4.1. Therapeutic indications

Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is indicated for the treatment of chronic hepatitis C virus (HCV) infection in patients aged 12 years and older and weighing at least 30 kg (see sections 4.2, 4.4 and 5.1).

4.2. Posology and method of administration

Sofosbuvir/Velpatasvir/Voxilaprevir 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/Voxilaprevir Gilead in patients aged 12 years and older and weighing at least 30 kg is one 400 mg/100 mg/100 mg tablet or two 200 mg/50 mg/50 mg tablets, taken orally, once daily with food (see section 5.2).

The recommended durations of treatment applicable to all HCV genotypes are shown in Table 1.

Table 1: Recommended treatment durations for Sofosbuvir/Velpatasvir/Voxilaprevir Gilead for all HCV genotypes in patients 12 years and older and weighing at least 30 kg

Patient population

Treatment duration

DAA naïve patients without cirrhosis

8 weeks

DAA naïve patients with compensated cirrhosis

12 weeks

8 weeks may be considered in genotype 3 infected patients (see section 5.1)

DAA experienced patients* without cirrhosis or with compensated cirrhosis

12 weeks

DAA: direct-acting antiviral agent

* In clinical studies the DAA experienced patients had been exposed to combination regimens containing any of the following: daclatasvir, dasabuvir, elbasvir, grazoprevir, ledipasvir, ombitasvir, paritaprevir, sofosbuvir, velpatasvir, voxilaprevir (administered with sofosbuvir and velpatasvir for less than 12 weeks).

Missed dose

If a dose of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is missed and it is within 18 hours of the normal time, patients should be instructed to take the tablet(s) 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/Voxilaprevir Gilead at the usual time. Patients should be instructed not to take a double dose of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead.

Patients should be instructed that if vomiting occurs within 4 hours of dosing an additional dose of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead should be taken. If vomiting occurs more than 4 hours after dosing, no further dose of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is needed (see section 5.1).

Elderly

No dose adjustment is warranted for elderly patients (see section 5.2).

Renal impairment

No dose adjustment of Sofosbuvir/Velpatasvir/Voxilaprevir 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/Voxilaprevir Gilead has not been studied in patients with ESRD requiring dialysis. Sofosbuvir/Velpatasvir/Voxilaprevir 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/Voxilaprevir Gilead is required for patients with mild hepatic impairment (Child-Pugh-Turcotte [CPT] Class A). Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is not recommended in patients with moderate or severe hepatic impairment (CPT Class B or C) (see section 5.2).

Paediatric population

The safety and efficacy of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead in children aged less than 12 years and weighing less than 30 kg have not yet been established. No data are available.

Method of administration

For oral use.

Patients should be instructed to swallow the tablet(s) whole with 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.

Concomitant use with medicinal products that are strong P-glycoprotein (P-gp) and/or strong cytochrome P450 (CYP) inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort) (see section 4.5).

Concomitant use with rosuvastatin or dabigatran etexilate (see section 4.5).

Concomitant use with ethinylestradiol-containing medicinal products such as combined oral contraceptives or contraceptive vaginal rings or transdermal patches (see section 4.5).

4.4. Special warnings and precautions for use

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/Voxilaprevir 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/Voxilaprevir 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 co-infection

There are no data on the use of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead in patients with HCV/hepatitis B virus (HBV) co-infection. Cases of HBV reactivation, some of them fatal, have been reported during or after treatment with DAAs. HBV screening should be performed in all patients before initiation of treatment. HCV/HBV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.

Renal impairment

Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) and ESRD requiring haemodialysis.

Sofosbuvir/Velpatasvir/Voxilaprevir 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).

Hepatic impairment

No dose adjustment of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is required for patients with mild hepatic impairment (CPT Class A). Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is not recommended in patients with moderate or severe hepatic impairment (CPT Class B or C) (see section 5.2).

Liver transplant patients

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

Use with moderate P-gp inducers 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, velpatasvir and/or voxilaprevir plasma concentrations leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead. Co-administration of such medicinal products with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is not recommended (see section 4.5).

Use with strong OATP1B inhibitors

Medicinal products that are strong OATP1B inhibitors (e.g. ciclosporin) may substantially increase voxilaprevir plasma concentrations, the safety of which has not been established. Co-administration of strong OATP1B inhibitors with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is not recommended (see section 4.5).

Use with certain HIV antiretroviral regimens

Sofosbuvir/Velpatasvir/Voxilaprevir Gilead has been shown to increase tenofovir exposure 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/Voxilaprevir Gilead and a pharmacokinetic enhancer has not been established. The potential risks and benefits associated with co-administration of Sofosbuvir/Velpatasvir/Voxilaprevir 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. darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving Sofosbuvir/Velpatasvir/Voxilaprevir 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 DAA treatment. Glucose levels of diabetic patients initiating DAA 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 DAA therapy is initiated.

Excipients

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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

Pharmacokinetic interactions

Potential for Sofosbuvir/Velpatasvir/Voxilaprevir Gilead to affect other medicinal products

Velpatasvir and voxilaprevir are inhibitors of drug transporters P-gp, breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with medicinal products that are substrates of these transporters may increase the exposure of such medicinal products.

Medicinal products that are sensitive substrates of these transporters and for which elevated plasma levels are associated with serious events are contraindicated (see Table 2). Dabigatran etexilate (P-gp substrate) and rosuvastatin (OATP1B and BCRP substrate) are contraindicated (see section 4.3 and Table 2).

Potential for other medicinal products to affect Sofosbuvir/Velpatasvir/Voxilaprevir Gilead

Sofosbuvir, velpatasvir and voxilaprevir are substrates of drug transporters P-gp and BCRP. Velpatasvir and voxilaprevir are substrates of drug transporters OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir primarily by CYP2B6, CYP2C8 and CYP3A4 and of voxilaprevir primarily by CYP3A4 was observed.

Medicinal products that may decrease plasma exposure of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead

Medicinal products that are strong inducers of P-gp and/or strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort) may decrease plasma concentrations of sofosbuvir, velpatasvir and/or voxilaprevir leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead. The use of such medicinal products with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is contraindicated (see section 4.3 and Table 2).

Medicinal products that are moderate P-gp inducers and/or moderate CYP inducers (e.g. efavirenz, modafinil, oxcarbazepine or rifapentine) may decrease sofosbuvir, velpatasvir and/or voxilaprevir plasma concentrations leading to reduced therapeutic effect of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead. Co-administration with such medicinal products is not recommended with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead (see section 4.4 and Table 2).

Medicinal products that may increase plasma exposure of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead

Co-administration with medicinal products that inhibit P-gp or BCRP may increase sofosbuvir, velpatasvir or voxilaprevir plasma concentrations. Medicinal products that inhibit OATP1B, CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentrations of velpatasvir or voxilaprevir. The use of strong inhibitors of OATP1B (e.g. ciclosporin) with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is not recommended (see section 4.4 and Table 2). Clinically significant medicinal product interactions with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead mediated by P-gp, BCRP and CYP inhibitors are not expected. Sofosbuvir/Velpatasvir/Voxilaprevir Gilead may be co-administered with P-gp, BCRP and CYP inhibitors.

Pharmacodynamic interactions

Patients treated with vitamin K antagonists

As liver function may change during treatment with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead, 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 agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV.

Patients treated with ethinylestradiol-containing medicinal products

Concomitant use with ethinylestradiol-containing medicinal products may increase the risk of alanine aminotransferase (ALT) elevations and is contraindicated (see section 4.3 and Table 2).

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

Table 2 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/voxilaprevir, its components (sofosbuvir, velpatasvir, and/or voxilaprevir), or are predicted medicinal product interactions that may occur with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead. The table is not all-inclusive.

Table 2: Interactions between Sofosbuvir/Velpatasvir/Voxilaprevir 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/Voxilaprevir Gilead

Active

Cmax

AUC

Cmin

ACID REDUCING AGENTS

Antacids

e.g. Aluminium or magnesium hydroxide; calcium carbonate

(Increase in gastric pH decreases velpatasvir solubility)

Interaction not studied.

Expected:

↔ Sofosbuvir

↓ Velpatasvir

↔ Voxilaprevir

It is recommended to separate antacid and

Sofosbuvir/Velpatasvir/Voxilaprevir Gilead administration by 4 hours.

H2‑receptor antagonists

Famotidine

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

Famotidine dosed simultaneously with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead

Cimetidined

Nizatidined

Ranitidined

(Increase in gastric pH decreases velpatasvir solubility)

Observed:

Sofosbuvir

↔

↔

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

Velpatasvir

↔

↔

Voxilaprevir

↔

↔

Famotidine

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

Famotidine dosed 12 hours prior to Sofosbuvir/Velpatasvir/Voxilaprevir Gilead

(Increase in gastric pH decreases velpatasvir solubility)

Observed:

Sofosbuvir

↔

↔

Velpatasvir

↔

↔

Voxilaprevir

↔

↔

Proton pump inhibitors

Omeprazole

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

Omeprazole dosed 2 hours prior to Sofosbuvir/Velpatasvir/Voxilaprevir Gilead

Lansoprazoled

Rabeprazoled

Pantoprazoled

Esomeprazoled

(Increase in gastric pH decreases velpatasvir solubility)

Observed:

Sofosbuvir

↓

0.77 (0.65, 0.91)

↓

0.73 (0.67, 0.79)

Proton pump inhibitors may be administered with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead at a dose that does not exceed doses comparable with omeprazole 20 mg.

Velpatasvir

↓

0.43 (0.38, 0.49)

↓

0.46 (0.41, 0.52)

Voxilaprevir

↓

0.76 (0.69, 0.85)

↔

Omeprazole

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

Omeprazole dosed 4 hours after Sofosbuvir/Velpatasvir/Voxilaprevir Gilead

(Increase in gastric pH decreases velpatasvir solubility)

Observed:

Sofosbuvir

↔

↔

Velpatasvir

↓

0.49 (0.43, 0.55)

↓

0.49 (0.43, 0.55)

Voxilaprevir

↔

↔

ANTIARRHYTHMICS

Amiodarone

Effect on amiodarone, voxilaprevir, 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/Voxilaprevir Gilead (see sections 4.4 and 4.8).

Digoxin

Interaction only studied with velpatasvir.

Expected:

↔ Sofosbuvir

↔ Voxilaprevir

Co‑administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended.

Digoxin (0.25 mg single dose)e + velpatasvir (100 mg single dose)

(Inhibition of P‑gp)

Effect on velpatasvir exposure not studied

Expected:

↔ Velpatasvir

Observed:

Digoxin

↑

1.88 (1.71, 2.08)

↑

1.34 (1.13, 1.60)

ANTICOAGULANTS

Dabigatran etexilate (75 mg single dose) + sofosbuvir/velpatasvir/ voxilaprevir (400/100/ 100 mg single dose) + voxilaprevir (100 mg single dose)f

(Inhibition of P‑gp)

Effect on sofosbuvir, velpatasvir and voxilaprevir concentrations not studied Expected:

↔ Sofosbuvir

↔ Velpatasvir

↔ Voxilaprevir

Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is contraindicated with dabigatran etexilate (see section 4.3).

Observed:

Dabigatran

↑

2.87 (2.61, 3.15)

↑

2.61 (2.41, 2.82)

Edoxaban

(Inhibition of OATP1B1)

Interaction not studied.

Expected:

↑ Edoxaban (active metabolite)

↔ Sofosbuvir

↔ Velpatasvir

↔ Voxilaprevir

Co‑administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with edoxaban is not recommended. Should direct Xa inhibitor use be deemed necessary, apixaban or rivaroxaban may be considered.

Vitamin K antagonists

(Liver function changes during treatment with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead).

Interaction not studied.

Close monitoring of INR is recommended when Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is co-administered with all vitamin K antagonists.

ANTICONVULSANTS

Phenytoin

Phenobarbital

(Induction of P‑gp and CYPs)

Interaction not studied.

Expected:

↓ Sofosbuvir

↓ Velpatasvir

↓ Voxilaprevir

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

Carbamazepine

(Induction of P‑gp and CYPs)

Interaction not studied.

Expected:

↓ Velpatasvir

↓ Voxilaprevir

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

Observed:

Sofosbuvir

↓

0.52 (0.43, 0.62)

↓

0.52 (0.46, 0.59)

ANTIFUNGALS

Ketoconazole

(Inhibition of P‑gp and CYP3A)

Interaction only studied with velpatasvir

Expected:

↔ Sofosbuvir

↑ Voxilaprevir

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

Ketoconazole (200 mg twice daily) + velpatasvir (100 mg single dose)f

Itraconazoled

Posaconazoled

Isavuconazoled

(Inhibition of P‑gp and CYP3A)

Effect on ketoconazole exposure not studied.

Expected:

↔ Ketoconazole

Observed:

Velpatasvir

↑

1.29 (1.02, 1.64)

↑

1.71 (1.35, 2.18)

Voriconazole

(Inhibition of CYP3A)

Interaction only studied with voxilaprevir.

Expected:

↔ Sofosbuvir

↑ Velpatasvir

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

Voriconazole (200 mg twice daily) + voxilaprevir (100 mg single dose)f

Observed:

Voxilaprevir

↔

↑

1.84 (1.66, 2.03)

ANTIMYCOBACTERIALS

Rifampicin (single dose)

(Inhibition of OATP1B)

Interaction only studied with velpatasvir and voxilaprevir.

Expected:

↔ Rifampicin

↔ Sofosbuvir

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

Rifampicin (600 mg single dose) + velpatasvir (100 mg single dose)f

Observed:

Velpatasvir

↑

1.28 (1.05, 1.56)

↑

1.46 (1.17, 1.83)

Rifampicin (600 mg single dose) + voxilaprevir (100 mg single dose)f

Voxilaprevir

↑

11.10 (8.23, 14.98)

↑

7.91 (6.20, 10.09)

Rifampicin (multiple dose)

(Induction of P‑gp and CYPs)

Effect on rifampicin exposure not studied.

Expected:

↔ Rifampicin

Rifampicin (600 mg once daily) + sofosbuvir (400 mg single dose)f

Observed:

Sofosbuvir

↓

0.23 (0.19, 0.29)

↓

0.28 (0.24, 0.32)

Rifampicin (600 mg once daily) + velpatasvir (100 mg single dose)f

Velpatasvir

↓

0.29 (0.23, 0.37)

↓

0.18 (0.15, 0.22)

Rifampicin (600 mg once daily) + voxilaprevir (100 mg single dose)f

Voxilaprevir

↔

↓

0.27 (0.23, 0.31)

Rifabutin

(Induction of P‑gp and CYPs)

Interaction not studied.

Expected:

↓ Velpatasvir

↓ Voxilaprevir

Sofosbuvir/Velpatasvir/Voxilaprevir 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

↓ Voxilaprevir

Co‑administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with rifapentine is not recommended (see section 4.4).

HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS

Tenofovir disoproxil fumarate

(Inhibition of P-gp)

Sofosbuvir/Velpatasvir/Voxilaprevir Gilead has been shown to increase tenofovir exposure (P-gp inhibition). There was an increase in tenofovir exposure (AUC and Cmax) of around 40% during co-treatment with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead and darunavir + ritonavir + tenofovir disoproxil fumarate/emtricitabine.

Patients receiving tenofovir disoproxil fumarate and Sofosbuvir/Velpatasvir/Voxilaprevir 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)g + sofosbuvir/ velpatasvir (400/100 mg once daily)f, h

(Induction of CYPs)

Interaction only studied with sofosbuvir/velpatasvir

Expected:

↓ Voxilaprevir

Co‑administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with efavirenz/emtricitabine/tenofovir disoproxil fumarate is not recommended (see section 4.4).

Observed:

Efavirenz

↔

↔

↔

Sofosbuvir

↑

1.38 (1.14, 1.67)

↔

Velpatasvir

↓

0.53 (0.43, 0.64)

↓

0.47 (0.39, 0.57)

↓

0.43 (0.36, 0.52)

Emtricitabine/rilpivirine/ tenofovir alafenamide (200/25/25 mg once daily)i + sofosbuvir/velpatasvir/ voxilaprevir (400/100/ 100 mg once daily) + voxilaprevir (100 mg once daily)f

Observed:

Rilpivirine

↔

↔

↔

No dose adjustment of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead or emtricitabine/rilpivirine/tenofovir alafenamide is required.

Sofosbuvir

↔

↔

Velpatasvir

↔

↔

↔

Voxilaprevir

↔

↔

↔

HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS

Atazanavir boosted with ritonavir (300 + 100 mg single dose) + sofosbuvir/ velpatasvir/voxilaprevir (400/100/100 mg single dose)f

(Inhibition of OATP1B, P‑gp and CYP3A)

Effect on atazanavir and ritonavir exposure not studied.

Expected:

↔ Atazanavir

↔ Ritonavir

Co-administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with atazanavir is expected to increase the concentration of voxilaprevir. Co-administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with atazanavir-containing regimens is not recommended.

Observed:

Sofosbuvir

↑

1.29 (1.09, 1.52)

↑

1.40 (1.25, 1.57)

Velpatasvir

↑

1.29 (1.07, 1.56)

↑

1.93 (1.58, 2.36)

Voxilaprevir

↑

4.42 (3.65, 5.35)

↑

4.31 (3.76, 4.93)

Darunavir boosted with ritonavir (800 + 100 mg once daily) + emtricitabine/ tenofovir disoproxil fumarate (200/300 mg once daily)j + sofosbuvir/ velpatasvir/voxilaprevir (400/100/100 mg once daily) + voxilaprevir (100 mg once daily)f

(Inhibition of OATP1B, P‑gp, and CYP3A)

Observed:

Darunavir

↔

↔

↓

0.66 (0.58, 0.74)

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

Ritonavir

↑

1.60 (1.47, 1.75)

↑

1.45 (1.35, 1.57)

↔

Sofosbuvir

↓

0.70 (0.62, 0.78)

↔

Velpatasvir

↔

↔

↔

Voxilaprevir

↑

1.72 (1.51, 1.97)

↑

2.43 (2.15, 2.75)

↑

4.00 (3.44, 4.65)

Lopinavir

(Inhibition of OATP1B)

Interaction not studied.

Expected:

↔ Lopinavir

↔ Sofosbuvir

↔ Velpatasvir

↑ Voxilaprevir

Co-administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with lopinavir-containing regimens is not recommended.

HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS

Raltegravir (400 mg twice daily)k + emtricitabine/ tenofovir disoproxil fumarate (200/300 mg once daily)j + sofosbuvir/ velpatasvir (400/100 mg once daily)f, h

Interaction only studied with sofosbuvir/velpatasvir

Expected:

↔ Voxilaprevir

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

Observed:

Raltegravir

↔

↔

↓

0.79 (0.42, 1.48)

Sofosbuvir

↔

↔

Velpatasvir

↔

↔

↔

Elvitegravir/cobicistat/ emtricitabine/tenofovir alafenamide fumarate (150/150/200/10 mg once daily)l + sofosbuvir/velpatasvir/ voxilaprevir (400/100/ 100 mg once daily) + voxilaprevir (100 mg once daily)f

(Inhibition of OATP1B, P‑gp/BCRP and CYP3A)

Observed:

Elvitegravir

↔

↔

↑

1.32 (1.17, 1.49)

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

Cobicistat

↔

↑

1.50 (1.44, 1.58)

↑

3.50 (3.01, 4.07)

Tenofovir

↓

0.79 (0.68, 0.92)

↔

Sofosbuvir

↑

1.27 (1.09, 1.48)

↔

Velpatasvir

↔

↔

↑

1.46 (1.30, 1.64)

Voxilaprevir

↑

1.92 (1.63, 2.26)

↑

2.71 (2.30, 3.19)

↑

4.50 (3.68, 5.50)

Dolutegravir (50 mg once daily) + sofosbuvir/ velpatasvir (400/100 mg once daily)h

Interaction only studied with sofosbuvir/velpatasvir

Expected:

↔ Voxilaprevir

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

Observed:

Dolutegravir

↔

↔

↔

Sofosbuvir

↔

↔

Velpatasvir

↔

↔

↔

HERBAL SUPPLEMENTS

St. John's wort

(Induction of P‑gp and CYPs)

Interaction not studied.

Expected:

↓ Sofosbuvir

↓ Velpatasvir

↓ Voxilaprevir

Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is contraindicated with St. John's wort (see section 4.3).

HMG‑CoA REDUCTASE INHIBITORS

Atorvastatin

Interaction only studied with sofosbuvir/ velpatasvir.

Expected:

↔ Voxilaprevir

Atorvastatin may be administered with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead at a dose that does not exceed atorvastatin 20 mg.

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

Observed:

atorvastatin

↑

1.7 (1.5, 1.9)

↑

1.5 (1.5, 1.6)

Rosuvastatin

Effect on sofosbuvir, velpatasvir and voxilaprevir not studied.

Expected:

↔ Sofosbuvir

↔ Velpatasvir

↔ Voxilaprevir

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

Rosuvastatin (10 mg single dose) + sofosbuvir/ velpatasvir/voxilaprevir (400/100/100 mg once daily) + voxilaprevir (100 mg once daily)f

(Inhibition of OATP1B and BCRP)

Observed:

Rosuvastatin

↑

18.9 (16.2, 22.0)

↑

7.4 (6.7, 8.2)

Pravastatin

Effect on sofosbuvir, velpatasvir and voxilaprevir not studied.

Expected:

↔ Sofosbuvir

↔ Velpatasvir

↔ Voxilaprevir

Pravastatin may be administered with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead at a dose that does not exceed pravastatin 40 mg.

Pravastatin (40 mg single dose) + sofosbuvir/ velpatasvir/voxilaprevir (400/100/100 mg once daily) + voxilaprevir (100 mg once daily)f

(Inhibition of OATP1B)

Observed:

Pravastatin

↑

1.89 (1.53, 2.34)

↑

2.16 (1.79, 2.60)

Other statins

(Inhibition of OATP1B)

Effect on fluvastatin, lovastatin, pitavastatin and simvastatin not studied.

Interactions cannot be excluded with other HMG‑CoA reductase inhibitors. Co‑administration with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is not recommended.

NARCOTIC ANALGESICS

Methadone

Interaction only studied with sofosbuvir

Expected:

↔ Velpatasvir

↔ Voxilaprevir

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

Methadone

(Methadone maintenance therapy [30 to 130 mg daily]) + sofosbuvir (400 mg once daily)f

Observed:

R‑methadone

↔

↔

↔

S‑methadone

↔

↔

↔

Sofosbuvir

↔

↑

1.30 (1.00, 1.69)

IMMUNOSUPPRESSANTS

Ciclosporin

(600 mg single dose)f + sofosbuvir (400 mg single dose)e

(Inhibition of OATP1B or P‑gp or BCRP)

Observed:

Ciclosporin

↔

↔

Co-administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with ciclosporin is not recommended (see section 4.4).

Sofosbuvir

↑

2.54 (1.87, 3.45)

↑

4.53 (3.26, 6.30)

Ciclosporin

(600 mg single dose)e + velpatasvir (100 mg single dose)f

Ciclosporin

↔

↓

0.88 (0.78, 1.0)

Velpatasvir

↑

1.56 (1.22, 2.01)

↑

2.03 (1.51, 2.71)

Ciclosporin

(600 mg single dose)e + voxilaprevir (100 mg single dose)f

Ciclosporin

↔

↔

Voxilaprevir

↑

19.0 (14.1, 25.6)

↑

9.4 (7.4, 12.0)

Tacrolimus

Effect on velpatasvir or voxilaprevir exposure not studied.

Expected:

↔ Velpatasvir

↔ Voxilaprevir

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

Tacrolimus (5 mg single dose)e + sofosbuvir (400 mg single dose)f

Observed:

Tacrolimus

↓

0.73 (0.59, 0.90)

↑

1.09 (0.84, 1.40)

Sofosbuvir

↓

0.97 (0.65, 1.43)

↑

1.13 (0.81, 1.57)

HORMONAL CONTRACEPTIVES

Oral norgestimate/ethinyl estradiol (norgestimate 0.180 mg/0.215 mg/0.25 mg/ethinyl estradiol 0.025 mg) + sofosbuvir/velpatasvir/ voxilaprevir (400/100/ 100 mg once daily) + voxilaprevir (100 mg once daily)f

Observed:

Norelgestromin

↔

↔

↔

Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is contraindicated with ethinylestradiol-containing medicinal products (see section 4.3). Alternative methods of contraception (e.g. progestin only contraception or non-hormonal methods) should be considered.

Norgestrel

↔

↔

↔

Ethinyl estradiol

↔

↔

↔

STIMULANTS

Modafinil

(Induction of P‑gp and CYPs)

Interaction not studied.

Expected:

↔ Modafinil

↓ Sofosbuvir

↓ Velpatasvir

↓ Voxilaprevir

Co‑administration of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead with modafinil is not recommended (see section 4.4).

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. Lack of pharmacokinetics interaction lower bound 70%.

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

e. Bioequivalence/Equivalence boundary 80-125%.

f. Lack of pharmacokinetics interaction bounds 70-143%.

g. Administered as efavirenz, emtricitabine and tenofovir DF fixed-dose combination.

h. Administered as sofosbuvir, velpatasvir fixed-dose combination.

i. Administered as emtricitabine, rilpivirine, and tenofovir alafenamide fixed-dose combination.

j. Administered as emtricitabine, tenofovir disoproxil fumarate fixed-dose combination.

k. Lack of pharmacokinetics interaction bounds 50-200%.

l. Administered as elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide fixed-dose combination.

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, voxilaprevir or Sofosbuvir/Velpatasvir/Voxilaprevir 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).

Voxilaprevir

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

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

Breast-feeding

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

Available pharmacokinetic data in animals have shown excretion of velpatasvir and metabolites of sofosbuvir in milk. When administered to lactating rats, voxilaprevir was detected in the plasma of nursing pups.

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

In Phase 2 and 3 clinical studies, the proportion of patients who permanently discontinued treatment due to adverse reactions was 0.1% for patients receiving sofosbuvir/velpatasvir/voxilaprevir for 8 weeks. There were no patients receiving sofosbuvir/velpatasvir/voxilaprevir for 12 weeks who permanently discontinued treatment due to adverse reactions in the Phase 2 and 3 pivotal clinical studies.

Tabulated summary of adverse reactions

Assessment of adverse reactions for Sofosbuvir/Velpatasvir/Voxilaprevir Gilead is based on safety data from clinical studies and post-marketing experience. All adverse reactions are presented in Table 3. 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 3: Adverse reactions identified with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead

Frequency

Adverse reaction

Nervous system disorders:

Very common

headache

Gastrointestinal disorders:

Very common

diarrhoea, nausea

Common

abdominal pain, decreased appetite, vomiting

Skin and subcutaneous tissue disorders:

Common

rash

Uncommon

angioedemaa

Musculoskeletal and connective tissue disorders:

Common

myalgia

Uncommon

muscle spasm

Laboratory investigations:

Common

total bilirubin increased

a. 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

Laboratory abnormalities

Total bilirubin

In the Phase 3 studies increases in total bilirubin less than or equal to 1.5 x the upper limit of normal were observed in 4% of patients without cirrhosis and 10% of patients with compensated cirrhosis, due to inhibition of OATP1B1 and OATP1B3 by voxilaprevir. Total bilirubin levels decreased after completing Sofosbuvir/Velpatasvir/Voxilaprevir Gilead treatment.

Patients with renal impairment

The safety of sofosbuvir in a fixed dose combination with either ledipasvir or velpatasvir has been studied in 154 patients with ESRD requiring dialysis (Study 4062 and Study 4063). In this setting, exposure of sofosbuvir metabolite GS-331007 is 20- fold increased, exceeding levels where adverse reactions have been observed in preclinical studies. 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.

Paediatric population

The safety assessment of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead in paediatric patients aged 12 years and older is based on data from 21 DAA-naïve patients with genotype 1, 2, 3, or 4 HCV infection (without cirrhosis) who were treated with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead for 8 weeks in a Phase 2, open-label clinical study (study 1175). The adverse reactions observed were consistent with those observed in clinical studies of Sofosbuvir/Velpatasvir/Voxilaprevir Gilead in adults.

4.9. Overdose

The highest documented doses of sofosbuvir, velpatasvir and voxilaprevir were single doses of 1,200 mg, 500 mg, and 900 mg, respectively. In healthy adult volunteer studies with sofosbuvir and velpatasvir, 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 most common adverse reactions in patients receiving voxilaprevir 900 mg were diarrhoea (34%), nausea (17%) and headache (9%).

No specific antidote is available for overdose with Sofosbuvir/Velpatasvir/Voxilaprevir Gilead. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sofosbuvir/Velpatasvir/Voxilaprevir 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 or voxilaprevir since velpatasvir and voxilaprevir are highly bound to plasma proteins.