`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
` EPCLUSA safely and effectively. See full prescribing information
` for EPCLUSA.
`
`
`
`EPCLUSA® (sofosbuvir and velpatasvir) tablets, for oral use
`
`
`
`
`Initial U.S. Approval: 2016
`
`
`
`WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
`
`PATIENTS COINFECTED WITH HCV AND HBV
`
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`Hepatitis B virus (HBV) reactivation has been reported, in some
`
`
`
`
`cases resulting in fulminant hepatitis, hepatic failure, and death.
`
`
`(5.1)
`
`
`------------------------------RECENT MAJOR CHANGES ----------------------­
`
`
`
`02/2017
`Boxed Warning
`
`
`Dosage and Administration (2.1)
`02/2017
`
`
`Dosage and Administration (2.2)
`08/2017
`
`
`Warnings and Precautions (5.1)
`02/2017
`
`
`Warnings and Precautions (5.2)
`08/2017
`
`
`
`-------------------------------INDICATIONS AND USAGE------------------------­
`
`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 adult patients 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
`
`
`
`
`
`------------------------DOSAGE AND ADMINISTRATION----------------------­
`
`• Testing Prior to the Initiation of Therapy: Test all patients for HBV
`
`
`
`
`infection by measuring HBsAg and anti-HBc. (2.1)
`
`• Recommended dosage: One tablet (400 mg of sofosbuvir and
`
`
`
`100 mg of velpatasvir) taken orally once daily with or without food
`
`
`
`
`(2.2)
`
`• See recommended treatment regimen and duration in patients with
`
`
`
`genotypes 1, 2, 3, 4, 5, or 6 HCV in table below: (2.2)
`
`
`
`
`
`
`Regimen
`
`and Duration
`
`
`
`
`
`
`Patient Population
`
`
`
`
` EPCLUSA 12 weeks
`
`
`
`
`
`
`
`Treatment-naïve and treatment­
`
` experienceda, without cirrhosis
` and with compensated cirrhosis
`
`
` (Child-Pugh A)
`Treatment-naïve and treatment­
`
` experienceda, with
`
`
` decompensated cirrhosis
`
` (Child-Pugh B and C)
` a. In clinical trials, regimens contained peginterferon alfa/ribavirin with or without
`
`
`
`
`
`
` an HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir).
`
`
`
`
`
` EPCLUSA + ribavirin 12 weeks
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
`
`
`
`PATIENTS COINFECTED WITH HCV AND HBV
`
`
`1 INDICATIONS AND USAGE
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`2.1 Testing Prior to Initiation of Therapy
`
`
`
`2.2 Recommended Dosage
`
`
`
`2.3 No Dosage Recommendations in Severe Renal Impairment
`
`and End Stage Renal Disease
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Risk of Hepatitis B Virus Reactivation in Patients
`
`
`Coinfected with HCV and HBV
`
`
`
`5.2 Serious Symptomatic Bradycardia When Coadministered
`
`with Amiodarone
`
`
`
`
`
`Reference ID: 4133087
`
`
`
`
`1
`
`
` • HCV/HIV-1 coinfection: For patients with HCV/HIV-1 coinfection,
`
`
` follow the dosage recommendations in the table above (2.2)
` • A dosage recommendation cannot be made for patients with severe
`
`
`
`
` renal impairment or end stage renal disease (2.3)
`
`
`
`
`
`
`
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`
`Tablets: 400 mg sofosbuvir and 100 mg velpatasvir (3)
`
`--------------------------------CONTRAINDICATIONS-----------------------------­
`
`
`
`EPCLUSA and ribavirin combination regimen is contraindicated in
`
`
`
`
`patients for whom ribavirin is contraindicated. (4)
`
`
`
`-------------------------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)
`
`
`
`
`-------------------------------ADVERSE REACTIONS----------------------------­
`
`
`
`
`• The most common adverse reactions (incidence greater than or
`
`equal to 10%, all grades) observed 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%, all grades) observed with treatment with EPCLUSA
`
`
`
`and ribavirin for 12 weeks in 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.
`
`
`---------------------------------DRUG INTERACTIONS--------------------------­
`
`
`
`
`
`• P-gp inducers and/or moderate to potent CYP inducers (e.g.,
`
`rifampin, St. John’s wort, carbamazepine): May decrease
`
`
`
`concentrations of sofosbuvir and/or velpatasvir. Use of EPCLUSA
`
`
`
`
`with P-gp inducers and/or moderate to potent 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)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`Revised: 08/2017
`
`
`
`
`
`
`
`
`
`
`5.3 Risk of Reduced Therapeutic Effect Due to Concomitant
`
`
`Use of EPCLUSA with Inducers of P-gp and/or Moderate
`
`
`to Potent Inducers of CYP
`
`
`5.4 Risks Associated with Ribavirin and EPCLUSA
`
`Combination Treatment
`
`
`6 ADVERSE REACTIONS
`
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`
`
`
`
`
`7.1 Potential for Other Drugs to Affect EPCLUSA
`
`
`
`
`
`
`7.2 Potential for EPCLUSA to Affect Other Drugs
`
`
`
`7.3 Established and Potentially Significant Drug Interactions
`
`
`
`7.4 Drugs without Clinically Significant Interactions with
`
`EPCLUSA
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`8.1 Pregnancy
`
`
`
`8.2 Lactation
`
`

`

`
`
`
`
`
` 8.3 Females and Males of Reproductive Potential
`
`
` 8.4 Pediatric Use
`
`
`
` 8.5 Geriatric Use
`
`
`
`
` 8.6 Renal Impairment
`
`
` 8.7 Hepatic Impairment
`
`10 OVERDOSAGE
`
`
` 11 DESCRIPTION
` 12 CLINICAL PHARMACOLOGY
`
`
`
`
` 12.1 Mechanism of Action
`
`
` 12.2 Pharmacodynamics
`
`
`
` 12.3 Pharmacokinetics
`
`
`
` 12.4 Microbiology
`
`
`
`
`
`
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` 14 CLINICAL STUDIES
`
`
`
`
`
` 14.1 Description of Clinical Trials
`
`
` 14.2 Clinical Trials in Subjects without Cirrhosis and Subjects
` with Compensated Cirrhosis
`
`
`
`
` 14.3 Clinical Trial in Subjects Coinfected with HCV and HIV-1
`
`
`
` 14.4 Clinical Trials in Subjects with Decompensated Cirrhosis
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
` * Sections or subsections omitted from the full prescribing
`
`
`
`
` information are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4133087
`
`
`
`
`
`
`2
`
`

`

`
` FULL PRESCRIBING INFORMATION
`
` WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS
`
`
`
`COINFECTED WITH HCV AND HBV
`
`
`
`Test all patients for evidence of current or prior hepatitis B virus (HBV) infection
`
`before initiating treatment with EPCLUSA. 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)].
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`EPCLUSA is indicated for the treatment of adult patients with chronic hepatitis C virus
`
`
`
`
`(HCV) genotype 1, 2, 3, 4, 5, or 6 infection [see Dosage and Administration (2.2) and
`
`
`
`Clinical Studies (14)]:
`
`• without cirrhosis or with compensated cirrhosis
`
`
`• with decompensated cirrhosis for use in combination with ribavirin.
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`Testing Prior to the Initiation of Therapy
`2.1
`
`
`
`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 Dosage
`
`
`
`
`
`The recommended dosage of EPCLUSA is one tablet taken orally once daily with or
`
`
`
`
`without food [see Clinical Pharmacology (12.3)]. One tablet of EPCLUSA contains
`
`400 mg of sofosbuvir and 100 mg of velpatasvir. 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
`[see Clinical Studies (14.3)]. Refer to Drug Interactions (7) for dosage recommendations
`
`
`
`for concomitant HIV-1 antiviral drugs.
`
`
`
`
`Reference ID: 4133087
`
`
`
`
`
`
`3
`
`

`

`
`
` Table 1
`
`
`
` Recommended Treatment Regimen in Patients with Genotype 1, 2, 3,
`
`
`
`
` 4, 5, or 6 HCV
` Patient Population
`
`Treatment-naïve and treatment­
`
` experienceda, without cirrhosis and
`
` with compensated cirrhosis
`
` (Child-Pugh A)
`Treatment-naïve and treatment­
`experienceda, with decompensated
`
`
` cirrhosis (Child-Pugh B or C)
`
` In clinical trials, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor (boceprevir,
`
`
` a.
` simeprevir, or telaprevir).
`
`
` b. When administered with EPCLUSA, the recommended dosage of ribavirin is based on weight (administered with food): 1000 mg
`
`
`
`
`
` per day for patients less than 75 kg and 1200 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.
`
` 2.3 No Dosage Recommendations in Severe Renal Impairment and End Stage
`
` Renal Disease
`
` No dosage recommendation can be given for patients with severe renal impairment
` (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73 m2) or with end
`
`
`
`
`stage renal disease (ESRD), due to higher exposures (up to 20-fold) of the predominant
`
`
`
`
`sofosbuvir metabolite [see Use in Specific Populations (8.6) and Clinical Pharmacology
`
`(12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Treatment Regimen and Duration
`
`
`
` EPCLUSA 12 weeks
`
`
`
` EPCLUSA + ribavirinb 12 weeks
`
`
`
`
`
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`Each EPCLUSA tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir. The
`
`
`
`
`tablets are pink, diamond-shaped, film-coated, and debossed with “GSI” on one side
`
`
`and “7916” on the other side.
`
`
`CONTRAINDICATIONS
`4
`
`
`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.
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`
`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
`
`
`Reference ID: 4133087
`
`
`
`
`
`
`4
`
`

`

`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
`
`
`
`Reference ID: 4133087
`
`
`
`
`
`
`5
`
`

`

`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 Potent Inducers of CYP
`
`Drugs that are inducers of P-gp and/or moderate to potent 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)].
`
`
`
`ADVERSE REACTIONS
`6
`
`
`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)].
`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.
`
`
`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
`
`
`
`Reference ID: 4133087
`
`
`
`
`
`
`6
`
`

`

`
`
` 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.
`
`
`Reference ID: 4133087
`
`
`
`
`
`
`7
`
`

`

` 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 3xULN 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 1.5xULN.
`
`Isolated, asymptomatic lipase elevations of greater than 3xULN 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 10xULN 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 10xULN 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
`
`Reference ID: 4133087
`
`
`
`
`
`
`8
`
`

`

`
`
`
`
`
` 12 weeks of EPCLUSA without dose adjustment or treatment interruption of either
` EPCLUSA or HIV antiretroviral agents.
`
`
`
`
`
` 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
`
`
`
`
`DRUG INTERACTIONS
`7
`
`
`7.1 Potential for Other Drugs to Affect EPCLUSA
`
`
`
`Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while
`
`GS-331007 (the predominant circulating metabolite of sofosbuvir) is not. In vitro, slow
`
`
`metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed.
`
`
`Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6,
`
`
`CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may decrease
`
`
`plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic
`
`
`effect of EPCLUSA. The use of these agents with EPCLUSA is not recommended [see
`
`
`
`Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. EPCLUSA may be
`
`
`
`coadministered with P-gp, BCRP, and CYP inhibitors.
`
`7.2 Potential for EPCLUSA to Affect Other Drugs
`
`
`
`
`
`Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance
`
`protein (BCRP), OATP1B1, OATP1B3, and OATP2B1. Coadministration of EPCLUSA
`
`
`
`
`
`with drugs that are substrates of these transporters may increase the exposure of such
`drugs.
`
`7.3 Established and Potentially Significant Drug Interactions
`
`
`Table 2 provides a listing of established or potentially clinically significant drug
`
`
`
`
`interactions. The drug interactions described are based on studies conducted with either
`
`
`
`EPCLUSA, the components of EPCLUSA (sofosbuvir and velpatasvir) as individual
`
`
`
`
`agents, or are predicted drug interactions that may occur with EPCLUSA [see Warnings
`
`
`
`
`and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].
`
`
`
`
`Reference ID: 4133087
`
`
`
`
`
`
`9
`
`

`

`
`
` Table 2
`
` Potentially Significant Drug Interactions: Alteration in Dose or
`
`
` Regimen May Be Recommended Based on Drug Interaction Studies
`
`
` or Predicted Interactiona
`
`Concomitant Drug Class:
` Effect on
`
`
`Concentrationb
`Drug Name
`
`
` Acid Reducing Agents:
`
`
` ↓ velpatasvir
`
`
`
`
`Clinical Effect/Recommendation
` Velpatasvir solubility decreases as pH increases. Drugs
`
`
` that increase gastric pH are expected to decrease
`
`
`concentration of velpatasvir.
` Separate antacid and EPCLUSA administration by
`
`
`
` 4 hours.
` H2 -receptor antagonists may be administered
`
`
` simultaneously with or 12 hours apart from EPCLUSA
` at a dose that does not exceed doses comparable to
`
`
`famotidine 40 mg twice daily.
`Coadministration of omeprazole or other proton-pump
`
` inhibitors is not recommended. If it is considered
` medically necessary to coadminister, EPCLUSA should
`
`
`be administered with food and taken 4 hours before
`
`omeprazole 20 mg. Use with other proton-pump
`
`
`
` inhibitors has not been studied.
` Coadministration of amiodarone with a sofosbuvir­
`
` containing regimen may result in serious symptomatic
`
`
` bradycardia. The mechanism of this effect is unknown.
`
` Coadministration of amiodarone with EPCLUSA is not
`
` recommended; if coadministration is required, cardiac
`
` monitoring is recommended [see Warnings and
`
`
`Precautions (5.2) and Adverse Reactions (6.2)].
`
` Therapeutic concentration monitoring of digoxin is
`
`
` recommended when coadministered with EPCLUSA.
`
`Refer to digoxin prescribing information for monitoring
`
`and dose modification recommendations for
`
`concentration increases of less than 50%.
`
`Coadministration is not recommended.
`
` Antacids (e.g., aluminum
`
`
`and magnesium hydroxide)
`H2 -receptor antagonistsc
`
`
`(e.g., famotidine)
`
`
` Proton-pump inhibitorsc
`
`(e.g., omeprazole)
`
`
`
` Antiarrhythmics:
`
`amiodarone
`
`
`digoxinc
`
`Effect on
` amiodarone,
`
`sofosbuvir, and
` velpatasvir
`
` concentrations
`
`
`unknown
`
`
` ↑ digoxin
`
`
`
`
` Anticancers:
`
`topotecan
` Anticonvulsants:
`
` carbamazepine
`
` phenytoin
` phenobarbital
`
`
`oxcarbazepine
` Antimycobacterials:
`
` rifabutin
`rifampinc
`
`
`rifapentine
`HIV Antiretrovirals:
`
`
`efavirenzc
`Regimens containing
`
`tenofovir DF
`
`
`
`
`tipranavir/ritonavir
`
`Reference ID: 4133087
`
`
` ↑ topotecan
`
`
`
`
`
` ↓ sofosbuvir
`
`
` ↓ velpatasvir
`
`
`
` ↓ sofosbuvir
`
`
` ↓ velpatasvir
`
`
` ↓ velpatasvir
`
`
`
`
` ↑ tenofovir
`
`
`
`
`
` ↓ sofosbuvir
`
`
` ↓ velpatasvir
`
`
`
`
`
`
`Coadministration is not recommended.
`
`
`Coadministration is not recommended.
`
` Coadministration of EPCLUSA with
`
`
`efavirenz-containing regimens is not recommended.
`Monitor for tenofovir-associated adverse reactions in
`
` patients receiving EPCLUSA concomitantly with a
`regimen containing tenofovir DF. Refer to the
`
` prescribing information of the tenofovir DF-containing
`
`product for recommendations on renal monitoring.
`
`Coadministration is not recommended.
`
`
`
`
`
`
`10
`
`

`

`
`Clinical Effect/Recommendation
`
`Coadministration is not recommended.
`
`Concomitant Drug Class:
`
`Drug Name
` Herbal Supplements:
`
`
`
` St. John’s wort (Hypericum
`
`perforatum)
`HMG-CoA Reductase
`
` Inhibitors:
`
`rosuvastatinc
`
` Effect on
`
`
`Concentrationb
`
`
` ↓ sofosbuvir
`
`
` ↓ velpatasvir
`
`
` ↑ rosuvastatin
`
`
`
`
`atorvastatin
`
`
` ↑ atorvastatin
`
`
`
` Coadministration of EPCLUSA with rosuvastatin may
`
`
`
` significantly increase the concentration of rosuvastatin,
` which is associated with increased risk of myopathy,
`
`
`
` including rhabdomyolysis. Rosuvastatin may be
` administered with EPCLUSA at a dose that does not
`
`
`exceed 10 mg.
` Coadministration of EPCLUSA with atorvastatin is
`
`
`
` expected to increase the concentrations of atorvastatin,
` which is associated with increased risk of myopathy,
`
`
` including rhabdomyolysis. Monitor closely for HMG-
`
` CoA reductase inhibitor-associated adverse reactions,
`
`
`such as myopathy and rhabdomyolysis.
`
`
`
`
`
`
`
`
`
`
` DF = disoproxil fumarate.
` a. This table is not all inclusive.
`
`
` b. ↓ = decrease, ↑ = increase.
`
`
`
`
`
` c. These interactions have been studied in healthy adults.
`
`
`
`
`
`7.4 Drugs without Clinically Significant Interactions with EPCLUSA
`
`
`Based on drug interaction studies conducted with the components of EPCLUSA
`
`
`(sofosbuvir or velpatasvir) or EPCLUSA, no clinically significant drug interactions have
`
`
`been observed with the following drugs [see Clinical Pharmacology (12.3)]:
`
`
`
`• EPCLUSA: atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir,
`
`
`elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine,
`
`
`raltegravir, or rilpivirine
`
`
`
`
`• Sofosbuvir: ethinyl estradiol/norgestimate, methadone, or tacrolimus
`
`
`
`• Velpatasvir: ethinyl estradiol/norgestimate, ketoconazole, or pravastatin. See
`
`
`
`
`
`Table 2 for use of EPCLUSA with certain HIV antiretroviral regimens [see Drug
`
`
`Interactions (7.3)].
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`8.1 Pregnancy
`
`Risk Summary
`
`
`If EPCLUSA is administered with ribavirin, the combination regimen is contraindicated in
`
`pregnant women and in men whose female partners are pregnant. Refer to the ribavirin
`
`prescribing information for more information on ribavirin-associated risks of use during
`
`pregnancy.
`
`
`
`
`
`No adequate human data are available to establish whether or not EPCLUSA poses a
`
`
`risk to pregnancy outcomes. In animal repro