Sofomax DUO Tablet

Sofosbuvir 400mg + Ledipasvir 90mg

Composition
Sofomax Duo® Tablet: Each coated tablet contains Sofosbuvir INN 400 mg and Ledipasvir 90 mg as Acetone Solvate INN.


Pharmacology
Sofomax Duo® is the preparation of Sofosbuvir and Ledipasvir. Sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase and Ledipasvir is an HCV NS5A inhibitor.


Mechanism of action: Sofomax Duo® is a fixed dose combination of sofosbuvir and ledipasvir which are direct acting antiviral agents against the hepatitis C virus.


Pharmacodynamics: The effect of sofosbuvir 400 mg (maximum recommended dosage) 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 dose three times the maximum recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent. The effect of ledipasvir 120 mg twice daily (2.67 times the maximum recommended dosage) for 10 days on QTc interval was evaluated in a randomized, multiple-dose, placebo, and active-controlled three period crossover thorough QT trial in 59 healthy subjects. At the dose of 120 mg twice daily (2.67 times the
maximum recommended dosage), ledipasvir does not prolong QTc interval to any clinically relevant extent.

Pharmacokinetics
Absorption: The pharmacokinetic properties of ledipasvir, sofosbuvir, 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 Duo®, ledipasvir median peak concentrations were observed 4 to 4.5 hours post-dose. Sofosbuvir was absorbed quickly and the peak median plasma concentration was observed ~0.8 to 1 hour post-dose. Median peak plasma concentration of GS-331007 was observed between 3.5 to 4 hours post-dose.

Distribution: Ledipasvir is greater than 99.8% bound to human plasma proteins. After a single 90 mg dose of ledipasvir in healthy subjects, the blood to plasma ratio of C radioactivity ranged between 0.51 and 0.66. 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. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of sofosbuvir in healthy subjects, the blood to plasma ratio of radioactivity was approximately 0.7.


Metabolism: Sofosbuvir 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. Dephosphorylation results in the formation of 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, GS-331007 accounted for approximately greater than 90% of total systemic exposure.


Elimination: Following a single 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 GS-331007. The median terminal half-lives of sofosbuvir and GS-331007 following administration of Sofomax Duo® were 0.5 and 27 hours, respectively.

Following a single oral dose of ledipasvir, mean total recovery of the radioactivity in feces and urine was approximately 87%, with most of the radioactive dose recovered from feces (approximately 86%). Unchanged ledipasvir excreted in feces accounted for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for 2.2% of the dose. These data indicate that biliary excretion of unchanged ledipasvir is a major route of elimination, with renal excretion being a minor pathway (approximately 1%). The median terminal half-life of ledipasvir following administration of Sofomax Duo® was 47 hours.

Indication
Adults
Sofomax Duo® is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV)

  • Genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
  • Genotype 1 infection with decompensated cirrhosis, for use in combination with ribavirin
  • Genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin.

Children
Sofomax Duo® is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kg with HCV genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis

Dose and administration
Route of administration: Sofomax Duo® should be taken in oral route. 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 Sofomax Duo

Adult: The recommended dosage of Sofomax Duo® is one tablet taken orally once daily with or without food. Table 1 shows the recommended Sofomax Duo® treatment regimen and duration based on patient population.

Table 1: Recommended treatment regimen and duration for Sofomax Duo® inadult patients with genotype 1, 4, 5, or 6 HCV
  Patient population Treatment regimenand duration
Genotype 1 Treatment - naive without cirrhosis or with
compensated cirrhosis (Child Pugh A)
Sofomax Duo® 12 weeks*
Treatment - experienced ** without cirrhosis Sofomax Duo® 12 weeks*
Treatment - experienced ** with compensated
cirrhosis (Child Pugh A)
Sofomax Duo® 24 weeks*
Treatment - naive and treatment experienced **
with decompensated cirrhosis (Child Pugh B or C)
Sofomax Duo® plus Ribavirin 12 weeks
Genotype 1 or 4 Treatment - naive and treatment – experienced
**
liver transplant recipients without cirrhosis, or
with compensated cirrhosis (Child Pugh A)
Sofomax Duo® + Ribavirin 12 weeks
Genotype 4, 5, or 6 Treatment - naive and treatment experienced**,
without cirrhosis or with compensated cirrhosis
(Child Pugh A)
Sofomax Duo® 12 weeks
* Sofomax Duo® for 8 weeks can be considered in treatment naive genotype 1 patients without cirrhosis who have pretreatment HCV RNA less than 6 million U/ml.
** Treatment - experienced patients have failed a peginterferon alfa + ribavirin based regimen with or without an HCV protease inhibitor.

 

Children: The recommended dosage of Sofomax Duo® in pediatric patients 12 years of age and older or weighing at least 35 kg is one tablet taken orally once daily with or without food for 12 weeks. Table 2 shows the recommended Sofomax Duo® duration based on pediatric patient population.

Table 2: Recommended regimen and duration for harvoni in pediatric patients 12 years of age or older or weighing at least 35 kg with genotype 1, 4, 5, or 6 HCV without cirrhosis or with compensated cirrhosis
  Patient population Treatment regimenand duration
Genotype 1 Treatment - naive without cirrhosis or with
compensated cirrhosis (Child Pugh A)
Sofomax Duo® 12 weeks*
Treatment - experienceda without cirrhosis Sofomax Duo® 12 weeks
Treatment - experienceda with compensated
cirrhosis (Child Pugh A)
Sofomax Duo® 12 weeks*
Genotype 4, 5 or 6 Treatment - naive and treatment experienceda
without cirrhosis or with compensated cirrhosis
(Child Pugh A)
Sofomax Duo® 12 weeks
a. Treatment - experienced patients have failed an interferon based regimen with or without ribavirin.

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

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

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

Contraindication
This combination is contraindicated in patients with known hypersensitivity to sofosbuvir and ledipasvir or any of the components of this product.

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.

Serious symptomatic bradycardia when coadministered with amiodarone: Postmarketing cases of symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is co-administered with this combination. Patients also taking beta blockers, or those with underlying cardiac comorbidities 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. However, co-administration of amiodarone with this combination is not recommended.

Risk of reduced therapeutic effect due to P-gp inducers: The concomitant use of the combination and P-gp inducers (e.g., rifampin, St. John’s wort) may significantly decrease ledipasvir and sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of this combination. Therefore, the use of this combination with P-gp inducers (e.g., rifampin or St. John’s wort) is not recommended.

Side effects
The most common side effects of this combination are asthenia, fatigue, cough, headache, nausea, diarrhea, myalgia, dizziness, insomnia, skin rashes sometimes with blisters or angioedema.

Use in pregnancy and lactation
Pregnancy: There are no adequate and well controlled studies with this combination in pregnant women. Because animal reproduction studies are not always predictive of human response, this combination should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Co-administered with ribavirin, this combination is contraindicated in pregnant women and in men whose female partners are pregnant.

Lactation: It is not known whether this combination 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 ledipasvir combination and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Use in children and adolescents
The safety, pharmacokinetics, and efficacy of this combination for treatment of HCV genotype 1 infection in treatment-naïve and treatment-experienced pediatric patients 12 years of age and older without cirrhosis or with compensated cirrhosis have been established in an open-label, multicenter clinical trial (Study 1116, N=100; 80 treatment naïve, 20 treatment-experienced) and are comparable to that observed in adults.

The safety and efficacy of this combination for treatment of HCV genotypes 4, 5, or 6 infection in pediatric patients 12 years of age and older or weighing at least 35 kg without cirrhosis or with compensated cirrhosis is supported by comparable ledipasvir, sofosbuvir, and GS-331007 exposures between adults and adolescents with HCV genotype 1 and similar efficacy and exposures across HCV genotypes 1, 4, 5, and 6 in adults.

The safety and efficacy of this combination have not been established in pediatric patients less than 12 years of age and weighing less than 35 kg, in pediatric patients with decompensated cirrhosis, or in pediatric liver transplant recipients.

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). This combination 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
No specific antidote is available for overdose with this combination. If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with this combination consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis is unlikely to result in significant removal of ledipasvir since ledipasvir is highly bound to plasma protein.

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

Packing
Sofomax Duo® Tablet: Carton of 7 tablets in blister pack.