It is a fixed-dose combination of sofosbuvir,a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor,and velpatasvir,an HCV NS5A inhibitor,and is indicated for the treatment of adult patients with chronic HCV genotype 1,2,3,4,5 or 6 infection : ? without cirrhosis or with compensated cirrhosis ? with decompensated cirrhosis for use in combination with ribavirin
NS5B polymerase inhibitor,HCV NS5A inhibitor
Mechanism of Action: Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with an IC50 value ranging from 0.36 to 3.3 micromolar. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase. Velpatasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate Velpatasvir targets NS5A as its mode of action.
Pharmacodynamics: Cardiac Electrophysiology: The effect of Sofosbuvir 400 mg (recommended dosage) and 1200 mg (three times the recommended dosage) on QTc interval was evaluated in an active-controlled (Moxifloxacin 400 mg) thorough QT trial. At a dose three times the recommended dose, Sofosbuvir does not prolong QTc to any clinically relevant extent. The effect of Velpatasvir 500 mg (five times the recommended dosage) was evaluated in an active-controlled (Moxifloxacin 400 mg) thorough QT trial. At a dose five times the recommended dose, Velpatasvir does not prolong QTc interval to any clinically relevant extent.
Recommended dosage: One tablet (400 mg of sofosbuvir and 100 mg of velpatasvir) taken orally once daily with or without food ? See recommended treatment regimen and duration in patients with genotypes 1,2,3,4,5,or 6 HCV in table below: Patient Population Recommended Treatment Regimen Patients without cirrhosis and patients with compensated cirrhosis (Child-Pugh A) It for 12 weeks Patients with decompensated cirrhosis (Child-Pugh B and C) It + ribavirin for 12 weeks ? A dosage recommendation cannot be made for patients with severe renal impairment or end stage renal disease
Potential for Other Drugs to Affect Sofosbuvir & Velpatasvir: Sofosbuvir and Velpatasvir are substrates of drug transporters P-gp and BCRP while GS-331007 (the predominant circulating metabolite of Sofosbuvir) is not. In vitro, slow metabolic turnover of Velpatasvir by CYP2B6, CYP2C8 and CYP3A4 was observed. Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6, CYP2C8 or CYP3A4 (e.g., Rifampin, St. John’s wort, Carbamazepine) may decrease plasma concentrations of Sofosbuvir and/or Velpatasvir, leading to reduced therapeutic effect of Sofosbuvir & Velpatasvir. The use of these agents with Sofosbuvir & Velpatasvir is not recommended. Sofosbuvir & Velpatasvir may be coadministered with P-gp, BCRP and CYP inhibitors.
Potential for Sofosbuvir & Velpatasvir to Affect Other Drugs: Velpatasvir is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP), OATP1B1, OATP1B3 and OATP2B1. Coadministration of Sofosbuvir & Velpatasvir with drugs that are substrates of these transporters may increase the exposure of such drugs.
Established and Potentially Significant Drug Interactions: Table below provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either Sofosbuvir & Velpatasvir, the components of Sofosbuvir & Velpatasvir as individual agents or are predicted drug interactions that may occur with Sofosbuvir & Velpatasvir.
It and ribavirin combination regimen is contraindicated in patients for whom ribavirin is contraindicated
Headache and fatigue,cirrhosis are fatigue,anemia,nausea,headache,insomnia and diarrhea.
No adequate human data are available to establish whether or not Sofosbuvir and Velpatasvir combination poses a risk to pregnancy outcomes. If Sofosbuvir and Velpatasvir combination administered with Ribavirin,the combination regimen is contraindicated in pregnant women and in men whose female partner is pregnant or going to be pregnant in next six months.
No specific antidote is available for overdose with Sofosbuvir & Velpatasvir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sofosbuvir & Velpatasvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis can efficiently remove the predominant circulating metabolite of Sofosbuvir, GS-331007, with an extraction ratio of 53%. Hemodialysis is unlikely to result in significant removal of Velpatasvir since Velpatasvir is highly bound to plasma protein.
Store in a cool and dry place (preferably below 30°C). Keep out of reach of children.
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