Sofosbuvir/ Velpatasvir

Registered South African indications:

• Chronic hepatitis C virus infection

Contraindications

South African recommendations

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Pregnancy with or without the use of ribavirin
• Breastfeeding with or without the use of ribavirin
• Coadministration with moderate to strong P-glycoprotein (P-gp) inducers and moderate to strong CYP inducers
  - Moderate P-gp inducers or moderate CYP inducers include rifapentine, oxcarbazepine, modafinil and efavirenz
  - Strong P-glycoprotein (P-gp) or strong cytochrome P450 (CYP) inducers (rifampicin, rifabutin, St. John’s wort (Hypericum perforatum), carbamazepine, phenobarbital and phenytoin)

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If sofosbuvir/ velpatasvir is used in combination with ribavirin the contraindications of ribavirin must be adhered to

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Recommendations in other jurisdictions

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Coadministration with strong P-glycoprotein (P-gp) and/or strong cytochrome P450 (CYP) inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin and St. John's wort (Hypericum perforatum))

Cautions

South African recommendations

• Renal impairment (when coadministered with ribavirin, refer to ribavirin)
• Severe hepatic impairment (Child-Pugh (CPT) class C cirrhosis)
  - Liver transplant patients (post-liver transplant)
• Hepatitis C virus/ hepatitis B virus (HCV/HBV) co-infection
• Diabetic patients
• Coadministration with other medicinal products containing sofosbuvir
• Coadministration with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat) (See additional prescribing points)
• May impair ability to drive and operate machinery  

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Severe renal impairment (eGFR<30ml/min/1.73m²) (monotherapy)
  - End-stage renal disease (ESRD) requiring haemodialysis
• Renal impairment (when coadministered with ribavirin, refer to ribavirin)
• Severe hepatic impairment (Child-Pugh (CPT) class C cirrhosis)
  - Liver transplant patients (post-liver transplant)
• Hepatitis C virus/ hepatitis B virus (HCV/HBV) co-infection 
• Patients who have previously failed therapy with an NS5A-containing regimen
• Diabetic patients
• Coadministration with other medicinal products containing sofosbuvir
• Coadministration with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat) (See additional prescribing points)

Forms avail. in SA and covered in this monograph: fct

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Sofosbuvir/ velpatasvir treatment should only be initiated and monitored by a medical practitioner experienced in the management of patients with HCV infection

Chronic hepatitis C virus (HCV) infection (Additional agent may be required)
Irrespective of genotype in treatment naïve or treatment-experienced patients
- Without cirrhosis or with compensated cirrhosis

Sofosbuvir/ Velpatasvir
400/100 (mg)

• Oral (fct): ≥30kg: 1 tab, dly; Treatment duration: 12 weeks

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No evidence that the addition of ribavirin to sofosbuvir/ velpatasvir in patients with compensated cirrhosis will improve outcome

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- With decompensated cirrhosis in combination with ribavirin

Sofosbuvir/ Velpatasvir
400/100 (mg)

• Oral (fct): ≥30kg: 1 tab, dly; Treatment duration: 12 weeks

Guidance for ribavirin dosing when coadministered with sofosbuvir/ velpatasvir for Child-Pugh-Turcotte (CPT) Class B cirrhosis

• Oral (fct): <75kg: 1000mg/day, in 2 divided doses with food
• Oral (fct): ≥75 kg: 1200mg/day, in 2 divided doses with food

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When coadministered with ribavirin, refer to ribavirin

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Guidance for ribavirin dosing when coadministered with sofosbuvir/ velpatasvir for decompensated cirrhosis: Safety and efficacy of sofosbuvir/ velpatasvir have not been established in patients with Child-Pugh C decompensated cirrhosis The safety and efficacy of sofosbuvir/ velpatasvir have not been established in CPT Class B or C post-transplant patients

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The safety and efficacy of sofosbuvir/ velpatasvir weighing <30kg has not yet been established

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Patients should be instructed that if vomiting occurs within 3 hours of dosing an additional tablet should be taken. If vomiting occurs more than 3 hours after dosing, no further dose is needed. If a dose 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 at the usual time. Patients should be instructed not to take a double dose

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Method of administration: For oral use. Patients should be instructed to swallow the tablet whole with or without food. Due to the bitter taste, it is recommended that the film-coated tablet is not chewed or crushed

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Indications and dosages registered in other jurisdictions

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

Chronic hepatitis C virus (HCV) infection
Regardless of HCV genotypes
- Without cirrhosis or with compensated cirrhosis

Sofosbuvir/ Velpatasvir
400/100 (mg) 

• Oral (fct): ≥30kg: 1 tab, dly; Treatment duration: 12 weeks

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Addition of ribavirin may be considered for genotype 3 infected patients with compensated cirrhosis

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- Patients with decompensated cirrhosis

Sofosbuvir/ Velpatasvir
400/100 (mg)

• Oral (fct): ≥30kg: 1 tab, dly; Treatment duration: 12 weeks

Guidance for ribavirin dosing when coadministered with sofosbuvir/ velpatasvir

Patient	Ribavirin dose
Child-Pugh-Turcotte (CPT) Class B cirrhosis pre-transplant	Oral (fct): <75kg: 1000mg/day, in 2 divided doses with food Oral (fct): ≥75kg: 1200mg/day, in 2 divided doses with food
CPT Class C cirrhosis pre-transplant CPT Class B or C post-transplant	Oral (fct): <75kg: Initial: 600mg/day, in 2 divided doses; Titrate until max is reached; Max: 1000mg/24hrs (with food) Oral (fct): ≥75kg: Initial: 600mg/day, in 2 divided doses; Titrate until max is reached; Max: 1200mg/24hrs (with food) If well tolerated. If the starting dose is not well tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels

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Patients with decompensated cirrhosis: Sofosbuvir/ velpatasvir coadministered with ribavirin, refer to ribavirin for dose modifications

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Patients with decompensated cirrhosis: If ribavirin is used in genotype 3 infected adult patients with compensated cirrhosis (pre- or post-transplant) the recommended dose of ribavirin is 1000/1200mg (1000mg for adult patients weighing <75kg and 1200mg for adult patients weighing ≥75kg)

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Patient population includes patients coinfected with human immunodeficiency virus (HIV) and patients with recurrent HCV post-liver transplant 

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Patients who have previously failed therapy with an NS5A-containing regimen: Sofosbuvir/ velpatasvir coadministered with ribavirin for 24 weeks may be considered

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Patients should be instructed that if vomiting occurs within 3 hours of dosing an additional tablet of sofosbuvir/ velpatasvir should be taken. If vomiting occurs more than 3 hours after dosing, no further dose of sofosbuvir/ velpatasvir is needed. If a dose of sofosbuvir/ velpatasvir is missed and it is within 18 hours of the normal time, patients should be instructed to take the tablet as soon as possible and then patients should take the next dose at the usual time. If it is after 18 hours then patients should be instructed to wait and take the next dose of sofosbuvir/ velpatasvir at the usual time. Patients should be instructed not to take a double dose of sofosbuvir/ velpatasvir 

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Method of administration For oral use. Patients should be instructed to swallow the tablet(s) whole with or without food. Due to the bitter taste, it is recommended that film-coated tablets are not chewed or crushed

Paed. forms avail. in SA and covered in this monograph: fct

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Sofosbuvir/ velpatasvir treatment should only be initiated and monitored by a medical practitioner experienced in the management of patients with HCV infection

Chronic hepatitis C virus (HCV) infection (Additional agent may be required)
Irrespective of genotype in treatment naïve or treatment-experienced patients
- Without cirrhosis or with compensated cirrhosis
- With decompensated cirrhosis in combination with ribavirin

Sofosbuvir/ Velpatasvir
400/100 (mg)

• Younger than 12 years: Not established for use
• Older than 12 years: See adult dosage

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Indications and dosages registered in other jurisdictions

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

Chronic hepatitis C virus (HCV) infection
- Regardless of HCV genotypes

Sofosbuvir/ Velpatasvir
400/100 (mg)
200/50 (mg)

• Younger than 3 years: Not established for use
• Older than 3 years: Oral (fct): 17-<30kg: 200mg/50mg, dly; Treatment duration: 12 weeks
• Older than 3 years: Oral (fct): ≥30kg: 400mg/100mg, dly; Treatment duration: 12 weeks

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Sofosbuvir/ velpatasvir is also available as granules for paediatric patients with chronic HCV infection aged 3 years and above

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For patients weighing <17kg: Refer to sofosbuvir/ velpatasvir 200mg/50mg or 15mg/37.5mg granules (available in other jurisdictions)

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Patients should be instructed that if vomiting occurs within 3 hours of dosing an additional tablet of sofosbuvir/ velpatasvir should be taken. If vomiting occurs more than 3 hours after dosing, no further dose of sofosbuvir/ velpatasvir is needed. If a dose of sofosbuvir/ velpatasvir is missed and it is within 18 hours of the normal time, patients should be instructed to take the tablet as soon as possible and then patients should take the next dose at the usual time. If it is after 18 hours then patients should be instructed to wait and take the next dose of sofosbuvir/ velpatasvir at the usual time. Patients should be instructed not to take a double dose of sofosbuvir/ velpatasvir 

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Method of administration For oral use. Patients should be instructed to swallow the tablet(s) whole with or without food. Due to the bitter taste, it is recommended that film-coated tablets are not chewed or crushed

Pregnancy

South African recommendations

• Contraindicated
• Use of sofosbuvir/ velpatasvir is contraindicated in pregnancy as the possibility of teratogenicity in humans of the velpatasvir component cannot be excluded
• Use of sofosbuvir/ velpatasvir combined with ribavirin is contraindicated in pregnancy as ribavirin is teratogenic. There are no or limited amount of data (<300 pregnancy outcomes) from the use of sofosbuvir, velpatasvir or sofosbuvir/ velpatasvir in pregnant women
• Sofosbuvir: Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. 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
•  Velpatasvir: Velpatasvir use in rabbits showed an increase in total visceral malformations in velpatasvir-exposed animals at AUC exposures up to 0.7-fold the human exposed at clinical recommended doses. The human relevance of this finding is not known. Teratogenicity in humans cannot be excluded

Recommendations in other jurisdictions

• Caution; not recommended
• There are no or limited amount of data (<300 pregnancy outcomes) from the use of sofosbuvir, velpatasvir or sofosbuvir/ velpatasvir in pregnant women
• Sofosbuvir: Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. 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
• Velpatasvir: Animal studies have shown a possible link to reproductive toxicity. As a precautionary measure, sofosbuvir/ velpatasvir a use is not recommended during pregnancy

Breastfeeding

South African recommendations

• Contraindicated
• It is unknown whether sofosbuvir, metabolites of sofosbuvir or velpatasvir are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of velpatasvir and metabolites of sofosbuvir in milk. A risk to the newborns/infants cannot be excluded. Therefore, sofosbuvir/ velpatasvir should not be used in women breastfeeding their babies. Women on treatment with sofosbuvir/ velpatasvir in combination with ribavirin, should not breastfeed their babies 

Recommendations in other jurisdictions

• Caution; not recommended 
• 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 newborns/ infants cannot be excluded. Therefore, sofosbuvir/ velpatasvir should not be used during breastfeeding

Fertility 

• No human data on the effect of sofosbuvir/ velpatasvir on fertility are available. Animal studies do not indicate harmful effects of sofosbuvir or velpatasvir on fertility. If ribavirin is coadministered with sofosbuvir/ velpatasvir, consult the ribavirin monograph for detailed recommendations regarding pregnancy, contraception, and breastfeeding

Renal Impairment 

South African recommendations

Monotherapy

• No dose adjustment recommended 
  No dose adjustment of sofosbuvir/ velpatasvir is required for patients with renal impairment, including end-stage renal disease (ESRD) requiring dialysis

Combination therapy

• eGFR≥50ml/min/1.73m²: Caution; no dose adjustment recommended
  When coadministered with ribavirin, refer to ribavirin 
• eGFR<50ml/min/1.73m²: Caution; no information available 
  When coadministered with ribavirin, refer to ribavirin 

Recommendations in other jurisdictions

Monotherapy

• Mild to moderate (eGFR≥30ml/min/1.73m²): No dose adjustment recommended 
• Severe (eGFR<30ml/min/1.73m²) and end-stage renal disease (ESRD): Caution; no dose adjustment recommended 
  Safety data are limited in patients with severe renal impairment and ESRD requiring haemodialysis. Sofosbuvir/ velpatasvir can be used in these patients with no dose adjustment when no other relevant treatment options are available

Combination therapy

• eGFR≥50ml/min/1.73m²: Caution; no dose adjustment recommended 
  When coadministered with ribavirin, refer to ribavirin 
• eGFR<50ml/min/1.73m²: Caution; no information available 
  When coadministered with ribavirin, refer to ribavirin 

Hepatic Impairment

South African recommendations

• Mild to moderate (Child-Pugh class (CPT) A or B): No dose adjustment recommended 
• Severe (Child-Pugh (CPT) class C cirrhosis): Caution; no information available 
  Safety and efficacy of sofosbuvir/ velpatasvir have been established in patients with Child-Pugh (CPT) Class B cirrhosis, but not in CPT class C

Recommendations in other jurisdictions

• Mild to moderate (Child-Pugh (CPT) class A or B): No dose adjustment recommended 
• Child-Pugh (CPT) class C cirrhosis: Caution; no dose adjustment recommended
  No dose adjustment of sofosbuvir/ velpatasvir is required for patients with mild, moderate, or severe hepatic impairment (CPT Class A, B, or C). Safety and efficacy of sofosbuvir/ velpatasvir have been assessed in patients with CPT Class B cirrhosis, but not in patients with CPT Class C cirrhosis

  Elderly 

• No dose adjustment recommended 

Drugs in Sport

• Permitted - No warnings

Cardiovascular Disorders 

• Cardiac arrhythmias
  - Severe bradycardia
  - Heart block

Gastrointestinal Disorders

• Vomiting (paediatric patients aged 3-<6 years)

• Strong P-glycoprotein (P-gp) inducers and/or strong CYP2B6, CYP2C8, or CYP3A4 inducers
• Strong cytochrome P450 (CYP) inducers
• Carbamazepine
• Phenobarbitone 
• Phenytoin
• Rifampicin
• Rifabutin
• Moderate P-glycoprotein (P-gp) inducers and/or moderate CYP inducers
• Efavirenz
• Modafinil
• Oxcarbazepine
• Rifapentine
• P-glycoprotein (P-gp) transporter substrates
• Breast cancer resistance protein (BCRP) transporter substrates
• Organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3 transporter substrates
• Agents that are metabolized by the liver
• Immunosuppressive medicinal products
• Calcineurin inhibitors
• Antacids (e.g. aluminium or magnesium hydroxide; calcium carbonate) 
• Proton pump inhibitors
• Omeprazole
• Lansoprazole
• Rabeprazole
• Pantoprazole
• Esomeprazole
• Amiodarone
• Digoxin
• Dabigatran etexilate 
• Vitamin K antagonists
• Tenofovir disoproxil fumarate
• Efavirenz/ emtricitabine/ tenofovir disoproxil fumarate
• Statins
• Rosuvastatin
• Ciclosporin
• Tacrolimus
• Acid reducing agents

Other interactions

• St. John's wort (Hypericum perforatum)

• Hepatic function
  - Quantitative hepatitis C virus (HCV) RNA (HCV viral load)
  - Serum albumin
  - Total and direct bilirubin
  - Alanine aminotransferase (ALT)
  - Aspartate aminotransferase (AST)
  - Alkaline phosphatase
• Assessment for active hepatitis B virus coinfection
  - Hepatitis B virus (HBV) surface antigen (HBsAg)
  - HBV core antibody (anti-HBc)
  - HBV surface antibody (anti-HBs)
• HIV antigen/antibody
• Full blood count
• International normalized ratio (INR)
• Renal function

Specific cases may require

• Pregnancy status
• Baseline NS5A resistance-associated substation testing for Y93H (patients with genotype 3)
• HBV DNA level (if evidence of hepatitis B viral coinfection exists. HBsAg positive patients not already receiving HBV suppressive therapy should be initiated on prophylactic HBV antiviral therapy (if HBV DNA levels are low or undetectable), treatment duration: 12 weeks after completion of HCV therapy. Alternatively, monitor HBV DNA levels monthly during and directly after HCV therapy)
• Blood glucose (patients with diabetes mellitus)
• Cardiac function (if coadministered with amiodarone or in patients who discontinued amiodarone just prior to initiating sofosbuvir/ velpatasvir)

Additional observations

• Pretreatment assessment
  - Evaluate for advanced hepatic fibrosis and hepatocellular carcinoma
  - Potential drug-drug interactions 
  - Patient's readiness for adherence 
  - Confirm vaccination against hepatitis A and B 
• Symptoms of hepatic impairment
  - Weakness
  - Nausea and vomiting
  - Jaundice 
  - Significantly elevated bilirubin, alkaline phosphatase or international normalized ratio
• Signs/symptoms of hypoglycemia (patients with diabetes mellitus)

Coadministration recommendations

• It is recommended to separate antacid and sofosbuvir/ velpatasvir administration by 4 hours
• H2-receptor antagonists may be administered simultaneously with or staggered from sofosbuvir/ velpatasvir at a dose that does not exceed doses comparable to famotidine 40mg twice daily
• Coadministration with proton pump inhibitors is not recommended. If it is considered necessary to coadminister, then sofosbuvir/ velpatasvir should be administered with food and taken 4 hours before proton pump inhibitor at max doses comparable to omeprazole 20mg
• 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. Patients who are identified as being at high risk of brady-dysrhythmia should be continuously monitored for 48 hours in an appropriate in-patient (hospital) setting after which outpatient or self-monitoring of heart rate should be done daily for at least the first 2 weeks of treatment. Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on sofosbuvir/ velpatasvir
• Coadministration of sofosbuvir/ velpatasvir with digoxin may increase the concentration of digoxin. Caution is warranted and therapeutic concentration monitoring of digoxin is recommended when coadministered with sofosbuvir/ velpatasvir
• Clinical monitoring, looking for signs of bleeding and anaemia, is recommended when dabigatran etexilate is coadministered with sofosbuvir/ velpatasvir. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure
• Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with sofosbuvir/ velpatasvir
• Coadministration of sofosbuvir/ velpatasvir with rifapentine is expected to decrease the concentration of sofosbuvir and velpatasvir, leading to reduced therapeutic effect of sofosbuvir/ velpatasvir. Coadministration is not recommended
• Coadministration of sofosbuvir/ velpatasvir with rosuvastatin increases the concentration of rosuvastatin, which is associated with increased risk of myopathy, including rhabdomyolysis. Rosuvastatin, at a dose that does not exceed 10mg, may be administered with sofosbuvir/ velpatasvir
• Interactions cannot be excluded with other HMG-CoA reductase inhibitors. When coadministered with sofosbuvir/ velpatasvir, careful monitoring for statin adverse reactions should be undertaken and a reduced dose of statins should be considered if required
• Ciclosporin or tacrolimus: No dose adjustment of sofosbuvir/ velpatasvir, ciclosporin or tacrolimus is required at initiation of coadministration. Afterwards, close monitoring and potential dose adjustment of ciclosporin or tacrolimus may be required

Coadministration with certain HIV antiretroviral regimens

• Sofosbuvir/ velpatasvir has been shown to increase tenofovir exposure, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in the setting of sofosbuvir/ velpatasvir and a pharmacokinetic enhancer has not been established
• The potential risks and benefits associated with coadministration of sofosbuvir/ velpatasvir with the fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal impairment

Sofosbuvir is a pan-genotypic inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) ribonucleic acid (RNA)-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analogue triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. GS-461203 (the active metabolite of sofosbuvir) is neither an inhibitor of human deoxyribonucleic acid (DNA) and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. Velpatasvir is a HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA replication and the assembly of HCV virions. In vitro resistance selection and cross-resistance studies indicate velpatasvir targets NS5A as its mode of action.

COMBINATION PREPARATIONS

Sofosbuvir/ Velpatasvir

Film-coated tablet 400mg/100mg

• Epclusa 400mg/100mg (Gilead Sciences) originator