Sofosbuvir, Velpatasvir and Voxilaprevir interacts in the following cases:
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 is not recommended.
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 combination has not been studied in patients with ESRD requiring dialysis. Sofosbuvir/velpatasvir/voxilaprevir can be used in these patients with no dose adjustment when no other relevant treatment options are available.
Sofosbuvir/velpatasvir/voxilaprevir combination is not recommended in patients with moderate or severe hepatic impairment (CPT Class B or C).
It is recommended to separate antacid and sofosbuvir/velpatasvir/voxilaprevir administration by 4 hours.
H2-receptor antagonists may be administered simultaneously with or staggered from Vosevi at a dose that does not exceed doses comparable with famotidine 40 mg twice daily.
Proton pump inhibitors may be administered with sofosbuvir/velpatasvir/voxilaprevir at a dose that does not exceed doses comparable with omeprazole 20 mg.
Co-administration of sofosbuvir/velpatasvir/voxilaprevir with efavirenz/emtricitabine/tenofovir disoproxil fumarate is not recommended.
Co-administration of sofosbuvir/velpatasvir/voxilaprevir with atazanavir is expected to increase the concentration of voxilaprevir. Co-administration of sofosbuvir/velpatasvir/voxilaprevir with atazanavir-containing regimens is not recommended.
Atorvastatin may be administered with sofosbuvir/velpatasvir/voxilaprevir at a dose that does not exceed atorvastatin 20 mg.
Co-administration of sofosbuvir/velpatasvir/voxilaprevir with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended.
Co-administration of sofosbuvir/velpatasvir/voxilaprevir with edoxaban is not recommended. Should direct Xa inhibitor use be deemed necessary, apixaban or rivaroxaban may be considered.
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. Co-administration with such medicinal products is not recommended with sofosbuvir/velpatasvir/voxilaprevir.
Effect on fluvastatin, lovastatin, pitavastatin and simvastatin not studied.
Interactions cannot be excluded with HMG-CoA reductase inhibitors. Co-administration with sofosbuvir/velpatasvir/voxilaprevir is not recommended.
Pravastatin may be administered with sofosbuvir/velpatasvir/voxilaprevir at a dose that does not exceed pravastatin 40 mg.
No dose adjustment of sofosbuvir/velpatasvir/voxilaprevir or tacrolimus is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required.
Sofosbuvir/velpatasvir/voxilaprevir combination has been shown to increase tenofovir exposure (P-gp inhibition). There was an increase in tenofovir exposure (AUC and Cmax) of around 40% during cotreatment with sofosbuvir/velpatasvir/voxilaprevir and darunavir + ritonavir + tenofovir disoproxil fumarate/emtricitabine.
Patients receiving tenofovir disoproxil fumarate and sofosbuvir/velpatasvir/voxilaprevir 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.
There are no data on the use of sofosbuvir/velpatasvir/voxilaprevi 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.
The safety and efficacy of sofosbuvir/velpatasvir/voxilaprevir in the treatment of HCV infection in patients who are post-liver transplant have not been assessed. Treatment with sofosbuvir/velpatasvir/voxilaprevir, in accordance with the recommended posology, should be guided by an assessment of the potential benefits and risks for the individual patient.
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir, velpatasvir, voxilaprevir or sofosbuvir/velpatasvir/voxilaprevir combination in pregnant women.
As a precautionary measure, sofosbuvir/velpatasvir/voxilaprevir use is not recommended during pregnancy.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
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.
Animal studies have shown a possible link to reproductive toxicity.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
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 should not be used during breast-feeding.
No human data on the effect of sofosbuvir/velpatasvir/voxilaprevir on fertility are available. Animal studies do not indicate harmful effects of sofosbuvir, velpatasvir or voxilaprevir on fertility.
Sofosbuvir/velpatasvir/voxilaprevir combination has no or negligible influence on the ability to drive and use machines.
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.
Assessment of adverse reactions for sofosbuvir/velpatasvir/voxilaprevir is based on safety data from clinical studies and postmarketing experience. All adverse reactions are presented in the table below. 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).
Adverse reactions identified with sofosbuvir/velpatasvir/voxilaprevir:
| 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.
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.
Frequency not known: Stevens-Johnson syndrome
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 treatment.
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.
The safety assessment of sofosbuvir/velpatasvir/voxilaprevir 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 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 in adults.
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