`
` 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
`
`
`03/2020
`
`03/2020
`
`
`
`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 ----------------------
`
`
`
`03/2020
`Indications and Usage (1)
`
`
`Dosage and Administration
`
`Recommended Treatment Regimen and Duration in
`
`Patients 6 Years of Age and Older or Weighing at Least 17
`
`
`
`
`kg (2.2)
`
`
`
`Recommended Dosage in Adults (2.3)
`
`Recommended Dosage in Pediatric Patients 6 Years of
`
`
`
`
`Age and Older or Weighing at Least 17 kg (2.4)
`
`
`
`
`Renal Impairment (2.5)
`
`
`03/2020
`
`11/2019
`
`
`
`-------------------------------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 and pediatric patients 6 years of age and older or
`
`
`
`weighing at least 17 kg 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)
`
`
`
`• See recommended treatment regimen and duration in patients 6
`
`
`years of age and older or weighing at least 17 kg with genotypes 1,
`
`
`
`
`
`
`2, 3, 4, 5, or 6 HCV in table below: (2.2)
`
`
`
`
`
`
`Patient Population
`
`
` Regimen
`
` and Duration
`
`
`
`
`
` EPCLUSA 12 weeks
`
`
`
`
`
`
`
` EPCLUSA + ribavirin 12 weeks
`
`
`
`
`• HCV/HIV-1 coinfection: For patients with HCV/HIV-1 coinfection,
`
`
`follow the dosage recommendations in the table above. (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.
`
`(2.5)
`
`
`
`
`
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------
`
`
`
`
`Tablets: 400 mg of sofosbuvir and 100 mg of velpatasvir; 200 mg of
`
`
`sofosbuvir and 50 mg of 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 adult patients with decompensated
`
`
`cirrhosis are fatigue, anemia, nausea, headache, insomnia, and
`
`diarrhea. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Gilead
`
`Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`
`---------------------------------DRUG INTERACTIONS--------------------------
`
`
`
`
`• P-gp inducers and/or moderate to strong CYP inducers (e.g.,
`
`
`rifampin, St. John’s wort, carbamazepine): May decrease
`
`
`
`concentrations of sofosbuvir and/or velpatasvir. Use of EPCLUSA
`
`
`
`with P-gp inducers and/or moderate to strong CYP inducers is not
`
`
`recommended. (5.3, 7)
`
`
`
`
`• Consult the full prescribing information prior to use for potential drug
`
`
`interactions. (5.2, 5.3, 7)
`
`
`
`• Clearance of HCV infection with direct acting antivirals may lead to
`
`
`changes in hepatic function, which may impact safe and effective
`
`
`
`
`use of concomitant medications. Frequent monitoring of relevant
`
`
`laboratory parameters (INR or blood glucose) and dose adjustments
`
`
`
`of certain concomitant medications may be necessary. (7.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 03/2020
`
`
`
`
`
`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).
`
`
`
`
`
`• 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 6 years and older:
`
`
`Recommended dosage of EPCLUSA in pediatric patients 6 years of
`
`
`
`
`
`
`age and older or weighing at least 17 kg is based on weight. Refer
`
`to Table 2 of the full prescribing information for specific dosing
`
`guidelines based on body weight (2.4)
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4577615
`
`
`
`
`
`
`1
`
`
`
`
`
`
`
`
`
`
`
` 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 the Initiation of Therapy
`
`
`
`
` 2.2 Recommended Treatment Regimen and Duration in
`
`
`
`
` Patients 6 Years of Age and Older or Weighing at Least 17
`
` kg
`
`
`
` 2.3 Recommended Dosage in Adults
`
` 2.4 Recommended Dosage in Pediatric Patients 6 Years of
`
`
`
`
` Age and Older or Weighing at Least 17 kg
` 2.5 Renal Impairment
`
`
`
` 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
`
`
`
`
` 5.3 Risk of Reduced Therapeutic Effect Due to Concomitant
`
` Use of EPCLUSA with Inducers of P-gp and/or Moderate to
`
`
` Strong Inducers of CYP
`
`
` 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
`
`
` 14.5 Clinical Trial in Subjects with Severe Renal Impairment
`
`
`
` Requiring Dialysis
`
`
` 14.6 Clinical Trial in Pediatric Subjects
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 17 PATIENT COUNSELING INFORMATION
`
`
` * Sections or subsections omitted from the full prescribing
`
`
`
` information are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4577615
`
`
`Gilead Sciences
`
`
`
`
`
`
`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 adults and pediatric patients 6 years of age
`
`
`
`
`
`
`and older or weighing at least 17 kg 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.
`
`
`
`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 Treatment Regimen and Duration in Patients 6 Years of Age
`
`
`and Older or Weighing at Least 17 kg
`
`
`
`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: 4577615
`
`
`
`
`3
`
`
`
`
`
` Table 1
`
`
`
` Treatment Regimen and Duration
`
`
`EPCLUSA 12 weeks
`
`
`
` EPCLUSA + ribavirinb 12 weeks
`
`
`
` Recommended Treatment Regimen and Duration in Patients 6 Years
`
`
`of Age and Older or Weighing at Least 17 kg 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 in adults, regimens contained peginterferon alfa/ribavirin with or without an HCV NS3/4A protease inhibitor
`
`
`
`(boceprevir, simeprevir, or telaprevir).
`
`
`b. See Dosage and Administration 2.3 and 2.4 for ribavirin dosage recommendations.
`
`
`
`
` 2.3 Recommended Dosage in Adults
`
`
`The recommended dosage of EPCLUSA in adults is one tablet (400 mg sofosbuvir and
`
`
`
` 100 mg velpatasvir) taken orally once daily with or without food [see Clinical
`
`Pharmacology (12.3)].
`
`
`When administered with EPCLUSA, the recommended dosage of ribavirin is based on
`weight (administered with food): 1,000 mg per day for patients less than 75 kg and
`1,200 mg for those weighing at least 75 kg, divided and administered twice daily. The
`
`
` starting dosage and on-treatment dosage of ribavirin can be decreased based on
`
`
`
`hemoglobin and creatinine clearance. For ribavirin dosage modifications refer to the
` ribavirin prescribing information [see Use in Specific Populations (8.6) and Clinical
`
`
`
`
` Studies (14.4)].
` 2.4 Recommended Dosage in Pediatric Patients 6 Years of Age and Older or
`
`
`
`
`Weighing at Least 17 kg
`
`
`
`
`The recommended dosage of EPCLUSA in pediatric patients 6 years of age and older
`
`
`
`
`
`
`or weighing at least 17 kg is based on weight and provided in Table 2. Table 3 provides
`
`
`the weight-based dosage of ribavirin when used in combination with EPCLUSA for
`
`
`
`pediatric patients. Take EPCLUSA once daily with or without food [see Use in Specific
`
`
`Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.6)].
`
`
`
`Table 2
`
`
`
` a.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Dosing for Pediatric Patients 6 Years and Older or Weighing at Least
`
`
`
`
`
`
`
`17 kg with Genotype 1, 2, 3, 4, 5, or 6 HCV
`Body Weight
`
`(kg)
`
`
`
`at least 30
`
`
`Dosing of EPCLUSA
`
`
`one 400 mg/100 mg tablet once daily
`
`or
`
`two 200 mg/50 mg tablets once daily
`
`
`
`EPCLUSA Daily Dose
`
`
`400 mg/100 mg per day
`
`17 to less than 30
`
`
`one 200 mg/50 mg tablet once daily
`
`
`200 mg/50 mg per day
`
`
`Reference ID: 4577615
`
`
`
`
`4
`
`
`
`
`
`Table 3
`
`
`
` less than 47
`
`47–49
`
`
`
`50–65
`
`
`
`
`Recommended Dosing for Ribavirin in Combination Therapy with
`
`
` EPCLUSA for Pediatric Patients 6 Years and Older
`
`Oral Ribavirin Daily Dosagea
`
` Body Weight (kg)
`
`
` 15 mg per kg per day
`
` (divided dose AM and PM)
`
`600 mg per day
`
`(1 x 200 mg AM, 2 x 200 mg PM)
`
`800 mg per day
`
`(2 x 200 mg AM, 2 x 200 mg PM)
`
`1,000 mg per day
`
`(2 x 200 mg AM, 3 x 200 mg PM)
`
`1,200 mg per day
`
`(3 x 200 mg AM, 3 x 200 mg PM)
`
`
` a. The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.
`
`
` 2.5 Renal Impairment
`
`No dosage adjustment of EPCLUSA is recommended in patients with any degree of
`
` renal impairment, including patients requiring dialysis. Administer EPCLUSA with or
`
` without ribavirin according to the recommendations in Table 1 [see Adverse Reactions
`
`
` (6.1), Use in Specific Populations (8.6), and Clinical Studies (14.5)]. Refer to ribavirin
`
`tablet prescribing information for ribavirin dosage modification for patients with CrCl less
`
`
`
`
`than or equal to 50 mL per minute.
`
`66–80
`
`
`
`
`greater than 80
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`
`EPCLUSA tablets are available in two dose strengths:
`
`
`
`
`
`
`• 400 mg/100 mg Tablets: pink, diamond-shaped, film-coated tablet debossed with
`
`
`
`
`
`“GSI” on one side and “7916” on the other side. Each tablet contains 400 mg of
`
`sofosbuvir and 100 mg of velpatasvir.
`
`
`
`
`
`
`
`• 200 mg/50 mg Tablets: pink, oval-shaped, film-coated tablet debossed with “GSI”
`
`
`
`on one side and “S/V” on the other side. Each tablet contains 200 mg of
`
`
`sofosbuvir and 50 mg of velpatasvir.
`
`
`
`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 [see Dosage and Administration (2.2, 2.3, 2.4)].
`
`
`
`
`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
`
`
`
`
`5
`
`Reference ID: 4577615
`
`
`
`
`who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant
`
`hepatitis, hepatic failure, and death. Cases have been reported in patients who are
`HBsAg positive and also in patients with serologic evidence of resolved HBV infection
`
`
`(i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported
`
`in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk
`
`of HBV reactivation associated with treatment with HCV direct-acting antivirals may be
`increased in these patients.
`
`HBV reactivation is characterized as an abrupt increase in HBV replication manifesting
`
`as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection,
`
`
`reappearance of HBsAg can occur. Reactivation of HBV replication may be
`accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe
`cases, increases in bilirubin levels, liver failure, and death can occur.
`
`Test all patients for evidence of current or prior HBV infection by measuring HBsAg and
`
`
`
`anti-HBc before initiating HCV treatment with EPCLUSA. In patients with serologic
`
`evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or
`
`
`
`
`
`HBV reactivation during HCV treatment with EPCLUSA and during post-treatment
`
`
`follow-up. Initiate appropriate patient management for HBV infection as clinically
`
`
`
`indicated.
`
`5.2 Serious Symptomatic Bradycardia When Coadministered with Amiodarone
`
`
`Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker
`
`
`intervention have been reported when amiodarone is coadministered with a sofosbuvir
`containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone
`
`
`
`who was coadministered a sofosbuvir-containing regimen (HARVONI®
`
` [ledipasvir/sofosbuvir]). Bradycardia has generally occurred within hours to days, but
`
`
` cases have been observed up to 2 weeks after initiating HCV treatment. Patients also
` taking beta blockers, or those with underlying cardiac comorbidities and/or advanced
`
`
`
` liver disease may be at increased risk for symptomatic bradycardia with
` coadministration of amiodarone. Bradycardia generally resolved after discontinuation of
`
`
`
`
`
` HCV treatment. The mechanism for this effect is unknown.
`
` Coadministration of amiodarone with EPCLUSA is not recommended. For patients
`
`
`
`
` taking amiodarone who have no other alternative viable treatment options and who will
`
` be coadministered EPCLUSA:
`
`
`
`
`
`
`
`
`
`
`• Counsel patients about the risk of symptomatic bradycardia.
`
`
`
`
`• Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration
`
`
`
`
`is recommended, after which outpatient or self-monitoring of the heart rate should
`
`
`occur on a daily basis through at least the first 2 weeks of treatment.
`
`
`
`
`
`Patients who are taking EPCLUSA who need to start amiodarone therapy due to no
`
`
`
`other alternative viable treatment options should undergo similar cardiac monitoring as
`
`
`outlined above.
`
`
`Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to
`
`
`
`starting EPCLUSA should also undergo similar cardiac monitoring as outlined above.
`
`
`
`
`Reference ID: 4577615
`
`
`
`
`6
`
`
`
`
`
`
`
`Patients who develop signs or symptoms of bradycardia should seek medical evaluation
`
`
`immediately. Symptoms may include near-fainting or fainting, dizziness or
`
`
`lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest
`
`
`
`pains, confusion, or memory problems [see Adverse Reactions (6.2) and Drug
`
`Interactions (7.3)].
`
`
`
`5.3 Risk of Reduced Therapeutic Effect Due to Concomitant Use of EPCLUSA
`
`
`with Inducers of P-gp and/or Moderate to Strong Inducers of CYP
`
`
`Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6,
`
`
`
`CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may significantly
`
`
`
`decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to potentially
`
`
`
`
`
`
`reduced therapeutic effect of EPCLUSA. The use of these agents with EPCLUSA is not
`
`recommended [see Drug Interactions (7.3)].
`
`
`
`
`
`5.4 Risks Associated with Ribavirin and EPCLUSA Combination Treatment
`
`
`If EPCLUSA is administered with ribavirin, the warnings and precautions for ribavirin
`
`
`apply to this combination regimen. Refer to the ribavirin prescribing information for a full
`
`
`list of the warnings and precautions for ribavirin [see Dosage and Administration (2.2)].
`
`
`
`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.
`
`
`
`Clinical Trials in Adult Subjects
`
`Adverse Reactions in Subjects without Cirrhosis or with Compensated Cirrhosis
`
`The adverse reactions data for EPCLUSA in patients without cirrhosis or with
`
`
`
`
`
`compensated cirrhosis were derived from three Phase 3 clinical trials (ASTRAL-1,
`
`ASTRAL-2, and ASTRAL-3) which evaluated a total of 1035 subjects infected with
`
`
`
`genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis, who
`
`
`
`
`received EPCLUSA for 12 weeks. EPCLUSA was studied in placebo- and active-
`
`
`
`
`
`controlled trials [see Clinical Studies (14.2)].
`
`
`
`The proportion of subjects who permanently discontinued treatment due to adverse
`events was 0.2% for subjects who received EPCLUSA for 12 weeks.
`
`
`
`
`
`
`Reference ID: 4577615
`
`
`
`
`7
`
`
`
`
`
` The most common adverse reactions (adverse events assessed as causally related by
`
`
`
`
` the investigator and at least 10%) were headache and fatigue in subjects treated with
` EPCLUSA for 12 weeks.
`
`
`
`
`
`
`
`Adverse reactions, all grades, observed in greater than or equal to 5% of subjects
`
`
`
`
`
`
`
`
`receiving 12 weeks of treatment with EPCLUSA in ASTRAL-1 include headache (22%),
`
`
`fatigue (15%), nausea (9%), asthenia (5%), and insomnia (5%). Of subjects receiving
`
`
`
`EPCLUSA who experienced these adverse reactions, 79% had an adverse reaction of
`
`
`
`
`
`
`mild severity (Grade 1). With the exception of asthenia, each of these adverse reactions
`
`
`occurred at a similar frequency or more frequently in subjects treated with placebo
`
`
`compared to subjects treated with EPCLUSA (asthenia: 3% versus 5% for the placebo
`
`and EPCLUSA groups, respectively).
`
`
`
`
`The adverse reactions observed in subjects treated with EPCLUSA in ASTRAL-2 and
`
`
`
`
`ASTRAL-3 were consistent with those observed in ASTRAL-1. Irritability was also
`
`
`
`
`
`observed in greater than or equal to 5% of subjects treated with EPCLUSA in
`
`ASTRAL-3.
`
`
`
`Adverse Reactions in Subjects Coinfected with HCV and HIV-1
`
`The safety assessment of EPCLUSA in subjects with HCV/HIV-1 coinfection was based
`
`on an open-label clinical trial (ASTRAL-5) in 106 subjects who were on stable
`
`
`
`antiretroviral therapy [see Clinical Studies (14.3)]. The safety profile in HCV/HIV-1
`
`coinfected subjects was similar to that observed in HCV mono-infected subjects. The
`
`most common adverse reactions occurring in at least 10% of subjects were fatigue
`
`(22%) and headache (10%).
`
`
`Adverse Reactions in Subjects with Decompensated Cirrhosis
`
`The safety assessment of EPCLUSA in subjects infected with genotype 1, 2, 3, 4, or 6
`
`
`
`
`HCV with decompensated cirrhosis was based on one Phase 3 trial (ASTRAL-4)
`
`including 87 subjects who received EPCLUSA with ribavirin for 12 weeks. All
`
`
`
`
`87 subjects had Child-Pugh B cirrhosis at screening. On the first day of treatment with
`
`
`
`
`EPCLUSA with ribavirin, 6 subjects and 4 subjects were assessed to have Child-Pugh A
`
`
`and Child-Pugh C cirrhosis, respectively [see Clinical Studies (14.4)].
`
`
`
`
`The most common adverse reactions (adverse events assessed as causally related by
`
`
`
`the investigator, all grades with frequency of 10% or greater) in the 87 subjects who
`
`
`received EPCLUSA with ribavirin for 12 weeks were fatigue (32%), anemia (26%),
`
`
`
`
`
`
`nausea (15%), headache (11%), insomnia (11%), and diarrhea (10%). Of subjects who
`
`experienced these adverse reactions, 98% had adverse reactions of mild to moderate
`
`severity.
`
`
`A total of 4 (5%) subjects permanently discontinued EPCLUSA with ribavirin due to an
`
`
`adverse event; there was no adverse event leading to discontinuation that occurred in
`more than 1 subject.
`
`
`
`Reference ID: 4577615
`
`
`
`
`8
`
`
`
`Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were
`observed in 23% and 7% of subjects treated with EPCLUSA with ribavirin for 12 weeks,
`
`
`
`
`
`
`
`respectively. Ribavirin was permanently discontinued in 17% of subjects treated with
`
`
`
`
`
`EPCLUSA with ribavirin for 12 weeks, due to adverse reactions.
`
`
`
`
`
` Less Common Adverse Reactions Reported in Clinical Trials
`
`The following adverse reactions occurred in less than 5% of subjects without cirrhosis or
`
`
`
`with compensated cirrhosis treated with EPCLUSA for 12 weeks and are included
`
`
`because of a potential causal relationship.
`
`
`
`
`
`
`
`
`Rash: In the ASTRAL-1 study, rash occurred in 2% of subjects treated with
`
`EPCLUSA and in 1% of subjects treated with placebo. No serious adverse reactions
`
`
`
`of rash occurred, and all rashes were mild or moderate in severity.
`
`
`
`
` Depression: In the ASTRAL-1 study, depressed mood occurred in 1% of subjects
`
`
`treated with EPCLUSA and was not reported by any subject taking placebo. No
`
` serious adverse reactions of depressed mood occurred, and all events were mild or
`
` moderate in severity.
`
`
` The following adverse reactions occurred in less than 10% of subjects with
`
`
` decompensated cirrhosis (ASTRAL-4) treated with EPCLUSA with ribavirin for
`
`
`
`
` 12 weeks and are included because of a potential causal relationship.
`
`
` Rash: Rash occurred in 5% of subjects treated with EPCLUSA with ribavirin. No
`
`
`
`
`
`
`
` serious adverse reactions of rash occurred, and all rashes were mild or moderate in
`
` severity.
`
`
`
`
` Laboratory Abnormalities
`
`Lipase Elevations: In ASTRAL-1, isolated, asymptomatic lipase elevations of greater
`
`
`than 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.
`
`
`
`
`Reference ID: 4577615
`
`
`
`
`9
`
`
`
`
`
`
`
`Indirect Bilirubin: Increases in indirect bilirubin up to 3 mg/dL above baseline were
`
`
`noted among HIV-1/HCV coinfected subjects treated with EPCLUSA and an
`atazanavir/ritonavir-based antiretroviral regimen. The elevated indirect bilirubin
`
` values were not associated with clinical adverse events, and all subjects completed
` 12 weeks of EPCLUSA without dose adjustment or treatment interruption of either
`
`
`
`
`
`
` EPCLUSA or HIV antiretroviral agents.
`
`
`
`Adverse Reactions in Adults with Severe Renal Impairment Requiring Dialysis
`In an open-label trial (Trial 4062), in which a total of 59 adults with HCV with
`
`compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis
`
`received EPCLUSA for 12 weeks, the most common adverse reaction was nausea (7%)
`
`
`
`
`[see Clinical Studies (14.5)].
`
`Adverse Reactions in Pediatric Subjects 6 Years of Age and Older
`
`
`
`
`The safety assessment of EPCLUSA in pediatric subjects 6 years of age and older or
`
`
`
`
`weighing at least 17 kg is based on data from a Phase 2, open-label clinical trial (Study
`
`
`
`
`1143) that enrolled 175 subjects who were treated with EPCLUSA for 12 weeks. The
`
`
`adverse reactions observed were consistent with those observed in clinical trials of
`
`
`EPCLUSA in adults [see Use in Specific Populations (8.4) and Clinical Studies (14.6)].
`
`
`
`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 strong inducers of CYP2B6,
`
`CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may decrease
`
`
`plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic
`
`
`
`
`effect of EPCLUSA. The use of these agents with EPCLUSA is not recommended
`
`Reference ID: 4577615
`
`
`
`
`
`10
`
`
`
`
`
` [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
`
`
`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
`
`
`
`
`conce