HEPCVIR Tablets (Sofosbuvir )

Table of Content

Globally, it is estimated that 170-185 million people (about 3% of the world’s population) are chronically infected with hepatitis C virus (HCV). Untreated chronic hepatitis C increases the risk of cirrhosis of liver, liver failure and liver cancer. In India alone, it is estimated that 12-18 million patients are infected with hepatitis C which is several fold greater than those with HIV/AIDS. Globally, HCV is implicated in 28% of cases of liver cirrhosis and 26% of cases of liver cancer, which accounts for almost 500,000 deaths per year.

Existing hepatitis C treatment with the conventional peg-interferon and ribavirin combination achieves modest cure or sustained virologic response (SVR) rates of 40-50% in HCV genotype 1 (over 48 weeks) and 70-80% in HCV genotype 2 and 3 (over 24 weeks). Sofosbuvir is the first directly acting antiviral and first-in-class NS5B nucleotide analogue to be approved in India for chronic hepatitis C treatment in adults. This drug in combination with ribavirin and/or peg–interferon alfa, over 12-24 weeks has shown to have high cure rates or achievement of SVR of almost 90% and above in treatment–naïve HCV patients.

It is also recommended for the treatment of HIV-HCV co-infection and in patients with liver cancer due to HCV and awaiting a liver transplant.

The key features of this drug include:

  • High potency and SVR rates
  • High barrier to resistance
  • Pangenotypic activity (across HCV genotypes 1,2,3 and 4)
  • Once-daily dosage
  • Excellent safety and tolerability  
  • Limited drug-drug interactions  

Hence sofosbuvir (HEPCVIR ) is an ideal breakthrough drug for successful hepatitis C treatment and represents a paradigm shift in the existing hepatitis C management. The introduction of HEPCVIR indeed marks a new era in the management of hepatitis C.

To be sold by retail on the prescription of a Hepatologist only

Black Box Warning

WARNING: RISK OF HEPATITIS B VIRUS (HBV) REACTIVATION IN PATIENTS CO-INFECTED WITH HEPATITIS C VIRUS (HCV) AND HBV

Test all patients for evidence of current or prior HBV infection before initiating treatment with HEPCVIR Tablets. HBV reactivation has been reported in HCV/HBV co-infected patients who were undergoing or had completed treatment with HCV direct-acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV co-infected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Qualitative and Quantitative Composition

HEPCVIR Tablets

Each film-coated tablet contains:

Sofosbuvir ……………………………400 mg

Excipients ...................................……………..q.s.

Colors: Titanium Dioxide IP and Sunset Yellow FCF Aluminum Lake

Dosage Form(s) and Strength(s)

Tablet containing 400 mg of sofosbuvir.

Clinical Particulars

Therapeutic Indications

HEPCVIR Tablets are indicated “in combination with other medication products for the treatment of chronic hepatitis C (CHC) in adults”.

Posology and Method of Administration

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 HEPCVIR Tablets.

Recommended Dosage in Adults

The recommended dose of HEPCVIR Tablets is one 400 mg tablet, taken orally, once daily with or without food .

Administer sofosbuvir in combination with ribavirin or in combination with pegylated (peg)-interferon and ribavirin for the treatment of HCV. The recommended regimen and treatment duration for sofosbuvir combination therapy is provided in Table 1.

For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to Drug Interactions for dosage recommendations for concomitant HIV-1 antiviral drugs.

Table 1: Recommended Treatment Regimen and Duration in Adult Patients with Genotype 1, 2, 3, or 4 HCV

 

Patient Population

Treatment Regimen

Duration

Patients with genotype 1 or 4 CHC

Treatment-naïve without cirrhosis or with

compensated cirrhosis (Child-Pugh A)

Sofosbuvir+ peg-interferon alfaa + ribavirinb

12 weeks

Patients with genotype 2 CHC

Treatment-naïve and treatment-experiencedc

without cirrhosis or with

compensated cirrhosis (Child-Pugh A)

Sofosbuvir + ribavirinb

12 weeks

Patients with genotype 3 CHC

Treatment-naïve and treatment-experiencedc

without cirrhosis or with

compensated cirrhosis (Child-Pugh A)

Sofosbuvir + ribavirinb

24 weeks

aSee peg-interferon alfa prescribing information for dosing recommendation for patients with genotype 1 or 4 HCV.

bDose of ribavirin is weight-based (<75 kg = 1,000 mg and ≥75 kg = 1,200 mg). The daily dose of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (creatinine clearance ≤50 mL/min) require ribavirin dose reduction; refer to ribavirin prescribing information.

c Treatment-experienced patients have failed an interferon-based regimen with or without ribavirin

Patients with Genotype 1 HCV Who are Ineligible to Receive an Interferon-based Regimen

Sofosbuvir in combination with ribavirin for 24 weeks can be considered as a therapeutic option for patients with genotype 1 infection who are ineligible to receive an interferon-based regimen. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient.

Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation

Sofosbuvir in combination with ribavirin is recommended for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection.

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 medicinal product, the peginterferon alfa dose should be reduced or discontinued.

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. Table 2 provides guidelines for dose modifications and discontinuation based on the patient’s haemoglobin concentration and cardiac status.

Table 2: Ribavirin dose modification guideline for co-administration with sofosbuvir in adults

Laboratory values

Reduce ribavirin dose to 600 mg/day if:

Discontinue ribavirin if:

Haemoglobin in patients with no cardiac disease

<10 g/dL

<8.5 g/dL

Haemoglobin in patients with history of stable cardiac disease

≥2 g/dL decrease in haemoglobin during any 4 week treatment period

<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 agents used in combination with sofosbuvir are permanently discontinued, sofosbuvir should also be discontinued.

Severe Renal Impairment and End-Stage Renal Disease (ESRD)

No dose recommendation can be given for patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) or with ESRD due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite .

Contraindications

When sofosbuvir is used in combination with ribavirin or peg-interferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peg-interferon alfa and ribavirin for a list of their contraindications.

Special Warnings and Precautions for Use

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 sofosbuvir are permanently discontinued, sofosbuvir should also be discontinued.

Risk of HBV Reactivation in Patients Co-infected with HCV and HBV

HBV reactivation has been reported in HCV/HBV co-infected patients who were undergoing or had completed treatment with HCV DAAs, 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 immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs 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. 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 and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Serious Symptomatic Bradycardia When Co-administered with Amiodarone

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co-administered with sofosbuvir in combination with an investigational agent (NS5A inhibitor) or simeprevir. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). 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 co-administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.

Co-administration of amiodarone with sofosbuvir in combination with another DAA is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be co-administered sofosbuvir and another DAA:

  • Counsel patients about the risk of serious symptomatic bradycardia.
  • Cardiac monitoring in an in-patient setting for the first 48 hours of co-administration 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 who 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 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 .

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 .

Risks Associated with Combination Treatment

Because sofosbuvir is used in combination with other antiviral drugs for treatment of HCV infection, consult the prescribing information for these drugs used in combination with sofosbuvir. Warnings and precautions related to these drugs also apply to their use in sofosbuvir combination treatment.

Drug Interactions

Potentially Significant Drug Interactions

Sofosbuvir is a substrate of the drug transporter P-glycoprotein (P­gp) and breast cancer resistance protein (BCRP) while the predominant circulating metabolite GS­331007 is not. Drugs that are P­gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of sofosbuvir, and thus concomitant use with sofosbuvir is not recommended.

Clearance of HCV infection with DAAs may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.

Frequent monitoring of relevant laboratory parameters (e.g. International Normalized Ratio in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as cytochrome (CY) P450 substrates with a narrow therapeutic index (e.g., certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.

Information on potential drug interactions with sofosbuvir is summarized in Table 3. The table is not all­inclusive.      

Table 3: Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interactiona

Concomitant Drug Class: Drug Name

Effect on Concentrationb

Clinical Comment

Anti-arrhythmics:

Amiodarone

 

 

Effect on

amiodarone and sofosbuvir

concentrations unknown

 

Co-administration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Co-administration of amiodarone with sofosbuvir in combination with another DAA is not recommended; if co-administration is required, cardiac monitoring is recommended

 

Anticonvulsants: Carbamazepine

Phenytoin Phenobarbital Oxcarbazepine

↓ sofosbuvir

↓ GS-331007

Co-administration of sofosbuvir with carbamazepine, phenytoin, phenobarbital or oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of sofosbuvir. Co-administration is not recommended.

Antimycobacterials: Rifabutin

Rifampin

Rifapentine

↓ sofosbuvir

↓ GS-331007

Co-administration of sofosbuvir with rifabutin or rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of sofosbuvir. Co-administration is not recommended. Sofosbuvir should not be used with rifampin, a potent intestinal P-gp inducer.

Herbal Supplements: St. John’s wort (Hypericum perforatum)

↓ sofosbuvir

↓ GS-331007

Co-administration of sofosbuvir with St. John’s wort, an intestinal P­gp inducer, is not recommended

HIV Protease Inhibitors: Tipranavir/ritonavir

↓ sofosbuvir

↓ GS-331007

Co-administration of sofosbuvir with tipranavir/ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of sofosbuvir. Co-administration is not recommended.

aThis table is not all-inclusive.

b↓ = decrease.

Drugs without Clinically Significant Interactions with Sofosbuvir

Based on drug interaction studies conducted with sofosbuvir, no clinically significant drug interactions have been either observed or are expected when sofosbuvir is combined with the following drugs: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, oral contraceptives, or tenofovir disoproxil fumarate.

Assessment of Drug Interactions

Sofosbuvir is a substrate of P­gp and BCRP while GS­331007 is not. Drugs that are P­gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of sofosbuvir and, thus, concomitant use with sofosbuvir is not recommended.

Co-administration of sofosbuvir with drugs that inhibit P­gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS­331007 plasma concentration; accordingly, sofosbuvir may be co-administered with P­gp and/or BCRP inhibitors.

Sofosbuvir and GS­331007 are not inhibitors of P­gp and BCRP and, thus, are not expected to increase exposures of drugs 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 drugs.

The effects of co-administered drugs on the exposure of sofosbuvir and GS­331007 are shown in Table 4. The effects of sofosbuvir on the exposure of co-administered drugs are shown in Table 5.

Table 4: Drug Interactions: Changes in Pharmacokinetic Parameters for Sofosbuvir and the Predominant Circulating Metabolite GS­331007 in the Presence of the Co-administered Druga

 

Co-administered Drug

 

Dose of Co-administered Drug (mg)

 

Sofosbuvir Dose (mg)

 

 

N

Mean Ratio (90% CI) of Sofosbuvir and GS­ 331007 PK with/without Co-administered Drug

No Effect=1.00

 

Cmax

AUC

Cmin

 

 

Cyclosporine

 

 

600 single dose

 

400 single dose

 

 

19

sofosbuvir

2.54

(1.87, 3.45)

4.53

(3.26, 6.30)

NA

GS­331007

0.60

(0.53, 0.69)

1.04

(0.90, 1.20)

NA

 

Darunavir

(boosted with ritonavir)

 

800/100 once daily

 

400 single dose

 

 

18

sofosbuvir

1.45

(1.10, 1.92)

1.34

(1.12, 1.59)

NA

GS­331007

0.97

(0.90, 1.05)

1.24

(1.18, 1.30)

NA

Efavirenzc

600 once daily

 

400 single dose

 

 

16

 

sofosbuvir

0.81

(0.60, 1.10)

0.94

(0.76, 1.16)

NA

Emtricitabinec

200 once daily

Tenofovir disoproxil fumaratec

 

300 once daily

 

GS­331007

0.77

(0.70, 0.84)

0.84

(0.76, 0.92)

 

NA

 

 

Methadone

 

30 to 130 once daily

 

400 once daily

 

 

14

sofosbuvir

0.95b (0.68, .33)

1.30b (1.00, .69)

NA

GS­331007

0.73b (0.65,0.83)

 

 

 1.04b (0.89, .22)

NA

 

 

Rilpivirine

 

 

25 once daily

 

400 single dose

 

 

17

sofosbuvir

1.21

(0.90, 1.62)

1.09

(0.94, 1.27)

NA

GS­331007

1.06

(0.99, 1.14)

1.01

(0.97, 1.04)

NA

 

 

Tacrolimus

 

 

5 single dose

 

400 single dose

 

 

16

sofosbuvir

0.97

(0.65, 1.43)

1.13

(0.81, 1.57)

NA

GS­331007

0.97

(0.83, 1.14)

1.00

(0.87, 1.13)

NA

NA = not available/not applicable; PK = pharmacokinetics
  1. All interaction studies conducted in healthy volunteers
  2. Comparison based on historic control
  3. Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed-dose tablet

No effect on the pharmacokinetic parameters of sofosbuvir and GS­331007 was observed with raltegravir.

Table 5: Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Sofosbuvira

 

Co-administered Drug

 

Dose of Co-administered Drug (mg)

 

Sofosbuvir Dose (mg)

 

 

N

Mean Ratio (90% CI) of Co-administered Drug PK with/without Sofosbuvir

No Effect=1.00

Cmax

AUC

Cmin

Norelgestromin

 

 

norgestimate 0.18/0.215/0.25/

ethinyl estradiol

0.025 once daily

 

 

 

400 once daily

 

 

 

15

1.07

(0.94, 1.22)

1.06

(0.92, 1.21)

1.07

(0.89, 1.28)

Norgestrel

1.18

(0.99, 1.41)

1.19

(0.98, 1.45)

1.23

(1.00, 1.51)

Ethinyl estradiol

1.15

(0.97, 1.36)

1.09

(0.94, 1.26)

0.99

(0.80, 1.23)

Raltegravir

400 twice daily

400 single dose

19

0.57

(0.44, 0.75)

0.73

(0.59, 0.91)

0.95

(0.81, 1.12)

Tacrolimus

5 single dose

400 single dose

16

0.73

(0.59, 0.90)

1.09

(0.84, 1.40)

NA

Tenofovir disoproxil fumarateb

 

300 once daily

400 single dose

 

16

1.25

(1.08, 1.45)

0.98

(0.91, 1.05)

0.99

(0.91, 1.07)

NA = not available/not applicable; PK = pharmacokinetics
  1. All interaction studies conducted in healthy volunteers
  2. Administered as efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed dose tablet

No effect on the pharmacokinetic parameters of the following co-administered drugs was observed with sofosbuvir: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, or rilpivirine.

Use in Special Populations

Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation

Sofosbuvir was studied in HCV-infected subjects with hepatocellular carcinoma prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of sofosbuvir and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) defined as HCV RNA less than the lower limit of quantification (LLOQ) at 12 weeks post-transplant. HCV-infected subjects, regardless of genotype, with hepatocellular carcinoma meeting the MILAN criteria (defined as the presence of a tumor, 5 cm or less in diameter, in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter, in patients with multiple tumors and no extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor) received 400 mg sofosbuvir and weight-based 1,000–1,200 mg ribavirin daily for 24–48 weeks or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 subjects who received sofosbuvir and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a baseline CPT score less than 7, and all subjects had a baseline unadjusted MELD score ≤14. Of these 61 subjects, 41 subjects underwent liver transplantation following up to 48 weeks of treatment with sofosbuvir and ribavirin; 37 had HCV RNA less than the LLOQ at the time of transplantation. Of the 37 subjects, the post-transplant virologic response (pTVR) rate was 64% (23/36) in the 36 evaluable subjects who had reached the 12 week post-transplant time point. The safety profile of sofosbuvir and ribavirin in HCV-infected subjects prior to liver transplantation was comparable with that observed in subjects treated with sofosbuvir and ribavirin in Phase 3 clinical trials.

Post-Liver Transplant Patients

The safety and efficacy of sofosbuvir has not been established in post-liver transplant patients.

CHC Patients with Genotype 5 or 6 HCV Infection

Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing recommendations.

Patients with Renal Impairment

No dose 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 <30 mL/min/1.73 m2) or ESRD requiring hemodialysis. No dose recommendation can be given for patients with severe renal impairment or ESRD .

Patients with Hepatic Impairment

No dose adjustment of sofosbuvir is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B or C) . Safety and efficacy of sofosbuvir have not been established in patients with decompensated cirrhosis.

Pregnant Women

Risk Summary

If sofosbuvir is administered with ribavirin or peg-interferon alfa and ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin and/or peg-interferon alfa prescribing information for more information on ribavirin­ and peg-interferon alfa associated risks of use during pregnancy.

No adequate human data are available to establish whether or not sofosbuvir poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with sofosbuvir at exposures greater than those in humans at the recommended human dose (RHD) . During organogenesis in the rat and rabbit, systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS­331007) were ≥5 (rats) and 12 (rabbits) times the exposure in humans at the RHD. In the rat pre/postnatal development study, maternal systemic exposure (AUC) to GS­331007 was ≥6 times the exposure in humans at the RHD.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

ANIMAL DATA

Sofosbuvir was administered orally to pregnant rats (up to 500 mg/kg/day) and rabbits (up to 300 mg/kg/day) on gestation days 6 to 18 and 6 to 19, respectively, and also to rats (oral doses up to 500 mg/kg/day) on gestation day 6 to lactation/post­partum day 20. No significant effects on embryo­fetal (rats and rabbits) or pre/postnatal (rats) development were observed at the highest doses tested. Systemic exposures (AUC) to the predominant circulating metabolite of sofosbuvir (GS­331007) were ≥5 (rats) and  12 (rabbits) times the exposure in humans at the RHD, with exposures increasing during gestation from approximately 5 to 10 (rats) and 12 to 28 (rabbits) times the exposure in humans at the RHD.

Lactating Women

Risk Summary

It is not known whether sofosbuvir or its metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. The predominant circulating metabolite of sofosbuvir (GS­331007) was the primary component observed in the milk of lactating rats, without effect on nursing pups .

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 sofosbuvir or from the underlying maternal condition.

If sofosbuvir is administered with ribavirin, the nursing mother’s information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation.

Data

ANIMAL DATA

No effects of sofosbuvir on growth and postnatal development were observed in nursing pups at the highest dose tested in rats. Maternal systemic exposure (AUC) to the predominant circulating metabolite of sofosbuvir (GS­331007) was approximately 12 times the exposure in humans at the RHD, with exposure of approximately 2% that of maternal exposure observed in nursing pups on lactation day 10. In a lactation study, sofosbuvir metabolites (primarily GS­331007) were excreted into the milk of lactating rats following administration of a single oral dose of sofosbuvir (20 mg/kg) on lactation day 2, with milk concentrations of approximately 10% that of maternal plasma concentrations observed 1 hour post­dose.

Females and Males of Reproductive Potential

If sofosbuvir is administered with ribavirin or peg-interferon alfa and ribavirin, the information for ribavirin and peg-interferon alfa with regard to pregnancy testing, contraception, and infertility also applies to these combination regimens. Refer to ribavirin and/or peg-interferon prescribing information for additional information.

Pediatric Patients

Safety and effectiveness of HEPCVIR Tablets have not been established in pediatric patients

Geriatric Patients

Sofosbuvir was administered to 90 subjects aged 65 years and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups. No dose adjustment of sofosbuvir is warranted in geriatric patients.

Effects on Ability to Drive and Use Machines

Sofosbuvir has moderate influence on the ability to drive and use machines. Patients should be informed that fatigue and disturbance in attention, dizziness and blurred vision have been reported during treatment with sofosbuvir in combination with peg-interferon alfa and ribavirin.

Undesirable Effects

The following serious adverse reaction has been discussed in the Special Warnings and Precautions for Use section of the labeling:

  • Serious Symptomatic Bradycardia When Co-administered with Amiodarone

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

When sofosbuvir is administered with ribavirin or peg-interferon alfa/ribavirin, refer to the respective prescribing information for a description of adverse reactions associated with their use.

Adverse Reactions in Adult Subjects

The safety assessment of sofosbuvir was based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) and included

  • 650 subjects who received sofosbuvir + ribavirin combination therapy for 12 weeks;
  • 98 subjects who received sofosbuvir + ribavirin combination therapy for 16 weeks;
  • 250 subjects who received sofosbuvir + ribavirin combination therapy for 24 weeks;
  • 327 subjects who received sofosbuvir + peg-interferon (peg­IFN) alfa + ribavirin combination therapy for 12 weeks;
  • 243 subjects who received peg-interferon alfa + ribavirin for 24 weeks; and
  • 71 subjects who received placebo (PBO) for 12 weeks.

The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving sofosbuvir + ribavirin for 12 weeks, <1% for subjects receiving sofosbuvir + ribavirin for 24 weeks, 11% for subjects receiving peg-interferon alfa + ribavirin for 24 weeks, and 2% for subjects receiving sofosbuvir + peg-interferon alfa + ribavirin for 12 weeks.

Treatment-emergent Adverse events observed in at least ≥15% of subjects in the Phase 3 clinical trials are provided in Table 6. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

The most common adverse events (at least ≥20%) for the sofosbuvir + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥20%) for the sofosbuvir + peg-interferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

Table 6: Treatment-Emergent Adverse Events (All Grades) Reported in ≥15% of Subjects in Any Treatment Arm

 

Interferon-free Regimens

Interferon-containing Regimens

 

 

PBO 12 Weeks

Sofosbuvir + RBVa

12 Weeks

Sofosbuvir + RBVa

24 Weeks

Peg-IFN Alfa + RBVb

24 Weeks

 

Sofosbuvir + Peg-IFN Alfa + RBVa                12 Weeks

 

N=71

N=650

N=250

 

N=243

 

 

N=327

Fatigue

24%

38%

30%

55%

59%

Headache

20%

24%

30%

44%

36%

Nausea

18%

22%

13%

29%

34%

Insomnia

4%

15%

16%

29%

25%

Pruritus

8%

11%

27%

17%

17%

Anemia

0%

10%

6%

12%

21%

Asthenia

3%

6%

21%

3%

5%

Rash

8%

8%

9%

18%

18%

Decreased Appetite

10%

6%

6%

18%

18%

Chills

1%

2%

2%

18%

17%

Influenza-like Illness

3%

3%

6%

18%

16%

Pyrexia

0%

4%

4%

14%

18%

Diarrhea

6%

9%

12%

17%

12%

Neutropenia

0%

<1%

<1%

12%

17%

Myalgia

0%

6%

9%

16%

14%

Irritability

1%

10%

10%

16%

13%

Peg-IFN=peg-interferon; RBV=ribavirin; PBO=placebo

a Subjects received weight-based ribavirin (1,000 mg per day if weighing <75 kg or 1,200 mg per day if weighing ≥75 kg).

b Subjects received 800 mg ribavirin per day regardless of weight.

With the exception of anemia and neutropenia, the majority of events presented in Table 5 occurred at severity of grade 1 in sofosbuvir-containing regimens.

Less Common Adverse Reactions Reported in Clinical Trials (<1%):

The following adverse events occurred in <1% of subjects receiving sofosbuvir in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.

Hematologic Effects: Pancytopenia (particularly in subjects receiving concomitant peg-interferon).

Psychiatric Disorders: Severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide.

Laboratory Abnormalities

Changes in selected hematological parameters are described in Table 7. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

Table 7: Percentage of Subjects Reporting Selected Hematological Parameters

Hematological Parameters

Interferon-free Regimens

Interferon-containing Regimens

 

PBO

12 Weeks

Sofosbuvir + RBVa

12 Weeks

Sofosbuvir + RBVa

24 Weeks

Peg-IFN + RBVb 24 Weeks

Sofosbuvir + Peg-IFN + RBVa

12 Weeks

 

 

N=71

N=647

N=250

N=242

N=327

Hemoglobin (g/dL)

 

<10

0

8%

6%

14%

23%

 

<8.5

0

1%

<1%

2%

2%

 

Neutrophils (×109/L)

 

≥0.5 to – <0.75

1%

<1%

0

12%

15%

 

<0.5

0

<1%

0

2%

5%

 

Platelets (×109/L)

 

≥25 to – <50

3%

<1%

1%

7%

<1%

 

<25

0

0

0

0

0

 

               



Peg-IFN=peg-interferon; RBV=ribavirin; PBO=placebo

a Subjects received weight-based ribavirin (1,000 mg per day if weighing <75 kg or 1,200 mg per day if weighing ≥75 kg).

b Subjects received 800 mg ribavirin per day regardless of weight.

Bilirubin Elevations

Total bilirubin elevation of more >2.5×ULN was observed in none of the subjects in the 12-week sofosbuvir + peg-interferon alfa + ribavirin group and in 1%, 3% and 3% of subjects in the 24-week peg-interferon alfa + ribavirin, 12-week sofosbuvir + ribavirin, and 24-week sofosbuvir + ribavirin groups, respectively. Bilirubin levels peaked during the first 1–2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment week 4. These bilirubin elevations were not associated with transaminase elevations.

Creatine Kinase Elevations

Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of ≥10×ULN was observed in <1%, 1% and 2% of subjects in the peg-interferon alfa + ribavirin 24-week, sofosbuvir + peg-interferon alfa + ribavirin 12-week and sofosbuvir + ribavirin 12-week groups, respectively.

Lipase Elevations

Isolated, asymptomatic lipase elevation of >3×ULN was observed in <1%, 2%, 2%, and 2% of subjects in the sofosbuvir + peg-interferon alfa + ribavirin 12-week, sofosbuvir + ribavirin 12-week, sofosbuvir + ribavirin 24-week, and peg-interferon alfa + ribavirin 24-week groups, respectively.

Patients with HCV/HIV-1 Co-infection

Sofosbuvir used in combination with ribavirin was assessed in 223 HCV/HIV-1 co-infected subjects. The safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving sofosbuvir + ribavirin in Phase 3 trials.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of sofosbuvir. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders: Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with a sofosbuvir-containing regimen .

Skin and Subcutaneous Tissue Disorders: Skin rashes, sometimes with blisters or angioedema­like swelling; angioedema.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side effects, write to drugsafety@cipla com You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

The highest documented dose of sofosbuvir was a single dose of sofosbuvir 1,200 mg administered to 59 healthy subjects. In that trial, there were no untoward effects observed at this dose level, and adverse events were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are not known.

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. A 4-hour hemodialysis session removed 18% of the administered dose.

Pharmacological Properties

Mechanism of Action

Sofosbuvir is a DAA (direct-acting antiviral) agent against HCV

Sofosbuvir is an inhibitor of the HCV NS5B RNA­dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS­461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS­461203 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. GS­461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Antiviral Activity

In HCV replicon assays, the EC50 values of sofosbuvir against full­length replicons from genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a ranged from 0.014 to 0.11 micromolar. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.062 micromolar for genotype 1a (range: 0.029–0.128 micromolar; N=67), 0.102 micromolar for genotype 1b (range: 0.045–0.170 micromolar; N=29),

0.029 micromolar for genotype 2 (range: 0.014–0.081 micromolar; N=15) and 0.081 micromolar for genotype 3a (range: 0.024–0.181 micromolar; N=106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 micromolar, respectively. The presence of 40% human serum had no effect on the anti­HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Resistance

In Cell Culture

HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. An M289L substitution developed along with the S282T substitution in genotype 2a, 5 and 6 replicons. Site­directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2 to 18­fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89–99% compared with the corresponding wild­type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS­461203 compared with the respective wild­types.

In Clinical Trials

In a pooled analysis of 982 subjects who received sofosbuvir in Phase 3 trials, 224 subjects had post­baseline NS5B genotypic data from next-generation nucleotide sequencing (assay cutoff of 1%).

Treatment­emergent substitutions L159F (n=6) and V321A (n=5) were detected in post­ baseline samples from GT3a­infected subjects across the Phase 3 trials. No detectable shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. The sofosbuvir­associated resistance substitution S282T was not detected at baseline or in the failure isolates from Phase 3 trials. However, an S282T substitution was detected in one genotype 2b subject who relapsed at week 4 post­treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977­ 0523 . The isolate from this subject displayed a mean 13.5­fold reduced susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer detectable at week 12 post­treatment by next-generation sequencing with an assay cutoff of 1%.

In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced virologic failure (breakthrough and relapse). Furthermore, the presence of substitutions L159F and/or C316N at baseline was associated with sofosbuvir breakthrough and relapse post­transplant in multiple subjects infected with GT1b HCV. In addition, S282R and L320F substitutions were detected on­treatment by next-generation sequencing in a subject infected with GT1a HCV with a partial treatment response.

The clinical significance of these substitutions is not known.

Cross-Resistance

HCV replicons expressing the sofosbuvir­associated resistance substitution S282T were susceptible to NS5A inhibitors and ribavirin. HCV replicons expressing the ribavirin­ associated substitutions T390I and F415Y were susceptible to sofosbuvir. Sofosbuvir was active against HCV replicons with NS3/4A protease inhibitor, NS5B non­nucleoside inhibitor and NS5A inhibitor-resistant variants.

Pharmacodynamic Properties

Effect on Electrocardiogram

The effect of sofosbuvir 400 and 1,200 mg (three times the recommended dosage) on the QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover through a QT trial in 59 healthy subjects. At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

Pharmacokinetic Properties

Absorption

The pharmacokinetic properties of sofosbuvir and its predominant circulating metabolite (GS-331007) have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration, sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5–2 hours post-dose, regardless of dose level. Peak plasma concentration of the metabolite was observed between 2 and 4 hours post-dose. Based on population pharmacokinetic analysis in subjects with genotype 1–6 HCV infection who were co-administered ribavirin (with or without peg-interferon), the geometric mean, steady-state AUC0–24 of sofosbuvir (N=838) and GS-331007 (N=1.695) were 828 ng.hr/mL and 6,790 ng.hr/mL, respectively. Relative to healthy subjects administered sofosbuvir alone (N=272), the sofosbuvir AUC0–24 was 39% higher and, GS-331007 AUC0–24 was 39% lower, respectively, in HCV-infected subjects. Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 1,200 mg.

Effect of Food

Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardized high-fat meal did not substantially affect the sofosbuvir Cmax or AUC0–inf. The exposure of GS-331007 was not altered in the presence of a high-fat meal. Therefore, sofosbuvir can be administered without regard to food.

Distribution

Sofosbuvir is approximately 61–65% bound to human plasma proteins and the binding is independent of drug concentration over the range of 1 μg/mL to 20 μg/mL. Protein-binding of the sofosbuvir metabolite was minimal in human plasma. After a single 400 mg dose of -sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.

Metabolism

Sofosbuvir is extensively metabolized in the liver to form a 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) is followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of a nucleoside metabolite, GS-331007, that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro.

After a single 400 mg oral dose of -sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and >90% of drug-related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively.

Excretion

Following a single 400 mg oral dose of -sofosbuvir, 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. The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major elimination pathway for GS­331007. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively.

Special Populations

Gender

No clinically relevant pharmacokinetic differences have been observed between men and women for sofosbuvir and GS-331007.

Race

Population pharmacokinetics analysis in HCV-infected subjects indicated that race had no clinically relevant effect on the exposure of sofosbuvir and GS-331007.

Geriatric Patients

Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (19 to 75 years) analyzed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007.

Pediatric Patients

The pharmacokinetics of HEPCVIR Tablets in pediatric patients has not been evaluated.

Patients with Renal Impairment

The pharmacokinetics of sofosbuvir were studied in HCV-negative subjects with mild (estimated glomerular filtration rate ≥50 and <80 mL/min/1.73 m2), moderate (eGFR ≥30 and <50 mL/ min/ 1.73   m2), severe renal impairment (eGFR <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 >80 mL/min/1.73 m2), the sofosbuvir AUC0-inf  was 61%, 107% and 171% higher in 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 1,280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2,070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. A 4-hour hemodialysis session removed approximately 18% of the administered dose. No dose adjustment is required for patients with mild or moderate renal impairment. The safety and efficacy of sofosbuvir has not been established in patients with severe renal impairment or ESRD. No dose recommendation can be given for patients with severe renal impairment or ESRD .

Patients with Hepatic Impairment

The pharmacokinetics of sofosbuvir was studied following 7-day dosing of 400 mg sofosbuvir in HCV-infected subjects with moderate and severe hepatic impairment (Child-Pugh classes B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUCs0–24 were 126% and 143% higher in moderate and severe hepatic impairment while the GS-331007 AUCs0–24 were 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV-infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure of sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic impairment .

Non-Clinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Use with Ribavirin and/or PEG-Interferon alfa: Refer to the prescribing information for ribavirin and/or peg-interferon alfa for information on carcinogenesis and mutagenesis.

Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.

In 2­year carcinogenicity studies conducted with sofosbuvir in mice and rats , mice were administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in females while rats were administered doses of up to 750 mg/kg/day in males and females. No increase in the incidence of drug­related neoplasms were observed at the highest doses tested in mice and rats, resulting in AUC exposure to the predominant circulating metabolite GS­331007 of approximately 7 and 30 times (in mice) and 13 and 17 times (in rats), in males and females respectively, the exposure in humans at the recommended clinical dose.

Impairment of Fertility

Use with Ribavirin and/or PEG-Interferon alfa: Refer to the prescribing information for ribavirin and/or peg-interferon alfa for information on impairment of fertility.

Sofosbuvir had no effects on embryo­fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS­331007 was approximately 8 times the exposure in humans at the recommended clinical dose.

Description

HEPCVIR Tablets contain sofosbuvir, which is a nucleotide analog inhibitor of HCV NS5B polymerase.

The IUPAC name for sofosbuvir is (S)­isopropyl 2­((S)­(((2R,3R,4R,5R)­5­(2,4­dioxo­ 3,4­dihydropyrimidin­1(2H)­yl)­4­fluoro­3­hydroxy­4­methyltetrahydrofuran­2­yl)methoxy)­(phenoxy) phosphorylamino) propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:

 

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf-Life

As seen on the pack.

Packaging Information

HEPCVIR Tablets are available in a HDPE container of 28 tablets.

Storage and Handling Instructions

  • Store protected from moisture at a temperature not exceeding 30°C.
  • Keep HEPCVIR Tablets in their original container. Keep container tightly closed.
  • Do not use HEPCVIR Tablets if the seal on the bottle mouth is broken or missing.
  • Keep HEPCVIR Tablets and all medicines out of the reach of children.

Patient Counseling Information

What is HEPCVIR Tablets?

HEPCVIR Tablets are a prescription medicine containing sofosbuvir, which is used as a component of a combination antiviral treatment regimen for the treatment of chronic hepatitis C infection.

It is not known if sofosbuvir is safe and effective in people who have had a liver transplant.

Before taking HEPCVIR Tablets, tell your healthcare provider about all of your medical conditions, including the following:

  • Have ever had hepatitis B virus infection
  • Have liver problems other than hepatitis C infection
  • Have had a liver transplant
  • Have severe kidney problems or you are on dialysis
  • Have HIV infection
  • Are pregnant or plan to become pregnant.
  • It is not known if HEPCVIR Tablets will harm your unborn baby. Males and females who take HEPCVIR Tablets in combination with ribavirin should also read the ribavirin Medication Guide for important pregnancy, contraception, and infertility information.
  • Are breastfeeding or plan to breastfeed.
  • It is not known if sofosbuvir passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with HEPCVIR Tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over­the­counter medicines, vitamins, and herbal supplements. HEPCVIR Tablets and other medicines may affect each other. This can cause you to have too much or not enough HEPCVIR or other medicines in your body. This may affect the way HEPCVIR Tablets or your other medicines work, or may cause side effects.

Keep a list of your medicines to show your healthcare provider and pharmacist.

  • You can ask your healthcare provider or pharmacist for a list of medicines that interact with HEPCVIR Tablets.

Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take HEPCVIR Tablets with other medicines.

What is the most important information I should know about HEPCVIR Tablets

HEPCVIR Tablets can cause serious side effects, including the following:

  • Hepatitis B virus reactivation: Before starting treatment with HEPCVIR Tablets, your healthcare provider will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment of hepatitis C virus with HEPCVIR Tablets. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems, including liver failure and death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking HEPCVIR Tablets.

For more information about side effects, see the section “What are the possible side effects of HEPCVIR Tablets?”

How should I take HEPCVIR Tablets?

  • Take HEPCVIR Tablets exactly as your healthcare provider tells you to take it. Do not change your dose unless your healthcare provider tells you to.
  • Do not stop taking HEPCVIR Tablets without first talking with your healthcare provider.
  • Take HEPCVIR Tablets by mouth, with or without food.
  • For adults the usual dose of HEPCVIR Tablet is one 400 mg tablet each day.
  • Do not miss a dose of HEPCVIR Tablet. Missing a dose lowers the amount of medicine in your blood. Refill your HEPCVIR Tablets prescription before you run out of medicine.

If you take too much HEPCVIR Tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of HEPCVIR Tablets?

HEPCVIR Tablets can cause serious side effects, including the following:

  • Hepatitis B virus reactivation. See “What is the most important information I should know about HEPCVIR Tablets?”
  • Slow heart rate (bradycardia). HEPCVIR Tablets treatment may result in slowing of the heart rate along with other symptoms when taken with amiodarone, a medicine used to treat certain heart problems. In some cases bradycardia has led to death or the need for a heart pacemaker when amiodarone is taken with HEPCVIR Tablets. Get medical help right away if you take amiodarone with HEPCVIR Tablets and get any of the following symptoms:
    • fainting or near­fainting  
    • weakness  
    • chest pain
    • dizziness or         
    • extreme tiredness
    • confusion, lightheadedness      
    • shortness of breath       
    • memory problems
    • not feeling well

The most common side effects of sofosbuvir when used in combination with ribavirin include the following:

  • tiredness   
  • headache

The most common side effects of sofosbuvir when used in combination with peg-interferon alfa and ribavirin include the following:

  • tiredness   
  • nausea     
  • low red blood cell count
  • headache  
  • difficulty sleeping

These are not all the possible side effects of HEPCVIR Tablets. For more information, ask your healthcare provider or pharmacist.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 18002677779. By reporting side effects, you can help provide more information on the safety of this product.

How should I store HEPCVIR Tablets?

  • Store HEPCVIR Tablets protected from moisture at a temperature not exceeding 30°C.
  • Keep HEPCVIR Tablets in the original container. Keep container tightly closed.
  • Do not use HEPCVIR Tablets if the seal over the bottle mouth is broken or missing.
  • Keep HEPCVIR Tablets and all medicines out of the reach of children.

What are the ingredients in HEPCVIR Tablets?

  Active ingredient: Sofosbuvir

General information about the safe and effective use of HEPCVIR Tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use HEPCVIR Tablets for a condition for which it was not prescribed. Do not give HEPCVIR Tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about HEPCVIR Tablets that is written for health professionals.

Details of The Manufacturer

Hetero Labs Limited (Unit-II),

Village Kalyanpur, Chakkan Road,

Tehsil - Baddi, Dist. Solan,

Himachal Pradesh-173205

Marketed By: Cipla Ltd.

Regd. Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai - 400 013, India

Details of Permission or License Number with Date

MF-72/2015 dated 12-03-2015

Date of Revision

31/01/2022