EPCLUSA (sofosbuvir 400 mg/velpatasvir 100 mg, sofosbuvir 200 mg/velpatasvir 50 mg tablets) is indicated for the treatment of patients 6 years of age and older or weighing at least 17 kg with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis and in combination with ribavirin for those with decompensated cirrhosis.

Please see below for Important Safety Information for EPCLUSA.

BOXED WARNING:
RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS1

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 (DAAs) and 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, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. 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.

Contraindications

If EPCLUSA is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information.

Warnings and Precautions1

Serious Symptomatic Bradycardia When Coadministered with Amiodarone

Coadministration of amiodarone with EPCLUSA is not recommended due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered EPCLUSA:

Patients who are taking EPCLUSA who need to start amiodarone therapy due to no other alternative viable treatment options and patients discontinuing amiodarone just prior to starting EPCLUSA should undergo similar cardiac monitoring as outlined above.

Risk of Reduced Therapeutic Effect Due to Concomitant Use of EPCLUSA with Inducers of P-gp and/or Moderate to Strong Inducers of CYP2B6, CYP2C8, or CYP3A4

Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (eg, 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.

Adverse Reactions (All Grades) Reported in ≥5% of EPCLUSA-treated Subjects in ASTRAL-11

EPCLUSA
12 Weeks
Adverse Reactions

(N=624)

Headache 22%
Fatigue 15%
Nausea 9%
Asthenia 5%
Insomnia 5%
  • The majority of these adverse reactions in ASTRAL-1 were of mild severity (Grade 1, 79%)
  • With the exception of asthenia (3% vs 5% for placebo and EPCLUSA groups, respectively), each of these adverse reactions occurred at a similar frequency or more frequently in subjects treated with placebo compared with subjects treated with EPCLUSA
  • 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 ≥5 % of subjects treated with EPCLUSA in ASTRAL-3

EPCLUSA discontinuation rates due to adverse events were <1% in the ASTRAL trials (ASTRAL-1, -2, -3)3,4

Discontinuation due to adverse events in GT 1-6 subjects:

<1%

EPCLUSA (n=1/624)

vs 2%

placebo (n=2/116)

ASTRAL-13
<1%

EPCLUSA (n=1/134)

vs 0%

SOF + RBV (n=0/132)

ASTRAL-24
0%

EPCLUSA (n=0/277)

vs 3%

SOF + RBV (n=0/132)

ASTRAL-34

Drug interactions1

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 in patients taking warfarin and blood glucose levels in diabetic patients) and dose adjustments of certain concomitant medications may be necessary.

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 Clinical Effect/Recommendation
Acid-reducing agents

Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of velpatasvir.

antacids

(eg, aluminum and magnesium hydroxide)

velpatasvir

Separate antacid and EPCLUSA administration by 4 hours.

H2-receptor antagonistsc

(eg, famotidine)

velpatasvir

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.

proton-pump inhibitorsc

(eg, omeprazole)

velpatasvir

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.

Antiarrhythmics
amiodarone

Effect on amiodarone, sofosbuvir, and velpatasvir concentrations unknown

Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with EPCLUSA is not recommended; if coadministration is required, cardiac monitoring is recommended.

digoxinc

digoxin

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%.

Anticancers
topotecan

topotecan

Coadministration is not recommended.

Anticonvulsants
carbamazepinec, phenytoin, phenobarbital

sofosbuvir

velpatasvir

Coadministration is not recommended.

Antimycobacterials
rifabutinc, rifampinc, rifapentine

sofosbuvir

velpatasvir

Coadministration is not recommended.

HIV Antiretrovirals
efavirenzc

velpatasvir

Coadministration of EPCLUSA with efavirenz-containing regimens is not recommended.

regimens containing tenofovir DF

tenofovir

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.

tipranavir/ritonavir

sofosbuvir

velpatasvir

Coadministration is not recommended.

Herbal Supplements
St. John’s wort (Hypericum perforatum)

sofosbuvir

velpatasvir

Coadministration is not recommended.

HMG-CoA Reductase Inhibitors
rosuvastatinc

rosuvastatin

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.

atorvastatinc

atorvastatin

Coadministration of EPCLUSA with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis.

Acid-reducing agents
Clinical Effect/Recommendation

Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of velpatasvir.

antacids
(eg, aluminum and magnesium hydroxide)
Effect on Concentrationb

velpatasvir

Clinical Effect/Recommendation

Separate antacid and EPCLUSA administration by 4 hours.

H2-receptor antagonistsc
(eg, famotidine)
Effect on Concentrationb

velpatasvir

Clinical Effect/Recommendation

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.

proton-pump inhibitorsc
(eg, omeprazole)
Effect on Concentrationb

velpatasvir

Clinical Effect/Recommendation

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.

Antiarrhythmics
amiodarone
Effect on Concentrationb

Effect on amiodarone, sofosbuvir, and velpatasvir concentrations unknown

Clinical Effect/Recommendation

Coadministration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with EPCLUSA is not recommended; if coadministration is required, cardiac monitoring is recommended.

digoxinc
Effect on Concentrationb

digoxin

Clinical Effect/Recommendation

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%.

Anticancers
topotecan
Effect on Concentrationb

topotecan

Clinical Effect/Recommendation

Coadministration is not recommended.

Anticonvulsants
carbamazepinec, phenytoin, phenobarbital
Effect on Concentrationb

sofosbuvir

velpatasvir

Clinical Effect/Recommendation

Coadministration is not recommended.

Antimycobacterials
rifabutinc, rifampinc, rifapentine
Effect on Concentrationb

sofosbuvir

velpatasvir

Clinical Effect/Recommendation

Coadministration is not recommended.

HIV Antiretrovirals
efavirenzc
Effect on Concentrationb

velpatasvir

Clinical Effect/Recommendation

Coadministration of EPCLUSA with efavirenz-containing regimens is not recommended.

regimens containing tenofovir DF
Effect on Concentrationb

tenofovir

Clinical Effect/Recommendation

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.

tipranavir/ritonavir
Effect on Concentrationb

sofosbuvir

velpatasvir

Clinical Effect/Recommendation

Coadministration is not recommended.

Herbal Supplements
St. John’s wort (Hypericum perforatum)
Effect on Concentrationb

sofosbuvir

velpatasvir

Clinical Effect/Recommendation

Coadministration is not recommended.

HMG-CoA Reductase Inhibitors
rosuvastatinc
Effect on Concentrationb

rosuvastatin

Clinical Effect/Recommendation

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.

atorvastatinc
Effect on Concentrationb

atorvastatin

Clinical Effect/Recommendation

Coadministration of EPCLUSA with atorvastatin may be associated with increased risk of myopathy, including rhabdomyolysis. Monitor closely for HMG-CoA reductase inhibitor-associated adverse reactions, such as myopathy and rhabdomyolysis.

aThis table is not all inclusive

b = decrease, = increase

cThese interactions have been studied in healthy adults.

Consult the full Prescribing Information for EPCLUSA for more information on potentially significant drug interactions, including clinical comments.

POLARIS Trials5

Adverse Events (All Grades) Reported in ≥5% of Subjects in POLARIS-2 and -3

EPCLUSA
12 Weeks
Adverse Events POLARIS-2

(N=440)

POLARIS-3

(N=109)

Headache 23% 29%
Fatigue 20% 28%
Nausea 9% 9%
Diarrhea 7% 5%
Asthenia 6% 5%
Insomnia 5% 5%
Arthralgia 5% <5%
Myalgia <5% 6%
Upper abdominal pain <5% 6%
Back pain <5% 6%
Abdominal pain <5% 5%

Discontinuations due to AEs in POLARIS-2: <1% (n=2/440).5

Discontinuations due to AEs in POLARIS-3: 1% (n=1/109).5

REAL-WORLD INTEGRATED ANALYSIS2

SIMPLIFY CLINICAL STUDY6

Adverse Events (All Grades) Reported in ≥5% of Subjects in SIMPLIFY

EPCLUSA
12 Weeks
Adverse Events

(N=103)

Fatigue 22%
Headache 18%
Nausea 14%
Insomnia 9%
Arthralgia 6%
Dizziness 5%
Nasopharyngitis 5%
  • The majority of subjects reported experiencing a mild or moderate (Grades 1-2) adverse reaction up to 28 days after the last dose
  • Seven (7%) patients had at least 1 serious AE; one (1%) was possibly treatment-related (rhabdomyolysis, resolved)

Discontinuations due to AEs: 1% (n=1/103)

This study is not included in the EPCLUSA full Prescribing Information.

  • The majority of subjects reported experiencing a mild or moderate (Grades 1-2) adverse reaction up to 28 days after the last dose
  • Seven (7%) patients had at least 1 serious AE; one (1%) was possibly treatment-related (rhabdomyolysis, resolved)

Discontinuations due to AEs: 1% (n=1/103)

This study is not included in the EPCLUSA full Prescribing Information.

TRIAL 40621

Single-arm trial of TN and TE adults with ESRD without cirrhosis
or with compensated cirrhosis

PPI Analysis7

Low rates of AEs leading to EPCLUSA discontinuation and low rates of treatment-related Grade 3 or 4 or serious AEs were similarly observed among patients taking EPCLUSA with or without concomitant PPI use

AEs EPCLUSA With PPI Use
(n=87)
n (%)
EPCLUSA Without PPI Use
(n=2517)
n (%)
Treatment-emergent

68 (78)

1662 (66)

Grade 3 or 4

7 (8)

58 (2)

Treatment-related Grade 3 or 4

1 (1)

11 (<1)

Serious

10 (11)

45 (2)

Treatment-related Serious

0 (0)

0 (0)

Discontinuations due to AEs

1 (1)

9 (<1)

Deaths

0 (0)

5 (<1)

See Dosing
See Access and Support

Important Safety Information

BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS 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 (DAAs) and 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, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. 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.

INDICATION

EPCLUSA (sofosbuvir 400 mg/velpatasvir 100 mg, sofosbuvir 200 mg/velpatasvir 50 mg tablets) is indicated for the treatment of patients 6 years of age and older or weighing at least 17 kg with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis and in combination with ribavirin for those with decompensated cirrhosis.

Contraindications

  • If EPCLUSA is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information.

Warnings and Precautions

  • Serious Symptomatic Bradycardia when Coadministered with Amiodarone: Amiodarone is not recommended for use with EPCLUSA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen. In patients without alternative viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.
  • Risk of Reduced Therapeutic Effect Due to Concomitant Use of EPCLUSA with P-gp Inducers and/or Moderate to Strong Inducers of CYP2B6, CYP2C8 or CYP3A4: Rifampin, St. John’s wort, and carbamazepine are not recommended for use with EPCLUSA as they may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations.

Adverse Reactions

  • The most common adverse reactions (≥10%, all grades) with EPCLUSA were headache and fatigue; and when used with RBV in decompensated cirrhotics were fatigue, anemia, nausea, headache, insomnia, and diarrhea.

Drug Interactions

  • Coadministration of EPCLUSA is not recommended with topotecan due to increased concentrations of topotecan.
  • Coadministration of EPCLUSA is not recommended with proton-pump inhibitors, phenobarbital, phenytoin, rifabutin, rifapentine, efavirenz, and tipranavir/ritonavir due to decreased concentrations of sofosbuvir and/or velpatasvir.

Consult the full Prescribing Information for EPCLUSA for more information on potentially significant drug interactions, including clinical comments.


Please see full Prescribing Information for EPCLUSA, including BOXED WARNING.

VIEW ALL

Important Safety Information

BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION: IN HCV/HBV COINFECTED PATIENTS 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 (DAAs) and 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, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. 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.

INDICATION

EPCLUSA (sofosbuvir 400 mg/velpatasvir 100 mg, sofosbuvir 200 mg/velpatasvir 50 mg tablets) is indicated for the treatment of patients 6 years of age and older or weighing at least 17 kg with chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis and in combination with ribavirin for those with decompensated cirrhosis.

AE = adverse event; DF = disoproxil fumarate; ESRD = end-stage renal disease; GT = genotype; HIV = human immunodeficiency virus; INR = international normalized ratio; PPI = proton-pump inhibitor; RBV = ribavirin; SOF = sofosbuvir.

References:

  1. EPCLUSA [prescribing information]. Foster City, CA: Gilead Sciences, Inc; July 2020.
  2. Data on file. Data for Real-World Integrated Analysis. Accessed July 2020.
  3. Feld JJ, C, Hézode T, et al. Sofosbuvir and velpatsivir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373(27):2599‐2607.
  4. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatsivir for HCV genotype 2 or 3 infection. N Engl J Med. 2015;373(27):2608‐2617.
  5. Jacobson IM, Lawitz E, Gane EJ, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology. July 2017; 153(1):113-122.
  6. Grebely J, Dalgard O, Conway B, et al. Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open label, single-arm, phase 4, multicentre trial. Lancet Gastroenterol Hepatol. 2018;3(3):153-161.
  7. Esteban R, Agarwal K, Calleja J, et al. Sofosbuvir/velpatasvir is effective and safe in patients with concomitant proton pump inhibitor use in clinical studies. Poster presented at: AASLD The Liver Meeting®; November 9-13, 2018: San Francisco, CA.