Vosevi · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-217619 · has-adverse-reaction-information · PDF-Seite 18

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 Vosevi 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 Vosevi 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 Vosevi 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 40

Auszug; vollständigen Abschnitt im Original lesen.

HOS-217615 · has-contraindication-information · PDF-Seite 4

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).

HOS-217614 · has-indication-information · PDF-Seite 2

Vosevi 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). 2

HOS-217617 · has-interaction-information · PDF-Seite 6

As Vosevi contains sofosbuvir, velpatasvir and voxilaprevir, any interactions that have been identified with these active substances individually may occur with Vosevi. Pharmacokinetic interactions Potential for Vosevi 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 Vosevi 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 Vosevi 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 Vosevi 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 Vosevi. The use of such medicinal products with Vosevi 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 Vosevi. Co-administration with such medicinal products is not recommended with Vosevi (see section 4.4 and Table 2). Medicinal products that may increase plasma exposure of Vosevi 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 inhibitor

Auszug; vollständigen Abschnitt im Original lesen.

HOS-217618 · has-pregnancy-information · PDF-Seite 17

Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir, velpatasvir, voxilaprevir or Vosevi 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, Vosevi 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, Vosevi should not be used during breast-feeding. Fertility No human data on the effect of Vosevi on fertility are available. Animal studies do not indicate harmful effects of sofosbuvir, velpatasvir or voxilaprevir on fertility.

HOS-217616 · has-warning-information · PDF-Seite 4

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 Vosevi 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 Vosevi. 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 Vosevi 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. 4 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. Vosevi 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 Vosevi is required for patients with mild hepatic impairment (CPT Class A). Vosevi 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 Vosevi in the treatment of HCV infection in patients who are post-liver transplant have not been assessed.

Auszug; vollständigen Abschnitt im Original lesen.