Date of approval.
Date of revision.
Sofosbuvir Vipatavir Tablets Instructions
Please read the instructions carefully and use under the guidance of a doctor
Drug Name
Generic name: Sofosbuvir-velpatasvir Tablets
Trade name: Protonixa® (Epclusa®)
English name: Sofosbuvir and velpatasvir Tablets
Hanyu Pinyin Name: Suolinbuwei Weipatawei Pian
Ingredients
This product is a compound preparation containing 400 mg of sofosbuvir and 100 mg of velpatasvir per tablet.
Properties
This product is a film-coated tablet, which appears white to brownish yellow after removing the coating.
One side of the film-coated tablet is engraved with “GSI” and the other side is engraved with “7916”.
Indications
This product is used for the treatment of chronic hepatitis C virus (HCV) infection in adults (see [Dosage], [Precautions] and [Pharmacology and Toxicology]).
Specification
Each tablet contains 400 mg of Sofosbuvir and 100 mg of Vipatavir.
Dosage and Administration
Dosage
The recommended dose of Epclusa is one oral tablet once daily with or without food (see [Pharmacokinetics]).
Table 1: Recommended treatment regimens and durations for all HCV genotypes
Patient populationa Treatment regimen and duration 12-week Epclusa treatment in patients without cirrhosis and in patients with compensated cirrhosis
For genotype 3 infected patients with compensated cirrhosis, consider adding ribavirin (see [Pharmacology and Toxicology]). 12-week Epclusa + ribavirin therapy in patients with decompensated cirrhosis a. Includes patients co-infected with human immunodeficiency virus (HIV) and patients with HCV relapse after liver transplantation (see [Precautions]).
When used in combination with ribavirin, also refer to the prescribing information for ribavirin-containing drugs.
The following dosing regimen is recommended, with ribavirin doses taken twice daily with food.
Table 2: Dosing guidelines for ribavirin when administered in combination with Epclusa to patients with decompensated cirrhosis
Patients Ribavirin dose Pre-transplant ChildPughTurcotte (CPT) Grade B cirrhosis 1,000 mg/day for patients weighing < 75 kg; 1,200 mg/day for patients weighing ≥ 75 kg Pre-transplant CPT Grade C cirrhosis
The starting dose for post-transplant CPT grade B or C is 600 mg and may be increased to a maximum of 1,000/1,200 mg if well tolerated (1,000 mg for patients weighing < 75 kg; 1,200 mg for patients weighing ≥ 75 kg). If the starting dose is not well tolerated, the dose should be reduced based on hemoglobin levels as clinically indicated If ribavirin is used in genotype 3 infected patients with compensated cirrhosis (pre- or post-transplant), the recommended dose of ribavirin is 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 1,200 mg for patients weighing ≥ 75 kg). (1,200 mg for patients weighing ≥ 75 kg).
For ribavirin dose adjustments, refer to the prescribing information for ribavirin-containing drugs.
Patients should be instructed to take one additional Epclusa tablet if vomiting occurs within 3 hours of dosing. If vomiting occurs more than 3 hours after dosing, no Epclusa refill is required (see [Pharmacology and Toxicology]).
If a dose of Epclusa is missed within 18 hours of normal time, the patient should be instructed to take the tablet as soon as possible, after which the patient should take the next dose of medication at the usual dosing time. If more than 18 hours have elapsed, the patient should be instructed to wait until the usual dosing time to take the next dose of Epclusa and should be instructed not to take twice the dose of Epclusa.
Patients who have failed prior treatment with an NS5A-containing regimen
Consider 24 weeks of Epclusa + ribavirin therapy (see [Precautions]).
Geriatric patients
No dose adjustment is necessary in elderly patients (see [Pharmacokinetics]).
Renal Impairment
No Epclusa dose adjustment is necessary for patients with mild or moderate renal impairment. The safety and efficacy of Epclusa have not been evaluated in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or in patients with end-stage renal disease (ESRD) requiring hemodialysis (see [Pharmacokinetics]).
Hepatic Impairment
No Epclusa dose adjustment is required in patients with mild, moderate, or severe hepatic impairment (CPT Class A, B, or C) (see [Pharmacokinetics]). The safety and efficacy of Epclusa have been evaluated in patients with CPT class B cirrhosis, but have not been evaluated in patients with CPT class C cirrhosis (see [Precautions], [Adverse Reactions], and [Pharmacology and Toxicology]).
Pediatric Population
The safety and efficacy of Epclusa in children and adolescents under 18 years of age have not been established. No data are available.
Method of Administration
Oral.
Patients should be instructed to swallow the tablet whole, with or without food (see [Pharmacokinetics]). Due to the bitter taste, it is recommended not to chew or crush the film-coated tablets.
[Adverse Reactions].
Summary of Safety Profile
The safety evaluation of Epclusa was based on data from a pooled phase 3 clinical study in patients with genotype 1, 2, 3, 4, 5, or 6 HCV infection (with or without compensated cirrhosis), including 1,035 patients treated with 12 weeks of Epclusa.
For patients receiving 12 weeks of Epclusa, the proportion of patients who permanently discontinued treatment due to adverse events was 0.2% and the proportion of patients who experienced any serious adverse events was 3.2%. In the clinical study, headache, fatigue and nausea were the most common (≥10%) treatment-triggered adverse events reported in patients receiving 12 weeks of Epclusa. These and other adverse events were reported with similar frequency in patients treated with placebo as in those treated with Epclusa.
Patients with decompensated cirrhosis
The safety profile of Epclusa has been evaluated in an open-label study in which patients with CPT grade B cirrhosis received 12 weeks of Epclusa (n = 90), 12 weeks of Epclusa + RBV (n = 87), or 24 weeks of Epclusa (n = 90). The adverse events observed in the study were consistent with the expected clinical sequelae of decompensated liver disease or the known toxicity profile of ribavirin when patients received Epclusa in combination with ribavirin.
Of the 87 patients treated with 12 weeks of Epclusa + RBV, 23% and 7% had a decrease in hemoglobin to less than 10 mg/dL and 8.5 mg/dL, respectively, during treatment. 15% of patients treated with 12 weeks of Epclusa + RBV discontinued ribavirin due to adverse events.
Description of Selected Adverse Reactions
Cardiac Arrhythmias
Severe cases of bradycardia and heart block were observed when sofosbuvir was combined with other direct-acting antivirals in combination with the drug amiodarone and/or other drugs that lower the heart rate (see [Precautions] and [Drug Interactions]).
Report of suspected adverse reactions
It is important to report suspected adverse reactions after a drug has been approved for marketing. This allows for continuous monitoring of the benefit/risk balance of the use of the drug. In China, healthcare professionals are required to report any suspected adverse reactions through the national reporting system.
Contraindications
Hypersensitivity reactions to the active ingredient or to any of the excipients.
Combination with potent P-gp inducers and potent CYP inducers
Potent P-glycoprotein (P-gp) inducers or potent cytochrome P450 (CYP) inducers (rifampin, rifabutin, St. John’s wort [Hypericum perforatum], carbamazepine, phenobarbital, and phenytoin). Co-administration significantly reduces plasma concentrations of sofosbuvir or vepatavir and may result in loss of efficacy of Epclusa (see [Drug Interactions]).
Caution
Warning: Risk of Hepatitis B Virus Reactivation in HCV and HBV Coinfected Patients
Test all patients for signs of current or prior hepatitis B virus (HBV) infection prior to initiating EPCLUSA therapy. HBV reactivation has been reported in HCV/HBV co-infected patients who are receiving or have completed HCV direct-acting antiviral therapy and in those who are not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, liver failure, and death. Monitor HCV/HBV co-infected patients for hepatitis flares or HBV reactivation during HCV treatment and post-treatment follow-up. Administer appropriate patient management for HBV infection based on clinical indications.
Epclusa should not be administered concomitantly with other sofosbuvir-containing drugs.
Severe bradycardia and heart block
Severe bradycardia and heart block have been observed when sofosbuvir is co-administered with other direct-acting antiviral agents (DAAs) in combination with the drug amiodarone (with or without other heart rate-lowering drugs). The mechanism has not been determined.
There have been a very limited number of cases of combined use of amiodarone throughout the clinical development of sofosbuvir plus DAA. These conditions are potentially life-threatening and therefore amiodarone should be used in patients receiving Epclusa only when other alternative antiarrhythmic therapies are not tolerated or contraindicated.
If the combination of amiodarone is deemed necessary, close monitoring of the patient at the time of initiation of Epclusa therapy is recommended. Patients who are clearly at high risk of bradycardia should be monitored continuously for 48 hours in an appropriate clinical setting.
Due to the long half-life of amiodarone, appropriate monitoring should also be performed in patients who have discontinued amiodarone within the last few months and are about to start Epclusa therapy.
All patients receiving Epclusa in combination with amiodarone (with or without other heart rate-lowering drugs) should be warned of symptoms of bradycardia and heart block and advised to seek immediate medical advice if they develop such symptoms.
Patients who have failed prior treatment with an NS5A-containing regimen
There are no clinical data to support the efficacy of sofosbuvir-vipatasvir in the treatment of patients who have failed prior treatment with a regimen containing another NS5A inhibitor. However, based on the NS5A resistance-associated variants (RAVs) typically observed in patients who have failed treatment with regimens containing other NS5A inhibitors, the in vitro pharmacology of vepatavir, and the treatment outcomes of sofosbuvir/vipatavir in patients with baseline NS5A RAVs who were not treated with NS5A-related therapy included in the ASTRAL study, there is no evidence to support the use of sofosbuvir/vipatavir in patients who have failed treatment with regimens containing NS5A and who are considered to have a higher risk of NS5A-related treatment. Failure and patients considered to be at high risk of clinical disease progression and for whom no alternative treatment options are available, 24 weeks of Epclusa + RBV therapy may be considered.
Renal impairment
No Epclusa dose adjustment is required for patients with mild or moderate renal impairment. The safety of Epclusa has not been evaluated in patients with ESRD who have severe renal impairment (eGFR < 30 mL/min/1.73 m2) or who require hemodialysis. For patients with creatinine clearance < 50 mL/min, when Epclusa is used in combination with ribavirin, see also prescribing information for ribavirin (see [Pharmacokinetics]).
Combination with Moderate Pgp Inducer or Moderate CYP Inducer
Moderate P-gp inducers or moderate CYP inducers such as oxcarbazepine, modafinil, or efavirenz may decrease plasma concentrations of sofosbuvir or vepatavir, resulting in reduced efficacy of Epclusa. The combination of these drugs with Epclusa is not recommended (see [Drug Interactions]).
Combination with specific HIV antiretroviral regimens
Epclusa has been shown to increase tenofovir exposure, especially when used with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of Epclusa with a pharmacokinetic booster has not been established. The potential risks and benefits of Epclusa in combination with fixed-dose combination tablets containing everolimus/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with an enhanced HIV protease inhibitor (e.g., atazanavir or dirinavir) should be considered, particularly in patients at increased risk of renal insufficiency. Patients receiving Epclusa in combination with everolimus/cobicistat/emtricitabine/tenofovir disoproxil fumarate or in combination with tenofovir disoproxil fumarate and an enhanced HIV protease inhibitor should be monitored for the presence of adverse reactions associated with tenofovir. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or everolimus/cobicistat/emtricitabine/tenofovir disoproxil fumarate prescribing information for recommendations on renal monitoring.
CPT Class C cirrhosis
The safety and efficacy of Epclusa have not been evaluated in patients with CPT Class C cirrhosis (see [Adverse Reactions] and [Pharmacologic Toxicology]).
Liver Transplant Patients
The safety and efficacy of Epclusa treatment in patients with HCV infection after liver transplantation have not been evaluated. Individual patients should be evaluated for potential benefit and risk and treated with Epclusa according to the recommended dose (see [DOSAGE]).
Effects on Driving and Ability to Operate Machinery
Epclusa has no or negligible effect on the ability to drive and operate machinery.
Pregnant and lactating women
Pregnancy
There are no or very limited data on the use of sofosbuvir, vepatavir, or Epclusa in pregnant women (less than 300 pregnancy outcomes).
Sofosbuvir
With regard to reproductive toxicity, animal studies have not demonstrated direct or indirect adverse effects (see [Pharmacologic Toxicology]).
The exposure threshold for sofosbuvir in rats cannot be adequately estimated relative to the human exposure at the recommended clinical dose (see [Pharmacologic Toxicology]).
Vipatavir
Animal studies have shown a possible association with reproductive toxicity (see [Pharmacologic Toxicology]).
Epclusa is not recommended for use during pregnancy as a precautionary measure.
Lactation
It is not known whether sofosbuvir, metabolites of sofosbuvir, or tipatavir are secreted into human milk.
Pharmacokinetic data from animal studies indicate that metabolites of velpatasvir and sofosbuvir are excreted in breast milk.
A risk to the neonate/infant cannot be excluded. Therefore, Epclusa should not be used during breastfeeding.
Fertility
No data are available on the effect of Epclusa on human fertility. Animal studies have not demonstrated a deleterious effect of sofosbuvir or vepatasvir on fertility.
If ribavirin is used in combination with Epclusa, refer to the prescribing information for ribavirin for detailed recommendations regarding pregnancy, contraception, and breastfeeding.
Pediatric Dosage]
The safety and efficacy of Epclusa in children and adolescents under 18 years of age have not been established. No data are available.
Geriatric Use
The clinical study of Epclusa enrolled 156 patients aged 65 years and older (12% of the total number of patients in the Phase 3 clinical study). Response rates in patients ≥65 years of age were similar to those in patients < 65 years of age between treatment groups.
Drug Interactions]
Because Epclusa contains sofosbuvir and velpatasvir, any interactions found with these active substances alone may occur with Epclusa.
Potential for Epclusa to affect other drugs
Epclusa is an inhibitor of the drug transporters Pgp, breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Epclusa may increase exposure to such drugs when used in combination with substrate-based drugs for these transporters. See Table 3 for examples of interactions with sensitive substrates of P-gp (digoxin), BCRP (rosuvastatin), and OATP (pravastatin).
Potential for other drugs to affect Epclusa
Sofosbuvir and tipatavir are substrates of the drug transporters P-gp and BCRP. Vipatavir is also a substrate for the drug transporter OATP1B. In vitro, a slow metabolic conversion of velpatasvir via CYP2B6, CYP2C8 and CYP3A4 has been observed. Pgp potent inducers or CYP2B6, CYP2C8 or CYP3A4 potent inducer drugs (e.g., rifampin, rifabutin, St. John’s wort, carbamazepine, phenobarbital and phenytoin) may reduce the plasma concentration of sofosbuvir or velpatasvir, resulting in a decrease in sofosbuvir/velpatasvir plasma concentrations. This may result in reduced efficacy of sofosbuvir/vipatasvir. The combination of these drugs with Epclusa is contraindicated (see [Contraindications]). Moderate P-gp inducers or moderate CYP-inducing drugs (such as oxcarbazepine, modafinil, or efavirenz) may reduce plasma concentrations of sofosbuvir or vepatavir, resulting in reduced efficacy of Epclusa. Use of Epclusa in combination with these drugs is not recommended (see [Precautions]). Combination with drugs that inhibit P-gp or BCRP may increase plasma concentrations of sofosbuvir or gemcitabine. Drugs that inhibit OATP, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentrations of velpatasvir. Clinically meaningful drug-drug interactions with Epclusa mediated by P-gp, BCRP, OATP, or CYP450 inhibitors are not expected; Epclusa may be administered in combination with Pgp, BCRP, OATP, and CYP inhibitors.
Patients treated with vitamin K antagonists
Close monitoring of International Normalized Ratio (INR) values is recommended due to possible changes in liver function during Epclusa treatment.
Interactions between Epclusa and other drugs
Table 3 provides a list of drug interactions that have been identified or are likely to be clinically significant (where the 90% confidence interval [CI] for the geometric mean least squares [GLSM] ratio is labeled as follows: “↔” within a predefined interaction threshold, “↑” above this range, or “↓” below this range). Drug interactions described are based on studies conducted with sofosbuvir/vipatavir or with vipatavir and sofosbuvir as a single agent, or are expected drug interactions that may occur with sofosbuvir/vipatavir. This table is not exhaustive.
Table 3: Interactions between Epclusa and other drugs
Drug effects on drug levels listed by therapeutic area/possible mechanism of interaction.
Mean ratios (90% confidence interval)a,b for the proposed active ingredient CmaxAUCCmin in combination with Epclusa. Drugs that increase the pH in the stomach are expected to decrease the concentration of Vipatavir. Antacids such as aluminum hydroxide or magnesium hydroxide; calcium carbonate
(increased gastric pH) have not been studied for interaction.
Expected.
↔ Sofosbuvir
↓ H2 receptor antagonist famotidine
(40 mg single dose)/sofosbuvir/vipatasvir (400/100 mg single dose)
Famotidine administered concomitantly with Epclusad
Cimetidine e
Nizatidine e
Ranitidine e
(elevated intragastric pH)
Sofosbuvir
↔
↔
H2 receptor antagonists may be administered concurrently or staggered with Epclusa, but not in doses exceeding the equivalent of 40 mg famotidine twice daily.
Vipatavir ↓
0.80 (0.70, 0.91)↓
0.81 (0.71, 0.91) Famotidine
(40 mg single dose)/sofosbuvir/vipatavir (400/100 mg single dose)c
Famotidine given 12 hours prior to Epclusa administrationd
(elevated intragastric pH) Sofosbuvir
↓
0.77 (0.68, 0.87)↓
0.80 (0.73, 0.88) Vipatavir ↔
↔
Proton pump inhibitor omeprazole
(20 mg once daily)/sofosbuvir/vipatavir (400/100 mg single dose in fasted state)c
Omeprazole administered concomitantly with Epclusad
Lansoprazolee
Rabeprazolee
Pantoprazolee
Esomeprazolee
(elevated intragastric pH) Sofosbuvir
↓
0.66 (0.55, 0.78) ↓
0.71 (0.60, 0.83) Combination with proton pump inhibitors is not recommended. If a combination is deemed necessary, Epclusa should be taken with food and 4 hours prior to administration of a proton pump inhibitor (maximum dose equivalent to omeprazole 20 mg). Vipatavir↓
0.63 (0.50, 0.78)↓
0.64 (0.52, 0.79) Omeprazole (20 mg once daily)/sofosbuvir/vipatasvir (400/100 mg single dose in fed state)c
Omeprazole given 4 hours after Epclusa administrationd
(elevated intragastric pH) Sofosbuvir
↓
0.79 (0.68, 0.92) ↔
Vipatavir
↓
0.67 (0.58, 0.78) ↓
0.74 (0.63, 0.86) Interactions have not been studied with the antiarrhythmic drug amiodarone.
Effects on amiodarone, velpatasvir and sofosbuvir concentrations have not been clarified. Use only in the absence of other alternative drugs. Close monitoring is recommended if this drug is used in combination with Epclusa (see [Precautions] and [Adverse Reactions]). Digoxin has only been studied for interaction with vepatavir.
Expected.
↔ Sofosbuvir Epclusa in combination with digoxin may increase digoxin concentrations. Care must be taken when combining with Epclusa and monitoring of therapeutic concentrations of digoxin is recommended. Digoxin (0.25 mg single dose)f/vipratasvir (100 mg single dose)
(Pgp inhibition) Not studied for effect on exposure to vepatavir
Expected.
↔ Vipatavir observations.
Digoxin ↑
1.9 (1.7, 2.1) ↑
1.3 (1.1, 1.6) Anticoagulant dabigatranate
(Pgp inhibition) Interactions have not been studied.
Expected.
↑ Dabigatran
↔ Sofosbuvir
↔ Vipatavir When dabigatranate is used in combination with Epclusa, clinical monitoring is recommended to look for signs of bleeding and anemia. Coagulation testing can help identify patients at increased risk of bleeding due to increased dabigatran exposure. Vitamin K antagonists have not been studied for interaction. Close monitoring of INR is recommended with all vitamin K antagonists due to changes in liver function with Epclusa therapy. Anticonvulsants Carbamazepine
Phenytoin
Phenobarbital
(Pgp and CYP induced) Interactions have not been studied.
Expected.
↓ sofosbuvir
↓ Vipatavir prohibits Epclusa in combination with carbamazepine, phenobarbital, and phenytoin (potent Pgp and CYP inducers) (see [Contraindications]). Oxcarbazepine
(Pgp and CYP inducer) Interactions have not been studied.
Expected.
↓ Sofosbuvir
↓ Epclusa in combination with oxcarbazepine is expected to decrease concentrations of sofosbuvir and vepatavir, resulting in reduced efficacy of Epclusa. Combination use is not recommended (see [Precautions]). The antifungal drug ketoconazole was studied only for interaction with vepatavir
Expected.
↔ No dose adjustment for Epclusa or ketoconazole is required for sofosbuvir. Ketoconazole (200 mg twice daily)/vipatavir (100 mg single dose)d
(Pgp and CYP inhibition)
Itraconazolee
Voriconazolee
Posaconazolee
Esaconazolee Not studied for effect on ketoconazole exposure.
Expected.
↔ Ketoconazole observations.
Vipatavir ↑
1.3 (1.0, 1.6) ↑
1.7 (1.4, 2.2) Anti-brancherella drug rifampicin (600 mg once daily)/sofosbuvir (400 mg single dose)d
(Pgp and CYP induction) Effect on rifampicin exposure was not studied.
Expected.
↔ Rifampin prohibits Epclusa in combination with rifampin, a potent P-gp and CYP inducer (see [Contraindications]).
Observation.
Sofosbuvir ↓
0.23 (0.19, 0.29) ↓
0.28 (0.24, 0.32) Rifampin (600 mg once daily)/velpatasvir (100 mg single dose)
(Pgp and CYP induction) Effect on rifampicin exposure was not studied.
Expected.
↔ Rifampicin observations.
Vipatavir
↓
0.29 (0.23, 0.37) ↓
0.18 (0.15, 0.22) Rifabutin
Rifapentine
(Pgp and CYP induction) Interactions have not been studied.
Expected.
↓ Sofosbuvir
↓ Vipatavir prohibits Epclusa in combination with rifabutin, a potent P-gp and CYP inducer (see [Contraindications]).
The combination of Epclusa with rifapentine is expected to decrease the concentration of sofosbuvir and tipatavir, resulting in a decrease in the efficacy of Epclusa. The combination is not recommended (see [Precautions]). HIV antivirals: The reverse transcriptase inhibitor tenofovir disoproxil fumarate has been shown to increase tenofovir exposure (P-gp inhibition) with Epclusa. Tenofovir exposure (AUC and Cmax) increases by approximately 40-80% during the combination of Epclusa with tenofovir disoproxil fumarate/emtricitabine (as part of various HIV regimens).
Patients receiving tenofovir disoproxil fumarate and Epclusa co-administration should be monitored for the presence of adverse reactions associated with tenofovir disoproxil fumarate. Refer to the prescribing information for tenofovir disoproxil fumarate-containing drugs for recommendations on renal monitoring (see [Precautions]). Efavirenz/emtricitabine/tenofovir disoproxil fumarate
(600/200/300 mg once daily)/sofosbuvir/vipatasvir (400/100 mg once daily)c, dEfavirenz↔↔ Epclusa in combination with efavirenz/emtricitabine/tenofovir disoproxil fumarate is expected to decrease the concentration of vipatasvir. Epclusa is not recommended in combination with efavirenz-containing regimens (see [Precautions]). Sofosbuvir↑
1.4 (1.1, 1.7)↔ Vipatavir ↓
0.53 (0.43, 0.64)↓
0.47 (0.39, 0.57)↓
0.43 (0.36, 0.52)emtricitabine/ribivirine/tenofovir disoproxil fumarate
(200/25/300 mg once daily)/sofosbuvir/vipatasvir (400/100 mg once daily)c, d rilpivirine ↔↔ No dose adjustment for Epclusa or emtricitabine/ribivirine/tenofovir disoproxil fumarate is required. Sofosbuvir ↔ ↔ Vipatavir ↔↔ HIV antivirals: HIV protease inhibitor atazanavir enhanced by ritonavir (300 mg/100 mg once daily) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg once daily)/sofosbuvir/vipatavir (400/100 mg once daily)c, d atazanavir ↔ ↑
1.4 (1.2, 1.6) No dose adjustment for Epclusa, atazanavir (boosted by ritonavir), or emtricitabine/tenofovir disoproxil fumarate is required. Ritonavir ↔ ↑
1.3 (1.5, 1.4) Sofosbuvir ↔ Vipatasvir ↑
1.6 (1.4, 1.7) ↑
2.4 (2.2, 2.6) ↑
4.0 (3.6, 4.5) Ritonavir-boosted dirinavir (800 mg/100 mg once daily) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg once daily)/sofosbuvir/vipatavir (400/100 mg once daily)c, dirinavir ↔↔ No need for Epclusa, dirinavir (ritonavir-boosted) or emtricitabine/fumetavir (400/100 mg once daily) ) or emtricitabine/tenofovir disoproxil fumarate for dose adjustment. Ritonavir↔↔↔ Sofosbuvir↓
0.62 (0.54, 0.71) ↓
0.72 (0.66, 0.80) Vipatasvir ↓
0.76 (0.65, 0.89) ↔ Lopinavir (4×200 mg/50 mg once daily) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg once daily)/sofosbuvir/vipatavir (400/100 mg once daily)c, d lopinavir ↔↔ No need for Epclusa, lopinavir ( via ritonavir booster) or emtricitabine/tenofovir disoproxil fumarate dose adjustment is not required.
Ritonavir↔↔↔ Sofosbuvir↓
0.59 (0.49 0.71) ↓
0.7 (0.6, 0.8) Vipatasvir ↓
0.70 (0.59, 0.83) ↔ ↑
1.6 (1.4, 1.9) HIV antivirals: integrase inhibitor raltegravir (400 mg twice daily)g + emtricitabine/tenofovir disoproxil fumarate (200/300 mg once daily)/sofosbuvir/vipatasvir (400/100 mg once daily)c, d raltegravir ↔ ↔ ↓
0.79 (0.42, 1.5) No dose adjustment for Epclusa, raltegravir, or emtricitabine/tenofovir disoproxil fumarate is required. Sofosbuvir ↔ ↔ Vipatavir ↔ ↔ Efavirevir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate
(150/150/200/10 mg once daily)/sofosbuvir/vipatasvir (400/100 mg once daily)c, d Efavirevir ↔↔ No dose adjustment for Epclusa or Efavirevir/Cobicistat/emtricitabine/fospropatofovir fumarate is required.
Cobicistat ↔ ↑
2.0 (1.7, 2.5) Fospropatofovir ↔ Sofosbuvir ↔ ↑
1.4 (1.2, 1.5) Vipatasvir ↑
1.3 (1.2, 1.5) ↑
1.5 (1.4, 1.7) ↑
1.6 (1.4, 1.8) Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (150/150/200/300 mg once daily)/sofosbuvir/velpatasvir (400/100 mg once daily)c, d Elvitegravir↔↔ No Epclusa or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Dose adjustment.
Cobicistat ↔ ↑
1.7 (1.5, 1.9) Sofosbuvir ↔ Vipatasvir ↔ ↑
1.4 (1.2, 1.5) Dolutegravir (50 mg once daily)/sofosbuvir/vipatasvir (400/100 mg once daily) Dolutegravir↔↔↔ No dose adjustment for Epclusa or dolutegravir is required. Sofosbuvir↔↔ Vipatavir↔↔↔ Herbal supplement St. John’s Wort
(Pgp and CYP induction) has not been studied for interactions.
Expected.
↓ Sofosbuvir
↓ Vipatavir prohibits Epclusa in combination with St. John’s wort (a potent P-gp and CYP inducer) (see [Contraindications]).HMG-CoA reductase inhibitor resulvastatin has only been studied for interaction with vipatavir
Expected.
↔ The combination of sofosbuvir Epclusa with risulvastatin increases the concentration of risulvastatin, which is associated with an increased risk of myopathy, including rhabdomyolysis. Rosuvastatin can be combined with Epclusa at doses up to 10 mg. Rosuvastatin (10 mg single dose)/viparatavir (100 mg once daily)d
(OATP1 and BCRP inhibition) Observation.
Rosuvastatin ↑
2.6 (2.3, 2.9) ↑
2.7 (2.5, 2.9) Not studied for effect on vepatavir exposure
Expected.
↔ Vipatavir Pravastatin only studied for interaction with Vipatavir
Expected.
↔ No dose adjustment for Epclusa or pravastatin is required for sofosbuvir. Pravastatin (40 mg single dose)/vipatavir (100 mg once daily)d
(OATP1B inhibition) Observation.
Pravastatin
↑
1.3 (1.1, 1.5)
↑
1.4 (1.2, 1.5) Not studied for effect on vepatavir exposure
Expected.
↔ Vipatavir other statins expected.
↑ Statins cannot exclude interactions with other HMG-CoA reductase inhibitors. When used in combination with Epclusa, statins should be closely monitored for adverse effects and a reduction in the statin dose (if necessary) should be considered. Narcotic Analgesics Methadone
(methadone maintenance therapy [30 to 130 mg/day])/sofosbuvir (400 mg once daily) dR methadone
↔
↔
↔
No dose adjustment for Epclusa or methadone required. sMethadone ↔
↔
↔
Sofosbuvir ↔
↑
1.3 (1.0, 1.7) Methadone is only studied for interaction with sofosbuvir
Expected.
↔ Vipatavir immunosuppressant cyclosporine
(600 mg single dose)/sofosbuvir (400 mg single dose)f cyclosporine ↔
↔
No dose adjustment for Epclusa or cyclosporine is required. Sofosbuvir ↑
2.5 (1.9, 3.5) ↑
4.5 (3.3, 6.3) Cyclosporine
(600 mg single dose) f/vipatavir (100 mg single dose) d cyclosporine ↔
↓
0.88 (0.78, 1.0) Vipatavir ↑
1.6 (1.2, 2.0) ↑
2.0 (1.5, 2.7) Tacrolimus
(5 mg single dose)f/sofosbuvir (400 mg single dose)d
Tacrolimus ↓
0.73 (0.59, 0.90) ↑
1.1 (0.84, 1.4) No dose adjustment for Epclusa or tacrolimus is required. Sofosbuvir ↓
0.97 (0.65, 1.4) ↑
1.1 (0.81, 1.6) Tacrolimus was not studied for effect on exposure to velpatasvir.
Expected.
↔ Vipatavir oral contraceptives norgestimate/ethinyl estradiol (norgestimate 0.180 mg/0.215 mg/ 0.25 mg/ethinyl estradiol 0.025 mg)/sofosbuvir (400 mg once daily) d methyl progesterone ↔
↔
↔
No dose adjustment is required for oral contraceptives. Methylpregnanolone ↔
↑
1.2 (0.98, 1.5) ↑
1.2 (1.0, 1.5) Ethinylestradiol ↔↔ Norethindrone/ethinylestradiol (norethindrone 0.180 mg/0.215 mg/ 0.25 mg/ethinylestradiol 0.025 mg)/vipatavir (100 mg once daily) d methylgestradiol ↔
↔
Methylprogesterone ↔
↔
↔
Ethinylestradiol ↑
1.4 (1.2, 1.7) ↔
↓
0.83 (0.65, 1.1) a. Combined drug pharmacokinetic mean ratio (90% CI) for study drugs alone or in combination. No effect = 1.00.
b. All interaction studies were conducted in healthy volunteers.
c. Dosed with Epclusa.
d. The cut-off range for no pharmacokinetic interactions is 70143%.
e. These drugs fall into the category where similar interactions can be predicted.
f. The bioequivalence/equivalence cut-off range is 80125%.
g. The threshold for no pharmacokinetic interactions ranges from 50-200%.
[Drug Overdose].
The highest documented doses of sofosbuvir and vepatavir were 1,200 mg and 500 mg administered as a single dose. In these healthy volunteer studies, no adverse effects were observed at these dose levels, and the frequency and severity of adverse events reported were similar to those in the placebo group. The effect of higher doses/exposures is not known.
A specific antidote for Epclusa overdose is not available. If an overdose occurs, patients must be monitored for signs of toxicity. Treatment of Epclusa overdose requires general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Hemodialysis effectively removes GS331007, the major circulating metabolite of sofosbuvir, with an extraction rate of 53%. Hemodialysis is unlikely to significantly remove velpatasvir due to its high binding rate to plasma proteins.
Clinical trials]
Clinical Efficacy and Safety
The efficacy of Epclusa was evaluated in patients with genotypes 1 to 6 HCV infection with or without compensated cirrhosis in three phase 3 studies, in patients with genotypes 1 to 6 HCV infection with decompensated cirrhosis in one phase 3 study, and in HCV/HIV-1 co-infected patients with genotypes 1 to 6 HCV infection in one phase 3 study, as summarized in Table 4.
Table 4: Epclusa Studies in Patients with Genotype 1, 2, 3, 4, 5, or 6 HCV Infection
Study Population Study Group
(number of patients treated) ASTRAL1 genotypes 1, 2, 4, 5, and 6
TN and TE, without cirrhosis or with compensated cirrhosis Epclusa 12 weeks (624)
Placebo 12 weeks (116) ASTRAL2 genotype 2
TN and TE, without cirrhosis or with compensated cirrhosis Epclusa 12 weeks (134)
SOF+RBV 12 weeks (132) ASTRAL3 genotype 3
TN and TE, without cirrhosis or with compensated cirrhosis Epclusa 12 weeks (277)
SOF+RBV 24 weeks (275) ASTRAL4 genotypes 1, 2, 3, 4, 5 and 6
TN and TE with CPT class B decompensated cirrhosis Epclusa 12 weeks (90)
Epclusa + RBV 12 weeks (87)
Epclusa 24 weeks (90) ASTRAL5 genotypes 1, 2, 3, 4, 5, and 6
TN and TE, without cirrhosis or with compensated cirrhosis, with HCV/HIV-1 co-infection Epclusa 12 weeks (106) TN = patients who have not received treatment; TE = patients who have received treatment (including patients who have received a regimen based on pegylated interferon alpha + ribavirin, with or without HCV protease inhibitors, but have failed treatment)
When ribavirin was used in combination with sofosbuvir in the ASTRAL2 and ASTRAL3 studies or with Epclusa in the ASTRAL4 study, the ribavirin dose was derived based on body weight (1,000 mg in two daily doses for patients at < 75 kg; 1,200 mg for patients ≥ 75 kg) and given in two doses The dose was derived (1,000 mg in two doses for < 75 kg; 1,200 mg for ≥ 75 kg) and given in two doses. Ribavirin dose adjustments were performed according to the ribavirin prescribing information. Serum HCV RNA values were measured during the clinical study using the COBAS AmpliPrep/COBAS Taqman HCV assay (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. Sustained virologic response (SVR12) was the primary endpoint for determining HCV cure rates, defined as HCV RNA below the LLOQ at 12 weeks after treatment discontinuation. LLOQ.
Clinical studies in patients without cirrhosis and in patients with compensated cirrhosis
Genotype 1, 2, 4, 5 and 6 HCV-infected adults – ASTRAL-1 (Study 1138)
ASTRAL1 is a randomized, double-blind, placebo-controlled study evaluating 12 weeks of Epclusa treatment compared to 12 weeks of placebo treatment in patients with genotype 1, 2, 4, 5, or 6 HCV infection. Patients with genotype 1, 2, 4, or 6 HCV infection were randomized in a 5:1 ratio to either the 12-week Epclusa treatment group or the 12-week placebo group. Patients with genotype 5 HCV infection were included in the Epclusa group. Random assignment was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence of cirrhosis.
Demographic information and baseline characteristics were balanced between the Epclusa and placebo groups. Of the 740 treated patients, the median age was 56 years (range: 18 to 82); 60% were male; 79% were white; 9% were black; 21% had a baseline body mass index of at least 30 kg/m2; 53%, 17%, 19%, 5%, and 7% were genotype 1, 2, 4, 5, or 6 HCV-infected patients, respectively; and 69% carried the non The proportion of patients with genotype 1, 2, 4, 5, or 6 HCV infection was 53%, 17%, 19%, 5%, and 7%, respectively; 69% had a non-CC IL28B allele (CT or TT); 74% had a baseline HCV RNA level of at least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% had received treatment.
Table 5 shows the SVR12 by HCV genotype for the ASTRAL1 study. no patients in the placebo group achieved SVR12.
Table 5: SVR12 in study ASTRAL-1 by HCV genotype
Epclusa 12 weeks
(n = 624) Total (all GT)
(n = 624) GT1 GT2
(n=104) GT4
(n=116) GT5
(n=35) GT6
(n=41) GT1a
(n=210) GT1b
(n=118) Total
(n=328) 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) Virological failure in SVR12 patients during outcome treatment 0/624 0/210 0/118 0/328 0/104 0/116 0/35 0/41 Relapsea< 1%
(2/623) < 1%
(1/209) 1%
(1/118) 1%
(2/327) 0/104 0/116 0/35 0/41 Otherb1%
(4/624) 1%
(3/210) 0/118 1%
(3/328) 0/104 0/116 3%
(1/35) 0/41 GT = genotype
a. Denominator for recurrence is the number of patients with HCV RNA < LLOQ at the last assessment during treatment.
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.
Genotype 2 HCV-Infected Adults – ASTRAL2 (Study 1139)
ASTRAL2 is a randomized, open-label study evaluating 12 weeks of Epclusa treatment compared to 12 weeks of SOF+RBV treatment in patients with genotype 2 HCV infection. Patients were randomized in a 1:1 ratio to either the 12-week Epclusa treatment group or the 12-week SOF+RBV treatment group. Random assignment was stratified by presence or absence of cirrhosis and prior treatment experience (untreated vs. treated).
Demographic information and baseline characteristics were more balanced between the two treatment groups. Of the 266 treated patients, the median age was 58 years (range: 23 to 81); 59% were male; 88% were white; 7% were black; 33% had a baseline body mass index of at least 30 kg/m2; 62% carried a non-CC IL28B allele (CT or TT); 80% had a baseline HCV RNA level of at least 800, 000 IU/mL; 14% had compensated cirrhosis; and 15% were treated.
The SVRs for the ASTRAL2 study are listed in Table 612.
Table 6: SVR12 (HCV genotype 2) in study ASTRAL2
Epclusa 12 weeks
(n=134) SOF+RBV 12 weeks
(n=132) SVR12 99% (133/134) 94% (124/132) Outcome for patients who did not achieve SVR12 Virologic failure during treatment 0/134 0/132 Relapsea0/133 5% (6/132) Otherb1% (1/134) 2% (2/132) a. Denominator for relapse is HCV RNA at last assessment during treatment < number of patients with LLOQ.
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.
12-week Epclusa treatment was shown to be statistically superior (p = 0.018) to 12-week SOF+RBV treatment (treatment difference +5.2%; 95% confidence interval: +0.2% to +10.3%).
Genotype 3 HCV-infected adults – ASTRAL3 (Study 1140)
ASTRAL3 is a randomized, open-label study evaluating 12 weeks of Epclusa treatment compared to 24 weeks of SOF+RBV treatment in patients with genotype 3 HCV infection. Patients were randomized in a 1:1 ratio to either the 12-week Epclusa treatment group or the 24-week SOF+RBV treatment group. Random assignment was stratified by presence or absence of cirrhosis and prior treatment experience (untreated vs. treated).
Demographic information and baseline characteristics were more balanced between the two treatment groups. Of the 552 treated patients, median age was 52 years (range: 19 to 76); 62% were male; 89% were white; 9% were Asian; and 1% were black; 20% had a baseline body mass index of at least 30 kg/m2; 61% carried a non-CC IL28B allele (CT or TT); and 70% had a baseline HCV RNA level of at least The baseline HCV RNA level was at least 800,000 IU/mL in 70% of patients; 30% had compensated cirrhosis; and 26% were on treatment.
The SVRs for the ASTRAL3 study12 are shown in Table 7.
Table 7: SVR12 (HCV genotype 3) in Study ASTRAL3
Epclusa 12 weeks
(n = 277) SOF+RBV 24 weeks
(n = 275) SVR12 95% (264/277) 80% (221/275) Outcome treatment period virologic failure in patients who did not achieve SVR12 0/277 < 1% (1/275) Recurrencea 4% (11/276) 14% (38/272) Otherb 1% (2/277) 5% (15/275) a. The denominator for recurrence was number of patients with HCV RNA < LLOQ at the last assessment during treatment.
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.
Twelve weeks of Epclusa treatment was shown to be statistically superior (p < 0.001) to 24 weeks of SOF+RBV treatment (treatment difference +14.8%; 95% confidence interval: +9.6% to +20.0%).
SVR12 for selected subgroups are presented in Table 8.
Table 8: SVR12 (HCV genotype 3) in selected subgroups of study ASTRAL3
Epclusa 12 weeks SOF+RBV 24 weeks aSVR12 No treatment received
(n = 206) Treated
(n = 71) Not treated
(n = 201) Treated
(n = 69) Without cirrhosis 98% (160/163) 91% (31/34) 90% (141/156) 71% (22/31) With cirrhosis 93% (40/43) 89% (33/37) 73% (33/45) 58% (22/38) a. This subgroup analysis excluded the five patients in the SOF+RBV 24-week group with missing cirrhosis status. b. This subgroup analysis excluded the five patients in the SOF+RBV 24-week group with missing cirrhosis status. c. This subgroup analysis excluded the five patients in the SOF+RBV 24-week group with missing cirrhosis status. patients.
Clinical study in patients with decompensated cirrhosis – ASTRAL4 (Study 1137)
ASTRAL4 is a randomized, open-label study in patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection and CPT grade B cirrhosis. Patients were randomized in a 1:1:1 ratio to the 12-week Epclusa treatment group, the 12-week Epclusa + RBV treatment group, or the 24-week Epclusa treatment group. Random assignment was stratified by HCV genotype (1, 2, 3, 4, 5, 6, and indeterminate).
Demographic information and baseline characteristics were more balanced across treatment groups. Of the 267 treated patients, the median age was 59 years (range: 40 to 73); 70% were male; 90% were white; 6% were black; and 42% had a baseline body mass index of at least 30 kg/m2. The proportion of patients with genotype 1, 2, 3, 4, or 6 HCV infection was 78%, 4%, 15%, 3%, and < 1% (1 patient), respectively. ). Patients with genotype 5 HCV infection were not included. 76% of patients carried a non-CC IL28B allele (CT or TT); 56% had a baseline HCV RNA level of at least 800,000 IU/mL; 55% were treated; and 90% and 95% of patients had CPT grade B cirrhosis and model for end-stage liver disease (MELD) score ≤ 15, respectively, at baseline.
Table 9 shows the SVR12 of the ASTRAL4 study by HCV genotype.
Table 9: SVR12 in Study ASTRAL4 by HCV Genotype
Epclusa 12 weeks
(n = 90)Epclusa + RBV 12 weeks
(n = 87) Epclusa 24 weeks
(n = 90) Total SVR12 83% (75/90) 94% (82/87) 86% (77/90) Genotype 188% (60/68) 96% (65/68) 92% (65/71) Genotype 1a 88% (44/50) 94% (51/54) 93% (51/55) Genotype 1b 89% (16/18) 100% (14/14)88% (14/16) Genotype 350% (7/14)85% (11/13)50% (6/12) Genotypes 2, 4, and 6100% (8/8)a100% (6/6)b86% (6/7)ca. For genotype 2, n = 4; for genotype 4, n = 4
b. For genotype 2, n = 4; for genotype 4, n = 2
c. For genotype 2, n = 4; for genotype 4, n = 2; and for genotype 6, n = 1.
Table 10 presents the virological results of patients with genotype 1 or 3 HCV infection from the ASTRAL4 study.
No virologic failure was observed in patients with genotype 2, 4, or 6 HCV infection.
Table 10: Virologic outcomes in genotype 1 and 3 HCV-infected patients in the ASTRAL4 study
Epclusa 12 weeks Epclusa + RBV 12 weeks Epclusa 24 weeks Virologic failure (relapse and treatment phase failure) Genotype 1a7% (5/68)1% (1/68)4% (3/71) Genotype 1a6% (3/50) 2% (1/54)4% (2/55) Genotype 1b11% (2/18)0% (0/14) 6% (1/16) Genotype 343% (6/14) 15% (2b/13) 42% (5c/12) Other d5% (4/82) 2% (2/81) 5% (4/83) a. No patient with genotype 1 HCV infection presented with treatment-phase virologic failure.
b. One patient experienced treatment-phase virologic failure; pharmacokinetic data for this patient were consistent with poor treatment adherence.
c. One patient with treatment-phase virologic failure.
d. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.
The parameter changes found in the CPT scoring system for patients achieving SVR12 in ASTRAL-4 (all 3 regimens) are shown in Table 11.
Table 11: Changes in CPT score parameters from baseline to weeks 12 and 24 post-treatment in patients achieving SVR12, ASTRAL-4
albumin bilirubin INR ascites hepatic encephalopathy at week 12 post-treatment (N=236), % (n/N) reduction (improvement) in scores 34.5%
(79/229) 17.9% (41/229) 2.2%
(5/229) 7.9% (18/229) 5.2% (12/229) No change 60.3% (138/229) 76.4% (175/229) 96.5% (221/229) 89.1% (204/229) 91.3% (209/229) Elevated (worsened) scores 5.2% (12/229) 5.7% ( 13/229) 1.3%
(3/229) 3.1%
(7/229) 3.5%
(8/229) Number of assessments7 7 7 7 7 7 Week 24 after treatment (N=236), % (n/N)
Reduction (improvement) in scores 39.4% (84/213) 16.4% (35/213) 2.3%
(5/213) 15.0% (32/213) 9.4% (20/213) No change 54.0% (115/213) 80.8% (172/213) 94.8% (202/213) 81.2% (173/213) 88.3% (188/213) Elevated (worsened) scores 6.6% (14/213) 2.8%
(6/213) 2.8%
(6/213) 3.8%
(8/213) 2.3%
(5/213) Number of assessments 23 23 23 23 23 23 Note: Baseline frequencies for ascites were: 20% non-existent, 77% mild/moderate, 3% severe
The baseline frequency of encephalopathy was 38% non-existent, 62% grade 1-2.
Clinical Study in HCV/HIV-1 Coinfected Patients – ASTRAL5 (Study 1202)
ASTRAL5 evaluated 12 weeks of Epclusa treatment in HCV-infected patients co-infected with HIV-1 genotypes 1, 2, 3, or 4 (HCV genotypes 5 and 6 were allowed, but no such patients were enrolled). Patients received stable HIV-1 antiretroviral therapy consisting of emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine in combination with a ritonavir-enhanced protease inhibitor (atazanavir, dirinavir, or lopinavir), rilpivirine, raltegravir, or emtricitabine/tenofovir disoproxil fumarate/aviraprevir/cobicistat.
Of the 106 patients treated, the median age was 57 years (range: 25 to 72); 86% were male; 51% were white; 45% were black; 22% had a baseline body mass index of at least 30 kg/m2; 19 patients (18%) had compensated cirrhosis; and 29% had received treatment. The overall mean CD4+ count was 598/μL (range: 183-1513/μL).
Table 12 shows the SVR12 of the ASTRAL5 study by HCV genotype.
Table 12: SVR12 in study ASTRAL5 by HCV genotype
Epclusa 12 weeks
(n = 106) Total
(all GTs)
(n = 106) GT1GT2
(n = 11) GT3
(n = 12) GT4
(n = 5) GT1a
(n = 66) GT1b
(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 treatment-phase virologic failure in patients who did not achieve SVR 0/106 0/66 0/12 0/78 0/11 0/12 0/5 Relapsea2%
(2/103) 3%
(2/65) 0/11 3%
(2/76) 0/11 0/11 0/5 Otherb3%
(3/106) 2%
(1/66) 8%
(1/12) 3%
(2/78) 0/11 8%
(1/12) 0/5 GT = genotype
a. Denominator for recurrence is the number of patients with HCV RNA < LLOQ at the last assessment during treatment.
b. Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.
All 19 patients with cirrhosis achieved SVR12. Patients with HIV-1 did not rebound during treatment and CD4+ counts remained stable during treatment.
Pharmacology and Toxicology]
Pharmacological effects
This product is a combination of sofosbuvir and vepatasvir.
Sofosbuvir is a hepatitis C non-structural protein 5B-dependent RNA polymerase inhibitor and a nucleotide drug precursor. The metabolite GS-461203 (uridine analogue triphosphate) is embedded in HCV RNA by NS5B polymerase and terminates replication. GS-461203 is neither a human DNA and RNA polymerase inhibitor nor a mitochondrial RNA polymerase inhibitor.
Vipatavir is a hepatitis C non-structural protein 5A-dependent RNA polymerase inhibitor, and in vitro resistance selection and cross-resistance studies suggest that the mechanism of action of vipatavir is targeting NS5A.
Antiviral activity
The 50% effective concentration (EC50) values of sofosbuvir and tipatavir against full-length or chimeric replicons encoding NS5B and NS5A sequences in laboratory isolates are shown in Table 13.
Table 13: Activity of Sofosbuvir and Vipatavir against full-length or chimeric laboratory replicons
Replicon genotype Sofosbuvir EC50, nMa Vipatavir EC50, nMa1a 40 0.014 1b 110 0.016 2a 50 0.0050.016c2b 15b0.0020.006c3a 50 0.004 4a 40 0.009 4d NA 0.004 5a 15b0.0210.054d6a 14b0.0060.009 6eNA 0.130dNA = not provided
a. Average of multiple experiments from replicates from the same laboratory.
b. Stable chimeric 1b replicons carrying the NS5B gene derived from genotypes 2b, 5a, or 6a were utilized in the assay.
c. Data were obtained from different isolates of the full-length NS5A replicon or different isolates of the chimeric NS5A replicon carrying the full-length NS5A gene containing the L31 or M31 polymorphism.
d. Data are from chimeric NS5A replicons carrying NS5A amino acid 9184.
Table 14: Replicon EC50 values of sofosbuvir and vepatavir against clinical isolates
Replicon genotype containing clinical isolate NS5B Number of replicons containing clinical isolate NS5A Number of replicons clinical isolate Sofosbuvir EC50
Median value, nM (range) Number of clinical isolates of Vipatavir EC50
Median value, nM (range) 1a 67 62 (29128) 23 0.019 (0.0110.078) 1b 29 102 (45170) 34 0.012 (0.0050.500) 2a 15 29 (1481) 8 0.011 (0.0060.364) 2b NA NA 16 0.002 (0.00030.007 ) 3a 106 81 (24181) 38 0.005 (0.0021.871) 4a NA NA 5 0.002 (0.0010.004) 4d NA NA 10 0.007 (0.0040.011) 4r NA NA 7 0.003 (0.0020.006) 5a NA NA 42 0.005 (0.0010. 019) 6a NA NA 26 0.007 (0.00050.113) 6e NA NA 15 0.024 (0.0050.433)) NA = not provided
A 40% human serum had no effect on the anti-HCV activity of sofosbuvir, but reduced the anti-HCV activity of vipatavir against the genotype 1a HCV replicon by 13-fold. Evaluation of sofosbuvir in combination with vepatavir showed no antagonistic effect in reducing replicon cell HCV RNA levels.
Toxicological studies
Sofosbuvir
Genotoxicity: Sofosbuvir Ames test, human peripheral blood lymphocyte chromosome aberration test, and mouse micronucleus test results were all negative.
Reproductive toxicity: Sofosbuvir did not affect embryo-fetal development or fertility in rats at doses of 20, 100, and 500 mg/kg/day, and exposure to the major circulating metabolite (GS-331007) at 500 mg/kg/day was approximately 8 times higher than exposure at human clinical doses. Exposure to GS-331007 in pregnant rats and rabbits increased with time of administration and was 5 to 10 and 12 to 28 times the human clinical dose, respectively. GS-331007 was secreted through milk and had no effect on fetuses.
Carcinogenicity: In a 2-year carcinogenicity test in mice and rats, sofosbuvir was administered at doses up to 600 mg/kg/day and 200 mg/kg/day in female and male mice, respectively, and 750 mg/kg/day in female and male rats, and no carcinogenicity was observed. GS-331007 exposure in mice was equivalent to 3 times (male) and 15 times (female) the human clinical dose exposure, and in rats was 7 (male) and 9 (female) times the human administered dose exposure.
Vipatavir
Genotoxicity: The results of the Ames test, human peripheral blood lymphocyte chromosome aberration test and rat micronucleus test were all negative.
Reproductive toxicity: Mating and fertility in rats were not affected by the doses of 20, 60, and 200 mg/kg/day of Vipatavir. In developmental toxicity studies in mice and rats, no teratogenic effects were observed when the AUC exposure to velpatasvir was approximately 31 and 6 times the human clinical dose exposure, respectively. Increased visceral malformations were observed in rabbits when the AUC exposure of vepatavir was equivalent to 0.7 times the human clinical dose exposure, suggesting a possible teratogenic effect, but the relevance to humans is unclear. In a perinatal toxicity study in rats, no effects on offspring behavior, reproduction, or development were observed when the AUC exposure to vepatavir was equivalent to five times the human clinical dose exposure. Vipatavir can be secreted through rat milk.
Carcinogenicity: The results of 104-week carcinogenicity test in SD rats and 27-week carcinogenicity test in RasH2 mice suggest that the administration of Vipatavir at doses of 20, 60 and 200 mg/kg in SD rats and 30, 100 and 1000 mg/kg in RasH2 transgenic mice did not show carcinogenicity.
Pharmacokinetics
Absorption
The pharmacokinetic properties of sofosbuvir, GS331007 and vepatavir were evaluated in healthy adult subjects and patients with chronic hepatitis C. Following oral administration of Epclusa, sofosbuvir was rapidly absorbed, with peak median plasma concentrations observed at 1 hour post-dose. Peak median plasma concentrations of GS331007 were observed at 3 hours post-dose. A peak median plasma concentration of vepatavir was observed 3 hours after dosing.
Based on a population pharmacokinetic analysis of HCV-infected patients, steady-state AUC024 was 1,260, 13,970, and 2,970 ng-h/mL for sofosbuvir (n = 982), GS331007 (n = 1,428), and vepatavir (n = 1,425), respectively. The steady-state Cmax for sofosbuvir and GS331007 were similar in healthy adult subjects and in HCV-infected patients. 37% and 41% lower than healthy subjects (n = 331) for AUC0-24 and Cmax, respectively, were observed for VIPATAV in HCV-infected patients.
Effect of food
Relative to the fasting condition, a single administration of Epclusa with a moderate fat meal (~600 kcal, 30% fat) or a high fat meal (~800 kcal, 50% fat) resulted in a 34% and 21% increase in the AUC0inf of vepatavir and a 31% and 5% increase in the Cmax of vepatavir, respectively. Moderate or high-fat meals increased sofosbuvir AUC0inf by 60% and 78%, respectively, but did not significantly affect sofosbuvir Cmax. moderate or high-fat meals did not change GS331007 AUC0inf but increased Cmax by 25% and 37%, respectively. Patients with HCV infection who took Epclusa with or without food had similar response rates in the phase 3 study. Epclusa can be given without food.
Distribution
Sofosbuvir binds to human plasma proteins at a rate of approximately 6165% over a range of 1 µg/mL to 20 µg/mL, independent of drug concentration. In human plasma, the protein binding of GS331007 was extremely low. After a single administration of 400 mg [14C]sofosbuvir to healthy subjects, the blood to plasma ratio of [14C]radioactivity was approximately 0.7.
The human plasma protein binding rate of vepatavir > 99.5% was independent of drug concentration at concentrations ranging from 0.09 µg/mL to 1.8 µg/mL. The blood to plasma ratio of [14C]radioactivity ranged from 0.52 to 0.67 after a single administration of 100 mg of [14C]vepatavir to healthy subjects.
Biotransformation
Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analogue triphosphate GS461203. The metabolic activation pathway includes sequential hydrolysis of the carboxylate ester fraction catalyzed by human histone A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleoside binding protein 1 (HINT1), followed by phosphorylation via the pyrimidine nucleotide phosphorylation via the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the nucleoside metabolite GS331007, which cannot be efficiently dephosphorylated and lacks in vitro anti-HCV activity. Sofosbuvir and GS331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes. Following a single oral administration of 400 mg of [14C]-sofosbuvir, GS331007 accounts for approximately more than 90% of total systemic exposure.
Vipatavir is a substrate for CYP2B6, CYP2C8, and CYP3A4 (with low conversion rates.) The majority (> 98%) of plasma radioactivity following a single administration of 100 mg [14C]-vipatavir is the parent drug. Mono-hydroxylated and demethylated-vipatavir are the metabolites identified in human plasma. Vipatavir in its prodrug form is the predominant type present in the feces.
Elimination
After a single oral administration of 400 mg of [14C]-sofosbuvir, the mean total recovery of [14C]-radioactivity was >92%, with approximately 80%, 14%, and 2.5% recovered in urine, feces, and breath, respectively. The majority of the sofosbuvir dose recovered in urine was GS331007 (78%), with an additional 3.5% recovered as sofosbuvir. The median terminal half-lives of sofosbuvir and GS331007 after Epclusa administration were 0.5 and 25 hours, respectively.
The mean total recovery of [14C]-radioactivity after a single oral administration of 100 mg of [14C]-vipatavir was 95%, with approximately 94% and 0.4% recovered in feces and urine, respectively. Vipatavir prodrug was the predominant type in feces, accounting for an average of 77% of the administered dose, followed by monohydroxylated vipatavir (5.9%) and demethylated vipatavir (3.0%). These data suggest that biliary excretion of the parent drug is the primary route of elimination of the drug, and that the median terminal half-life of the drug after Epclusa administration is approximately 15 hours.
Linear/non-linear
In the dose range of 25 mg to 150 mg, the AUC of tipatavir increases in a proportional manner to the dose. In the 200 mg to 1,200 mg dose range, sofosbuvir and GS331007 AUC are approximately proportional to the dose.
Sofosbuvir/vipatavir in vitro drug-drug interaction potential
Sofosbuvir and tipamivir are substrates for the drug transporters P-gp and BCRP, while GS331007 is not. Vipatavir is also a substrate for OATP1B. In vitro, a slow metabolic conversion of vipatavir through CYP2B6, CYP2C8 and CYP3A4 was observed.
Vipatavir is an inhibitor of the drug transporters P-gp, BCRP, OATP1B1 and OATP1B3, and its drug interactions with these transporters occur primarily during absorption. At clinically relevant plasma concentrations, vepatavir is not an inhibitor of the hepatic transporters bile salt export pump (BSEP), sodium taurocholate co-transport protein (NTCP), OATP2B1, OATP1A2 or organic cation transporter (OCT) 1, the renal transporters OCT2, OAT1, OAT3 or multidrug resistance-associated protein 2 (MRP2) or multidrug and toxin efflux transport protein (MATE) 1 or CYP or CYP. MATE) 1 or CYP or inhibitors of uridine glucuronosyltransferase (UGT) 1A1 enzymes.
Sofosbuvir and GS331007 are not inhibitors of the drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, and OCT1. GS331007 is not an inhibitor of OAT1, OCT2, or MATE1.
Pharmacokinetics in Special Populations
Race and gender
No clinically relevant pharmacokinetic differences due to race or gender were identified for sofosbuvir, GS331007, or vepatasvir.
Older Adults
Population pharmacokinetic analysis of HCV-infected patients showed no clinically relevant effect of age on sofosbuvir, GS331007, or vepatavir exposure within the age range analyzed (18 to 82 years).
Renal impairment
In HCV-negative patients with mild (eGFR ≥ 50 and < 80 mL/min/1.73 m2 ), moderate (eGFR ≥ 30 and < 50 mL/min/1.73 m2 ), and severe (eGFR < 30 mL/min/1.73 m2 ) renal impairment and ESRD requiring hemodialysis, a single dose of sofosbuvir at 400 mg The pharmacokinetics of sofosbuvir were studied after a single dose of sofosbuvir. Compared to patients with normal renal function (eGFR > 80 mL/min/1.73m2), sofosbuvir AUC0inf was 61%, 107% and 171% higher in patients with mild, moderate and severe renal impairment, respectively, and GS331007 AUC0inf was 55%, 88% and 451% higher, respectively. In ESRD patients, sofosbuvir AUC0inf was 28% higher when sofosbuvir was given 1 hour before hemodialysis, compared to 60% higher when sofosbuvir was given 1 hour after hemodialysis. GS331007 was effectively removed by hemodialysis with an extraction factor of approximately 53%. After a single dose of sofosbuvir 400 mg, hemodialysis removes 18% of the administered dose over 4 hours (see Dosage and Administration section).
The pharmacokinetics of tipatavir after a single dose of 100 mg tipatavir was studied in HCV-negative patients with severe renal impairment (eGFR < 30 mL/min according to the Cockcroft-Gault method). Vipatavir AUCinf was 50% higher in subjects with severe renal impairment compared to subjects with normal renal function (see [Dosage]).
Hepatic Impairment
The pharmacokinetics of sofosbuvir were studied after 7 days of 400 mg sofosbuvir administration in HCV-infected patients presenting with moderate and severe hepatic impairment (CPT classes B and C). The population pharmacokinetic analysis of HCV-infected patients showed no clinically relevant effect of cirrhosis (including decompensated cirrhosis) on sofosbuvir and GS331007 exposure. relevant effect.
The pharmacokinetics of tipatavir after a single dose of 100 mg tipatavir was studied in HCV-negative patients presenting with moderate and severe hepatic impairment (CPT classes B and C). The total plasma exposure (AUCinf) of vepatavir was similar in patients with moderate or severe hepatic impairment compared to subjects with normal liver function. population pharmacokinetic analysis in HCV-infected patients showed no clinically relevant effect of cirrhosis (including decompensated cirrhosis) on vepatavir exposure (see [Dosage]).
Body Weight
Based on population pharmacokinetic analysis, there was no clinically meaningful effect of body weight on sofosbuvir or vepatavir exposure.
Pediatric Population
The pharmacokinetics of sofosbuvir, GS331007, and vepatavir in pediatric patients have not been determined (see [DOSAGE AND ADMINISTRATION]).
Storage
Store at 30 °C or below.
Packaging
High-density polyethylene (HDPE) bottle with a polypropylene continuous threaded child-resistant cap with induction-activated aluminum foil liner, containing 28 film-coated tablets. Each bottle contains polyester packaging material.
Available in the following package sizes: 1 bottle per box, each bottle contains 28 tablets.
Expiration Date
24 months.
Execution Standard
Import registration standard: JX20170309.
Approval number
Imported drug registration certificate no.
[Manufacturer
Name: Gilead Sciences Ireland UC
Address: IDA Business and Technology Park, Carrigtohill, County Cork, Ireland
Tel: 00353 214825913
Fax: 00353 214825518
Adverse Drug Reaction Reports
Gilead (Shanghai) Pharmaceutical Technology Co.
Domestic contact name: Gilead (Shanghai) Pharmaceutical Technology Co.
Domestic contact address: 31F, No. 1198 Century Avenue, China (Shanghai) Pilot Free Trade Zone
Tel: 4008201135