4.1. Therapeutic indications

Sofosbuvir/Velpatasvir Gilead is indicated for the treatment of chronic hepatitis C virus (HCV) infection in patients 3 years of age and older (see sections 4.2, 4.4 and 5.1).

4.2. Posology and method of administration

Sofosbuvir/Velpatasvir Gilead 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 Gilead in adults is one 400 mg/100 mg tablet, taken orally, once daily with or without food (see section 5.2).

The recommended dose of Sofosbuvir/Velpatasvir Gilead in paediatric patients aged 3 years and above is based on weight as detailed in Table 3 (see section 5.2).

A granule formulation of Sofosbuvir/Velpatasvir Gilead is available for the treatment of chronic HCV infection in paediatric patients aged 3 years and above having difficulty swallowing film‑coated tablets. For patients weighing < 17 kg, please refer to the Summary of Product Characteristics for Epclusa 200 mg/50 mg or 150 mg/37.5 mg granules.

Table 1: Recommended treatment and duration for adults regardless of HCV genotypes

Adult patient populationa

Treatment and duration

Patients without cirrhosis and patients with compensated cirrhosis

Sofosbuvir/Velpatasvir Gilead 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 Gilead + 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 for adults where ribavirin is divided in two daily doses and given with food:

Table 2: Guidance for ribavirin dosing when administered with Sofosbuvir/Velpatasvir Gilead to adults with decompensated cirrhosis

Adult patient

Ribavirin dose

Child‑Pugh‑Turcotte (CPT) Class B cirrhosis pre-transplant

1,000 mg per day for patients < 75 kg and 1,200 mg for those weighing ≥ 75 kg

CPT Class C cirrhosis pre-transplant

CPT Class B or C post-transplant

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

If ribavirin is used in genotype 3 infected adult patients with compensated cirrhosis (pre- or post-transplant) the recommended dose of ribavirin is 1,000/1,200 mg (1,000 mg for adult patients weighing < 75 kg and 1,200 mg for adult patients weighing ≥ 75 kg).

For ribavirin dose modifications, refer to the Summary of Product Characteristics of the medicinal product containing ribavirin.

Table 3: Recommended treatment and duration for paediatric patients aged 3 to < 18 Years regardless of HCV genotype using Sofosbuvir/Velpatasvir Gilead Tablets*

Body weight (kg)

Dosing of Sofosbuvir/Velpatasvir Gilead tablets

Sofosbuvir/Velpatasvir daily dose

Recommended treatment regimen

≥ 30

one 400 mg/100 mg tablet once daily

or

two 200 mg/50 mg tablets once daily

400 mg/100 mg per day

Sofosbuvir/Velpatasvir Gilead for 12 weeks

17 to < 30

one 200 mg/50 mg tablet once daily

200 mg/50 mg per day

* Sofosbuvir/Velpatasvir Gilead is also available as granules for paediatric patients with chronic HCV infection aged 3 years and above. For patients weighing < 17 kg, please refer to the Summary of Product Characteristics for Epclusa 200 mg/50 mg or 150 mg/37.5 mg granules.

Patients should be instructed that if vomiting occurs within 3 hours of dosing an additional tablet of Sofosbuvir/Velpatasvir Gilead should be taken. If vomiting occurs more than 3 hours after dosing, no further dose of Sofosbuvir/Velpatasvir Gilead is needed (see section 5.1).

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

Adult patients who have previously failed therapy with an NS5A-containing regimen

Sofosbuvir/Velpatasvir Gilead + 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 Gilead 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 Gilead 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 Gilead 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 Gilead 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 Gilead in children aged less than 3 years have not been established. No data are available.

Method of administration

For oral use.

Patients should be instructed to swallow the tablet(s) whole with or without food (see section 5.2). Due to the bitter taste, it is recommended that film‑coated tablets are not chewed or crushed.

4.3. Contraindications

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

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).

4.4. Special warnings and precautions for use

Sofosbuvir/Velpatasvir Gilead should not be administered concurrently with other medicinal products containing sofosbuvir.

Severe bradycardia and heart block

Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir-containing regimens are used in combination with amiodarone. Bradycardia has generally occurred within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks after initiating HCV treatment.

Amiodarone should only be used in patients on Sofosbuvir/Velpatasvir Gilead 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 undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Sofosbuvir/Velpatasvir Gilead.

All patients with concurrent or recent use of amiodarone should 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 medicinal products. 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 Gilead + 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 Gilead 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 Gilead 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 Gilead. Co-administration of such medicinal products with Sofosbuvir/Velpatasvir Gilead is not recommended (see section 4.5).

Use with certain HIV antiretroviral regimens

Sofosbuvir/Velpatasvir Gilead 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 Gilead and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co‑administration of Sofosbuvir/Velpatasvir Gilead 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 Gilead 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 treatment 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 Gilead 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 Gilead in the treatment of HCV infection in patients who are post‑liver transplant have not been assessed. Treatment with Sofosbuvir/Velpatasvir Gilead 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.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium‑free'.

4.5. Interaction with other medicinal products and other forms of interaction

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

Potential for Sofosbuvir/Velpatasvir Gilead 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 Gilead with medicinal products that are substrates of these transporters may increase the exposure of such medicinal products. See Table 4 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 Gilead

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 Gilead 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 Gilead. Co‑administration with such medicinal products is not recommended with Sofosbuvir/Velpatasvir Gilead (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 Gilead mediated by P‑gp, BCRP, OATP, or CYP450 inhibitors are not expected; Sofosbuvir/Velpatasvir Gilead 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 Gilead, a close monitoring of International Normalised Ratio (INR) values is recommended.

Impact of DAA therapy on medicinal products metabolized by the liver

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

Interactions between Sofosbuvir/Velpatasvir Gilead and other medicinal products

Table 4 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 4: Interactions between Sofosbuvir/Velpatasvir Gilead 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 Gilead

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 Gilead administration by 4 hours.

H2‑receptor antagonists

Famotidine

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

Famotidine dosed simultaneously with Sofosbuvir/Velpatasvir Gileadd

Cimetidinee

Nizatidinee

Ranitidinee

(Increase in gastric pH)

Sofosbuvir

↔

↔

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

Velpatasvir

↓

0.80 (0.70, 0.91)

↓

0.81 (0.71, 0.91)

Famotidine

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

Famotidine dosed 12 hours prior to Sofosbuvir/Velpatasvir Gileadd

(Increase in gastric pH)

Sofosbuvir

↓

0.77 (0.68, 0.87)

↓

0.80 (0.73, 0.88)

Velpatasvir

↔

↔

Proton pump inhibitors

Omeprazole

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

Omeprazole dosed simultaneously with Sofosbuvir/Velpatasvir Gileadd

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 Gilead should be administered with food and taken 4 hours before proton pump inhibitor at max doses comparable to omeprazole 20 mg.

Velpatasvir

↓

0.63 (0.50, 0.78)

↓

0.64 (0.52, 0.79)

Omeprazole

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

Omeprazole dosed 4 hours after Sofosbuvir/Velpatasvir Gileadd

(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

Effect on amiodarone, velpatasvir, and sofosbuvir concentrations unknown.

Coadministration of amiodarone with a sofosbuvir containing regimen may result in serious symptomatic bradycardia.

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

Digoxin

Interaction only studied with velpatasvir.

Expected:

↔ Sofosbuvir

Co‑administration of Sofosbuvir/Velpatasvir Gilead 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 Gilead.

Digoxin (0.25 mg single dose)f/ velpatasvir (100 mg 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 Gilead. 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 Gilead.

ANTICONVULSANTS

Phenytoin

Phenobarbital

(Induction of P‑gp and CYPs)

Interaction not studied.

Expected:

↓ Sofosbuvir

↓ Velpatasvir

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

Carbamazepine

(Induction of P‑gp and CYPs)

Interaction not studied.

Expected:

↓ Velpatasvir

Sofosbuvir/Velpatasvir Gilead 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 Gilead with oxcarbazepine is expected to decrease the concentration of sofosbuvir and velpatasvir, leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir Gilead. Co‑administration is not recommended (see section 4.4).

ANTIFUNGALS

Ketoconazole

Interaction only studied with velpatasvir

Expected:

↔ Sofosbuvir

No dose adjustment of Sofosbuvir/Velpatasvir Gilead or ketoconazole is required.

Ketoconazole (200 mg twice daily)/ velpatasvir (100 mg 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 (600 mg once daily)/ sofosbuvir (400 mg single dose)d

(Induction of P‑gp and CYPs)

Effect on rifampicin exposure not studied.

Expected:

↔ Rifampicin

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

Observed:

Sofosbuvir

↓

0.23 (0.19, 0.29)

↓

0.28 (0.24, 0.32)

Rifampicin (600 mg once daily)/ velpatasvir (100 mg 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 Gilead 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 Gilead with rifapentine is expected to decrease the concentration of sofosbuvir and velpatasvir, leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir Gilead. Co‑administration is not recommended (see section 4.4).

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS

Tenofovir disoproxil fumarate

Sofosbuvir/Velpatasvir Gilead 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 Gilead and tenofovir disoproxil fumarate/emtricitabine as part of various HIV regimens.

Patients receiving tenofovir disoproxil fumarate and Sofosbuvir/Velpatasvir Gilead 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/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d

Efavirenz

↔

↔

↔

Co‑administration of Sofosbuvir/Velpatasvir Gilead with efavirenz/ emtricitabine/ tenofovir disoproxil fumarate is expected to decrease the concentration of velpatasvir. Co‑administration of Sofosbuvir/Velpatasvir Gilead 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/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d

Rilpivirine

↔

↔

↔

No dose adjustment of Sofosbuvir/Velpatasvir Gilead or emtricitabine/ rilpivirine/ tenofovir disoproxil fumarate is required.

Sofosbuvir

↔

↔

Velpatasvir

↔

↔

↔

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS

Atazanavir boosted with ritonavir (300/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d

Atazanavir

↔

↔

↑

1.4 (1.2, 1.6)

No dose adjustment of Sofosbuvir/Velpatasvir Gilead, 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/ 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d

Darunavir

↔

↔

↔

No dose adjustment of Sofosbuvir/Velpatasvir Gilead, 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 (4x200 mg/ 50 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d

Lopinavir

↔

↔

↔

No dose adjustment of Sofosbuvir/Velpatasvir Gilead, 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 (400 mg twice daily)g + emtricitabine/ tenofovir disoproxil fumarate (200/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d

Raltegravir

↔

↔

↓

0.79 (0.42, 1.5)

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

Sofosbuvir

↔

↔

Velpatasvir

↔

↔

↔

Elvitegravir/ cobicistat/ emtricitabine/ tenofovir alafenamide fumarate

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

Elvitegravir

↔

↔

↔

No dose adjustment of Sofosbuvir/Velpatasvir Gilead 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/ 300 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)c, d

Elvitegravir

↔

↔

↔

No dose adjustment of Sofosbuvir/Velpatasvir Gilead 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 (50 mg once daily)/ sofosbuvir/ velpatasvir (400/ 100 mg once daily)

Dolutegravir

↔

↔

↔

No dose adjustment of Sofosbuvir/Velpatasvir Gilead 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 Gilead is contraindicated with St. John's wort (see section 4.3).

HMG‑CoA REDUCTASE INHIBITORS

Atorvastatin (40 mg single dose) + sofosbuvir / velpatasvir (400/ 100 mg once daily)d

Observed:

Atorvastatin

↑

1.7

(1.5, 1.9)

↑

1.5

(1.5, 1.6)

No dose adjustment of Sofosbuvir/Velpatasvir Gilead or atorvastatin is required.

Rosuvastatin

Interaction only studied with velpatasvir

Expected:

↔ Sofosbuvir

Co‑administration of Sofosbuvir/Velpatasvir Gilead 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 10 mg, may be administered with Sofosbuvir/Velpatasvir Gilead.

Rosuvastatin (10 mg single dose)/ velpatasvir (100 mg 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 Gilead or pravastatin is required.

Pravastatin (40 mg single dose)/ velpatasvir (100 mg 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 Gilead, 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 130 mg daily])/ sofosbuvir (400 mg once daily)d

R‑methadone

↔

↔

↔

No dose adjustment of Sofosbuvir/Velpatasvir Gilead or methadone is required.

S‑methadone

↔

↔

↔

Sofosbuvir

↔

↑

1.3 (1.0, 1.7)

Methadone

Interaction only studied with sofosbuvir

Expected:

↔ Velpatasvir

IMMUNOSUPPRESSANTS

Ciclosporin

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

Ciclosporin

↔

↔

No dose adjustment of Sofosbuvir/Velpatasvir Gilead 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

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

Ciclosporin

↔

↓

0.88 (0.78, 1.0)

Velpatasvir

↑

1.6 (1.2, 2.0)

↑

2.0 (1.5, 2.7)

Tacrolimus

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

Tacrolimus

↓

0.73 (0.59, 0.90)

↑

1.1 (0.84, 1.4)

No dose adjustment of Sofosbuvir/Velpatasvir Gilead 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 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ sofosbuvir (400 mg 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 0.180 mg/ 0.215 mg/ 0.25 mg/ ethinyl estradiol 0.025 mg)/ velpatasvir (100 mg 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 Gilead.

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 Gilead 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 Gilead 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 Gilead should not be used during breast‑feeding.

Fertility

No human data on the effect of Sofosbuvir/Velpatasvir Gilead 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 Gilead, 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 Gilead has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The safety profile of Sofosbuvir/Velpatasvir Gilead has been determined in pooled Phase 3 clinical studies of patients with genotype 1, 2, 3, 4, 5 or 6 HCV infection and in the postmarketing setting. No adverse drug reactions to Sofosbuvir/Velpatasvir Gilead were identified from clinical trials. In the postmarketing setting, cases of severe bradycardia and heart block have been observed when SOF‑containing products are used in combination with amiodarone, and HBV reactivation has been observed in patients coinfected with HCV/HBV following treatment with DAAs (see section 4.4).

Tabulated summary of adverse reactions

Assessment of adverse reactions for Sofosbuvir/Velpatasvir Gilead is based on safety data from clinical studies and postmarketing experience. All adverse reactions are presented in Table 5. The adverse reactions are listed below by system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000) or very rare (< 1/10,000).

Table 5: Adverse drug reactions identified with Sofosbuvir/Velpatasvir Gilead

Frequency

Adverse drug reaction

Gastrointestinal disorders

Very common

vomitinga

Skin and subcutaneous tissue disorders:

Common

rashb

Uncommon

angioedemab

a. Adverse reaction was observed in paediatric patients aged 3 to < 6 years

b. Adverse reaction identified through post-marketing surveillance for sofosbuvir/velpatasvir-containing products

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

Paediatric population

The adverse reactions observed were consistent with those observed in clinical studies of Sofosbuvir/Velpatasvir Gilead in adults. The safety assessment of Sofosbuvir/Velpatasvir Gilead in paediatric patients aged 3 years and older is based on data from a Phase 2, open-label clinical study (study 1143) that enrolled 216 patients who were treated with sofosbuvir/velpatasvir for 12 weeks.

Other special populations

Patients with decompensated cirrhosis

The safety profile of Sofosbuvir/Velpatasvir Gilead has been evaluated in one open‑label study in which patients with CPT Class B cirrhosis received Sofosbuvir/Velpatasvir Gilead for 12 weeks (n = 90), Sofosbuvir/Velpatasvir Gilead + RBV for 12 weeks (n = 87) or Sofosbuvir/Velpatasvir Gilead 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 Gilead in combination with ribavirin.

Among the 87 patients who were treated with Sofosbuvir/Velpatasvir Gilead + 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 Gilead + RBV for 12 weeks due to adverse events.

Patients with renal impairment

The safety of Sofosbuvir/Velpatasvir Gilead 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.

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The highest documented doses of sofosbuvir and velpatasvir were a single dose of 1,200 mg and a single dose of 500 mg, respectively. In these healthy adult 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 Gilead. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sofosbuvir/Velpatasvir Gilead 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.