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
`EPCLUSA® (sofosbuvir and velpatasvir) oral pellets
`Initial U.S. Approval: 2016
`
`
`06/2021
`
`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 -----------------------
`Indications and Usage (1)
`06/2021
`Dosage and Administration
`Recommended Treatment Regimen and Duration in
`Patients 3 Years of Age and Older (2.2)
`Recommended Dosage in Pediatric Patients 3 Years of
`Age and Older (2.4)
`Preparation and Administration of Oral Pellets (2.5)
`
`06/2021
`06/2021
`
`
`-------------------------------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 adults and pediatric patients 3 years of age and older with chronic
`HCV genotype 1, 2, 3, 4, 5, or 6 infection (1):
`• without cirrhosis or with compensated cirrhosis
`• with decompensated cirrhosis for use in combination with
`ribavirin.
`------------------------DOSAGE AND ADMINISTRATION-----------------------
`• Testing prior to the initiation of therapy: Test all patients for HBV
`infection by measuring HBsAg and anti-HBc. (2.1)
`• See recommended treatment regimen and duration in patients 3
`years of age and older with genotypes 1, 2, 3, 4, 5, or 6 HCV in table
`below: (2.2)
`
`Patient Population
`
`Regimen
`and Duration
`
`EPCLUSA 12 weeks
`
`EPCLUSA + ribavirin 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).
`• Recommended dosage in adults: One tablet (400 mg of sofosbuvir
`and 100 mg of velpatasvir) taken orally once daily with or without
`food. (2.3)
`• Recommended dosage in pediatric patients 3 years and older:
`Recommended dosage is based on weight. Refer to Table 2 of the
`full prescribing information for specific dosing guidelines based on
`body weight. (2.4)
`• For pediatric patients less than 6 years of age, administer EPCLUSA
`oral pellets with food. (2.4)
`• Instructions for Use should be followed for preparation and
`administration of EPCLUSA oral pellets. (2.5)
`• HCV/HIV-1 coinfection: For patients with HCV/HIV-1 coinfection,
`follow the dosage recommendations in the table above. (2.2)
`
`• For treatment-naïve and treatment-experienced liver transplant
`recipients without cirrhosis or with compensated cirrhosis (Child-
`Pugh A), the recommended regimen is EPCLUSA once daily for 12
`weeks. (2.2)
`• If used in combination with ribavirin, follow the recommendations for
`ribavirin dosing and dosage modifications. (2.3, 2.4)
`• For patients with renal impairment including end stage renal disease
`on dialysis, follow the dosage recommendations in the table above.
`(2.6)
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`• Tablets: 400 mg of sofosbuvir and 100 mg of velpatasvir; 200 mg of
`sofosbuvir and 50 mg of velpatasvir. (3)
`• Oral Pellets: 200 mg of sofosbuvir and 50 mg of velpatasvir; 150 mg
`of sofosbuvir and 37.5 mg of velpatasvir. (3)
`--------------------------------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 in adults and pediatric subjects 6
`years of age and older with treatment with EPCLUSA for 12 weeks
`are headache and fatigue. (6.1)
`• The most common adverse reactions (incidence greater than or
`equal to 10%, grade 1 or 2) observed in pediatric subjects less than
`6 years of age are vomiting and product use issue (spitting up the
`drug). (6.1)
`• The most common adverse reactions (incidence greater than or
`equal to 10%, all grades) observed with treatment with EPCLUSA
`and ribavirin for 12 weeks in adult patients with decompensated
`cirrhosis are fatigue, anemia, nausea, headache, insomnia, and
`diarrhea. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Gilead
`Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`---------------------------------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: 04/2022
`
`
`
`
`
`Reference ID: 4974030
`
`
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`

`
`
`
`
`
`
`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 3 Years of Age and Older
`2.3 Recommended Dosage in Adults
`2.4 Recommended Dosage in Pediatric Patients 3 Years of
`Age and Older
`2.5 Preparation and Administration of Oral Pellets
`2.6 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
`8.8 People Who Inject Drugs (PWID), Including Those on
`Medication-Assisted Treatment (MAT) for Opioid Use
`Disorder
`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 Adult Liver Transplant Recipients without
`Cirrhosis and with Compensated Cirrhosis
`14.6 Clinical Trial in Subjects with Severe Renal Impairment
`Requiring Dialysis
`14.7 Clinical Trial in People Who Inject Drugs (PWID),
`Including Those on Medication-Assisted Treatment (MAT)
`for Opioid Use Disorder
`14.8 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.
`
`
`
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`
`Reference ID: 4974030
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`

`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 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.
`
`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 3 Years of Age
`and Older
`Table 1 shows the recommended treatment regimen and duration based on patient
`population.
`
`For patients with HCV/HIV-1 coinfection follow the dosage recommendations in Table 1.
`For treatment-naïve and treatment-experienced liver transplant recipients without
`cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is
`EPCLUSA once daily for 12 weeks [see Clinical Studies (14.3 and 14.5)]. Refer to Drug
`Interactions (7) for dosage recommendations for concomitant drugs.
`
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`Reference ID: 4974030
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`Recommended Treatment Regimen and Duration in Patients 3 Years
`of Age and Older with Genotype 1, 2, 3, 4, 5, or 6 HCV
`Patient Population
`Treatment Regimen and Duration
`Treatment-naïve and treatment-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 3 Years of Age and Older
`The recommended dosage of EPCLUSA in pediatric patients 3 years of age and older is
`based on weight and provided in Table 2. Table 3 provides the weight-based dosage of
`ribavirin when used in combination with EPCLUSA for pediatric patients. Take
`EPCLUSA oral pellets or tablets once daily with or without food. In pediatric patients
`less than 6 years of age, administer the oral pellets with food to increase tolerability
`related to palatability [see Use in Specific Populations (8.4), Clinical Pharmacology
`(12.3), and Clinical Studies (14.8)].
`
`Table 2
`
`Table 1
`
`a.
`
`
`
`Body
`Weight
`(kg)
`less than
`17
`
`17 to less
`than 30
`
`EPCLUSA 12 weeks
`
`EPCLUSA + ribavirinb 12 weeks
`
`Dosing for Pediatric Patients 3 Years and Older with Genotype 1, 2,
`3, 4, 5, or 6 HCV Using EPCLUSA Oral Pellets or Tablets
`
`
`
`EPCLUSA Daily Dose
`
`Dosing of EPCLUSA Oral
`Pellets
`
`Dosing of EPCLUSA Tablet
`
`150 mg/37.5 mg per
`day
`
`one 150 mg/37.5 mg packet
`of pellets once daily
`
`N/A
`
`200 mg/50 mg per day
`
`one 200 mg/50 mg packet of
`pellets once daily
`
`one 200 mg/50 mg tablet
`once daily
`
`at least 30
`
`400 mg/100 mg per day
`
`two 200 mg/50 mg packets of
`pellets once daily
`
`one 400 mg/100 mg tablet
`once dailya
`
`a. Two 200 mg/50 mg tablets once daily can be used for patients who cannot swallow the 400 mg/100
`mg tablet.
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`Table 3
`
`less than 47
`
`47–49
`
`Recommended Dosing for Ribavirin in Combination Therapy with
`EPCLUSA for Pediatric Patients 3 Years and Older
`Body Weight (kg)
`Oral Ribavirin Daily Dosagea
`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 Preparation and Administration of Oral Pellets
`See the EPCLUSA oral pellets full Instructions for Use for details on the preparation and
`administration of EPCLUSA oral pellets.
`Do not chew EPCLUSA oral pellets to avoid a bitter aftertaste. EPCLUSA oral pellets
`can be taken directly in the mouth or with food (See Instructions for Use). In pediatric
`patients less than 6 years of age, administer the oral pellets with food to increase
`tolerability related to palatability. Sprinkle the oral pellets on one or more spoonfuls of
`non-acidic soft food at or below room temperature. Examples of non-acidic foods
`include pudding, chocolate syrup, and ice cream. Take EPCLUSA oral pellets within 15
`minutes of gently mixing with food and swallow the entire contents without chewing.
`2.6 Renal Impairment
`No dosage adjustment of EPCLUSA is recommended in patients with any degree of
`renal impairment, including patients requiring dialysis. Administer EPCLUSA with or
`without ribavirin according to the recommendations in Table 1 [see Adverse Reactions
`(6.1), Use in Specific Populations (8.6), and Clinical Studies (14.6)]. Refer to ribavirin
`tablet prescribing information for ribavirin dosage modification for patients with CrCl less
`than or equal to 50 mL per minute.
`
`50–65
`
`66–80
`
`greater than 80
`
`DOSAGE FORMS AND STRENGTHS
`3
`EPCLUSA is available as tablets or pellets for oral use. Each dosage form is available
`in two dose strengths:
`• 400 mg/100 mg Tablets: pink, diamond-shaped, film-coated tablet debossed with
`“GSI” on one side and “7916” on the other side. Each tablet contains 400 mg of
`sofosbuvir and 100 mg of velpatasvir.
`• 200 mg/50 mg Tablets: pink, oval-shaped, film-coated tablet debossed with “GSI”
`on one side and “S/V” on the other side. Each tablet contains 200 mg of
`sofosbuvir and 50 mg of velpatasvir.
`• 200 mg/50 mg Oral Pellets: white to off-white, film-coated pellets in unit-dose
`packets. Each packet contains 200 mg of sofosbuvir and 50 mg of velpatasvir.
`• 150 mg/37.5 mg Oral Pellets: white to off-white, film-coated pellets in unit-dose
`packets. Each packet contains 150 mg of sofosbuvir and 37.5 mg of velpatasvir.
`
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`CONTRAINDICATIONS
`
`EPCLUSA and ribavirin combination regimen is contraindicated in patients for whom
`ribavirin is contraindicated. Refer to the ribavirin prescribing information for a list of
`contraindications for ribavirin [see Dosage and Administration (2.2, 2.3, 2.4)].
`
`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
`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.
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`• Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration
`is recommended, after which outpatient or self-monitoring of the heart rate should
`occur on a daily basis through at least the first 2 weeks of treatment.
`
`
`Patients who are taking EPCLUSA who need to start amiodarone therapy due to no
`other alternative viable treatment options should undergo similar cardiac monitoring as
`outlined above.
`
`Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to
`starting EPCLUSA should also undergo similar cardiac monitoring as outlined above.
`
`Patients who develop signs or symptoms of bradycardia should seek medical evaluation
`immediately. Symptoms may include near-fainting or fainting, dizziness or
`lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest
`pains, confusion, or memory problems [see Adverse Reactions (6.2) and Drug
`Interactions (7.3)].
`5.3 Risk of Reduced Therapeutic Effect Due to Concomitant Use of EPCLUSA
`with Inducers of P-gp and/or Moderate to Strong Inducers of CYP
`Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6,
`CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may significantly
`decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to potentially
`reduced therapeutic effect of EPCLUSA. The use of these agents with EPCLUSA is not
`recommended [see Drug Interactions (7.3)].
`5.4 Risks Associated with Ribavirin and EPCLUSA Combination Treatment
`If EPCLUSA is administered with ribavirin, the warnings and precautions for ribavirin
`apply to this combination regimen. Refer to the ribavirin prescribing information for a full
`list of the warnings and precautions for ribavirin [see Dosage and Administration (2.2)].
`
`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
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`received EPCLUSA for 12 weeks. EPCLUSA was studied in placebo- and active-
`controlled trials [see Clinical Studies (14.2)].
`
`The proportion of subjects who permanently discontinued treatment due to adverse
`events was 0.2% for subjects who received EPCLUSA for 12 weeks.
`
`The most common adverse reactions (adverse events assessed as causally related by
`the investigator and at least 10%) were headache and fatigue in subjects treated with
`EPCLUSA for 12 weeks.
`
`Adverse reactions, all grades, observed in greater than or equal to 5% of subjects
`receiving 12 weeks of treatment with EPCLUSA in ASTRAL-1 include headache (22%),
`fatigue (15%), nausea (9%), asthenia (5%), and insomnia (5%). Of subjects receiving
`EPCLUSA who experienced these adverse reactions, 79% had an adverse reaction of
`mild severity (Grade 1). With the exception of asthenia, each of these adverse reactions
`occurred at a similar frequency or more frequently in subjects treated with placebo
`compared to subjects treated with EPCLUSA (asthenia: 3% versus 5% for the placebo
`and EPCLUSA groups, respectively).
`
`The adverse reactions observed in subjects treated with EPCLUSA in ASTRAL-2 and
`ASTRAL-3 were consistent with those observed in ASTRAL-1. Irritability was also
`observed in greater than or equal to 5% of subjects treated with EPCLUSA in
`ASTRAL-3.
`
`Adverse Reactions in Subjects Coinfected with HCV and HIV-1
`The safety assessment of EPCLUSA in subjects with HCV/HIV-1 coinfection was based
`on an open-label clinical trial (ASTRAL-5) in 106 subjects who were on stable
`antiretroviral therapy [see Clinical Studies (14.3)]. The safety profile in HCV/HIV-1
`coinfected subjects was similar to that observed in HCV mono-infected subjects. The
`most common adverse reactions occurring in at least 10% of subjects were fatigue
`(22%) and headache (10%).
`
`Adverse Reactions in Subjects with Decompensated Cirrhosis
`The safety assessment of EPCLUSA in subjects infected with genotype 1, 2, 3, 4, or 6
`HCV with decompensated cirrhosis was based on one Phase 3 trial (ASTRAL-4)
`including 87 subjects who received EPCLUSA with ribavirin for 12 weeks. All
`87 subjects had Child-Pugh B cirrhosis at screening. On the first day of treatment with
`EPCLUSA with ribavirin, 6 subjects and 4 subjects were assessed to have Child-Pugh A
`and Child-Pugh C cirrhosis, respectively [see Clinical Studies (14.4)].
`
`The most common adverse reactions (adverse events assessed as causally related by
`the investigator, all grades with frequency of 10% or greater) in the 87 subjects who
`received EPCLUSA with ribavirin for 12 weeks were fatigue (32%), anemia (26%),
`nausea (15%), headache (11%), insomnia (11%), and diarrhea (10%). Of subjects who
`experienced these adverse reactions, 98% had adverse reactions of mild to moderate
`severity.
`
` 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.
`
` A
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`Reference ID: 4974030
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`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.
`
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`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
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`atazanavir/ritonavir-based antiretroviral regimen. The elevated indirect bilirubin
`values were not associated with clinical adverse events, and all subjects completed
`12 weeks of EPCLUSA without dose adjustment or treatment interruption of either
`EPCLUSA or HIV antiretroviral agents.
`
`Adverse Reactions in Adult Liver Transplant Recipients
`The safety assessment of EPCLUSA in liver transplant recipients was based on an
`open-label clinical trial (Trial 2104) in 79 adults without cirrhosis or with compensated
`cirrhosis who received EPCLUSA for 12 weeks [see Clinical Studies (14.5)]. One
`subject discontinued treatment due to an adverse event on Day 7. The adverse
`reactions observed were consistent with the known safety profile of EPCLUSA. Adverse
`reactions occurring in at least 5% of subjects were headache (18%), fatigue (15%),
`nausea (8%), diarrhea (6%), and asthenia (5%).
`
`Adverse Reactions in Adults with Severe Renal Impairment Requiring Dialysis
`In an open-label trial (Trial 4062), in which a total of 59 adults with HCV with
`compensated liver disease (with or without cirrhosis) and ESRD requiring dialysis
`received EPCLUSA for 12 weeks, the most common adverse reaction was nausea (7%)
`[see Clinical Studies (14.6)].
`
`Adverse Reactions in People Who Inject Drugs (PWID), Including Those on Medication-
`Assisted Treatment (MAT) for Opioid Use Disorder
`The safety of EPCLUSA in PWID is based on an open-label Phase 2 trial (SIMPLIFY)
`that enrolled 103 adult subjects with chronic HCV genotype 1, 2, 3, and 4 infection.
`Subjects who self-reported injection drug use within the 6 months prior to starting
`treatment were eligible and were treated with EPCLUSA for 12 weeks. The trial included
`a subset of 58 subjects on MAT for opioid use disorder.
`
`The adverse reactions observed from SIMPLIFY both overall and in subjects on MAT
`were consistent with the known safety profile of EPCLUSA. The most common adverse
`reactions overall were fatigue (18%), nausea (13%), and headache (11%) [see Use in
`Specific Populations (8.8) and Clinical Studies (14.7)]. Adverse reactions leading to
`permanent discontinuation of treatment were not observed in any subjects.
`
`Adverse Reactions in Pediatric Subjects 3 Years of Age and Older
`The safety assessment of EPCLUSA in pediatric subjects 3 years of age and older is
`based on data from a Phase 2, open-label clinical trial (Study 1143) that enrolled 216
`subjects who were treated with EPCLUSA for 12 weeks [see Clinical Studies (14.8)].
`The adverse reactions observed in pediatric subjects 6 years of age and older were
`consistent with those observed in clinical trials of EPCLUSA in adults.
`
`Among the 41 pediatric subjects less than 6 years of age, gastrointestinal adverse
`reactions were reported more commonly compared to subjects 6 years of age and
`older. Vomiting and product use issue (spitting up the drug) were reported in 15% and
`10% of subjects, respectively; these adverse reactions were mild (Grade 1 or 2) and led
`to treatment discontinuation in 5 (12%) subjects [see Use in Specific Populations (8.4)
`and Clinical Studies (14.8)].
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`Reference ID: 4974030
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`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