Fixvel Tablet

This 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 and pediatric patients 3 years of age and older 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

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.

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 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.

This medicine and Ribavirin combination regimen is contraindicated in patients for whom Ribavirin is contraindicated. Refer to the Ribavirin prescribing information for a list of contraindications for Ribavirin.

The most common side effects observed with Sofosbuvir & Velpatasvir combination were fatigue, nausea, headache, anemia, diarrhea, insomnia, pruritus, muscle spasm, dyspnea and cough. There are some rare adverse events including reduced hemoglobin level, reduced lymphocyte count, reduced neutrophil count and reduced platelet count. Serious symptomatic bradycardia developed when Sofosbuvir is coadministered with Amiodarone and another HCV Direct Acting Antiviral.

Pregnancy: If this medicine is administered with Ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the Ribavirin prescribing information for more information on Ribavirin-associated risks of use during pregnancy.

Lactation: It is not known whether the components of Velpatasvir & Sofosbuvir and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. 

Females and Males of Reproductive Potential: If Sofosbuvir & Velpatasvir is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information.

Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV: Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and in severe cases, increases in bilirubin levels, liver failure and death can occur. Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with Sofosbuvir & Velpatasvir. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with Sofosbuvir & Velpatasvir and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with a sofosbuvir-containing regimen. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir-containing regimen. Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown. Coadministration of amiodarone with Sofosbuvir & Velpatasvir is not recommended. For patients taking amiodarone who have no other alternative viable treatment options and who will be coadministered Sofosbuvir & Velpatasvir:

• Counsel patients about the risk of symptomatic bradycardia
• Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, 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. Patients who are taking Sofosbuvir & Velpatasvir, need to start amiodarone therapy due to no other alternative viable treatment options should undergo similar cardiac monitoring as outlined above. Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting Sofosbuvir & Velpatasvir should also undergo similar cardiac monitoring as outlined above. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems.

Risks Associated with Ribavirin and Sofosbuvir & Velpatasvir Combination Treatment: If Sofosbuvir & Velpatasvir is administered with ribavirin, the warnings and precautions for ribavirin apply to Fixvel regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin.

Geriatric Patients: Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 82 years) analyzed, age did not have a clinically relevant effect on the exposure to Sofosbuvir, GS-331007 or Velpatasvir.

Patients with Renal Impairment: The pharmacokinetics of Sofosbuvir were studied in HCV negative subjects with mild (eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to less than 50 mL/min/1.73 m2), severe renal impairment (eGFR less than 30 mL/min/1.73 m2), and subjects with ESRD requiring hemodialysis following a single 400 mg dose of Sofosbuvir. Relative to subjects with normal renal function (eGFR greater than 80 mL/min/1.73 m2), the Sofosbuvir AUC0-inf was 61%, 107% and 171% higher in subjects with mild, moderate and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, Sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when Sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when Sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4 hour hemodialysis session removed approximately 18% of administered dose. The pharmacokinetics of Velpatasvir were studied with a single dose of 100 mg Velpatasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in Velpatasvir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

Patients with Hepatic Impairment: The pharmacokinetics of Sofosbuvir were studied following 7-day dosing of 400 mg Sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C, respectively). Relative to subjects with normal hepatic function, the Sofosbuvir AUC0-24 were 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of Sofosbuvir and GS-331007. The pharmacokinetics of Velpatasvir were studied with a single dose of 100 mg Velpatasvir in HCV negative subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Velpatasvir plasma exposure (AUCinf ) was similar in subjects with moderate hepatic impairment, severe hepatic impairment and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of Velpatasvir.

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.

Hepatic viral infections (Hepatitis C)

Store in a cool and dry place (preferably below 30°C). Keep out of reach of children.