Pugh B cirrhosis at screening, 6% and 4% of subjects were assessed to have Child-Pugh A and Child-Pugh C cirrhosis, respectively, on the first day of treatment.

Treatment with sofosbuvir and velpatasvir with ribavirin for 12 weeks resulted in numerically higher SVR12 rates than treatment with sofosbuvir and velpatasvir for 12 weeks or 24 weeks. Because sofosbuvir and velpatasvir with ribavirin for 12 weeks is the recommended dosage regimen, the results of the 12- and 24-week sofosbuvir and velpatasvir treatment groups are not presented.

Table 18 presents the SVR12 for subjects treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks in the ASTRAL-4 trial by HCV genotype. No subjects with genotype 5 or 6 HCV were treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks.

All subjects with genotype 2 (N=4) and genotype 4 (N=2) HCV infection treated with sofosbuvir and velpatasvir and ribavirin achieved SVR12.

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 sofosbuvir and velpatasvir tablets (400 mg/100 mg), or sofosbuvir and velpatasvir as individual agents, or are predicted drug interactions that may occur with sofosbuvir and velpatasvir [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].

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 sofosbuvir and velpatasvir. The use of these agents with sofosbuvir and velpatasvir is not recommended [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Sofosbuvir and velpatasvir may be coadministered with P-gp, BCRP, and CYP inhibitors.

Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, and OATP2B1. Coadministration of sofosbuvir and velpatasvir with drugs that are substrates of these transporters may increase the exposure of such drugs.

The recommended dosage of sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir for pediatric patients. Take sofosbuvir and velpatasvir once daily with or without food. In pediatric patients less than 6 years of age, administer the sofosbuvir and velpatasvir (EPCLUSA) 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)].

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 sofosbuvir and velpatasvir is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered sofosbuvir and velpatasvir:

• 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir 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)].

Trial 4062 was an open-label clinical trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in 59 HCV-infected adults with ESRD requiring dialysis. The proportions of subjects with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%,12%, 27%, 7%, 3%, and 8%, respectively. At baseline, 29% of subjects had cirrhosis, 22% were treatment-experienced (subjects with prior exposure to any HCV NS5A inhibitor were excluded), 92% were on hemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59). Of the subjects completing 12 weeks of sofosbuvir and velpatasvir, 1 subject experienced virologic relapse.

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 sofosbuvir and velpatasvir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with sofosbuvir and velpatasvir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

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 sofosbuvir and velpatasvir once daily for 12 weeks [see Clinical Studies (14.3 and 14.5)]. Refer to Drug Interactions (7) for dosage recommendations for concomitant drugs.

Based on drug interaction studies conducted with sofosbuvir, velpatasvir, or sofosbuvir and velpatasvir tablets (400 mg/100 mg) no clinically significant drug interactions have been observed or are expected with the following drugs [see Clinical Pharmacology (12.3)]:

• Sofosbuvir and velpatasvir: 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 sofosbuvir and velpatasvir with certain HIV antiretroviral regimens [see Drug Interactions (7.3)].

See the sofosbuvir and velpatasvir (EPCLUSA) oral pellets full Instructions for Use for details on the preparation and administration of sofosbuvir and velpatasvir (EPCLUSA) oral pellets.

Do not chew sofosbuvir and velpatasvir (EPCLUSA) oral pellets to avoid a bitter aftertaste. Sofosbuvir and velpatasvir (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 sofosbuvir and velpatasvir (EPCLUSA) oral pellets within 15 minutes of gently mixing with food and swallow the entire contents without chewing.

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with sofosbuvir and velpatasvir. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions (5.1)].

If sofosbuvir and velpatasvir 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)].

Trial 2104 was an open-label clinical trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in 79 HCV-infected treatment-naïve and previously treated adult subjects who had undergone liver transplantation. The proportions of subjects with genotype 1, 2, 3, or 4 HCV infection were 47%, 4%, 44%, and 5%, respectively. The median age was 62 years (range: 45 to 81); 81% were male; 82% were White; 3% were Black; and 15% were Asian; 28% had a baseline body mass index at least 30 kg/m². At baseline, 18% had compensated cirrhosis, and 60% were treatment experienced (subjects with prior exposure to any HCV NS5A inhibitor were excluded). Immunosuppressants allowed for coadministration were tacrolimus, mycophenolate mofetil, cyclosporine, and azathioprine. The overall SVR12 rate was 96% (76/79). Of the subjects completing 12 weeks of sofosbuvir and velpatasvir, 2 subjects experienced virologic relapse.

Based on data from the Phase 2 trial SIMPLIFY, the safety and effectiveness of sofosbuvir and velpatasvir in subjects who self-reported injection drug use, including in those on concomitant MAT, were similar to the known safety and effectiveness profile of sofosbuvir and velpatasvir. No dosage adjustment of sofosbuvir and velpatasvir is recommended for PWID, including those on MAT for opioid use disorder [see Adverse Reactions (6.1) and Clinical Studies (14.7)].

SIMPLIFY was an open-label Phase 2 clinical trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in 103 HCV-infected PWID (defined as self-reported injection drug use within previous 6 months), including 58 subjects on MAT for opioid use disorder. The proportions of subjects with genotype 1, 2, 3, and 4 HCV infection were 35%, 5%, 58%, and 2%, respectively. The median age was 48 years (range: 24 to 67); 71% were male; 89% were White; and 2% were Black. At baseline, 74% and 26% of subjects reported injection drug use or daily injection drug use, respectively, in the past month; 56% had baseline HCV RNA levels at least 800,000 IU/mL; 10% had compensated cirrhosis; and all subjects were naïve to prior exposure with SOF or an HCV NS5A inhibitor. Subjects on MAT for opioid use disorder reported concomitant use of methadone (76%) and buprenorphine naloxone (17%) with sofosbuvir and velpatasvir. The overall SVR rate was 94% (97/103). One subject completed sofosbuvir and velpatasvir treatment and was re-infected with a phylogenetically different virus; the other 5 subjects who did not achieve SVR12 did not meet virologic failure criteria.

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 sofosbuvir and velpatasvir. The use of these agents with sofosbuvir and velpatasvir is not recommended [see Drug Interactions (7.3)].

Clinical Trials in Adult Subjects

Store below 30 °C (86 ºF).

No specific antidote is available for overdose with sofosbuvir and velpatasvir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with sofosbuvir and velpatasvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of velpatasvir since velpatasvir is highly bound to plasma protein.

Sofosbuvir and velpatasvir tablets (400 mg/100 mg) are fixed-dose combination tablets containing sofosbuvir and velpatasvir for oral administration. Sofosbuvir is a nucleotide analog HCV NS5B polymerase inhibitor and velpatasvir is an NS5A inhibitor.

Each tablet contains 400 mg sofosbuvir and 100 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.

The pharmacokinetics, safety, and effectiveness of sofosbuvir and velpatasvir for treatment of HCV genotype 1, 2, 3, 4, or 6 infection in treatment-naïve and treatment-experienced pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1143, N=216; 190 treatment-naïve, 26 treatment-experienced). No clinically meaningful differences in pharmacokinetics were observed in comparison to those observed in adults.

The safety and effectiveness in pediatric subjects were comparable to those observed in adults. However, among the 41 pediatric subjects less than 6 years of age, vomiting and product use issue (spitting up the drug) were reported more frequently (15% and 10%, respectively; all Grade 1 or 2) compared to subjects 6 years of age and older. Five subjects (12%) discontinued treatment after vomiting or spitting up the drug [see Dosage and Administration (2.4, 2.5), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.8)].

The safety and effectiveness of sofosbuvir and velpatasvir for treatment of HCV genotype 5 in pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis are supported by sofosbuvir, GS-331007, and velpatasvir exposures in adults and pediatric patients [see Dosage and Administration (2.2 and 2.4), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.8)]. Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection who have decompensated cirrhosis (Child-Pugh B or C).

In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased [see Clinical Pharmacology (12.3)]. No data are available regarding the safety of sofosbuvir and velpatasvir in pediatric patients with renal impairment [see Use in Specific Populations (8.6)].

The safety and effectiveness of sofosbuvir and velpatasvir have not been established in pediatric patients less than 3 years of age.

Clinical trials of sofosbuvir and velpatasvir included 156 subjects aged 65 and over (12% of total number of subjects in the Phase 3 clinical trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment of sofosbuvir and velpatasvir is warranted in geriatric patients [see Clinical Pharmacology (12.3)].

Sofosbuvir and velpatasvir 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)].

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)].

• 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 sofosbuvir and velpatasvir 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. (7.3)

No dosage adjustment of sofosbuvir and velpatasvir tablets (400 mg/100 mg) is recommended in patients with any degree of renal impairment, including patients requiring dialysis. Administer sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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.

No dosage adjustment of sofosbuvir and velpatasvir is recommended for patients with mild, moderate, or severe renal impairment, including ESRD requiring dialysis [see Dosage and Administration (2.6), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)]. No safety data are available in subjects with both decompensated cirrhosis and severe renal impairment, including ESRD requiring dialysis. Additionally, no safety data are available in pediatric patients with renal impairment [see Use in Specific Populations (8.4)]. Refer to ribavirin tablet prescribing information regarding use of ribavirin in patients with renal impairment.

The pharmacokinetic properties of sofosbuvir and velpatasvir are provided in Table 5. The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite, GS-331007, and velpatasvir are provided in Table 6.

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.

No dosage adjustment of sofosbuvir and velpatasvir is recommended for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Clinical and hepatic laboratory monitoring (including direct bilirubin), as clinically indicated, is recommended for patients with decompensated cirrhosis receiving treatment with sofosbuvir and velpatasvir and ribavirin [see Adverse Reactions (6.1)].

Sofosbuvir and velpatasvir 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.

Sofosbuvir and velpatasvir tablets (400 mg/100 mg) are a fixed-dose combination of sofosbuvir and velpatasvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].

• 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 sofosbuvir and velpatasvir is not recommended. In patients without alternative viable treatment options, cardiac monitoring is recommended. (5.2, 7.3)

• 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)

• 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 sofosbuvir and velpatasvir (EPCLUSA) oral pellets with food. (2.4)
• Instructions for Use should be followed for preparation and administration of sofosbuvir and velpatasvir (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 sofosbuvir and velpatasvir 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)

Each sofosbuvir and velpatasvir tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir. The tablets are pink, diamond-shaped, film-coated, and debossed with "ASE" on one side and "9761" on the other side.

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.

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 sofosbuvir and velpatasvir is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions.

The recommended dosage of sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir, 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)].

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Table 12 presents the clinical trial design including different treatment groups that were conducted with sofosbuvir and velpatasvir with and without ribavirin in subjects with chronic hepatitis C (HCV) genotype 1, 2, 3, 4, 5, and 6 infection. For detailed description of trial design and recommended regimen and duration [see Dosage and Administration (2.2, 2.3, and 2.4) and Clinical Studies (14.2, 14.3, 14.4, 14.5, 14.6, 14.7, and 14.8)].

The ribavirin dosage was weight-based (1000 mg daily administered in two divided doses for subjects less than 75 kg and 1200 mg for those greater than or equal to 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 trials or in combination with sofosbuvir and velpatasvir in the ASTRAL-4 trial. Ribavirin dosage adjustments were performed according to the ribavirin prescribing information. Serum HCV RNA values were measured during the clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. SVR12, defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in all the trials. Relapse is defined as HCV RNA greater than or equal to LLOQ during the post-treatment period after having achieved HCV RNA less than LLOQ at the end of treatment. On-treatment virologic failure is defined as breakthrough, rebound, or non-response.

Each sofosbuvir and velpatasvir tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir, is pink, diamond-shaped, film-coated, debossed with "ASE" on one side and "9761" on the other. Each carton contains 28 tablets (2 blister cards each containing 14 tablets) (NDC 72626-2701-1).

The efficacy of sofosbuvir and velpatasvir once daily for 12 weeks was evaluated in an open-label trial (Study 1143) in 214 genotype 1, 2, 3, 4, or 6 HCV treatment-naïve (N=188) or treatment-experienced (N=26) pediatric subjects 3 years of age and older without cirrhosis or with compensated cirrhosis.

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 sofosbuvir and velpatasvir [see Warnings and Precautions (5.1)].

If sofosbuvir and velpatasvir is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.

NDC 72626-2701-1

ASEGUA™

THERAPEUTICS

Sofosbuvir and Velpatasvir

400 mg/100 mg

tablets

Take 1 tablet once daily

Rx only

Note to pharmacist:

Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines that should

NOT be taken with Sofosbuvir and Velpatasvir

Contents:

28 tablets: Two blister cards containing 14 tablets per blister card

Authorized generic of Epclusa^®

ASTRAL-5 was an open-label trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection who were coinfected with HIV-1. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, raltegravir or elvitegravir/cobicistat.

Of the 106 treated subjects, the median age was 57 years (range: 25 to 72); 86% of the subjects were male; 51% were White; 45% were Black; 22% had a baseline body mass index at least 30 kg/m²; the proportions of patients with genotype 1, 2, 3, or 4 HCV infection were 74%, 10%, 11%, and 5%, respectively; no subjects with genotype 5 or 6 HCV were treated with sofosbuvir and velpatasvir; 77% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels of at least 800,000 IU/mL; 18% had compensated cirrhosis; and 29% were treatment experienced. The overall mean CD4+ count was 598 cells/µL (range: 183−1513 cells/µL) and 57% of subjects had CD4+ counts > 500 cells/μL.

Table 17 presents the SVR12 for the ASTRAL-5 trial by HCV genotype.

No subject had HIV-1 rebound during treatment and CD4+ counts were stable during treatment.

ASTRAL-4 was a randomized, open-label trial in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection and Child-Pugh B cirrhosis at screening. Subjects were randomized in a 1:1:1 ratio to treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 12 weeks (N=90), sofosbuvir and velpatasvir tablets (400 mg/100 mg) with ribavirin for 12 weeks (N=87), or sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 24 weeks (N=90). Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate).

Demographics and baseline characteristics were balanced across the treatment groups. Of the 267 treated subjects, the median age was 59 years (range: 40 to 73); 70% of the subjects were male; 90% were White; 6% were Black; 42% had a baseline body mass index at least 30 kg/m². The proportions of subjects with genotype 1, 2, 3, 4, or 6 HCV were 78%, 4%, 15%, 3%, and less than 1% (1 subject), respectively. No subjects with genotype 5 HCV infection were enrolled. 76% had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels at least 800,000 IU/mL; 55% were treatment-experienced; and 95% of subjects had Model for End Stage Liver Disease (MELD) score less than or equal to 15 at baseline. Although all subjects had Child-Pugh B cirrhosis at screening, 6% and 4% of subjects were assessed to have Child-Pugh A and Child-Pugh C cirrhosis, respectively, on the first day of treatment.

Treatment with sofosbuvir and velpatasvir with ribavirin for 12 weeks resulted in numerically higher SVR12 rates than treatment with sofosbuvir and velpatasvir for 12 weeks or 24 weeks. Because sofosbuvir and velpatasvir with ribavirin for 12 weeks is the recommended dosage regimen, the results of the 12- and 24-week sofosbuvir and velpatasvir treatment groups are not presented.

Table 18 presents the SVR12 for subjects treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks in the ASTRAL-4 trial by HCV genotype. No subjects with genotype 5 or 6 HCV were treated with sofosbuvir and velpatasvir with ribavirin for 12 weeks.

All subjects with genotype 2 (N=4) and genotype 4 (N=2) HCV infection treated with sofosbuvir and velpatasvir and ribavirin achieved SVR12.

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 sofosbuvir and velpatasvir tablets (400 mg/100 mg), or sofosbuvir and velpatasvir as individual agents, or are predicted drug interactions that may occur with sofosbuvir and velpatasvir [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].

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 sofosbuvir and velpatasvir. The use of these agents with sofosbuvir and velpatasvir is not recommended [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Sofosbuvir and velpatasvir may be coadministered with P-gp, BCRP, and CYP inhibitors.

Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, and OATP2B1. Coadministration of sofosbuvir and velpatasvir with drugs that are substrates of these transporters may increase the exposure of such drugs.

The recommended dosage of sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir for pediatric patients. Take sofosbuvir and velpatasvir once daily with or without food. In pediatric patients less than 6 years of age, administer the sofosbuvir and velpatasvir (EPCLUSA) 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)].

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 sofosbuvir and velpatasvir is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered sofosbuvir and velpatasvir:

• 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir 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)].

Trial 4062 was an open-label clinical trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in 59 HCV-infected adults with ESRD requiring dialysis. The proportions of subjects with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%,12%, 27%, 7%, 3%, and 8%, respectively. At baseline, 29% of subjects had cirrhosis, 22% were treatment-experienced (subjects with prior exposure to any HCV NS5A inhibitor were excluded), 92% were on hemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59). Of the subjects completing 12 weeks of sofosbuvir and velpatasvir, 1 subject experienced virologic relapse.

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 sofosbuvir and velpatasvir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with sofosbuvir and velpatasvir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

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 sofosbuvir and velpatasvir once daily for 12 weeks [see Clinical Studies (14.3 and 14.5)]. Refer to Drug Interactions (7) for dosage recommendations for concomitant drugs.

Based on drug interaction studies conducted with sofosbuvir, velpatasvir, or sofosbuvir and velpatasvir tablets (400 mg/100 mg) no clinically significant drug interactions have been observed or are expected with the following drugs [see Clinical Pharmacology (12.3)]:

• Sofosbuvir and velpatasvir: 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 sofosbuvir and velpatasvir with certain HIV antiretroviral regimens [see Drug Interactions (7.3)].

See the sofosbuvir and velpatasvir (EPCLUSA) oral pellets full Instructions for Use for details on the preparation and administration of sofosbuvir and velpatasvir (EPCLUSA) oral pellets.

Do not chew sofosbuvir and velpatasvir (EPCLUSA) oral pellets to avoid a bitter aftertaste. Sofosbuvir and velpatasvir (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 sofosbuvir and velpatasvir (EPCLUSA) oral pellets within 15 minutes of gently mixing with food and swallow the entire contents without chewing.

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with sofosbuvir and velpatasvir. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions (5.1)].

If sofosbuvir and velpatasvir 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)].

Trial 2104 was an open-label clinical trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in 79 HCV-infected treatment-naïve and previously treated adult subjects who had undergone liver transplantation. The proportions of subjects with genotype 1, 2, 3, or 4 HCV infection were 47%, 4%, 44%, and 5%, respectively. The median age was 62 years (range: 45 to 81); 81% were male; 82% were White; 3% were Black; and 15% were Asian; 28% had a baseline body mass index at least 30 kg/m². At baseline, 18% had compensated cirrhosis, and 60% were treatment experienced (subjects with prior exposure to any HCV NS5A inhibitor were excluded). Immunosuppressants allowed for coadministration were tacrolimus, mycophenolate mofetil, cyclosporine, and azathioprine. The overall SVR12 rate was 96% (76/79). Of the subjects completing 12 weeks of sofosbuvir and velpatasvir, 2 subjects experienced virologic relapse.

Based on data from the Phase 2 trial SIMPLIFY, the safety and effectiveness of sofosbuvir and velpatasvir in subjects who self-reported injection drug use, including in those on concomitant MAT, were similar to the known safety and effectiveness profile of sofosbuvir and velpatasvir. No dosage adjustment of sofosbuvir and velpatasvir is recommended for PWID, including those on MAT for opioid use disorder [see Adverse Reactions (6.1) and Clinical Studies (14.7)].

SIMPLIFY was an open-label Phase 2 clinical trial that evaluated 12 weeks of treatment with sofosbuvir and velpatasvir tablets (400 mg/100 mg) in 103 HCV-infected PWID (defined as self-reported injection drug use within previous 6 months), including 58 subjects on MAT for opioid use disorder. The proportions of subjects with genotype 1, 2, 3, and 4 HCV infection were 35%, 5%, 58%, and 2%, respectively. The median age was 48 years (range: 24 to 67); 71% were male; 89% were White; and 2% were Black. At baseline, 74% and 26% of subjects reported injection drug use or daily injection drug use, respectively, in the past month; 56% had baseline HCV RNA levels at least 800,000 IU/mL; 10% had compensated cirrhosis; and all subjects were naïve to prior exposure with SOF or an HCV NS5A inhibitor. Subjects on MAT for opioid use disorder reported concomitant use of methadone (76%) and buprenorphine naloxone (17%) with sofosbuvir and velpatasvir. The overall SVR rate was 94% (97/103). One subject completed sofosbuvir and velpatasvir treatment and was re-infected with a phylogenetically different virus; the other 5 subjects who did not achieve SVR12 did not meet virologic failure criteria.

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 sofosbuvir and velpatasvir. The use of these agents with sofosbuvir and velpatasvir is not recommended [see Drug Interactions (7.3)].