Sofosbuvir/Velpatasvir Tablets 400mg/100mg Taj Pharma

  1. Name of the medicinal product

Sofosbuvir/Velpatasvir 400mg/100mg film-coated tablets.

  1. Qualitative and quantitative composition

Each film-coated tablet contains 400mg sofosbuvir and 100mg velpatasvir.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Film-coated tablet.

  1. Clinical particulars

4.1 Therapeutic indications

Sofosbuvir/Velpatasvir is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults (see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

Sofosbuvir/Velpatasvir treatment should be initiated and monitored by a physician experienced in the management of patients with HCV infection.

Posology

The recommended dose of Sofosbuvir/Velpatasvir 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

 

Patient populationa Treatment and duration
Patients without cirrhosis and patients with compensated cirrhosis Sofosbuvir/Velpatasvir for 12 weeks

Addition of ribavirin may be considered for genotype 3 infected patients with compensated cirrhosis (see section 5.1.)

Patients with decompensated cirrhosis Sofosbuvir/Velpatasvir + ribavirin for 12 weeks

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 Sofosbuvir/Velpatasvir to patients with decompensated cirrhosis

Patient Ribavirin Dose
Child-Pugh-Turcotte (CPT) Class B cirrhosis pre-transplant 1,000mg per day for patients < 75 kg and 1,200mg for those weighing ≥ 75 kg
CPT Class C cirrhosis pre-transplant

CPT Class B or C post-transplant

Starting dose of 600mg, which can be titrated up to a maximum of 1,000/1,200mg (1,000mg for patients weighing < 75 kg and 1,200mg 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

If ribavirin is used in genotype 3 infected patients with compensated cirrhosis (pre- or post-transplant) the recommended dose of ribavirin is 1,000/1,200mg (1,000mg for patients weighing < 75 kg and 1,200mg 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 Sofosbuvir/Velpatasvir should be taken. If vomiting occurs more than 3 hours after dosing, no further dose of Sofosbuvir/Velpatasvir is needed (see section 5.1).

If a dose of Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir at the usual time. Patients should be instructed not to take a double dose of Sofosbuvir/Velpatasvir.

Patients who have previously failed therapy with an NS5A-containing regimen

Sofosbuvir/Velpatasvir + 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 Sofosbuvir/Velpatasvir is required for patients with mild or moderate renal impairment.

Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2)and end stage renal disease (ESRD) requiring haemodialysis. Sofosbuvir/Velpatasvir can be used in these patients with no dose adjustment when no other relevant treatment options are available (see section 4.4, 4.8, 5.1 and 5.2).

Hepatic impairment

No dose adjustment of Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir 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.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Use with strong P-gp and strong CYP inducers

Medicinal products that are strong P-glycoprotein (P-gp) and/or strong cytochrome P450 (CYP) inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John’s wort). Co-administration will significantly decrease sofosbuvir or velpatasvir plasma concentrations and could result in loss of efficacy of Sofosbuvir/Velpatasvir (see section 4.5).

4.4 Special warnings and precautions for use

Sofosbuvir/Velpatasvir 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-containing regimens are used in combination with 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. Cases are potentially life threatening, therefore amiodarone should only be used in patients on Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir. 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 Sofosbuvir/Velpatasvir.

All patients receiving Sofosbuvir/Velpatasvir 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.

HCV/HBV (hepatitis B virus) co-infection

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.

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 Sofosbuvir/Velpatasvir + 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

Safety data are limited in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Sofosbuvir/Velpatasvir can be used in these patients with no dose adjustment when no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Sofosbuvir/Velpatasvir 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 and/or moderate CYP inducers

Medicinal products that are moderate P-gp and/or moderate CYP inducers (e.g. efavirenz, modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir or velpatasvir plasma concentrations leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir. Co-administration of such medicinal products with Sofosbuvir/Velpatasvir is not recommended (see section 4.5).

Use with certain HIV antiretroviral regimens

Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir 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.

Use in diabetic patients

Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated.

CPT Class C cirrhosis

Safety and efficacy of Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir in the treatment of HCV infection in patients who are post-liver transplant have not been assessed. Treatment with Sofosbuvir/Velpatasvir 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.

4.5 Interaction with other medicinal products and other forms of interaction

As Sofosbuvir/Velpatasvir contains sofosbuvir and velpatasvir, any interactions that have been identified with these active substances individually may occur with Sofosbuvir/Velpatasvir.

Potential for Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir

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 strong inducers of P-gp and/or strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. carbamazepine, phenobarbital and phenytoin, rifampicin, rifabutin and St. John’s wort) may decrease plasma concentrations of sofosbuvir or velpatasvir leading to reduced therapeutic effect of sofosbuvir/velpatasvir. The use of such medicinal products with Sofosbuvir/Velpatasvir is contraindicated (see section 4.3). Medicinal products that are moderate P-gp inducers and/or moderate CYP inducers (e.g. efavirenz, modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir or velpatasvir plasma concentration leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir. Co-administration with such medicinal products is not recommended with Sofosbuvir/Velpatasvir (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 Sofosbuvir/Velpatasvir mediated by P-gp, BCRP, OATP, or CYP450 inhibitors are not expected; Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir, a close monitoring of International Normalised Ratio (INR) values is recommended.

Impact of DAA therapy on drugs metabolized by the liver

The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV.

Interactions between Sofosbuvir/Velpatasvir 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 Sofosbuvir/Velpatasvir and other medicinal products

Medicinal product by therapeutic areas/Possible Mechanism of Interaction Effects on medicinal product levels.

Mean ratio (90% confidence interval)a,b

Recommendation concerning co-administration with Sofosbuvir/Velpatasvir
Active Cmax AUC Cmin
ACID REDUCING AGENTS
Velpatasvir solubility decreases as pH increases. Medicinal products that increase gastric pH are expected to decrease the concentration of velpatasvir.
Antacids
e.g. Aluminium or magnesium hydroxide; calcium carbonate

(Increase in gastric pH)

Interaction not studied.

Expected.

↔ Sofosbuvir

↓ Velpatasvir

It is recommended to separate antacid and Sofosbuvir/Velpatasvir administration by 4 hours.
H2-receptor antagonists
Famotidine

(40mg single dose)/ sofosbuvir/ velpatasvir (400/ 100mg single dose)c

Famotidine dosed simultaneously with Sofosbuvir/Velpatasvird

Cimetidinee

Nizatidinee

Ranitidinee

(Increase in gastric pH)

Sofosbuvir H2-receptor antagonists may be administered simultaneously with or staggered from Sofosbuvir/Velpatasvir at a dose that does not exceed doses comparable to famotidine 40mg twice daily.
Velpatasvir

0.80 (0.70, 0.91)

0.81 (0.71, 0.91)

Famotidine

(40mg single dose)/ sofosbuvir/ velpatasvir (400/ 100mg single dose)c

Famotidine dosed 12 hours prior to Sofosbuvir/Velpatasvird

(Increase in gastric pH)

Sofosbuvir

0.77 (0.68, 0.87)

0.80 (0.73, 0.88)

Velpatasvir
Proton pump inhibitors
Omeprazole

(20mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg single dose fasted)c

Omeprazole dosed simultaneously with Sofosbuvir/Velpatasvird

Lansoprazolee

Rabeprazolee

Pantoprazolee

Esomeprazolee

(Increase in gastric pH)

Sofosbuvir

0.66 (0.55, 0.78)

0.71 (0.60, 0.83)

Co-administration with proton pump inhibitors is not recommended. If it is considered necessary to co-administer, then Sofosbuvir/Velpatasvir should be administered with food and taken 4 hours before proton pump inhibitor at max doses comparable to omeprazole 20mg.
Velpatasvir

0.63 (0.50, 0.78)

0.64 (0.52, 0.79)

Omeprazole

(20mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg single dose fed)c

Omeprazole dosed 4 hours after Sofosbuvir/Velpatasvird

(Increase in gastric pH)

Sofosbuvir

0.79 (0.68, 0.92)

Velpatasvir

0.67 (0.58, 0.78)

0.74 (0.63, 0.86)

ANTIARRHYTHMICS
Amiodarone Interaction not studied.

Effect on amiodarone, velpatasvir, and sofosbuvir concentrations unknown.

Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with Sofosbuvir/Velpatasvir (see sections 4.4 and 4.8).
Digoxin Interaction only studied with velpatasvir.

Expected:

↔ Sofosbuvir

Co-administration of Sofosbuvir/Velpatasvir with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended when co-administered with Sofosbuvir/Velpatasvir.
Digoxin (0.25mg single dose)f/ velpatasvir (100mg single dose)

(Inhibition of P-gp)

Effect on velpatasvir exposure not studied

Expected:

↔ Velpatasvir

Observed:

Digoxin

1.9 (1.7, 2.1)

1.3 (1.1, 1.6)

ANTICOAGULANTS
Dabigatran etexilate

(Inhibition of P-gp)

Interaction not studied.

Expected:

↑ Dabigatran

↔ Sofosbuvir

↔ Velpatasvir

Clinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is co-administered with Sofosbuvir/Velpatasvir. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure.
Vitamin K antagonists Interaction not studied Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Sofosbuvir/Velpatasvir.
ANTICONVULSANTS
Phenytoin

Phenobarbital

(Induction of P-gp and CYPs)

Interaction not studied.

Expected:

↓ Sofosbuvir

↓ Velpatasvir

Sofosbuvir/Velpatasvir is contraindicated with phenobarbital and phenytoin (see section 4.3).
Carbamazepine

(Induction of P-gp and CYPs)

Interaction not studied.

Expected:

↓ Velpatasvir

Sofosbuvir/Velpatasvir is contraindicated with carbamazepine (see section 4.3).
Observed:

Sofosbuvir

↓0.52 (0.43, 0.62) ↓ 0.52 (0.46, 0.59)
Oxcarbazepine

(Induction of P-gp and CYPs)

Interaction not studied.

Expected:

↓ Sofosbuvir

↓ Velpatasvir

Co-administration of Sofosbuvir/Velpatasvir with oxcarbazepine is expected to decrease the concentration of sofosbuvir and velpatasvir, leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir. Co-administration is not recommended (see section 4.4).
ANTIFUNGALS
Ketoconazole Interaction only studied with velpatasvir

Expected:

↔ Sofosbuvir

No dose adjustment of Sofosbuvir/Velpatasvir or ketoconazole is required.
Ketoconazole (200mg twice daily)/ velpatasvir (100mg single dose)d

(Inhibition of P-gp and CYPs)

Itraconazolee

Voriconazolee

Posaconazolee

Isavuconazolee

Effect on ketoconazole exposure not studied.

Expected:

↔ Ketoconazole

Observed:

Velpatasvir

1.3 (1.0, 1.6)

1.7 (1.4, 2.2)

ANTIMYCOBACTERIALS
Rifampicin (600mg once daily)/ sofosbuvir (400mg single dose)d

 

(Induction of P-gp and CYPs)

Effect on rifampicin exposure not studied.

Expected:

↔ Rifampicin

Sofosbuvir/Velpatasvir is contraindicated with rifampicin (see section 4.3).
Observed:

Sofosbuvir

0.23 (0.19, 0.29)

0.28 (0.24, 0.32)

Rifampicin (600mg once daily)/ velpatasvir (100mg single dose)

(Induction of P-gp and CYPs)

Effect on rifampicin exposure not studied.

Expected:

↔ Rifampicin

Observed:

Velpatasvir

0.29 (0.23, 0.37)

0.18 (0.15, 0.22)

Rifabutin

 

 

(Induction of P-gp and CYPs)

Interaction not studied.

Expected:

↓ Velpatasvir

Sofosbuvir/Velpatasvir is contraindicated with rifabutin (see section 4.3).
Observed:

Sofosbuvir

0.64 (0.53, 0.77)

0.76 (0.63, 0.91)

Rifapentine

(Induction of P-gp and CYPs)

Interaction not studied.

Expected:

↓ Sofosbuvir

↓ Velpatasvir

Co-administration of Sofosbuvir/Velpatasvir with rifapentine is expected to decrease the concentration of sofosbuvir and velpatasvir, leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir. Co-administration is not recommended (see section 4.4).
HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS
Tenofovir disoproxil fumarate Sofosbuvir/Velpatasvir has been shown to increase tenofovir exposure (P-gp-inhibition). The increase in tenofovir exposure (AUC and Cmax) was around 40-80% during co-treatment with Sofosbuvir/Velpatasvir and tenofovir disoproxil fumarate/emtricitabine as part of various HIV regimens.

Patients receiving tenofovir disoproxil fumarate and Sofosbuvir/Velpatasvir concomitantly should be monitored for adverse reactions associated with tenofovir disoproxil fumarate. Refer to the tenofovir disoproxil fumarate-containing product’s Summary of Product Characteristics for recommendations on renal monitoring (see section 4.4).

Efavirenz/ emtricitabine/ tenofovir disoproxil fumarate

(600/ 200/ 300mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg once daily)c, d

Efavirenz Co-administration of Sofosbuvir/Velpatasvir with efavirenz/ emtricitabine/ tenofovir disoproxil fumarate is expected to decrease the concentration of velpatasvir. Co-administration of Sofosbuvir/Velpatasvir with efavirenz-containing regimens is not recommended (see section 4.4).
Sofosbuvir

1.4 (1.1, 1.7)

Velpatasvir

0.53 (0.43, 0.64)

0.47 (0.39, 0.57)

0.43 (0.36, 0.52)

Emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate

(200/ 25/ 300mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg once daily)c, d

Rilpivirine No dose adjustment of Sofosbuvir/Velpatasvir or emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate is required.
Sofosbuvir
Velpatasvir
HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS
Atazanavir boosted with ritonavir (300/ 100mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg once daily)c, d Atazanavir

1.4 (1.2, 1.6)

No dose adjustment of Sofosbuvir/Velpatasvir, atazanavir (ritonavir boosted) or emtricitabine/ tenofovir disoproxil fumarate is required.
Ritonavir

1.3 (1.5, 1.4)

Sofosbuvir
Velpatasvir

1.6 (1.4, 1.7)

2.4 (2.2, 2.6)

4.0 (3.6, 4.5)

Darunavir boosted with ritonavir (800/ 100mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg once daily)c, d Darunavir No dose adjustment of Sofosbuvir/Velpatasvir, darunavir (ritonavir boosted) or emtricitabine/ tenofovir disoproxil fumarate is required.
Ritonavir
Sofosbuvir

0.62 (0.54, 0.71)

0.72 (0.66, 0.80)

Velpatasvir

0.76 (0.65, 0.89)

Lopinavir boosted with ritonavir (4x200mg/ 50mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg once daily)c, d Lopinavir No dose adjustment of Sofosbuvir/Velpatasvir, lopinavir (ritonavir boosted) or emtricitabine/ tenofovir disoproxil fumarate is required.
Ritonavir
Sofosbuvir

0.59 (0.49 0.71)

0.7 (0.6, 0.8)

Velpatasvir

0.70 (0.59, 0.83)

1.6 (1.4, 1.9)

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS
Raltegravir (400mg twice daily)g + emtricitabine/ tenofovir disoproxil fumarate (200/ 300mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg once daily)c, d Raltegravir

0.79 (0.42, 1.5)

No dose adjustment of Sofosbuvir/Velpatasvir, raltegravir or emtricitabine/ tenofovir disoproxil fumarate is required.
Sofosbuvir
Velpatasvir
Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide fumarate

(150/ 150/ 200/ 10mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg once daily)c, d

Elvitegravir No dose adjustment of Sofosbuvir/Velpatasvir or elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide fumarate is required.
Cobicistat

2.0 (1.7, 2.5)

Tenofovir alafenamide
Sofosbuvir

1.4 (1.2, 1.5)

Velpatasvir

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/ 300mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg once daily)c, d

Elvitegravir No dose adjustment of Sofosbuvir/Velpatasvir or elvitegravir/ cobicistat/ emtricitabine/ tenofovir disoproxil fumarate is required.
Cobicistat

1.7 (1.5, 1.9)

Sofosbuvir
Velpatasvir

1.4 (1.2, 1.5)

Dolutegravir (50mg once daily)/ sofosbuvir/ velpatasvir (400/ 100mg once daily) Dolutegravir No dose adjustment of Sofosbuvir/Velpatasvir or dolutegravir is required.
Sofosbuvir
Velpatasvir
HERBAL SUPPLEMENTS
St. John’s wort

(Induction of P-gp and CYPs)

Interaction not studied.

Expected:

↓ Sofosbuvir

↓ Velpatasvir

Sofosbuvir/Velpatasvir is contraindicated with St. John’s wort (see section 4.3).
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin (40mg single dose) + sofosbuvir / velpatasvir (400/ 100mg once daily)d Observed:

Atorvastatin

1.7 (1.5, 1.9)

1.5 (1.5, 1.6)

No dose adjustment of Sofosbuvir/Velpatasvir or atorvastatin is required.
Rosuvastatin Interaction only studied with velpatasvir

Expected:

↔ Sofosbuvir

Co-administration of Sofosbuvir/Velpatasvir with rosuvastatin increases the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Rosuvastatin, at a dose that does not exceed 10mg, may be administered with Sofosbuvir/Velpatasvir.
Rosuvastatin (10mg single dose)/ velpatasvir (100mg once daily)d

(Inhibition of OATP1B and BCRP)

Observed:

Rosuvastatin

2.6 (2.3, 2.9)

2.7 (2.5, 2.9)

Effect on velpatasvir exposure not studied

Expected:

↔ Velpatasvir

Pravastatin Interaction only studied with velpatasvir

Expected:

↔ Sofosbuvir

No dose adjustment of Sofosbuvir/Velpatasvir or pravastatin is required.
Pravastatin (40mg single dose)/ velpatasvir (100mg once daily)d

(Inhibition of OATP1B)

Observed:

Pravastatin

1.3 (1.1, 1.5)

1.4 (1.2, 1.5)

Effect on velpatasvir exposure not studied

Expected:

↔ Velpatasvir

Other statins Expected:

↑ Statins

Interactions cannot be excluded with other HMG-CoA reductase inhibitors. When co-administered with Sofosbuvir/Velpatasvir, careful monitoring for statin adverse reactions should be undertaken and a reduced dose of statins should be considered if required.
NARCOTIC ANALGESICS
Methadone

(Methadone maintenance therapy [30 to 130mg daily])/ sofosbuvir (400mg once daily)d

R-methadone No dose adjustment of Sofosbuvir/Velpatasvir or methadone is required.
S-methadone
Sofosbuvir

1.3 (1.0, 1.7)

Methadone Interaction only studied with sofosbuvir

Expected:

↔ Velpatasvir

IMMUNOSUPPRESSANTS
Ciclosporin

(600mg single dose)/ sofosbuvir (400mg single dose)f

Ciclosporin No dose adjustment of Sofosbuvir/Velpatasvir or ciclosporin is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of ciclosporin may be required.
Sofosbuvir

2.5 (1.9, 3.5)

4.5 (3.3, 6.3)

Ciclosporin

(600mg single dose)f/ velpatasvir (100mg single dose)d

Ciclosporin

0.88 (0.78, 1.0)

Velpatasvir

1.6 (1.2, 2.0)

2.0 (1.5, 2.7)

Tacrolimus

(5mg single dose)f/ sofosbuvir (400mg single dose)d

Tacrolimus

0.73 (0.59, 0.90)

1.1 (0.84, 1.4)

No dose adjustment of Sofosbuvir/Velpatasvir or tacrolimus is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required.
Sofosbuvir

0.97 (0.65, 1.4)

1.1 (0.81, 1.6)

Tacrolimus Effect on velpatasvir exposure not studied.

Expected:

↔ Velpatasvir

ORAL CONTRACEPTIVES
Norgestimate/ ethinyl estradiol (norgestimate 0.180mg/ 0.215mg/ 0.25mg/ ethinyl estradiol 0.025mg)/ sofosbuvir (400mg once daily)d Norel-gestromin No dose adjustment of oral contraceptives is required.
Norgestrel

1.2 (0.98, 1.5)

1.2 (1.0, 1.5)

Ethinyl estradiol
Norgestimate/ ethinyl estradiol (norgestimate 0.180mg/ 0.215mg/ 0.25mg/ ethinyl estradiol 0.025mg)/ velpatasvir (100mg once daily)d Norel-gestromin
Norgestrel
Ethinyl estradiol

1.4 (1.2, 1.7)

0.83 (0.65, 1.1)

a Mean ratio (90% CI) of co-administered drug pharmacokinetics of study medicinal products alone or in combination. No effect = 1.00.

b All interaction studies conducted in healthy volunteers.

c Administered as Sofosbuvir/Velpatasvir.

d Lack of pharmacokinetics interaction bounds 70-143%.

e These are medicinal products within class where similar interactions could be predicted.

f Bioequivalence/Equivalence boundary 80-125%.

g Lack of pharmacokinetics interaction bounds 50-200%.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir, velpatasvir or Sofosbuvir/Velpatasvir in pregnant women.

Sofosbuvir

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

It has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3).

Velpatasvir

Animal studies have shown a possible link to reproductive toxicity (see section 5.3).

As a precautionary measure, Sofosbuvir/Velpatasvir use is not recommended during pregnancy.

Breast-feeding

It is unknown whether sofosbuvir, metabolites of sofosbuvir or velpatasvir are excreted in human milk.

Available pharmacokinetic data in animals have shown excretion of velpatasvir and metabolites of sofosbuvir in milk.

A risk to the newborns/infants cannot be excluded. Therefore, Sofosbuvir/Velpatasvir should not be used during breast-feeding.

Fertility

No human data on the effect of Sofosbuvir/Velpatasvir on fertility are available. Animal studies do not indicate harmful effects of sofosbuvir or velpatasvir on fertility.

If ribavirin is co-administered with Sofosbuvir/Velpatasvir, refer to the Summary of Product Characterisitics for ribavirin for detailed recommendations regarding pregnancy, contraception, and breast-feeding.

4.7 Effects on ability to drive and use machines

Sofosbuvir/Velpatasvir has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The safety assessment of Sofosbuvir/Velpatasvir was based on pooled Phase 3 clinical study data from patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection (with or without compensated cirrhosis) including 1,035 patients who received Sofosbuvir/Velpatasvir for 12 weeks.

The proportion of patients who permanently discontinued treatment due to adverse events was 0.2% and the proportion of patients who experienced any severe adverse events was 3.2% for patients receiving Sofosbuvir/Velpatasvir for 12 weeks. In clinical studies, headache, fatigue and nausea were the most common (incidence ≥ 10%) treatment emergent adverse events reported in patients treated with 12 weeks of Sofosbuvir/Velpatasvir. These and other adverse events were reported at a similar frequency in placebo treated patients compared with Sofosbuvir/Velpatasvir treated patients.

Patients with decompensated cirrhosis

The safety profile of Sofosbuvir/Velpatasvir has been evaluated in one open-label study in which patients with CPT Class B cirrhosis received Sofosbuvir/Velpatasvir for 12 weeks (n = 90), Sofosbuvir/Velpatasvir + RBV for 12 weeks (n = 87) or Sofosbuvir/Velpatasvir for 24 weeks (n = 90). The adverse events observed were consistent with expected clinical sequelae of decompensated liver disease, or the known toxicity profile of ribavirin for patients receiving Sofosbuvir/Velpatasvir in combination with ribavirin.

Among the 87 patients who were treated with Sofosbuvir/Velpatasvir + RBV for 12 weeks, decreases in haemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were experienced by 23% and 7% patients, respectively. Ribavirin was discontinued in 15% of patients treated with Sofosbuvir/Velpatasvir + RBV for 12 weeks due to adverse events.

Patients with renal impairment

The safety of Sofosbuvir/Velpatasvir has been evaluated in a 12-week non-controlled study including 59 subjects with ESRD requiring dialysis (Study 4062). In this setting, exposure of sofosbuvir metabolite GS-331007 was 20-fold increased, exceeding levels where adverse reactions have been observed in preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not clearly elevated from what is expected in ESRD patients.

Description of selected adverse reactions

Cardiac arrhythmias

Cases of severe bradycardia and heart block have been observed when sofosbuvir-containing regimens are used in combination with amiodarone and/or other medicinal products that lower heart rate (see sections 4.4 and 4.5).

Skin disorders

Frequency not known: Stevens-Johnson syndrome

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:

4.9 Overdose

The highest documented doses of sofosbuvir and velpatasvir were a single dose of 1,200mg and a single dose of 500mg, respectively. In these healthy volunteer studies, there were no untoward effects observed at these dose levels, and adverse events were similar in frequency and severity to those reported in the placebo groups. The effects of higher doses/exposures are not known.

No specific antidote is available for overdose with Sofosbuvir/Velpatasvir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sofosbuvir/Velpatasvir consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient. Haemodialysis can efficiently remove the predominant circulating metabolite of sofosbuvir, GS-331007, with an extraction ratio of 53%. Haemodialysis is unlikely to result in significant removal of velpatasvir, since velpatasvir is highly bound to plasma protein.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Direct acting antiviral

Mechanism of action

Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Velpatasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. In vitro resistance selection and cross-resistance studies indicate velpatasvir targets NS5A as its mode of action.

Antiviral activity

The 50% effective concentration (EC50) values of sofosbuvir and velpatasvir against full-length or chimeric replicons encoding NS5B and NS5A sequences from the laboratory strains are presented in Table 4. The EC50 values of sofosbuvir and velpatasvir against clinical isolates are presented in Table 5.

Table 4: Activity of sofosbuvir and velpatasvir against full-length or chimeric laboratory replicons

Replicon genotype Sofosbuvir EC50, nMa Velpatasvir EC50, nMa
1a 40 0.014
1b 110 0.016
2a 50 0.005-0.016c
2b 15b 0.002-0.006c
3a 50 0.004
4a 40 0.009
4d NA 0.004
5a 15b 0.021-0.054d
6a 14b 0.006-0.009
6e NA 0.130d

NA = Not available

a Mean value from multiple experiments of same laboratory replicon.

b Stable chimeric 1b replicons carrying NS5B genes from genotype 2b, 5a or 6a were used for testing.

c Data from various strains of full length NS5A replicons or chimeric NS5A replicons carrying full-length NS5A genes that contain L31 or M31 polymorphisms.

d Data from a chimeric NS5A replicon carrying NS5A amino acids 9-184.

Table 5: Activity of sofosbuvir and velpatasvir against transient replicons containing NS5A or NS5B from clinical isolates

Replicon genotype Replicons containing NS5B from clinical isolates Replicons containing NS5A from clinical isolates
Number of clinical isolates Median sofosbuvir EC50, nM (range) Number of clinical isolates Median velpatasvir EC50, nM (range)
1a 67 62 (29-128) 23 0.019 (0.011-0.078)
1b 29 102 (45-170) 34 0.012 (0.005-0.500)
2a 15 29 (14-81) 8 0.011 (0.006-0.364)
2b NA NA 16 0.002 (0.0003-0.007)
3a 106 81 (24-181) 38 0.005 (0.002-1.871)
4a NA NA 5 0.002 (0.001-0.004)
4d NA NA 10 0.007 (0.004-0.011)
4r NA NA 7 0.003 (0.002-0.006)
5a NA NA 42 0.005 (0.001-0.019)
6a NA NA 26 0.007 (0.0005-0.113)
6e NA NA 15 0.024 (0.005-0.433))

NA = Not available

The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir but reduced the anti-HCV activity of velpatasvir by 13-fold against genotype 1a HCV replicons.

Evaluation of sofosbuvir in combination with velpatasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Resistance

In cell culture

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of genotype 1 to 6 conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, the ability of the active triphosphate of sofosbuvir (GS-461203) to inhibit recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution was reduced compared to its ability to inhibit wild-type recombinant NS5B polymerase, as indicated by a 8.5- to 24-fold increase in the 50% inhibitory concentration (IC50).

In vitro selection of HCV replicons with reduced susceptibility to velpatasvir was performed in cell culture for multiple genotypes including 1a, 1b, 2a, 3a, 4a, 5a and 6a. Variants were selected at NS5A resistance associated positions 24, 28, 30, 31, 32, 58, 92 and 93. The resistance associated variants (RAVs) selected in 2 or more genotypes were F28S, L31I/V and Y93H. Site-directed mutagenesis of known NS5A RAVs showed that substitutions conferring a > 100-fold reduction in velpatasvir susceptibility are M28G, A92K and Y93H/N/R/W in genotype 1a, A92K in genotype 1b, C92T and Y93H/N in genotype 2b, Y93H in genotype 3, and L31V and P32A/L/Q/R in genotype 6. No individual substitutions tested in genotypes 2a, 4a, or 5a conferred a > 100-fold reduction in velpatasvir susceptibility. Combinations of these variants often showed greater reductions in susceptibility to velpatasvir than single RAVs alone.

In clinical studies

Studies in patients without cirrhosis and patients with compensated cirrhosis

In a pooled analysis of patients without cirrhosis or with compensated cirrhosis who received Sofosbuvir/Velpatasvir for 12 weeks in three Phase 3 studies, 12 patients (2 with genotype 1 and 10 with genotype 3) qualified for resistance analysis due to virologic failure. One additional patient with genotype 3 HCV infection at baseline was reinfected with genotype 1a HCV at virologic failure and was excluded from the virological analysis. No patients with genotype 2, 4, 5, or 6 HCV infection experienced virologic failure.

Of the 2 genotype 1 virologic failure patients, one patient had virus with emergent NS5A RAV Y93N and the other patient had virus with emergent NS5A RAVs L31I/V and Y93H at virologic failure. Both patients had virus at baseline harboring NS5A RAVs. No NS5B nucleoside inhibitor (NI) RAVs were observed at failure in the 2 patients.

Of the 10 genotype 3 virologic failure patients, Y93H was observed in all 10 patients at failure (6 had Y93H emerge post-treatment and 4 patients had Y93H at baseline and post-treatment). No NS5B NI RAVs were observed at failure in the 10 patients.

Studies in patients with decompensated cirrhosis

In one Phase 3 study in patients with decompensated cirrhosis who received Sofosbuvir/Velpatasvir + RBV for 12 weeks, 3 patients (1 with genotype 1 and 2 with genotype 3) qualified for resistance analysis due to virologic failure. No patients with genotype 2 or 4 HCV infection in the Sofosbuvir/Velpatasvir + RBV 12 weeks group experienced virologic failure.

The 1 virologic failure patient with genotype 1 HCV had no NS5A or NS5B RAVs at failure.

Of the 2 genotype 3 virologic failure patients, one had NS5A RAV Y93H emerge at failure. Another patient had virus with Y93H at baseline and virologic failure and also developed low levels (< 5%) of NS5B NI RAVs N142T and E237G at failure. Pharmacokinetic data from this patient was consistent with non-adherence to treatment.

In this study, 2 patients treated with Sofosbuvir/Velpatasvir for 12 or 24 weeks without ribavirin had emergent NS5B S282T at low levels (< 5%) along with L159F.

Effect of baseline HCV resistance-associated variants on treatment outcome

Studies in patients without cirrhosis and patients with compensated cirrhosis

Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients without cirrhosis or with compensated cirrhosis in three Phase 3 clinical studies (ASTRAL-1, ASTRAL-2 and ASTRAL-3). Of the 1,035 patients treated with sofosbuvir/velpatasvir in the three Phase 3 clinical studies, 1,023 patients were included in the analysis of NS5A RAVs; 7 patients were excluded as they neither achieved sustained virologic response (SVR12) nor had virologic failure and 5 additional patients were excluded as NS5A gene sequencing failed. In the pooled analysis of the Phase 3 studies, 380/1,023 (37%) patients’ virus had baseline NS5A RAVs. Genotype 2, 4, and 6 HCV-infected patients had a higher prevalence of NS5A RAVs (70%, 63% and 52%, respectively) compared to genotype 1 (23%), genotype 3 (16%), and genotype 5 (18%) HCV-infected patients.

Baseline RAVs had no relevant impact on SVR12 rates in patients infected with genotype 1, 2, 4, 5 and 6 HCV, as summarised in Table 6. Genotype 3 infected patients with the NS5A RAV Y93H at baseline had a lower SVR12 rate than patients without Y93H after treatment with Sofosbuvir/Velpatasvir for 12 weeks, as summarised in Table 7. In the ASTRAL-3 study, the Y93H RAV was detected at baseline in 9% of patients treated with Sofosbuvir/Velpatasvir.

Table 6: SVR12 in patients with or without baseline NS5A RAVs by HCV genotype (studies ASTRAL-1, ASTRAL-2 and ASTRAL-3)

Sofosbuvir/Velpatasvir 12 weeks
Genotype 1 Genotype 3 Genotypes 2, 4, 5 or 6 Total
With any baseline NS5A RAVs 97% (73/75) 88% (38/43) 100% (262/262) 98% (373/380)
Without baseline NS5A RAVs 100% (251/251) 97% (225/231) 100% (161/161) 99% (637/643)

Table 7: SVR12 in patients with and without baseline Y93H, 1% Cut-off (Resistance Analysis Population Set) ASTRAL 3

Sofosbuvir/Velpatasvir 12 Weeks
All Subjects

(n=274)

Cirrhotic

(n=80)

Non-Cirrhotic

(n=197)

Overall 95.3% (263/274) 91.3% (73/80) 97.9% (190/194)
95% CI 92.9% to 98.0% 82.8% to 96.4% 92.8% to 98.6%
SVR with Y93H 84.0% (21/25) 50.0% (2/4) 90.5% (19/21)
95% CI 63.9% to 95.5% 6.8% to 93.2% 69.6% to 98.8%
SVR without Y93H 96.4% (242/249) 93.4% (71/76) 98.8% (171/173)
95% CI 94.3% to 98.9% 85.3% to 97.8% 95.9% to 99.9%

The NS5B NI RAV S282T was not detected in the baseline NS5B sequence of any patient in Phase 3 studies. SVR12 was achieved in all 77 patients who had baseline NS5B NI RAVs including N142T, L159F, E/N237G, C/M289L/I, L320F/I/V, V321A/I, and S282G+V321I.

Studies in patients with decompensated cirrhosis (CPT Class B)

Analyses were conducted to explore the association between pre-existing baseline NS5A RAVs and treatment outcome for patients with decompensated cirrhosis in one Phase 3 study (ASTRAL-4). Of the 87 patients treated with Sofosbuvir/Velpatasvir + RBV, 85 patients were included in the analysis of NS5A RAVs; 2 patients were excluded as they neither achieved SVR12 nor had virologic failure. Among the patients who received treatment with Sofosbuvir/Velpatasvir + RBV for 12 weeks, 29% (25/85) of patients had baseline virus with NS5A RAVs: 29% (19/66), 75% (3/4), 15% (2/13), and 50% (1/2) for patients with genotype 1, 2, 3 and 4 HCV, respectively.

SVR12 in patients with or without baseline NS5A RAVs in the Sofosbuvir/Velpatasvir + RBV 12 week group for this study is shown in Table 8.

Table 8: SVR12 in patients with or without baseline NS5A RAVs by HCV genotype (study ASTRAL-4)

Sofosbuvir/Velpatasvir + RBV 12 weeks
Genotype 1 Genotype 3 Genotypes 2 or 4 Total
With any baseline NS5A RAVs 100% (19/19) 50% (1/2) 100% (4/4) 96% (24/25)
Without baseline NS5A RAVs 98% (46/47) 91% (10/11) 100% (2/2) 98% (58/60)

The single genotype 3 patient who had baseline NS5A RAVs and failed to achieve SVR12 had NS5A substitution Y93H at baseline; pharmacokinetic data from this patient was consistent with non-adherence to treatment.

Three patients in the Sofosbuvir/Velpatasvir + RBV 12 week group had baseline NS5B NI RAVs (N142T and L159F) and all three patients achieved SVR12.

Cross-resistance

In vitro data suggests that the majority of NS5A RAVs that confer resistance to ledipasvir and daclatasvir remained susceptible to velpatasvir. Velpatasvir was fully active against the sofosbuvir resistance-associated substitution S282T in NS5B while all velpatasvir resistance-associated substitutions in NS5A were fully susceptible to sofosbuvir. Both sofosbuvir and velpatasvir were fully active against substitutions associated with resistance to other classes of direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors and NS3 protease inhibitors. The efficacy of Sofosbuvir/Velpatasvir has not been assessed in patients who have previously failed treatment with other regimens that include an NS5A inhibitor.

Clinical efficacy and safety

The efficacy of Sofosbuvir/Velpatasvir was evaluated in three Phase 3 studies in patients with genotype 1 to 6 HCV infection with or without compensated cirrhosis, one Phase 3 study in patients with genotype 1 to 6 HCV infection with decompensated cirrhosis, one Phase 3 study in HCV/HIV-1 co-infected patients with genotype 1 to 6 HCV infection and one Phase 2 trial in patients with HCV infection and ESRD requiring dialysis, as summarised in Table 9.

Table 9: Studies conducted with Sofosbuvir/Velpatasvir in patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection

Study Population Study arms

(Number of patients treated)

ASTRAL-1 Genotype 1, 2, 4, 5 and 6

TN and TE, without cirrhosis or with compensated cirrhosis

Sofosbuvir/Velpatasvir 12 weeks (624)

Placebo 12 weeks (116)

ASTRAL-2 Genotype 2

TN and TE, without cirrhosis or with compensated cirrhosis

Sofosbuvir/Velpatasvir 12 weeks (134)

SOF+RBV 12 weeks (132)

ASTRAL-3 Genotype 3

TN and TE, without cirrhosis or with compensated cirrhosis

Sofosbuvir/Velpatasvir 12 weeks (277)

SOF+RBV 24 weeks (275)

ASTRAL-4 Genotype 1, 2, 3, 4, 5 and 6

TN and TE, with CPT Class B decompensated cirrhosis

Sofosbuvir/Velpatasvir 12 weeks (90)

Sofosbuvir/Velpatasvir + RBV 12 weeks (87)

Sofosbuvir/Velpatasvir 24 weeks (90)

ASTRAL-5 Genotype 1, 2, 3, 4, 5 and 6

TN and TE, without cirrhosis or with compensated cirrhosis, with HCV/HIV-1 co-infection

Sofosbuvir/Velpatasvir 12 weeks (106)
GS-US-342-4062 TN and TE with or without cirrhosis, with ESRD requiring dialysis Sofosbuvir/Velpatasvir 12 weeks (59)

TN = treatment-naïve patients; TE = treatment-experienced patients (including those who have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor)

The ribavirin dose was weight-based (1,000mg daily administered in two divided doses for patients < 75 kg and 1,200mg for those ≥ 75 kg) and administered in two divided doses when used in combination with sofosbuvir in the ASTRAL-2 and ASTRAL-3 studies or in combination with Sofosbuvir/Velpatasvir in the ASTRAL-4 study. Ribavirin dose adjustments were performed according to the ribavirin prescribing information. Serum HCV RNA values were measured during the clinical studies using the COBAS AmpliPrep/COBAS Taqman HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL. Sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the cessation of treatment, was the primary endpoint to determine the HCV cure rate.

Clinical studies in patients without cirrhosis and patients with compensated cirrhosis

Genotype 1, 2, 4, 5 and 6 HCV-infected adults – ASTRAL-1 (study 1138)

ASTRAL-1 was a randomised, double-blind, placebo-controlled study that evaluated 12 weeks of treatment with Sofosbuvir/Velpatasvir compared with 12 weeks of placebo in patients with genotype 1, 2, 4, 5, or 6 HCV infection. Patients with genotype 1, 2, 4 or 6 HCV infection were randomised in a 5:1 ratio to treatment with Sofosbuvir/Velpatasvir for 12 weeks or placebo for 12 weeks. Patients with genotype 5 HCV infection were enrolled to the Sofosbuvir/Velpatasvir group. Randomisation was stratified by HCV genotype (1, 2, 4, 6, and indeterminate) and the presence or absence of cirrhosis.

Demographics and baseline characteristics were balanced between the Sofosbuvir/Velpatasvir and placebo group. Of the 740 treated patients, the median age was 56 years (range: 18 to 82); 60% of the patients were male; 79% were White, 9% were Black; 21% had a baseline body mass index of at least 30 kg/m2; the proportions of patients 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 of at least 800,000 IU/mL; 19% had compensated cirrhosis; and 32% were treatment-experienced.

Table 10 presents the SVR12 for the ASTRAL-1 study by HCV genotypes. No patients in the placebo group achieved SVR12.

Table 10: SVR12 in study ASTRAL-1 by HCV genotype

Sofosbuvir/Velpatasvir 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)

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 patients without SVR12
On-treatment virologic failure 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
Otherb 1%

(4/624)

1%

(3/210)

0/118 1%

(3/328)

0/104 0/116 3%

(1/35)

0/41

GT = genotype

a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

Genotype 2 HCV-infected adults – ASTRAL-2 (study 1139)

ASTRAL-2 was a randomised, open-label study that evaluated 12 weeks of treatment with Sofosbuvir/Velpatasvir compared with 12 weeks of treatment with SOF+RBV in patients with genotype 2 HCV infection. Patients were randomised in a 1:1 ratio to treatment with Sofosbuvir/Velpatasvir for 12 weeks or SOF+RBV for 12 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve versus treatment-experienced).

Demographics and baseline characteristics were balanced across the two treatment groups. Of the 266 treated patients, the median age was 58 years (range: 23 to 81); 59% of the patients were male; 88% were White, 7% were Black; 33% had a baseline body mass index of at least 30 kg/m2; 62% had non-CC IL28B alleles (CT or TT); 80% had baseline HCV RNA levels of at least 800,000 IU/mL; 14% had compensated cirrhosis and 15% were treatment-experienced.

Table 11 presents the SVR12 for the ASTRAL-2 study.

Table 11: SVR12 in study ASTRAL-2 (HCV genotype 2)

Sofosbuvir/Velpatasvir

12 weeks

(n = 134)

SOF+RBV

12 weeks

(n = 132)

SVR12 99% (133/134) 94% (124/132)
Outcome for patients without SVR12
On-treatment virologic failure 0/134 0/132
Relapsea 0/133 5% (6/132)
Otherb 1% (1/134) 2% (2/132)

a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

Treatment with Sofosbuvir/Velpatasvir for 12 weeks demonstrated the statistical superiority (p = 0.018) over treatment with SOF+RBV for 12 weeks (treatment difference +5.2%; 95% confidence interval: +0.2% to +10.3%).

Genotype 3 HCV-infected adults – ASTRAL-3 (study 1140)

ASTRAL-3 was a randomised, open-label study that evaluated 12 weeks of treatment with Sofosbuvir/Velpatasvir compared with 24 weeks of treatment with SOF+RBV in patients with genotype 3 HCV infection. Patients were randomised in a 1:1 ratio to treatment with Sofosbuvir/Velpatasvir for 12 weeks or SOF+RBV for 24 weeks. Randomisation was stratified by the presence or absence of cirrhosis and prior treatment experience (treatment-naïve versus treatment-experienced).

Demographics and baseline characteristics were balanced across the two treatment groups. Of the 552 treated patients, the median age was 52 years (range: 19 to 76); 62% of the patients were male; 89% were White, 9% were Asian; 1% were Black; 20% had a baseline body mass index of at least 30 kg/m2; 61% had non-CC IL28B alleles (CT or TT); 70% had baseline HCV RNA levels of at least 800,000 IU/mL, 30% had compensated cirrhosis and 26% were treatment-experienced.

Table 12 presents the SVR12 for the ASTRAL-3 study.

Table 12: SVR12 in study ASTRAL-3 (HCV genotype 3)

Sofosbuvir/Velpatasvir 12 weeks

(n = 277)

SOF+RBV

24 weeks

(n = 275)

SVR12 95% (264/277) 80% (221/275)
Outcome for patients without SVR12
On-treatment virologic failure 0/277 < 1% (1/275)
Relapsea 4% (11/276) 14% (38/272)
Otherb 1% (2/277) 5% (15/275)

a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

Treatment with Sofosbuvir/Velpatasvir for 12 weeks demonstrated the statistical superiority (p < 0.001) compared to treatment with SOF+RBV for 24 weeks (treatment difference +14.8%; 95% confidence interval: +9.6% to +20.0%).

SVR12 for selected subgroups are presented in Table 13.

Table 13: SVR12 for selected subgroups in study ASTRAL-3 (HCV genotype 3)

Sofosbuvir/Velpatasvir

12 weeks

SOF+RBV

24 weeksa

SVR12 Treatment-naïve

(n = 206)

Treatment-experienced

(n = 71)

Treatment-naïve

(n = 201)

Treatment-experienced

(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 Five patients with missing cirrhosis status in the SOF+RBV 24 week group were excluded from this subgroup analysis.

Clinical studies in patients with decompensated cirrhosis– ASTRAL-4 (study 1137)

ASTRAL-4 was a randomised, open-label study in patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection and CPT Class B cirrhosis. Patients were randomised in a 1:1:1 ratio to treatment with Sofosbuvir/Velpatasvir for 12 weeks, Sofosbuvir/Velpatasvir + RBV for 12 weeks or Sofosbuvir/Velpatasvir for 24 weeks. Randomisation 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 patients, the median age was 59 years (range: 40 to 73); 70% of the patients were male; 90% were White, 6% were Black; 42% had a baseline body mass index of at least 30 kg/m2. The proportions of patients with genotype 1, 2, 3, 4 or 6 HCV were 78%, 4%, 15%, 3%, and < 1% (1 patient), respectively. No patients with genotype 5 HCV infection were enrolled. 76% of the patients had non-CC IL28B alleles (CT or TT); 56% had baseline HCV RNA levels of at least 800,000 IU/mL, 55% were treatment-experienced; 90% and 95% of patients had CPT Class B cirrhosis and Model for End Stage Liver Disease (MELD) score ≤ 15 at baseline, respectively.

Table 14 presents the SVR12 for the ASTRAL-4 study by HCV genotype.

Table 14: SVR12 in study ASTRAL-4 by HCV genotype

Sofosbuvir/Velpatasvir

12 weeks

(n = 90)

Sofosbuvir/Velpatasvir + RBV

12 weeks

(n = 87)

Sofosbuvir/Velpatasvir

24 weeks

(n = 90)

Overall SVR12 83% (75/90) 94% (82/87) 86% (77/90)
Genotype 1 88% (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 3 50% (7/14) 85% (11/13) 50% (6/12)
Genotype 2, 4 and 6 100% (8/8)a 100% (6/6)b 86% (6/7)c

a n = 4 for genotype 2 and n = 4 for genotype 4.

b n = 4 for genotype 2 and n = 2 for genotype 4.

c n = 4 for genotype 2, n = 2 for genotype 4 and n = 1 for genotype 6.

Table 15 presents the virologic outcome for patients with genotype 1 or 3 HCV infection in the ASTRAL-4 study.

No patients with genotype 2, 4 or 6 HCV infection experienced virologic failure.

Table 15: Virologic outcome for patients with genotype 1 and 3 HCV infection in study ASTRAL-4

Sofosbuvir/Velpatasvir 12 weeks Sofosbuvir/Velpatasvir + RBV 12 weeks Sofosbuvir/Velpatasvir 24 weeks
Virologic failure (relapse and on-treatment failure)
Genotype 1a 7% (5/68) 1% (1/68) 4% (3/71)
Genotype 1a 6% (3/50) 2% (1/54) 4% (2/55)
Genotype 1b 11% (2/18) 0% (0/14) 6% (1/16)
Genotype 3 43% (6/14) 15% (2b/13) 42% (5c/12)
Otherd 5% (4/82) 2% (2/81) 5% (4/83)

a No patients with genotype 1 HCV had on-treatment virologic failure.

b One patient had on-treatment virologic failure; pharmacokinetic data from this patient was consistent with non-adherence to treatment.

c One patient had on-treatment virologic failure.

d Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

Changes in the parameters found in the CPT score system in patients achieving SVR12 in ASTRAL-4 (all 3 regimens) are shown in Table 16.

Table 16: Changes in CPT score parameters from baseline to week 12 and 24 post-treatment in patients achieving SVR12, ASTRAL-4

Albumin Bilirubin INR Ascites Encephalopathy
Post-treatment Week 12 (N=236), % (n/N)
Decreased score (Improvement) 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)
Increased score (Worsening) 5.2% (12/229) 5.7% (13/229) 1.3% (3/229) 3.1% (7/229) 3.5% (8/229)
No assessment 7 7 7 7 7
Post-treatment Week 24 (N=236), % (n/N)
Decreased score (Improvement) 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)
Increased score (Worsening) 6.6% (14/213) 2.8% (6/213) 2.8% (6/213) 3.8% (8/213) 2.3% (5/213)
No assessment 23 23 23 23 23
Note: Baseline frequency of ascites was: 20% none, 77% mild/moderate, 3% severe

Baseline frequency of encephalopathy was: 38% none, 62 % grade 1-2.

Clinical studies in patients with HCV/HIV-1 Co-infection – ASTRAL-5 (study 1202)

ASTRAL-5 evaluated 12 weeks of treatment with Sofosbuvir/Velpatasvir in patients with genotype 1, 2, 3, or 4 HCV infection who were co-infected with HIV-1 (HCV genotype 5 and 6 allowed, but no such patients were included). Patients were on a stable HIV-1 antiretroviral therapy that included emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine administered with a ritonavir boosted protease inhibitor (atazanavir, darunavir, or lopinavir), rilpivirine, raltegravir or emtricitabine/tenofovir disoproxil fumarate /elvitegravir/cobicistat.

Of the 106 treated patients, the median age was 57 years (range: 25 to 72); 86% of the patients were male; 51% were white; 45% were black; 22% had a baseline body mass index ≥ 30 kg/m2; 19 patients (18%) had compensated cirrhosis; and 29% were treatment experienced. The overall mean CD4+ count was 598 cells/μL (range: 183−1513 cells/μL).

Table 17 presents the SVR12 for the ASTRAL-5 study by HCV genotype.

Table 17: SVR12 in study ASTRAL-5 by HCV genotype

Sofosbuvir/Velpatasvir 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 patients without SVR
On-treatment virologic failure 0/106 0/66 0/12 0/78 0/11 0/12 0/5
Relapsea 2%

(2/103)

3%

(2/65)

0/11 3%

(2/76)

0/11 0/11 0/5
Otherb 3%

(3/106)

2%

(1/66)

8%

(1/12)

3%

(2/78)

0/11 8%

(1/12)

0/5

GT = genotype

a The denominator for relapse is the number of patients with HCV RNA < LLOQ at their last on-treatment assessment.

b Other includes patients who did not achieve SVR12 and did not meet virologic failure criteria.

SVR12 was achieved by 19/19 patients with cirrhosis. No patient had HIV-1 rebound during the study, and CD4+ counts were stable during treatment.

Clinical studies in patients with Renal Impairment – study 4062

Study 4062 was an open-label clinical trial that evaluated 12 weeks of treatment with Sofosbuvir/Velpatasvir in 59 HCV-infected patients with ESRD requiring dialysis. The proportions of patients with genotype 1, 2, 3, 4, 6 or indeterminate HCV infection were 42%, 12%, 27%, 7% , 3%, and 9%, respectively. At baseline, 29% of patients had cirrhosis, 22% were treatment experienced, 32% had received a kidney transplant, 92% were on haemodialysis, and 8% were on peritoneal dialysis; mean duration on dialysis was 7.3 years (range: 0 to 40 years). The overall SVR rate was 95% (56/59); of the three patients that did not achieve SVR12, one had completed Sofosbuvir/Velpatasvir treatment and relapsed and two did not meet virologic failure criteria.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Sofosbuvir/Velpatasvir in one or more subsets of the paediatric population in the treatment of chronic hepatitis C (see section 4.2 for information on paediatric use).

Elderly

Clinical studies of Sofosbuvir/Velpatasvir included 156 patients aged 65 and over (12% of total number of patients in the Phase 3 clinical studies). The response rates observed for patients ≥ 65 years of age were similar to that of patients < 65 years of age, across treatment groups.

5.2 Pharmacokinetic properties

Absorption

The pharmacokinetic properties of sofosbuvir, GS-331007 and velpatasvir have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Following oral administration of Sofosbuvir/Velpatasvir, sofosbuvir was absorbed quickly and the peak median plasma concentration was observed 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed 3 hours post-dose. Velpatasvir median peak concentrations were observed at 3 hours post-dose.

Based on the population pharmacokinetic analysis in HCV-infected patients, mean steady-state AUC0-24 for sofosbuvir (n = 982), GS-331007 (n = 1,428) and velpatasvir (n = 1,425) were 1,260, 13,970 and 2,970 ng•h/mL, respectively. Steady-state Cmax for sofosbuvir, GS-331007 and velpatasvir were 566, 868 and 259 ng/mL, respectively. Sofosbuvir and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and patients with HCV infection. Relative to healthy subjects (n = 331), velpatasvir AUC0-24 and Cmax were 37% lower and 41% lower, respectively in HCV-infected patients.

Effects of food

Relative to fasting conditions, the administration of a single dose of Sofosbuvir/Velpatasvir with a moderate fat (~600 kcal, 30% fat) or high fat (~800 kcal, 50% fat) meal resulted in a 34% and 21% increase in velpatasvir AUC0-inf, respectively, and a 31% and 5% increase in velpatasvir Cmax, respectively. The moderate or high fat meal increased sofosbuvir AUC0-inf by 60% and 78%, respectively, but did not substantially affect the sofosbuvir Cmax. The moderate or high fat meal did not alter GS-331007 AUC0-inf, but resulted in a 25% and 37% decrease in its Cmax, respectively. The response rates in Phase 3 studies were similar in HCV-infected patients who received Sofosbuvir/Velpatasvir with food or without food. Sofosbuvir/Velpatasvir can be administered without regard to food.

Distribution

Sofosbuvir is approximately 61-65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 μg/mL to 20 μg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity was approximately 0.7.

Velpatasvir is > 99.5% bound to human plasma proteins and binding is independent of drug concentration over the range of 0.09 μg/mL to 1.8 μg/mL. After a single 100mg dose of [14C]-velpatasvir in healthy subjects, the blood to plasma ratio of [14C]-radioactivity ranged between 0.52 and 0.67.

Biotransformation

Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes. After a single 400mg oral dose of [14C]-sofosbuvir, GS-331007 accounted for approximately > 90% of total systemic exposure.

Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4 with slow turnover. Following a single dose of 100mg [14C]-velpatasvir, the majority (> 98%) of radioactivity in plasma was parent drug. The monohydroxylated and desmethylated velpatasvir were the metabolites identified in human plasma. Unchanged velpatasvir is the major species present in faeces.

Elimination

Following a single 400mg oral dose of [14C]-sofosbuvir, mean total recovery of the [14C]-radioactivity was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of Sofosbuvir/Velpatasvir were 0.5 and 25 hours, respectively.

Following a single 100mg oral dose of [14C]-velpatasvir, mean total recovery of the [14C]-radioactivity was 95%, consisting of approximately 94% and 0.4% recovered from the faeces and urine, respectively. Unchanged velpatasvir was the major species in faeces accounting for a mean of 77% of the administered dose, followed by monohydroxylated velpatasvir (5.9%) and desmethylated velpatasvir (3.0%). These data indicate that biliary excretion of parent drug was a major route of elimination for velpatasvir. The median terminal half-life of velpatasvir following administration of Sofosbuvir/Velpatasvir was approximately 15 hours.

Linearity/non-linearity

Velpatasvir AUC increases in a nearly dose proportional manner over the dose range of 25mg to 150mg. Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200mg to 1,200mg.

In vitro potential for sofosbuvir/velpatasvir drug-drug interactions

Sofosbuvir and velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Velpatasvir is also a substrate of OATP1B. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed.

Velpatasvir is an inhibitor of drug transporter P-gp, BCRP, OATP1B1 and OATP1B3 and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant plasma concentration, velpatasvir is not an inhibitor of hepatic transporters bile salt export pump (BSEP), sodium taurocholate cotransporter protein (NTCP), OATP2B1, OATP1A2 or organic cation transporter (OCT) 1, renal transporters OCT2, OAT1, OAT3, multidrug resistance-associated protein 2 (MRP2) or multidrug and toxin extrusion protein (MATE) 1, or CYP or uridine glucuronosyltransferase (UGT) 1A1 enzymes.

Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1. GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.

Pharmacokinetics in special populations

Race and gender

No clinically relevant pharmacokinetic differences due to race or gender have been identified for sofosbuvir, GS-331007 or velpatasvir.

Elderly

Population pharmacokinetic analysis in HCV-infected patients showed that within the age range (18 to 82 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir, GS-331007, or velpatasvir.

Renal impairment

A summary of the effect of varying degrees of renal impairment (RI) on the exposures of the components of Sofosbuvir/Velpatasvir compared to subjects with normal renal function, as described in the text below, are provided in Table 18.

Table 18: Effect of Varying Degrees of Renal Impairment on Exposures (AUC) of Sofosbuvir, GS-331007, and Velpatasvir Compared to Subjects with Normal Renal Function

HCV-Negative Subjects HCV-Infected Subjects
Mild RI

(eGFR ≥50 and <80 mL/min/1.73m2)

Moderate RI

(eGFR ≥30 and <50 mL/min/1.73m2)

Severe RI

(eGFR <30 mL/min/1.73m2)

ESRD Requiring Dialysis Severe RI

(eGFR <30 mL/min/1.73m2)

ESRD Requiring Dialysis
Dosed 1 hr Before Dialysis Dosed 1 hr After Dialysis
Sofosbuvir 1.6-fold↑ 2.1-fold↑ 2.7-fold↑ 1.3-fold↑ 1.6-fold↑ ~2-fold↑ 1.8-fold↑
GS-331007 1.6-fold↑ 1.9-fold↑ 5.5-fold↑ ≥10-fold↑ ≥20-fold↑ ~7-fold↑ 18-fold↑
Velpatasvir 1.5-fold↑ 1.4-fold↑

The pharmacokinetics of sofosbuvir was studied 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), severe renal impairment (eGFR < 30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 400mg dose of sofosbuvir, relative to patients with normal renal function (eGFR > 80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction coefficient of approximately 53%. Following a single 400mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered dose.

In HCV-infected patients with severe renal impairment treated with sofosbuvir 200mg with ribavirin (n=10) or sofosbuvir 400mg with ribavirin (n=10) for 24 weeks or ledipasvir/sofosbuvir 90/400mg (n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistent with that observed in HCV negative patients with severe renal impairment.

The pharmacokinetics of velpatasvir was studied with a single dose of 100mg velpatasvir in HCV negative patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault).

The pharmacokinetics of sofosbuvir, GS-331007, and velpatasvir were studied in HCV-infected patients with ESRD requiring dialysis treated with Sofosbuvir/Velpatasvir (n=59) for 12 weeks, and compared to patients without renal impairment in the sofosbuvir/velpatasvir Phase 2/3 trials.

Hepatic impairment

The pharmacokinetics of sofosbuvir was studied following 7-day dosing of 400mg sofosbuvir in HCV-infected patients with moderate and severe hepatic impairment (CPT Class B and C). Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to sofosbuvir and GS-331007.

The pharmacokinetics of velpatasvir was studied with a single dose of 100mg velpatasvir in HCV negative patients with moderate and severe hepatic impairment (CPT Class B and C). Compared to subjects with normal hepatic function velpatasvir total plasma exposure (AUCinf) was similar in patients with moderate or severe hepatic impairment. Population pharmacokinetics analysis in HCV-infected patients indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure to velpatasvir (see section 4.2).

Body weight

Body weight did not have a clinically significant effect on sofosbuvir or velpatasvir exposure according to a population pharmacokinetic analysis.

Paediatric population

The pharmacokinetics of sofosbuvir, GS-331007 and velpatasvir in paediatric patients have not been established (see section 4.2).

5.3 Preclinical safety data

Sofosbuvir

Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity and exposure to the major metabolite GS-331007 was instead used to estimate exposure margins.

Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays. No teratogenic effects were observed in the rat and rabbit developmental toxicity studies with sofosbuvir. Sofosbuvir had no adverse effects on behaviour, reproduction, or development of the offspring in the rat pre- and post-natal development study.

Sofosbuvir was not a carcinogen in the 2-year mouse and rat carcinogenicity studies at GS-331007 exposures up to 15 and 9 times, respectively, higher than human exposure.

Velpatasvir

Velpatasvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.

Velpatasvir was not carcinogenic in the 6-month rasH2 transgenic mouse and 2-year rat carcinogenicity studies at exposures at least 50-times and 5-times higher than human exposure, respectively.

Velpatasvir had no adverse effects on mating and fertility. No teratogenic effects were observed in the mouse and rat developmental toxicity studies with velpatasvir at AUC exposures approximately 31- and 6-fold higher, respectively, than the human exposure at the recommended clinical dose. However, a possible teratogenic effect was indicated in rabbits where an increase in total visceral malformations was seen in exposed animals at AUC exposures up to 0.7 fold the human exposure at recommended clinical dose. The human relevance of this finding is not known. Velpatasvir had no adverse effects on behaviour, reproduction, or development of the offspring in the rat pre- and post-natal development study at AUC exposures approximately 5-fold higher than the human exposure at the recommended clinical dose.

  1. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Copovidone, Microcrystalline cellulose, Croscarmellose sodium

Magnesium stearate

Film-coating

Polyvinyl alcohol, Titanium dioxide, Polyethylene glycol, Talc

Iron oxide red

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Sofosbuvir/Velpatasvir tablets are supplied in high density polyethylene (HDPE) bottle with a polypropylene child-resistant closure containing 28 film-coated tablets with polyester coil.

The following pack sizes are available: outer cartons containing 1 bottle of 28 film-coated tablets.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

  1. Manufactured in india by:
    TAJ PHARMACEUTICALS LTD.
    Mumbai, India
    Unit No. 214.Old Bake House,
    Maharashtra chambers of  Commerce Lane,
    Fort, Mumbai – 400001
    at:Gujarat, INDIA.
    Customer Service and Product Inquiries:
    1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
    Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
    E-mail: tajgroup@tajpharma.com

 

Sofosbuvir/Velpatasvir 400 mg/100 mg Tablets Taj Pharma

Package leaflet: Information for the user

Sofosbuvir/Velpatasvir 400 mg/100 mg film-coated tablets

sofosbuvir/velpatasvir

▼This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Sofosbuvir/Velpatasvir is and what it is used for
    2. What you need to know before you take Sofosbuvir/Velpatasvir
    3. How to take Sofosbuvir/Velpatasvir
    4. Possible side effects
    5. How to store Sofosbuvir/Velpatasvir
    6. Contents of the pack and other information
  2. What Sofosbuvir/Velpatasvir is and what it is used for

Sofosbuvir/Velpatasvir is a medicine that contains the active substances sofosbuvir and velpatasvir in a single tablet. It is given to treat a chronic (long-term) viral infection of the liver called hepatitis C in adults of 18 years and older.

The active substances in this medicine work together by blocking two different proteins that the virus needs to grow and reproduce itself, allowing the infection to be permanently eliminated from the body.

Sofosbuvir/Velpatasvir is sometimes taken with another medicine, ribavirin.

It is very important that you also read the leaflets for the other medicines that you will be taking with Sofosbuvir/Velpatasvir. If you have any questions about your medicines, please ask your doctor or pharmacist.

  1. What you need to know before you take Sofosbuvir/Velpatasvir

Do not take Sofosbuvir/Velpatasvir

  • If you are allergic to sofosbuvir, velpatasvir or any of the other ingredients of this medicine (listed in section 6 of this leaflet).
  • If this applies to you, do not take Sofosbuvir/Velpatasvir and tell your doctor immediately.
  • If you are currently taking any of the following medicines:
    • rifampicin and rifabutin (antibiotics used to treat infections, including tuberculosis);
    • St. John’s wort (herbal medicine used to treat depression);
    • carbamazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and prevent seizures).

Warnings and precautions

Talk to your doctor if you:

  • have liver problems other than from hepatitis C, for instance
    • if you have a current or previous infection with the hepatitis B virus, since your doctor may want to monitor you more closely;
    • if you have had a liver transplant
  • have kidney problems or if you are on kidney dialysis, since Sofosbuvir/Velpatasvir has not been fully tested in patients with some severe kidney problems;
  • are taking treatment for human immunodeficiency virus (HIV) infection, since your doctor may want to monitor you more closely.

Talk to your doctor or pharmacist before taking Sofosbuvir/Velpatasvir if:

  • you currently take, or have taken in the last few months, the medicine amiodarone to treat irregular heartbeats (your doctor may consider alternative treatments if you have taken this medicine).
  • you have diabetes. You may need closer monitoring of your blood glucose levels and/or adjustment of your diabetes medication after starting Sofosbuvir/Velpatasvir. Some diabetic patients have experienced low sugar levels in the blood (hypoglycaemia) after starting treatment with medicines like Sofosbuvir/Velpatasvir.

Tell your doctor immediately if you are taking any medicines for heart problems and during treatment you experience:

  • shortness of breath;
  • light-headedness;
  • palpitations;
  • fainting.

Blood tests

Your doctor will test your blood before, during and after your treatment with Sofosbuvir/Velpatasvir. This is so that:

  • Your doctor can decide if you should take Sofosbuvir/Velpatasvir and for how long;
  • Your doctor can confirm that your treatment has worked and you are free of the hepatitis C virus.

Children and adolescents

Do not give this medicine to children and adolescents under 18 years of age. The use of Sofosbuvir/Velpatasvir in children and adolescents has not yet been studied.

Other medicines and Sofosbuvir/Velpatasvir

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Warfarin and other similar medicines called vitamin K antagonists used to thin the blood. Your doctor may need to increase the frequency of your blood tests to check how well your blood can clot.

Your liver function may change with treatment of hepatitis C and therefore may affect other medications (e.g. medicines used to suppress your immune system, etc.). Your doctor may need to closely monitor these other medicines you are taking and make adjustments after starting Sofosbuvir/Velpatasvir.

If you are not sure talk to your doctor or pharmacist.

Some medicines should not be taken with Sofosbuvir/Velpatasvir.

  • Do not take any other medicine that contains sofosbuvir, one of the active substances in Sofosbuvir/Velpatasvir.

Tell your doctor or pharmacist if you are taking any of the medicines below:

  • amiodarone used to treat irregular heartbeats;
  • rifapentine (antibiotic used to treat infections, including tuberculosis);
  • oxcarbazepine (medicine used to treat epilepsy and prevent seizures);
  • tenofovir disoproxil fumarate or any medicine containing tenofovir disoproxil fumarate, used to treat HIV infection;
  • efavirenz used to treat HIV infection;
  • digoxin used to treat heart conditions;
  • dabigatran used to thin the blood;
  • modafinil used to treat sleep disorders;
  • rosuvastatin or other statins used to treat high cholesterol.

Taking Sofosbuvir/Velpatasvir with any of these may stop your medicines from working properly, or make any side effects worse. Your doctor may need to give you a different medicine or adjust the dose of medicine you are taking. This change could be to Sofosbuvir/Velpatasvir or another medicine you are taking.

  • Get advice from a doctor or pharmacist if you take medicines used to treat stomach ulcers, heartburn or acid reflux as they can decrease the amount of velpatasvir in your blood. These medicines include:
    • antacids (such as aluminium/magnesium hydroxide or calcium carbonate). These should be taken at least 4 hours before or 4 hours after Sofosbuvir/Velpatasvir;
    • proton pump inhibitors (such as omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole). Sofosbuvir/Velpatasvir should be taken with food 4 hours before using a proton pump inhibitor.
    • H2-receptor antagonists (such as famotidine, cimetidine, nizatidine or ranitidine). If you need high doses of these medicines your doctor may give you a different medicine instead or adjust the dose of the medicine you are taking.

These medicines can decrease the amount of velpatasvir in your blood. If you are taking one of these medicines your doctor will either give you a different medicine for stomach ulcers, heartburn or acid reflux, or recommend how and when you take that medicine.

Pregnancy and contraception

The effects of Sofosbuvir/Velpatasvir during pregnancy are not known. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Sofosbuvir/Velpatasvir is sometimes used together with ribavirin. Ribavirin can harm your unborn baby. It is therefore very important that you (or your partner) do not become pregnant during this treatment or for a period of time after completing treatment. You must read the “Pregnancy” section in the ribavirin package leaflet very carefully. Ask your doctor for effective contraception method suitable for you and your partner.

Breast-feeding

Do not breast-feed during treatment with Sofosbuvir/Velpatasvir. It is not known whether sofosbuvir or velpatasvir, the two active substances of Sofosbuvir/Velpatasvir, pass into human breast milk.

Driving and using machines

Sofosbuvir/Velpatasvir should not affect your ability to drive or use any tools or machinery.

  1. How to take Sofosbuvir/Velpatasvir

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Recommended dose

The recommended dose is one tablet once a day for 12 weeks.

Swallow the tablet whole with or without food. Do not chew, crush or split the tablet as it has a very bitter taste.

If you are taking an antacid, take it at least 4 hours before or at least 4 hours after Sofosbuvir/Velpatasvir.

If you are taking a proton pump inhibitor, take Sofosbuvir/Velpatasvir with food 4 hours before using a proton pump inhibitor.

If you are sick (vomit) after taking Sofosbuvir/Velpatasvir it may affect the amount of Sofosbuvir/Velpatasvir in your blood. This may make Sofosbuvir/Velpatasvir work less well.

  • If you are sick (vomit) less than 3 hours after taking Sofosbuvir/Velpatasvir, take another tablet.
  • If you are sick (vomit) more than 3 hours after taking Sofosbuvir/Velpatasvir, you do not need to take another tablet until your next scheduled tablet.

If you take more Sofosbuvir/Velpatasvir than you should

If you accidentally take more than the recommended dose you should contact your doctor or nearest emergency department immediately for advice. Keep the tablet bottle with you so that you can easily describe what you have taken.

If you forget to take Sofosbuvir/Velpatasvir

It is important not to miss a dose of this medicine.

If you do miss a dose, work out how long it is since you last took your Sofosbuvir/Velpatasvir:

  • If you notice within 18 hours of the time you usually take Sofosbuvir/Velpatasvir, you must take the tablet as soon as possible. Then take the next dose at your usual time.
  • If it’s 18 hours or more after the time you usually take Sofosbuvir/Velpatasvir, wait and take the next dose at your usual time. Do not take a double dose (two doses close together).

Do not stop taking Sofosbuvir/Velpatasvir

Do not stop taking this medicine unless your doctor tells you to. It is very important that you complete the full course of treatment to give the medicine the best chance to treat your hepatitis C virus infection.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

  1. Possible side effects

Like all medicines, this medicine may cause side effects, although not everybody gets them.

Other effects that may be seen during treatment with sofosbuvir:

The frequency of the following side effects is not known (frequency cannot be estimated from the available data).

  • a wide spread severe rash with peeling skin which may be accompanied by fever, flu like symptoms, blisters in the mouth, eyes, and/or genitals (Stevens Johnson syndrome).
  • If you get any side effects tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store Sofosbuvir/Velpatasvir

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle and carton after “EXP”. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information

What Sofosbuvir/Velpatasvir contains

  • The active substances are sofosbuvir and velpatasvir. Each film-coated tablet contains 400 mg sofosbuvir and 100 mg velpatasvir.
  • The other ingredients are
    Tablet core:
    Copovidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate
    Film-coating:
    Polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red

What Sofosbuvir/Velpatasvir looks like and contents of the pack

Film-coated tablets

The following pack sizes are available:

  • outer cartons containing 1 bottle of 28 film-coated tablets

 

  1. Manufactured in india by:
    TAJ PHARMACEUTICALS LTD.
    Mumbai, India
    Unit No. 214.Old Bake House,
    Maharashtra chambers of  Commerce Lane,
    Fort, Mumbai – 400001
    at:Gujarat, INDIA.
    Customer Service and Product Inquiries:
    1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
    Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
    E-mail: tajgroup@tajpharma.com