Sofosbuvir and Velpatasvir (Page 2 of 11)

2.5 Preparation and Administration of Sofosbuvir and Velpatasvir (EPCLUSA) Oral Pellets

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.

2.6 Renal Impairment

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.

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

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)].

5 WARNINGS AND PRECAUTIONS

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 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.

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 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)].

5.3 Risk of Reduced Therapeutic Effect Due to Concomitant Use of Sofosbuvir and Velpatasvir 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 sofosbuvir and velpatasvir. The use of these agents with sofosbuvir and velpatasvir is not recommended [see Drug Interactions (7.3)].

5.4 Risks Associated with Ribavirin and Sofosbuvir and Velpatasvir Combination Treatment

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)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in labeling:

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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) for 12 weeks. Sofosbuvir and velpatasvir were 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir for 12 weeks.

Adverse reactions, all grades, observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with sofosbuvir and velpatasvir in ASTRAL-1 include headache (22%), fatigue (15%), nausea (9%), asthenia (5%), and insomnia (5%). Of subjects receiving sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir (asthenia: 3% versus 5% for the placebo and sofosbuvir and velpatasvir groups, respectively).

The adverse reactions observed in subjects treated with sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir in ASTRAL-3.

Adverse Reactions in Subjects Coinfected with HCV and HIV-1

The safety assessment of sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) with ribavirin for 12 weeks. All 87 subjects had Child-Pugh B cirrhosis at screening. On the first day of treatment with sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir with ribavirin for 12 weeks, respectively. Ribavirin was permanently discontinued in 17% of subjects treated with sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir with ribavirin for 12 weeks and are included because of a potential causal relationship.

Rash: Rash occurred in 5% of subjects treated with sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) and placebo for 12 weeks, respectively; and in 6% and 3% of subjects treated with sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) and placebo for 12 weeks, respectively; and in 2% and 1% of subjects treated with sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir without dose adjustment or treatment interruption of either sofosbuvir and velpatasvir or HIV antiretroviral agents.

Adverse Reactions in Adult Liver Transplant Recipients

The safety assessment of sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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 sofosbuvir and velpatasvir. 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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 sofosbuvir and velpatasvir. 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg), sofosbuvir and velpatasvir (EPCLUSA) tablets (200 mg/50 mg), or sofosbuvir and velpatasvir (EPCLUSA) oral pellets 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 sofosbuvir and velpatasvir 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 sofosbuvir and velpatasvir tablets (400 mg/100 mg) 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)].

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