Epclusa Drug Information
Generic name: VELPATASVIR AND SOFOSBUVIR
Hepatitis C Virus Nucleotide Analog NS5B Polymerase Inhibitor [EPC] Hepatitis C Virus NS5A Inhibitor [EPC]
Uses of 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 : without cirrhosis or with compensated cirrhosis with decompensated cirrhosis for use in combination with ribavirin. 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 : without cirrhosis or with compensated cirrhosis with decompensated cirrhosis for use in combination with ribavirin.
Dosage & Administration of Epclusa
| Treatment-naïve and treatment-experienced | EPCLUSA 12 weeks |
|---|---|
| Treatment-naïve and treatment-experienced | EPCLUSA + ribavirin 12 weeks |
Side Effects of Epclusa
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. If EPCLUSA is administered with ribavirin, refer to the prescribing information for ribavirin for a description of ribavirin-associated adverse reactions. Clinical Trials in Adult Subjects Adverse Reactions in Subjects without Cirrhosis or with Compensated Cirrhosis The adverse reactions data for EPCLUSA in patients without cirrhosis or with compensated cirrhosis were derived from three Phase 3 clinical trials (ASTRAL-1, ASTRAL-2, and ASTRAL-3) which evaluated a total of 1035 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis, who received EPCLUSA for 12 weeks.
EPCLUSA was studied in placebo- and active-controlled trials . 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 . 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 . The most common adverse reactions (adverse events assessed as causally related by the investigator, all grades with frequency of 10% or greater) in the 87 subjects who received EPCLUSA with ribavirin for 12 weeks were fatigue (32%), anemia (26%), nausea (15%), headache (11%), insomnia (11%), and diarrhea (10%). Of subjects who experienced these adverse reactions, 98% had adverse reactions of mild to moderate severity.
A total of 4 (5%) subjects permanently discontinued EPCLUSA with ribavirin due to an adverse event; there was no adverse event leading to discontinuation that occurred in more than 1 subject. Decreases in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 23% and 7% of subjects treated with EPCLUSA with ribavirin for 12 weeks, respectively. Ribavirin was permanently discontinued in 17% of subjects treated with EPCLUSA with ribavirin for 12 weeks, due to adverse reactions.
Less Common Adverse Reactions Reported in Clinical Trials The following adverse reactions occurred in less than 5% of subjects without cirrhosis or with compensated cirrhosis treated with EPCLUSA for 12 weeks and are included because of a potential causal relationship. Rash: In the ASTRAL-1 study, rash occurred in 2% of subjects treated with EPCLUSA and in 1% of subjects treated with placebo. No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity.
Depression: In the ASTRAL-1 study, depressed mood occurred in 1% of subjects treated with EPCLUSA and was not reported by any subject taking placebo. No serious adverse reactions of depressed mood occurred, and all events were mild or moderate in severity. The following adverse reactions occurred in less than 10% of subjects with decompensated cirrhosis (ASTRAL-4) treated with EPCLUSA with ribavirin for 12 weeks and are included because of a potential causal relationship.
Rash: Rash occurred in 5% of subjects treated with EPCLUSA with ribavirin. No serious adverse reactions of rash occurred, and all rashes were mild or moderate in severity. Laboratory Abnormalities Lipase Elevations: In ASTRAL-1, isolated, asymptomatic lipase elevations of greater than 3×ULN 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 1.5×ULN. Isolated, asymptomatic lipase elevations of greater than 3×ULN 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 10×ULN 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 10×ULN 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. 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 . 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%). 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%). 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 . 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 .
Postmarketing Experience
The following adverse reactions have been identified during post approval use of sofosbuvir. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with a sofosbuvir-containing regimen.
Skin and Subcutaneous Tissue Disorders Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema
Warnings & Cautions for Epclusa
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.
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 ® ). 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 .
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 .
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.
Drug Interactions with Epclusa
Potential for Other Drugs to Affect
EPCLUSA Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of sofosbuvir) is not. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Drugs that are inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., rifampin, St.
John's wort, carbamazepine) may decrease plasma concentrations of sofosbuvir and/or velpatasvir, leading to reduced therapeutic effect of EPCLUSA. The use of these agents with EPCLUSA is not recommended . EPCLUSA may be coadministered with P-gp, BCRP, and CYP inhibitors.
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.
Established and Potentially Significant Drug Interactions Clearance of
HCV infection with direct acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.
Frequent monitoring of relevant laboratory parameters (e.g., International Normalized Ratio in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary. Table 4 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 . Table 4 Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction This table is not all inclusive. Concomitant Drug Class: Drug Name Effect on Concentration ↓ = decrease, ↑ = increase. Clinical Effect/Recommendation DF = disoproxil fumarate.
Acid Reducing Agents: ↓ velpatasvir Velpatasvir solubility decreases as pH increases. Drugs that increase gastric pH are expected to decrease concentration of velpatasvir. Antacids (e.g., aluminum and magnesium hydroxide) Separate antacid and EPCLUSA administration by 4 hours.
H 2 -receptor antagonists These interactions have been studied in healthy adults. (e.g., famotidine) H 2 -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 inhibitors (e.g., omeprazole) 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. digoxin ↑ 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: carbamazepine phenytoin phenobarbital ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended. Antimycobacterials: rifabutin rifampin rifapentine ↓ sofosbuvir ↓ velpatasvir Coadministration is not recommended.
HIV Antiretrovirals: efavirenz ↓ 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: rosuvastatin ↑ 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. atorvastatin ↑ 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.
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 or are expected with the following drugs : EPCLUSA: atazanavir/ritonavir, buprenorphine/naloxone, cyclosporine, darunavir/ritonavir, dolutegravir, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, methadone, naltrexone, raltegravir, or rilpivirine. Sofosbuvir: ethinyl estradiol/norgestimate, or tacrolimus. Velpatasvir: ethinyl estradiol/norgestimate, ketoconazole, or pravastatin.
See Table 4 for use of EPCLUSA with certain HIV antiretroviral regimens .
Pregnancy Safety for Epclusa
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) . 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, 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.
Pediatric Use of Epclusa
Pediatric Use The pharmacokinetics, safety, and effectiveness of EPCLUSA for treatment of HCV genotype 1, 2, 3, 4, or 6 infection in treatment-naïve and treatment-experienced pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1143, N=216; 190 treatment-naïve, 26 treatment-experienced). No clinically meaningful differences in pharmacokinetics were observed in comparison to those observed in adults. The safety and effectiveness in pediatric subjects were comparable to those observed in adults. However, among the 41 pediatric subjects less than 6 years of age, vomiting and product use issue (spitting up the drug) were reported more frequently (15% and 10%, respectively; all Grade 1 or 2) compared to subjects 6 years of age and older.
Five subjects (12%) discontinued treatment after vomiting or spitting up the drug. The safety and effectiveness of EPCLUSA for treatment of HCV genotype 5 in pediatric patients 3 years of age and older without cirrhosis or with compensated cirrhosis are supported by sofosbuvir, GS-331007, and velpatasvir exposures in adults and pediatric patients . Similar rationale is used to support dosing recommendations for pediatric patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection who have decompensated cirrhosis (Child-Pugh B or C). In patients with severe renal impairment, including those requiring dialysis, exposures of GS-331007, the inactive metabolite of sofosbuvir, are increased . No data are available regarding the safety of EPCLUSA in pediatric patients with renal impairment. The safety and effectiveness of EPCLUSA have not been established in pediatric patients less than 3 years of age.
Contraindications for 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. EPCLUSA and ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated.
Overdosage Information for Epclusa
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 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 velpatasvir since velpatasvir is highly bound to plasma protein.
Clinical Studies of Epclusa
Description of Clinical Trials Table 12 presents the clinical trial design including
different treatment groups that were conducted with EPCLUSA with and without ribavirin in subjects with chronic hepatitis C (HCV) genotype 1, 2, 3, 4, 5, and 6 infection. For detailed description of trial design and recommended regimen and duration. Table 12 Trials Conducted with EPCLUSA in Subjects with Genotype 1, 2, 3, 4, 5, or 6 HCV Infection Trial Population EPCLUSA and Comparator Groups (Number of Subjects Treated) TN = treatment-naïve subjects; SOF = sofosbuvir; RBV = ribavirin; CP = Child-Pugh; ESRD = End Stage Renal Disease; PWID = People Who Inject Drugs; MAT = Medication-Assisted Treatment.
ASTRAL-1 Double-blind, placebo-controlled. (NCT02201940) Genotype 1, 2, 4, 5, and 6 TN and TE TE = treatment-experienced subjects are those who have failed a peginterferon alfa/ribavirin based regimen with or without an HCV protease inhibitor (boceprevir, simeprevir, or telaprevir)., without cirrhosis or with compensated cirrhosis EPCLUSA 12 weeks Placebo 12 weeks ASTRAL-2 Open-label. (NCT02220998) Genotype 2 TN and TE, without cirrhosis or with compensated cirrhosis EPCLUSA 12 weeks SOF + RBV 12 weeks ASTRAL-3 (NCT02201953) Genotype 3 TN and TE, without cirrhosis or with compensated cirrhosis EPCLUSA 12 weeks SOF + RBV 24 weeks ASTRAL-5 (NCT02480712) Genotype 1, 2, 3, 4, 5, and 6 HCV/HIV-1 coinfected TN and TE, without cirrhosis or with compensated cirrhosis EPCLUSA 12 weeks ASTRAL-4 (NCT02201901) Genotype 1, 2, 3, 4, 5, and 6 TN and TE, with CP class B decompensated cirrhosis EPCLUSA 12 weeks EPCLUSA + RBV 12 weeks EPCLUSA 24 weeks 2104 (NCT02781571) Genotype 1, 2, 3, and 4 TN and TE TE = treatment-experienced subjects are those who have failed a peginterferon alfa/ribavirin based regimen or an HCV-specific DAA-based regimen that does not include an NS5A inhibitor. liver transplant recipients, without cirrhosis or with compensated cirrhosis EPCLUSA 12 weeks 4062 (NCT03036852) Genotype 1, 2, 3, 4, and 6 TN and TE TE = treatment-experienced subjects are those who have failed a peginterferon alfa/ribavirin or interferon/ribavirin based regimen. without cirrhosis or with compensated cirrhosis, with ESRD requiring dialysis EPCLUSA 12 weeks SIMPLIFY (NCT02336139) Genotype 1, 2, 3, and 4 PWID, including those on MAT for opioid use disorder, without cirrhosis or with compensated cirrhosis EPCLUSA 12 weeks 1143 (NCT03022981) Genotype 1, 2, 3, 4, and 6 TN and TE TE = treatment-experienced subjects are those who have failed an interferon-based regimen with or without ribavirin and with or without an HCV protease inhibitor (boceprevir, simeprevir, or telaprevir). pediatric subjects 3 years of age and older EPCLUSA 12 weeks The ribavirin dosage was weight-based (1000 mg daily administered in two divided doses for subjects less than 75 kg and 1200 mg for those greater than or equal to 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 trials or in combination with EPCLUSA in the ASTRAL-4 trial. Ribavirin dosage adjustments were performed according to the ribavirin prescribing information. Serum HCV RNA values were measured during the clinical trials using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. SVR12, defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint in all the trials.
Relapse is defined as HCV RNA greater than or equal to LLOQ during the post-treatment period after having achieved HCV RNA less than LLOQ at the end of treatment. On-treatment virologic failure is defined as breakthrough, rebound, or non-response.
Clinical Trials in Subjects without Cirrhosis and Subjects with Compensated Cirrhosis Genotype
1, 2, 4, 5, and 6 HCV Infected Adults (ASTRAL-1) ASTRAL-1 was a randomized, double-blind, placebo-controlled trial that evaluated 12 weeks of treatment with EPCLUSA compared with 12 weeks of placebo in subjects with genotype 1, 2, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis. Subjects with genotype 1, 2, 4, or 6 HCV infection were randomized in a 5:1 ratio to treatment with EPCLUSA or placebo for 12 weeks. Subjects with genotype 5 HCV infection were enrolled to the EPCLUSA group.
Randomization was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence or absence of compensated cirrhosis. Demographics and baseline characteristics were balanced between the EPCLUSA and placebo group. Of the 740 treated subjects, the median age was 56 years (range: 18 to 82); 60% of the subjects were male; 79% were White, 9% were Black; 21% had a baseline body mass index at least 30 kg/m 2 ; the proportions of subjects with genotype 1, 2, 4, 5, or 6 HCV infection were 53%, 17%, 19%, 5%, and 7%, respectively; 69% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels at least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% were treatment-experienced.
Table 13 presents SVR12 and other virologic outcomes in EPCLUSA-treated subjects in the ASTRAL-1 trial by HCV genotype. No subjects in the placebo group achieved SVR12. Table 13 Study ASTRAL-1: Virologic Outcomes by HCV Genotype in EPCLUSA-Treated Subjects without Cirrhosis or with Compensated Cirrhosis (12 Weeks After Treatment) EPCLUSA 12 Weeks (N=624) Total (all GTs) (N=624) GT-1 GT-2 (N=104) GT-4 (N=116) GT-5 (N=35) GT-6 (N=41) GT-1a (N=210) GT-1b (N=118) Total (N=328) GT = genotype; no subjects in the placebo group achieved SVR12. SVR12 99% (618/624) 98% (206/210) 99% (117/118) 98% (323/328) 100% (104/104) 100% (116/116) 97% (34/35) 100% (41/41) Outcome for Subjects without SVR On-Treatment Virologic Failure 0/624 0/210 0/118 0/328 0/104 0/116 0/35 0/41 Relapse The denominator for relapse is the number of subjects with HCV RNA Randomization was stratified by the presence or absence of compensated cirrhosis and prior treatment experience (treatment-naïve vs treatment-experienced). Demographics and baseline characteristics were balanced across the two treatment groups. Of the 266 treated subjects, the median age was 58 years (range: 23 to 81); 59% of the subjects were male; 88% were White; 7% were Black; 33% had a baseline body mass index at least 30 kg/m 2 ; 62% had non-CC IL28B alleles (CT or TT); 80% had baseline HCV RNA levels at least 800,000 IU/mL; 14% had compensated cirrhosis; and 15% were treatment-experienced. Table 14 presents SVR12 and other virologic outcomes from the ASTRAL-2 trial. Table 14 Study ASTRAL-2: Virologic Outcomes in Subjects with Genotype 2 HCV without Cirrhosis or with Compensated Cirrhosis (12 Weeks After Treatment) EPCLUSA 12 Weeks (N=134) SOF + RBV 12 Weeks (N=132) SOF = sofosbuvir; RBV = ribavirin. SVR12 99% (133/134) 94% (124/132) Treatment difference +5.2%; 95% confidence interval (+0.2% to +10.3%) Outcome for subjects without SVR On-Treatment Virologic Failure 0/134 0/132 Relapse The denominator for relapse is the number of subjects with HCV RNA Randomization was stratified by the presence or absence of compensated cirrhosis and prior treatment experience (treatment-naïve vs treatment-experienced). Demographics and baseline characteristics were balanced across the treatment groups. Of the 552 treated subjects, the median age was 52 years (range: 19 to 76); 62% of the subjects were male; 89% were White; 9% were Asian; 20% had a baseline body mass index at least 30 kg/m 2 ; 61% had non-CC IL28B alleles (CT or TT); 70% had baseline HCV RNA levels at least 800,000 IU/mL; 30% had compensated cirrhosis; and 26% were treatment-experienced. Table 15 presents SVR12 and other virologic outcomes from the ASTRAL-3 trial. Table 15 Study ASTRAL-3: Virologic Outcomes in Subjects with Genotype 3 HCV without Cirrhosis or with Compensated Cirrhosis (12 Weeks After Treatment) EPCLUSA 12 Weeks (N=277) SOF + RBV 24 Weeks (N=275) SOF = sofosbuvir; RBV = ribavirin. SVR12 95% (264/277) 80% (221/275) Treatment difference +14.8%; 95% confidence interval (+9.6% to +20.0%) Outcome for subjects without SVR On-Treatment Virologic Failure 0/277 <1% (1/275) Relapse The denominator for relapse is the number of subjects with HCV RNA Without cirrhosis 98% (160/163) 94% (31/33) One treatment-experienced subject without cirrhosis treated with EPCLUSA had genotype 1a HCV infection at failure, indicating HCV re-infection, and is therefore excluded from this analysis. 90% (141/156) 71% (22/31) With compensated cirrhosis 93% (40/43) 89% (33/37) 73% (33/45) 58% (22/38) HCV and HIV-1 ASTRAL-5 was an open-label trial that evaluated 12 weeks of treatment with EPCLUSA in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection who were coinfected with HIV-1. Subjects were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, raltegravir or elvitegravir/cobicistat. Of the 106 treated subjects, the median age was 57 years (range: 25 to 72); 86% of the subjects were male; 51% were White; 45% were Black; 22% had a baseline body mass index at least 30 kg/m 2 ; the proportions of patients with genotype 1, 2, 3, or 4 HCV infection were 74%, 10%, 11%, and 5%, respectively; no subjects with genotype 5 or 6 HCV were treated with EPCLUSA; 77% had non-CC IL28B alleles (CT or TT); 74% had baseline HCV RNA levels of at least 800,000 IU/mL; 18% had compensated cirrhosis; and 29% were treatment experienced. The overall mean CD4+ count was 598 cells/µL (range: 183−1513 cells/µL) and 57% of subjects had CD4+ counts > 500 cells/μL. Table 17 presents the SVR12 for the ASTRAL-5 trial by HCV genotype. Table 17 Study ASTRAL-5: Virologic Outcomes by HCV Genotype in Subjects Coinfected with HIV-1 without Cirrhosis or with Compensated Cirrhosis (12 Weeks After Treatment) EPCLUSA 12 Weeks (N=106) Total (all GTs) (N=106) GT-1 GT-2 (N=11) GT-3 (N=12) GT-4 (N=5) GT-1a (N=66) GT-1b (N=12) Total (N=78) SVR12 95% (101/106) 95% (63/66) 92% (11/12) 95% (74/78) 100% (11/11) 92% (11/12) 100% (5/5) Outcome for Subjects without SVR On-Treatment Virologic Failure 0/106 0/66 0/12 0/78 0/11 0/12 0/5 Relapse The denominator for relapse is the number of subjects with HCV RNA ASTRAL-4 was a randomized, open-label trial in subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection and Child-Pugh B cirrhosis at screening. Subjects were randomized in a 1:1:1 ratio to treatment with EPCLUSA for 12 weeks (N=90), EPCLUSA with ribavirin for 12 weeks (N=87), or EPCLUSA for 24 weeks (N=90). Randomization was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate). Demographics and baseline characteristics were balanced across the treatment groups. Of the 267 treated subjects, the median age was 59 years (range: 40 to 73); 70% of the subjects were male; 90% were White; 6% were Black; 42% had a baseline body mass index at least 30 kg/m 2. The proportions of subjects with genotype 1, 2, 3, 4, or 6 HCV were 78%, 4%, 15%, 3%, and less than 1% (1 subject), respectively. No subjects with genotype 5 HCV infection were enrolled. 76% had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels at least 800,000 IU/mL; 55% were treatment-experienced; and 95% of subjects had Model for End Stage Liver Disease (MELD) score less than or equal to 15 at baseline. Although all subjects had Child-Pugh B cirrhosis at screening, 6% and 4% of subjects were assessed to have Child-Pugh A and Child-Pugh C cirrhosis, respectively, on the first day of treatment. Treatment with EPCLUSA with ribavirin for 12 weeks resulted in numerically higher SVR12 rates than treatment with EPCLUSA for 12 weeks or 24 weeks. Because EPCLUSA with ribavirin for 12 weeks is the recommended dosage regimen, the results of the 12- and 24-week EPCLUSA treatment groups are not presented. Table 18 presents the SVR12 for subjects treated with EPCLUSA with ribavirin for 12 weeks in the ASTRAL-4 trial by HCV genotype. No subjects with genotype 5 or 6 HCV were treated with EPCLUSA with ribavirin for 12 weeks. Table 18 Study ASTRAL-4: Virologic Outcomes in Subjects with Decompensated Cirrhosis After 12 Weeks of Treatment by HCV Genotype EPCLUSA + RBV 12 Weeks (N=87) SVR12 Virologic Failure (relapse and on-treatment failure) RBV = ribavirin. Overall SVR12 Includes subjects with baseline CPT C cirrhosis: all 4 subjects achieved SVR12. 94% (82/87) 3% (3/87) Genotype 1 96% (65/68) 1% (1/68) This subject with genotype 1a experienced relapse. Genotype 1a 94% (51/54) 2% (1/54) Genotype 1b 100% (14/14) 0% (0/14) Genotype 3 85% (11/13) 15% (2/13) One subject had on-treatment virologic failure; pharmacokinetic data from this subject was consistent with non- adherence. All subjects with genotype 2 (N=4) and genotype 4 (N=2) HCV infection treated with EPCLUSA and ribavirin achieved SVR12. Cirrhosis Trial 2104 was an open-label clinical trial that evaluated 12 weeks of treatment with EPCLUSA in 79 HCV-infected treatment-naïve and previously treated adult subjects who had undergone liver transplantation. The proportions of subjects with genotype 1, 2, 3, or 4 HCV infection were 47%, 4%, 44%, and 5%, respectively. The median age was 62 years (range: 45 to 81); 81% were male; 82% were White; 3% were Black; and 15% were Asian; 28% had a baseline body mass index at least 30 kg/m 2. At baseline, 18% had compensated cirrhosis, and 60% were treatment experienced (subjects with prior exposure to any HCV NS5A inhibitor were excluded). Immunosuppressants allowed for coadministration were tacrolimus, mycophenolate mofetil, cyclosporine, and azathioprine. The overall SVR12 rate was 96% (76/79). Of the subjects completing 12 weeks of EPCLUSA, 2 subjects experienced virologic relapse. was an open-label clinical trial that evaluated 12 weeks of treatment with EPCLUSA in 59 HCV-infected adults with ESRD requiring dialysis. The proportions of subjects with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%,12%, 27%, 7%, 3%, and 8%, respectively. At baseline, 29% of subjects had cirrhosis, 22% were treatment-experienced (subjects with prior exposure to any HCV NS5A inhibitor were excluded), 92% were on hemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59). Of the subjects completing 12 weeks of EPCLUSA, 1 subject experienced virologic relapse. Treatment (MAT) for Opioid Use Disorder SIMPLIFY was an open-label Phase 2 clinical trial that evaluated 12 weeks of treatment with EPCLUSA in 103 HCV-infected PWID (defined as self-reported injection drug use within previous 6 months), including 58 subjects on MAT for opioid use disorder. The proportions of subjects with genotype 1, 2, 3, and 4 HCV infection were 35%, 5%, 58%, and 2%, respectively. The median age was 48 years (range: 24 to 67); 71% were male; 89% were White; and 2% were Black. At baseline, 74% and 26% of subjects reported injection drug use or daily injection drug use, respectively, in the past month; 56% had baseline HCV RNA levels at least 800,000 IU/mL; 10% had compensated cirrhosis; and all subjects were naïve to prior exposure with SOF or an HCV NS5A inhibitor. Subjects on MAT for opioid use disorder reported concomitant use of methadone (76%) and buprenorphine naloxone (17%) with EPCLUSA. The overall SVR rate was 94% (97/103). One subject completed EPCLUSA treatment and was re-infected with a phylogenetically different virus; the other 5 subjects who did not achieve SVR12 did not meet virologic failure criteria. The efficacy of EPCLUSA once daily for 12 weeks was evaluated in an open-label trial (Study 1143) in 214 genotype 1, 2, 3, 4, or 6 HCV treatment-naïve (N=188) or treatment-experienced (N=26) pediatric subjects 3 years of age and older without cirrhosis or with compensated cirrhosis. Subjects 12 Years to <18 Years of Age: EPCLUSA was evaluated in 102 subjects 12 years to <18 years of age with genotype 1, 2, 3, 4, or 6 HCV infection. Among these subjects, 80 (78%) were treatment-naïve and 22 (22%) were treatment-experienced. The median age was 15 years (range: 12 to 17); 51% of the subjects were female; 73% were White, 9% were Black, and 11% were Asian; 14% were Hispanic/Latino; mean body mass index was 23 kg/m 2 (range: 13 to 49 kg/m 2 ); mean weight was 61 kg (range: 22 to 147 kg); 58% had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; the proportions of subjects with genotype 1, 2, 3, 4, or 6 HCV infection were 74%, 6%, 12%, 2%, and 6%, respectively; no subjects had known cirrhosis. The majority of subjects (89%) had been infected through vertical transmission. The SVR rate was 93% (71/76) in subjects with genotype 1 HCV infection and 100% in subjects with genotype 2 (6/6), genotype 3 (12/12), genotype 4 (2/2), and genotype 6 (6/6) HCV infection. One subject discontinued treatment at Week 4 and subsequently relapsed; the other four subjects who did not achieve SVR12 did not meet virologic failure criteria (lost to follow-up). Subjects 6 Years to <12 Years of Age: EPCLUSA was evaluated in 71 subjects 6 years to <12 years of age with genotype 1, 2, 3, or 4 HCV infection. Among these subjects, 67 (94%) were treatment-naïve and 4 (6%) were treatment-experienced. The median age was 8 years (range: 6 to 11); 54% of the subjects were female; 90% were White, 6% were Black, and 1% were Asian; 10% were Hispanic/Latino; mean body mass index was 17 kg/m 2 (range: 13 to 31 kg/m 2 ); mean weight was 30 kg (range: 18 to 78 kg); 48% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; the proportions of subjects with genotype 1, 2, 3, or 4 HCV infection were 76%, 3%, 15%, and 6%, respectively; no subjects had known cirrhosis. The majority of subjects (94%) had been infected through vertical transmission. The SVR rate was 93% (50/54) in subjects with genotype 1 HCV infection, 91% (10/11) in subjects with genotype 3 HCV infection, and 100% in subjects with genotype 2 (2/2) and genotype 4 (4/4) HCV infection. One subject had on-treatment virologic failure; the other four subjects who did not achieve SVR12 did not meet virologic failure criteria (lost to follow-up). Subjects 3 Years to <6 Years of Age: EPCLUSA was evaluated in 41 treatment-naïve subjects 3 years to <6 years of age with genotype 1, 2, 3, or 4 HCV infection. The median age was 4 years (range: 3 to 5); 59% of the subjects were female; 78% were White, 7% were Black; 10% were Hispanic/Latino; mean body mass index was 17.0 kg/m 2 (range: 13.9 to 22.0 kg/m 2 ); mean weight was 19 kg (range: 13 to 35 kg); 49% had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; the proportions of subjects with genotype 1, 2, 3, or 4 HCV infection were 78%, 15%, 5%, and 2%, respectively; no subjects had known cirrhosis. The majority of subjects (98%) had been infected through vertical transmission. The SVR12 rate among all subjects was 83% (34/41); with 88% (28/32) in subjects with genotype 1 HCV infection, 50% (3/6) in subjects with genotype 2 HCV infection, and 100% in subjects with genotype 3 (2/2) and genotype 4 (1/1) HCV infection. None of the 34 subjects who completed the treatment had virologic failure. Of the remaining seven subjects who did not achieve SVR12, five discontinued treatment on Day 1, one on Day 7, and one on Day 20 .Clinical Trial in Subjects Coinfected with
Clinical Trials in Subjects with Decompensated Cirrhosis
Clinical Trial in Adult Liver Transplant Recipients without Cirrhosis and with Compensated
Clinical Trial in Subjects with Severe Renal Impairment Requiring Dialysis Trial 4062
Clinical Trial in People who Inject Drugs (PWID), Including Those on Medication-Assisted
Clinical Trial in Pediatric Subjects
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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