This fixed-dose combination of Sofosbuvir and Velpatasvir is used for the treatment of chronic hepatitis C virus (HCV) infection. Sofosbuvir acts as an HCV NS5B polymerase inhibitor, while Velpatasvir is an NS5A inhibitor. It is indicated for adults and children aged 3 years and above with HCV genotypes 1, 2, 3, 4, 5, or 6:

• Patients without cirrhosis or with compensated cirrhosis.
• Patients with decompensated cirrhosis when used in combination with ribavirin

Mechanism of Action: Sofosbuvir inhibits the HCV NS5B RNA-dependent RNA polymerase, an essential enzyme for viral replication. It is a nucleotide prodrug that is metabolized داخل কোষে to form the active uridine analog triphosphate (GS-461203), which is incorporated into viral RNA and causes chain termination. GS-461203 demonstrates inhibitory activity against NS5B polymerase across multiple HCV genotypes (1b, 2a, 3a, and 4a) with IC50 values ranging from 0.36 to 3.3 micromolar. It does not inhibit human DNA or RNA polymerases nor mitochondrial RNA polymerase. Velpatasvir acts by inhibiting the HCV NS5A protein, which plays a critical role in viral replication. Resistance and cross-resistance studies confirm NS5A as the primary target of Velpatasvir.

Pharmacodynamics: Cardiac Electrophysiology: The effects of Sofosbuvir at 400 mg (recommended dose) and 1200 mg (three times the recommended dose) on QTc interval were assessed in controlled studies using moxifloxacin as a comparator. Even at three times the recommended dose, Sofosbuvir did not show clinically significant QTc prolongation. Similarly, Velpatasvir at 500 mg (five times the recommended dose) was evaluated and did not produce clinically meaningful QTc interval prolongation.

Testing prior to the initiation of therapy: Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with Sofosbuvir & Velpatasvir.

Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older: Below table shows the recommended treatment regimen and duration based on patient population. For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in table below. For treatment-naïve and treatment-experienced liver transplant recipients without cirrhosis or with compensated cirrhosis (Child-Pugh A), the recommended regimen is Sofosbuvir & Velpatasvir once daily for 12 weeks.

Recommended Treatment Regimen and Duration in Patients 3 Years of Age and Older with Genotype 1, 2, 3, 4, 5 or 6 HCV.

Recommended Dosage in Adults: The recommended dosage of Sofosbuvir & Velpatasvir in adults is one tablet (400 mg sofosbuvir and 100 mg velpatasvir) taken orally once daily with or without food. When administered with Sofosbuvir & Velpatasvir, the recommended dosage of ribavirin is based on weight (administered with food): 1,000 mg per day for patients less than 75 kg and 1,200 mg for those weighing at least 75 kg, divided and administered twice daily. The starting dosage and on-treatment dosage of ribavirin can be decreased based on hemoglobin and creatinine clearance. For ribavirin dosage modifications refer to the ribavirin prescribing information.

Recommended Dosage in Pediatric Patients 3 Years of Age and Older: The recommended dosage of Sofosbuvir & Velpatasvir in pediatric patients 3 years of age and older is based on weight and provided in table below

Dosing for Pediatric Patients 3 Years and Older with Genotype 1, 2, 3, 4, 5 or 6 HCV Using Sofosbuvir & Velpatasvir tablets.

Pediatric use: Recommended Dosing for Ribavirin in Combination Therapy with Sofosbuvir & Velpatasvir for Pediatric Patients 3 Years and Older

Potential for Other Drugs to Affect Sofosbuvir & Velpatasvir: Sofosbuvir and Velpatasvir are substrates of drug transporters such as P-gp and BCRP, whereas GS-331007 (the primary circulating metabolite of Sofosbuvir) is not. Velpatasvir is metabolized by CYP2B6, CYP2C8, and CYP3A4 enzymes. Strong inducers of P-gp or moderate to strong inducers of these CYP enzymes (e.g., rifampicin, St. John’s wort, carbamazepine) may significantly lower plasma concentrations of Sofosbuvir and Velpatasvir, thereby reducing their therapeutic efficacy. Concomitant use with these agents is not recommended. Sofosbuvir and Velpatasvir may also inhibit P-gp, BCRP, and CYP enzymes.

Potential for Sofosbuvir & Velpatasvir to Affect Other Drugs: Velpatasvir inhibits drug transporters including P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1. Co-administration with drugs that are substrates of these transporters may increase their plasma levels.

Established and Potentially Significant Drug Interactions: Clinically relevant drug interactions have been identified based on studies with Sofosbuvir, Velpatasvir, or their combination. These interactions should be carefully considered during therapy.

The combination of this medicine with ribavirin is contraindicated in patients where ribavirin use is not appropriate. Refer to ribavirin prescribing information for detailed contraindications.

The most commonly observed adverse effects with Sofosbuvir and Velpatasvir combination include fatigue, nausea, headache, anemia, diarrhea, insomnia, itching, muscle pain, shortness of breath, and cough. Less common but notable effects include reductions in hemoglobin, lymphocyte count, neutrophil count, and platelet count. Cases of symptomatic bradycardia have been reported when used with amiodarone and other direct-acting antivirals.

Pregnancy: When used in combination with ribavirin, this regimen is contraindicated in pregnant women and in men whose partners are pregnant due to the risk associated with ribavirin.

Lactation: It is unknown whether Sofosbuvir, Velpatasvir, or their metabolites are excreted in human milk or affect breastfed infants.

Females and Males of Reproductive Potential: If used with ribavirin, guidelines related to pregnancy testing, contraception, and infertility associated with ribavirin must be followed.

In patients co-infected with HCV and HBV, reactivation of hepatitis B virus has been reported during or after treatment, which may lead to severe complications including liver failure. Patients should be monitored for HBV infection before and during treatment. Serious symptomatic bradycardia has been observed when Sofosbuvir is used with amiodarone; caution is advised. Liver function should be monitored regularly during therapy.

No dose adjustment is required in elderly patients. No significant differences in safety or efficacy have been observed in this group.

Limited data are available regarding overdose. Patients should be monitored closely, and supportive care should be provided. Hemodialysis is unlikely to significantly remove Velpatasvir due to high protein binding.

Hepatitis C antiviral agents.

Store in a cool and dry place below 30°C. Protect from light. Keep out of reach of children.