Presentation and Status in Health Basket
Film Coated Tablets
28 X 400 mg
Treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
The recommended dose is one 400 mg tablet, taken orally, once daily with food.
Sofosbuvir should be used in combination with other medicinal products. Monotherapy of Sofosbuvir is not recommended. Refer also to the physician’s leaflet of the medicinal products that are used in combination with Sofosbuvir.
The recommended co-administered medicinal product(s) and treatment duration for Sofosbuvir combination therapy:
Patients with genotype 1, 4, 5 or 6 CHC (Includes patients co-infected with HIV): Sofosbuvir + ribavirin + peginterferon alfa for 12 weeks A,B. Sofosbuvir + ribavirin – Only for use in patients ineligible or intolerant to peginterferon alfa for 24 weeks.
Patients with genotype 2 CHC (Includes patients co-infected with HIV): Sofosbuvir + ribavirin for 12 weeks B.
Patients with genotype 3 CHC (Includes patients co-infected with HIV): Sofosbuvir + ribavirin + peginterferon alfa for 12 weeksB . Sofosbuvir + ribavirin for 24 weeks.
Patients with CHC awaiting liver transplantation (Includes patients co-infected with HIV): Sofosbuvir + ribavirin -until liver transplantation.
A) For previously treated patients with HCV genotype 1 infection, no data exists with the combination of Sofosbuvir, ribavirin and peginterferon alfa.
B) Consideration should be given to potentially extending the duration of therapy beyond 12 weeks and up to 24 weeks; especially for those subgroups who have one or more factors historically associated with lower response rates to interferon-based therapies (e.g. advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non CC genotype, prior null response to peginterferon alfa and ribavirin therapy).
The dose of ribavirin, when used in combination with Sofosbuvir is weight-based (<75 kg = 1,000 mg and ≥75 kg = 1,200 mg) and administered orally in two divided doses with food. Concerning co-administration with other direct-acting antivirals against HCV.
Dose modification: Dose reduction of Sofosbuvir is not recommended. If sofosbuvir is used in combination with peginterferon alfa, and a patient has a serious adverse reaction potentially related to this drug, the peginterferon alfa dose should be reduced or discontinued. Refer to the peginterferon alfa physician’s leaflet for additional information about how to reduce and/or discontinue the peginterferon alfa dose. If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity.
Ribavirin dose modification guideline for co-administration with Sovaldi
Reduce ribavirin dose to 600 mg/day if Haemoglobin in patients with no cardiac disease < 10 g/dL. Discontinue ribavirin if < 8.5 g/dL.
Reduce ribavirin dose to 600 mg/day if Haemoglobin in patients with history
of stable cardiac disease ≥ 2 g/dL decrease in haemoglobin during any 4-week treatment period. Discontinue ribavirin if < 12 g/dL despite 4 weeks at reduced dose.
Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that ribavirin be increased to the original assigned dose (1,000 mg to 1,200 mg daily).
Discontinuation of dosing: If the other medicinal products used in combination with Sofosbuvir are permanently discontinued, Sofosbuvir should also be discontinued.
Vomiting and missed doses: Patients should be instructed that if vomiting occurs within 2 hours of dosing an additional tablet should be taken. If vomiting occurs more than 2 hours after dosing, no further dose is needed. These recommendations are based on the absorption kinetics of sofosbuvir and GS-331007 suggesting that the majority of the dose is absorbed within 2 hours after dosing.
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.
Elderly: No dose adjustment is warranted for elderly patients.
Renal impairment: No dose adjustment of Sofosbuvir is required for patients with mild or moderate renal impairment. The safety and appropriate dose of Sofosbuvir have not been established in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) or end stage renal disease (ESRD) requiring haemodialysis.
Hepatic impairment: No dose adjustment of Sofosbuvir is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C). The safety and efficacy of Sofosbuvir have not been established in patients with decompensated cirrhosis.
Patients awaiting liver transplantation: The duration of administration of Sofosbuvir in patients awaiting liver transplantation should be guided by an assessment of the potential benefits and risks for the individual patient.
Paediatric population: The safety and efficacy of Sofosbuvir in children and adolescents aged <18 years have not yet been established. No data are available.
Method of administration: The film-coated tablet is for oral use. Patients should be instructed to swallow the tablet whole. The film-coated tablet should not be chewed or crushed, due to the bitter taste of the active substance. The tablet should be taken with food.
Sofosbuvir is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults.
Hypersensitivity to the active substance or to any of the excipients.
Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort). Co-administration will significantly decrease sofosbuvir plasma concentration and could result in loss of efficacy of Sovaldi.
General: Sofosbuvir is not recommended for administration as monotherapy and should be prescribed in combination with other medicinal products for the treatment of hepatitis C infection. If the other medicinal products used in combination with are permanently discontinued, Sofosbuvir should also be discontinued. Consult the physicians leaflet for co-prescribed medicinal products before starting therapy with Sofosbuvir.
Severe bradycardia and heart block: Cases of severe bradycardia and heart block have been observed when sofosbuvir-containing regimens are used in combination with amiodarone with or without other medicinal products that lower heart rate. The mechanism is not established.
Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection: This drug has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established.
Treatment of patients with genotype 5 or 6 HCV infection: The clinical data to support the use of in patients with genotype 5 and 6 HCV infection is very limited.
Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infection: Interferon-free regimens for patients with genotype 1, 4, 5 and 6 HCV infection with have not been investigated in Phase 3 studies. The optimal regimen and treatment duration have not been established. Such regimens should only be used for patients that are intolerant to or ineligible for interferon therapy, and are in urgent need of treatment.
Co-administration with other direct-acting antivirals against HCV: Sofosbuvir should only be co-administered with other direct-acting antiviral medicinal products if the benefit is considered to outweigh the risks based upon available data. There are no data to support the co-administration of and telaprevir or boceprevir. Such co-administration is not recommended.
Pregnancy and concomitant use with ribavirin: When is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during the treatment and for a period of time after the treatment as recommended in the physicians leaflet for ribavirin. Refer to the physicians leaflet for ribavirin for additional information.
Use with moderate P-gp inducers: Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration of such medicinal products is not recommended with Sovaldi.
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 medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated.
Renal impairment: The safety of Sovaldi has not been assessed in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or ESRD requiring haemodialysis. Furthermore, the appropriate dose has not been established. When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, refer also to the physician’s leaflet for ribavirin for patients with creatinine clearance (CrCl) <50 mL/min.
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 agents. 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.
Paediatric population: Sovaldi is not recommended for use in children and adolescents under 18 years of age because the safety and efficacy have not been established in this population.
See prescribing information for full details.
The most common adverse drug reactions occurring in patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia.
See prescribing information for full details.
Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolytic prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that accounts for greater than 90% of drug-related material systemic exposure is formed through pathways sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for
approximately 4% of drug-related material systemic exposure. In clinical
pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not.
Medicinal products that are strong P-gp inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort,) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi. Medicinal products that are moderate P-gp inducers in the intestine (e.g.
modafinil, oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommended with Sovaldi. Co-administration of Sovaldi with medicinal products that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration, thus Sovaldi may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of medicinal products that are substrates of these transporters.
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant medicinal products.
Patients treated with vitamin K antagonists: As liver function may change during treatment with Sovaldi, a close monitoring of International Normalised Ratio (INR) values is recommended.
Impact of DAA therapy on drugs metabolized by the liver: The pharmacokinetics of drugs 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.
See prescribing information for full details.
Pregnancy and Lactation
Pregnancy: There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir in pregnant women. As a precautionary measure, it is preferable to avoid the use of Sovaldi during pregnancy.
However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use of ribavirin during pregnancy apply.
Lactation: It is unknown whether sofosbuvir and its metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. Therefore, Sovaldi should not be used during breast-feeding.
See prescribing information for full details.
The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1,200 mg administered to 59 healthy subjects. In that study, there were no untoward effects observed at this dose level, and adverse reactions were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are unknown. No specific antidote is available for overdose with this drug. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sofosbuvir 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 (53% extraction ratio) the predominant circulating metabolite GS-331007. A 4-hour haemodialysis session removed 18% of the administered dose.
Storage: Do not store above 25°C.
Shelf life after first opening: 45 days.