` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208341Orig1s000
`
`
`LABELING
`
`

`

`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
`
`-------------------------------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-----------------------
`• Recommended dosage: One tablet (400 mg of sofosbuvir and
`100 mg of velpatasvir) taken orally once daily with or without food
`(2.1)
`• See recommended treatment regimen and duration in patients with
`genotypes 1, 2, 3, 4, 5, or 6 HCV in table below: (2.1)
`Recommended
`Patient Population
`Treatment Regimen
`
`Patients without cirrhosis and
`patients with compensated
`cirrhosis (Child-Pugh A)
`EPCLUSA + ribavirin for
`Patients with decompensated
`12 weeks
`cirrhosis (Child-Pugh B and C)
`• A dosage recommendation cannot be made for patients with severe
`renal impairment or end stage renal disease (2.2)
`
`EPCLUSA for 12 weeks
`
`
`-----------------------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----------------------
`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. (5.1, 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 (5.2, 7)
`• Consult the full prescr bing information prior to use for potential drug
`interactions (5.1, 5.2, 7)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`
`
`
`
`
`
`
`
`
` Revised: 06/2016
`
`
`
` 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 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.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`
`2.2 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 Serious Symptomatic Bradycardia When Sofosbuvir Is
`Coadministered with Amiodarone and Another HCV Direct
`Acting Antiviral
`5.2 Risk of Reduced Therapeutic Effect Due to Concomitant
`Use of EPCLUSA with Inducers of P-gp and/or Moderate to
`Potent Inducers of CYP
`5.3 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
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3951919
`
`
`
`1
`
`

`

`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
` 1
`
`INDICATIONS AND USAGE
`
`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 (2.1) and
`Clinical Studies (14)]:
`• without cirrhosis or with compensated cirrhosis
`• with decompensated cirrhosis for use in combination with ribavirin
`
`Recommended Treatment Regimen in Patients with Genotype 1, 2, 3,
`4, 5 or 6 HCV
`Patient Population
`Patients without cirrhosis and
`patients with compensated cirrhosis
`(Child-Pugh A)
`Patients with decompensated
`cirrhosis (Child-Pugh B or C)
`a. 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.
`
`Treatment Regimen and Duration
`
`EPCLUSA 12 weeks
`
`EPCLUSA + ribavirina 12 weeks
`
`
`2.2 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)].
`
` 3
`
`DOSAGE FORMS AND STRENGTHS
`
`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.
`
`
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`2
`
` 2
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 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.
`
`Table 1
`
`

`

`
`
`
`
`
`
`
`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.
`
` 5
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1 Serious Symptomatic Bradycardia When Sofosbuvir Is Coadministered
`with Amiodarone and Another HCV Direct Acting Antiviral
`Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker
`intervention have been reported when amiodarone is coadministered with sofosbuvir in
`combination with daclatasvir or simeprevir. 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
`pains, confusion, or memory problems [see Adverse Reactions (6.2) and Drug
`Interactions (7.3)].
`
`5.2 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
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`3
`
`

`

`
`
`
`
`
`
`
`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)].
`
`5.3 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 (2.1)].
`
` 6
`
`ADVERSE REACTIONS
`
`The following serious adverse reactions are described below and elsewhere in labeling:
`• Serious Symptomatic Bradycardia When Sofosbuvir Is Coadministered with
`Amiodarone and Another HCV Direct Acting Antiviral [see Warnings and
`Precautions (5.1)].
`
`
`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
`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).
`
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`4
`
`

`

`
`
`
`
`
`
`
`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 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 (14.3)].
`
`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 in
`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.
`
`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.
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`5
`
`

`

`
`
`
`
`
`
`
`
`
`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
`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
`initiated treatment with sofosbuvir in combination with another HCV direct acting
`antiviral [see Warnings and Precautions (5.1) and Drug Interactions (7.3)].
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`6
`
`

`

`
`
`
`
`
`
`
`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 (5.2) 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 (5.1, 5.2) and Clinical Pharmacology (12.3)].
`
`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
`
`Antacids (e.g., aluminum
`and magnesium hydroxide)
`H2-receptor antagonistsc
`(e.g., famotidine)
`
`Proton-pump inhibitorsc
`(e.g., omeprazole)
`
`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.
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`7
`
`

`

`
`
`
`Antiarrhythmics:
`amiodarone
`
`digoxinc
`
`Anticancers:
`topotecan
`Anticonvulsants:
`carbamazepine
`phenytoin
`phenobarbital
`oxcarbazepine
`Antimycobacterials:
`rifabutin
`rifampinc
`rifapentine
`HIV Antiretrovirals:
`efavirenzc
`
`Regimens containing
`tenofovir DF
`
`Effect on
`amiodarone,
`sofosbuvir, and
`velpatasvir
`concentrations
`unknown
`↑ digoxin
`
`↑ topotecan
`
`↓ sofosbuvir
`↓ velpatasvir
`
`↓ sofosbuvir
`↓ velpatasvir
`
`↓ velpatasvir
`
`↑ tenofovir
`
`tipranavir/ritonavir
`
`Herbal Supplements:
`St. John’s wort (Hypericum
`perforatum)
`HMG-CoA Reductase
`Inhibitors:
`rosuvastatinc
`
`↓ sofosbuvir
`↓ velpatasvir
`↓ sofosbuvir
`↓ velpatasvir
`↑ rosuvastatin
`
`atorvastatin
`
`↑ atorvastatin
`
`
`
`
`
`Coadministration of amiodarone with EPCLUSA 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 (5.1)
`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.
`
`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.
`
`Coadministration is not recommended.
`
`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.
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`8
`
`

`

`
`
`
`
`
`
`
`
`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)].
`
` 8
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`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 reproduction studies, no evidence of adverse
`developmental outcomes was observed with the components of EPCLUSA (sofosbuvir
`or velpatasvir) at exposures greater than those in humans at the recommended human
`dose (RHD) [see Data]. During organogenesis in the mouse, rat and rabbit, systemic
`exposures (AUC) to velpatasvir were approximately 31 (mice), 6 (rats), and 0.4 (rabbits)
`times the exposure in humans at the RHD, while exposures to the predominant
`circulating metabolite of sofosbuvir (GS-331007) were approximately 4 (rats) and
`10 (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development
`studies, maternal systemic exposures (AUC) to velpatasvir and GS-331007 were
`approximately 5 times the exposures of each component in humans at the RHD.
`
`The background risk of major birth defects and miscarriage for the indicated population
`is unknown. In the U.S. general population, the estimated background risk of major birth
`defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%,
`respectively.
`
`Data
`Sofosbuvir: Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day)
`and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively,
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`9
`
`

`

`
`
`
`
`
`
`
`and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post-
`partum day 20. No significant effects on embryo-fetal (rats and rabbits) or
`pre/postnatal (rats) development were observed at the highest doses tested. The
`systemic exposures (AUC) of the predominant circulating metabolite of sofosbuvir
`(GS-331007) during gestation were approximately 4 (rats) and 10 (rabbits) times the
`exposure in humans at the RHD.
`
`Velpatasvir: Velpatasvir was administered orally to pregnant mice (up to
`1000 mg/kg/day), rats (up to 200 mg/kg/day) and rabbits (up to 300 mg/kg/day) on
`gestation days 6 to 15, 6 to 17, and 7 to 20, respectively, and also to rats (oral doses up
`to 200 mg/kg) on gestation day 6 to lactation/post-partum day 20. No significant effects
`on embryo-fetal (mice, rats, and rabbits) or pre/postnatal (rats) development were
`observed at the highest doses tested. The systemic exposures (AUC) of velpatasvir
`during gestation were approximately 31 (mice), 6 (rats), and 0.4 (rabbits) times the
`exposure in humans at the RHD.
`
`Lactation
`8.2
`Risk Summary
`It is not known whether the components of EPCLUSA and its metabolites are present in
`human breast milk, affect human milk production, or have effects on the breastfed
`infant. The predominant circulating metabolite of sofosbuvir (GS-331007) was the
`primary component observed in the milk of lactating rats administered sofosbuvir,
`without effect on nursing pups. When administered to lactating rats, velpatasvir was
`detected in the milk of lactating rats and in the plasma of nursing pups without effects
`on the nursing pups [see Data].
`
`The development and health benefits of breastfeeding should be considered along with
`the mother’s clinical need for EPCLUSA and any potential adverse effects on the
`breastfed child from EPCLUSA or from the underlying maternal condition.
`
`If EPCLUSA is administered with ribavirin, the nursing mother’s information for ribavirin
`also applies to this combination regimen. Refer to the ribavirin prescribing information
`for more information on use during lactation.
`
`Data
`Sofosbuvir: No effects of sofosbuvir on growth and postnatal development were
`observed in nursing pups at the highest dose tested in rats. Maternal systemic
`exposure (AUC) to the predominant circulating metabolite of sofosbuvir (GS-331007)
`was approximately 5 times the exposure in humans at the RHD, with exposure of
`approximately 2% that of maternal exposure observed in nursing pups on lactation
`day 10. In a lactation study, sofosbuvir metabolites (primarily GS-331007) were
`excreted into the milk of lactating rats following administration of a single oral dose of
`sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10%
`that of maternal plasma concentrations observed 1 hour post-dose.
`
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`10
`
`

`

`
`
`
`
`
`
`
`Velpatasvir: No effects of velpatasvir on growth and postnatal development were
`observed in nursing pups at the highest dose tested in rats. Maternal systemic
`exposure (AUC) to velpatasvir was approximately 5 times the exposure in humans at
`the RHD. Velpatasvir was present in the milk (approximately 173% that of maternal
`plasma concentrations) of lactating rats following a single oral dose of velpatasvir
`(30 mg/kg), and systemic exposure (AUC) in nursing pups was approximately 4% that
`of maternal exposure on lactation day 10.
`
`Females and Males of Reproductive Potential
`8.3
`If EPCLUSA is administered with ribavirin, the information for ribavirin with regard to
`pregnancy testing, contraception, and infertility also applies to this combination regimen.
`Refer to ribavirin prescribing information for additional information.
`
`8.4 Pediatric Use
`Safety and effectiveness of EPCLUSA have not been established in pediatric patients.
`
`8.5 Geriatric Use
`Clinical trials of EPCLUSA included 156 subjects aged 65 and over (12% of total
`number of subjects in the Phase 3 clinical trials). No overall differences in safety or
`effectiveness were observed between these subjects and younger subjects, and other
`reported clinical experience has not identified differences in responses between the
`elderly and younger patients, but greater sensitivity of some older individuals cannot be
`ruled out. No dosage adjustment of EPCLUSA is warranted in geriatric patients [see
`Clinical Pharmacology (12.3)].
`
`8.6 Renal Impairment
`No dosage adjustment of EPCLUSA is required for patients with mild or moderate renal
`impairment. The safety and efficacy of EPCLUSA have not been established in patients
`with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or ESRD requiring
`hemodialysis. No dosage recommendation can be given for patients with severe renal
`impairment or ESRD [see Dosage and Administration (2.2) and Clinical Pharmacology
`(12.3)]. Refer to ribavirin prescribing information regarding use of ribavirin in patients
`with renal impairment.
`
`8.7 Hepatic Impairment
`No dosage adjustment of EPCLUSA is required for patients with mild, moderate, or
`severe hepatic impairment (Child-Pugh Class A, B, or C) [see Adverse Reactions (6.1),
`Clinical Pharmacology (12.3) and Clinical Studies (14)].
`
`Clinical and hepatic laboratory monitoring (including direct bilirubin), as clinically
`indicated, is recommended for patients with decompensated cirrhosis receiving
`treatment with EPCLUSA and ribavirin [see Adverse Reactions (6.1)].
`
`OVERDOSAGE
`10
`No specific antidote is available for overdose with EPCLUSA. If overdose occurs the
`patient must be monitored for evidence of toxicity. Treatment of overdose with
`
`
`
`Reference ID: 3951919
`
`Gilead Sciences
`
`11
`
`

`

`
`
`
`
`
`
`
`EPCLUSA consists of general supportive measures including monitoring of vital signs
`as well as observation of the clinical status of the patient. Hemodialysis can efficiently
`remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an
`extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of