Sofomax F/C Tablet

Sofosbuvir 400mg

Composition
Sofomax® 400 tablet: Each coated tablet contains Sofosbuvir INN 400 mg.


Pharmacology
Sofomax® is a preparation of Sofosbuvir which is a direct-acting antiviral agent against the hepatitis C virus (HCV).


Mechanism of action: Sofomax® is an inhibitor of the HCV NS5B RNA dependent RNA polymerase, which is essential for viral replication. Sofomax® 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 IC50 values ranging from 0.7 to 2.6 micromolar. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.


Pharmacodynamics: The effect of Sofomax® 400 on QTc interval was evaluated in a randomized, single-dose, placebo and active controlled four period crossover thorough QT trial in 59 healthy subjects. At a dosage three times the maximum recommended dosage, Sofomax® does not prolong QTc to any clinically relevant extent.


Pharmacokinetics
Absorption: The pharmacokinetic properties of Sofomax® and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration of Sofomax®, it was absorbed with a peak plasma concentration observed at ~0.5–2 hour post-dose, regardless of dose level.


Distribution: Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 microgram/mL to 20 microgram/mL.


Metabolism: Sofomax® is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.


Elimination: Following a single 400 mg oral dose of Sofomax®, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively.

Indication
Sofomax® is indicated for the treatment of genotype 1, 2, 3 or 4 chronic hepatitis C virus (HCV) infection as a component of a combination antiviral
treatment regimen. 

Dose and administration
Route of administration: Sofomax® should be taken in oral route. The recommended dosage of Sofomax® is one 400 mg tablet taken orally once daily with or without food. Administer Sofomax® in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of HCV. The recommended treatment regimen and duration for Sofomax® combination therapy is below -

Patient Population Treatment Regimen Duration
Genotype 1 or 4 Sofomax®+ Peginterferon Alfa + Ribavirin 12 weeks
Genotype 2 Sofomax® + Ribavirin 12 weeks
Genotype 3 Sofomax® + Ribavirin 24 weeks
  • HCV/HIV-1 co-infection: For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in the table above.
  • Sofomax® in combination with ribavirin for 24 weeks can be considered for patients with genotype 1 infection who are interferon ineligible.
  • Should be used in combination with ribavirin for treatment of HCV in patients with hepatocellular carcinoma awaiting liver transplantation for up to
    48 weeks or until liver transplantation, whichever occurs first.
  • A dosage recommendation cannot be made for patients with severe renal impairment or end stage renal disease.

Geriatric use: No dosage adjustment of sofosbuvir is warranted in geriatric patients.

Patients with renal impairment: No dosage adjustment of sofosbuvir is required for patients with mild or moderate renal impairment. The safety and efficacy of sofosbuvir have not been established in patients with severe renal impairment (eGFR less than 30 ml/min/1.73 m2) or ESRD requiring hemodialysis.

Patients with hepatic impairment: No dosage adjustment of sofosbuvir is required for patients with mild, moderate or severe hepatic impairment. Safety and efficacy of sofosbuvir have not been established in patients with decompensated cirrhosis.

Contraindication
Sofosbuvir is contraindicated in patients with known hypersensitivity to sofosbuvir or any of its components. And when sofosbuvir is used in combination with ribavirin or peginterferon alfa, the contraindications applicable to those agents are applicable to combination therapies.


Warning and precaution
HCV or HBV (hepatitis B virus) co-infection: Cases of hepatitis B virus (HBV) reactivation 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 or HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.

Bradycardia with amiodarone co-administration: Serious symptomatic bradycardia may occur in patients taking amiodarone and sofosbuvir plus ledipasvir combination with another direct acting antiviral (DAA), particularly in patients also receiving beta blockers or those with underlying cardiac comorbidities or advanced liver disease. Co administration of amiodarone with sofosbuvir in combination with another DAA is not recommended. In patients without alternative, viable treatment options, cardiac monitoring is recommended.

Risk of reduced therapeutic effect due to use with P-gp inducers: Drugs that are P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of sofosbuvir. The use of rifampin and St. John’s wort with sofosbuvir is not recommended.

Side effects
The most common side effects of sofosbuvir in combination with ribavirin are fatigue and headache. The most common side effects of sofosbuvir in combination with peginterferon alfa and ribavirin are fatigue, headache, nausea, insomnia and anemia.

Use in pregnancy and lactation

Pregnancy: Sofosbuvir is pregnancy category B drug. There are no adequate and well controlled studies with sofosbuvir in pregnant women. Because animal reproduction studies are not always predictive of human response, sofosbuvir should be used during pregnancy only if the potential for benefit justifies the potential risk to the fetus. If sofosbuvir is administered with ribavirin or peginterferon and ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant.

Lactation: It is not known whether sofosbuvir and its metabolites are present in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sofosbuvir and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. If sofosbuvir is administered in a regimen containing ribavirin, the information for ribavirin with regard to nursing mothers also applies to this combination regimen.

Use in children and adolescents
The safety, pharmacokinetics, and efficacy of sofosbuvir in pediatric patients 12 years of age and older or weighing at least 35 kg with genotype 2 and 3 infection have been established. The safety and efficacy of sofosbuvir in pediatric patients 12 years of age and older or weighing at least 35 kg with compensated cirrhosis is supported by comparable sofosbuvir and GS-331007 exposures between: 1) adults and adolescents without cirrhosis and 2) adults without cirrhosis and adults with compensated cirrhosis. Thus, similar efficacy would be expected for adolescent patients with compensated cirrhosis as adults with compensated cirrhosis. The safety and efficacy of sofosbuvir have not been established in pediatric patients less than 12 years of age and weighing less than 35 kg with HCV genotype 2 or 3. The safety and efficacy of sofosbuvir have not been established in pediatric patients with HCV genotype 1 or 4.

Drug interaction
Drug interaction with medications: INR value should be monitored closely during treatment of chronic HCV with direct acting antivirals (sofosbuvir) in patients receiving vitamin K antagonists (e.g. warfarin). Sofosbuvir has drug-drug interactions with cyclosporine, darunavir, efavirenz, emtricitabine, tenofovir disoproxil fumarate, methadone, rilpivirine and tacrolimus.

Drug interaction with foods: Not applicable

Drug interaction with others: Coadministration of sofosbuvir is not recommended in St. John’s wort, an intestinal P-gp inducer.

Overdose
The highest dosage of sofosbuvir was a single dose of sofosbuvir 1200 mg. No specific antidote is available for overdose with sofosbuvir. 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.

Storage
Sofomax® 400 mg tablet: Store in a cool (below 30°C) and dry place. Protect from light. Keep away from the reach of children

Packing
Sofomax® 400 mg tablet: Carton of 7 tablets in blister pack.