Epclusa 400 mg/100 mg film-coated tablets.
Each film-coated tablet contains 400 mg sofosbuvir and 100 mg velpatasvir.
For the full list of excipients, see section 6.1.
Film-coated tablet.
Pink, diamond-shaped, film-coated tablet of dimensions 20 mm x 10 mm, debossed on one side with “GSI” and “7916” on the other side.
Epclusa is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults (see sections 4.2, 4.4 and 5.1).
Epclusa treatment should be initiated and monitored by a physician experienced in the management of patients with HCV infection.
Posology
The recommended dose of Epclusa is one tablet, taken orally, once daily with or without food (see section 5.2).
Table 1: Recommended treatment and duration for all HCV genotypes
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Patient populationa
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Treatment and duration
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Patients without cirrhosis and patients with compensated cirrhosis
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Epclusa for 12 weeks
Addition of ribavirin may be considered for genotype 3 infected patients with compensated cirrhosis (see section 5.1.)
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Patients with decompensated cirrhosis
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Epclusa + ribavirin for 12 weeks
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a. Includes patients co-infected with human immunodeficiency virus (HIV) and patients with recurrent HCV post-liver transplant (see section 4.4.).
When used in combination with ribavirin, refer also to the Summary of Product Characteristics of the medicinal product containing ribavirin.
The following dosing is recommended where ribavirin is divided in two daily doses and given with food:
Table 2: Guidance for ribavirin dosing when administered with Epclusa to patients with decompensated cirrhosis
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Patient
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Ribavirin Dose
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Child-Pugh-Turcotte (CPT) Class B cirrhosis pre-transplant
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1,000 mg per day for patients < 75 kg and 1,200 mg for those weighing ≥ 75 kg
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CPT Class C cirrhosis pre-transplant
CPT Class B or C post-transplant
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Starting dose of 600 mg, which can be titrated up to a maximum of 1,000/1,200 mg (1,000 mg for patients weighing < 75 kg and 1,200 mg for patients weighing ≥ 75 kg) if well tolerated. If the starting dose is not well tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels
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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).
For ribavirin dose modifications, refer to the Summary of Product Characteristics of the medicinal product containing ribavirin.
Patients should be instructed that if vomiting occurs within 3 hours of dosing an additional tablet of Epclusa should be taken. If vomiting occurs more than 3 hours after dosing, no further dose of Epclusa is needed (see section 5.1).
If a dose of Epclusa is missed and it is within 18 hours of the normal time, patients should be instructed to take the tablet as soon as possible and then patients should take the next dose at the usual time. If it is after 18 hours then patients should be instructed to wait and take the next dose of Epclusa at the usual time. Patients should be instructed not to take a double dose of Epclusa.
Patients who have previously failed therapy with an NS5A-containing regimen
Epclusa + ribavirin for 24 weeks may be considered (see section 4.4).
Elderly
No dose adjustment is warranted for elderly patients (see section 5.2).
Renal impairment
No dose adjustment of Epclusa is required for patients with mild or moderate renal impairment. The safety and efficacy of Epclusa has not been assessed in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or end stage renal disease (ESRD) requiring haemodialysis (see section 5.2).
Hepatic impairment
No dose adjustment of Epclusa is required for patients with mild, moderate, or severe hepatic impairment (CPT Class A, B, or C) (see section 5.2). Safety and efficacy of Epclusa have been assessed in patients with CPT Class B cirrhosis, but not in patients with CPT Class C cirrhosis (see sections 4.4, 4.8 and 5.1).
Paediatric population
The safety and efficacy of Epclusa in children and adolescents aged less than 18 years have not yet been established. No data are available.
Method of administration
For oral use.
Patients should be instructed to swallow the tablet whole with or without food (see section 5.2). Due to the bitter taste, it is recommended that the film-coated tablet is not chewed or crushed.
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Use with potent P-gp and potent CYP inducers
Medicinal products that are potent P-glycoprotein (P-gp) or potent cytochrome P450 (CYP) inducers (rifampicin, rifabutin, St. John's wort [Hypericum perforatum], carbamazepine, phenobarbital and phenytoin). Co-administration will significantly decrease sofosbuvir or velpatasvir plasma concentrations and could result in loss of efficacy of Epclusa (see section 4.5).
Epclusa should not be administered concurrently with other medicinal products containing sofosbuvir.
Severe bradycardia and heart block
Cases of severe bradycardia and heart block have been observed when sofosbuvir used in combination with another direct acting antiviral (DAA), is used with concomitant amiodarone with or without other medicinal products that lower heart rate. The mechanism is not established.
The concomitant use of amiodarone was limited through the clinical development of sofosbuvir plus DAAs. Cases are potentially life threatening, therefore amiodarone should only be used in patients on Epclusa when other alternative anti-arrhythmic treatments are not tolerated or are contraindicated.
Should concomitant use of amiodarone be considered necessary, it is recommended that patients are closely monitored when initiating Epclusa. Patients who are identified as being at high risk of bradyarrhythmia should be continuously monitored for 48 hours in an appropriate clinical setting.
Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Epclusa.
All patients receiving Epclusa in combination with amiodarone with or without other medicinal products that lower heart rate should also be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.
Patients who have previously failed therapy with an NS5A-containing regimen
There are no clinical data to support the efficacy of sofosbuvir/velpatasvir for the treatment of patients who have failed treatment with a regimen containing another NS5A inhibitor. However, on the basis of NS5A resistance associated variants (RAVs) typically seen in patients who have failed therapy with other NS5A inhibitor containing regimens, the in vitro pharmacology of velpatasvir, and the outcomes of sofosbuvir/velpatasvir treatment in NS5A-naïve patients with baseline NS5A RAVs enrolled into the ASTRAL-studies, treatment with Epclusa + RBV for 24 weeks can be considered for patients who have failed therapy on an NS5A-containing regimen and who are deemed at high risk for clinical disease progression and who do not have alternative treatment options.
Renal impairment
No dose adjustment of Epclusa is required for patients with mild or moderate renal impairment. The safety of Epclusa has not been assessed in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) or ESRD requiring haemodialysis. When Epclusa is used in combination with ribavirin refer also to the Summary of Product Characteristics for ribavirin for patients with creatinine clearance < 50 mL/min (see section 5.2).
Use with moderate P-gp inducers or moderate CYP inducers
Medicinal products that are moderate P-gp or moderate CYP inducers (e.g. oxcarbazepine, modafinil or efavirenz) may decrease sofosbuvir or velpatasvir plasma concentrations leading to reduced therapeutic effect of Epclusa. Co-administration of such medicinal products with Epclusa is not recommended (see section 4.5).
Use with certain HIV antiretroviral regimens
Epclusa has been shown to increase tenofovir exposure, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of Epclusa and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of Epclusa with the fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving Epclusa concomitantly with elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir-associated adverse reactions. Refer to tenofovir disoproxil fumarate, emtricitabine/tenofovir disoproxil fumarate, or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate Summary of Product Characteristics for recommendations on renal monitoring.
HCV/HBV (hepatitis B virus) co-infection
There are no data on the use of Epclusa in patients with HCV/HBV co-infection. Clearance of HCV may lead to increased replication of HBV in patients who are HCV/HBV co-infected. HBV levels should be monitored during treatment with Epclusa, and during post-treatment follow-up.
CPT Class C cirrhosis
Safety and efficacy of Epclusa has not been assessed in patients with CPT Class C cirrhosis (see sections 4.8 and 5.1).
Liver transplant patients
The safety and efficacy of Epclusa in the treatment of HCV infection in patients who are post-liver transplant have not been assessed. Treatment with Epclusa in accordance with the recommended posology (see section 4.2) should be guided by an assessment of the potential benefits and risks for the individual patient.
As Epclusa contains sofosbuvir and velpatasvir, any interactions that have been identified with these active substances individually may occur with Epclusa.
Potential for Epclusa to affect other medicinal products
Velpatasvir is an inhibitor of drug transporter P-gp, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration of Epclusa with medicinal products that are substrates of these transporters may increase the exposure of such medicinal products. See Table 3 for examples of interactions with sensitive substrates of P-gp (digoxin), BCRP (rosuvastatin), and OATP (pravastatin).
Potential for other medicinal products to affect Epclusa
Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP. Velpatasvir is also a substrate of drug transporter OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8 and CYP3A4 was observed. Medicinal products that are potent inducers of P-gp or potent inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. rifampicin, rifabutin, St. John's wort, carbamazepine, phenobarbital and phenytoin) may decrease plasma concentrations of sofosbuvir or velpatasvir leading to reduced therapeutic effect of sofosbuvir/velpatasvir. The use of such medicinal products with Epclusa is contraindicated (see section 4.3). Medicinal products that are moderate P-gp inducers or moderate CYP inducers (e.g. oxcarbazepine, modafinil or efavirenz) may decrease sofosbuvir or velpatasvir plasma concentration leading to reduced therapeutic effect of Epclusa. Co-administration with such medicinal products is not recommended with Epclusa (see section 4.4). Co-administration with medicinal products that inhibit P-gp or BCRP may increase sofosbuvir or velpatasvir plasma concentrations. Medicinal products that inhibit OATP, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir. Clinically significant medicinal product interactions with Epclusa mediated by P-gp, BCRP, OATP, or CYP450 inhibitors are not expected; Epclusa may be co-administered with P-gp, BCRP, OATP and CYP inhibitors.
Patients treated with vitamin K antagonists
As liver function may change during treatment with Epclusa, a close monitoring of International Normalised Ratio (INR) values is recommended.
Interactions between Epclusa and other medicinal products
Table 3 provides a listing of established or potentially clinically significant medicinal product interactions (where 90% confidence interval [CI] of the geometric least-squares mean [GLSM] ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined interaction boundaries). The medicinal product interactions described are based on studies conducted with either sofosbuvir/velpatasvir or velpatasvir and sofosbuvir as individual agents, or are predicted medicinal product interactions that may occur with sofosbuvir/velpatasvir. The table is not all-inclusive.
Table 3: Interactions between Epclusa and other medicinal products
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Medicinal product by therapeutic areas/Possible Mechanism of Interaction
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Effects on medicinal product levels.
Mean ratio (90% confidence interval)a,b
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Recommendation concerning co-administration with Epclusa
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Active
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Cmax
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AUC
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Cmin
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ACID REDUCING AGENTS
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Velpatasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease the concentration of velpatasvir.
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Antacids
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e.g. Aluminium or magnesium hydroxide; calcium carbonate
(Increase in gastric pH)
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Interaction not studied.
Expected.
↔ Sofosbuvir
↓ Velpatasvir
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It is recommended to separate antacid and Epclusa administration by 4 hours.
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H2-receptor antagonists
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Famotidine
(40 mg single dose)/ sofosbuvir/ velpatasvir (400/ 100 mg single dose)c
Famotidine dosed simultaneously with Epclusad
Cimetidinee
Nizatidinee
Ranitidinee
(Increase in gastric pH)
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Sofosbuvir
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