`
`
`
`
`
`
` 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)
` Patients with decompensated
`
`
`
` EPCLUSA + ribavirin for
` cirrhosis (Child-Pugh B and C)
` 12 weeks
`
`
`
`
` • 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)
`
`
`
`
`
`
`
`
`
` 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
`
`--------------------------------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 prescribing 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
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`
`EPCLUSA is indicated for the treatment of adult patients with chronic hepatitis C virus
`
`
`(HCV) genotype 1, 2, 3, 4, 5 or 6 infection [see Dosage and Administration (2.1) and
`
`Clinical Studies (14)]:
`
`
`• without cirrhosis or with compensated cirrhosis
`
`
`• with decompensated cirrhosis for use in combination with ribavirin
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`2
`
`
`
`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
`
`
`
` Treatment Regimen and Duration
`
`
`
` EPCLUSA 12 weeks
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`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)].
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`
`Each EPCLUSA tablet contains 400 mg of sofosbuvir and 100 mg of velpatasvir. The
`
`tablets are pink, diamond-shaped, film-coated, and debossed with “GSI” on one side
`
`and “7916” on the other side.
`
`
`
`
`
`Reference ID: 3951919
`
`
`Gilead Sciences
`
`
`2
`
`
`
`
`
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`
`
`
`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
`
`
` 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)].
`
`
`
`ADVERSE REACTIONS
`6
`
`
`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
`
`
`
`
`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.
`
` Antacids (e.g., aluminum
`
`
`and magnesium hydroxide)
`H2 -receptor antagonistsc
`
`
`(e.g., famotidine)
`
`
` Proton-pump inhibitorsc
`
`(e.g., omeprazole)
`
`
`
`
`
`
`
`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)].
`
`
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`
`8
`
`
`8.1 Pregnancy
`
`
`Risk Summary
`
`
`If EPCLUSA is administered with ribavirin, the combination regimen is contraindicated in
`
`
`
`pregnant women and in men whose female partners are pregnant. Refer to the ribavirin
`
`
`prescribing information for more information on ribavirin-associated risks of use during
`
`
`pregnancy.
`
`
`
`No adequate human data are available to establish whether or not EPCLUSA poses a
`
`
`
`
`risk to pregnancy outcomes. In animal 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 pedi