Sovihep D

Uses

Daclatasvir is used for combination with Sofosbuvir for the treatment of chronic hepatitis C virus (HCV) infection in adults.

Sofosbuvir is used for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Sofosbuvir efficacy has been established in subjects with MCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection.

Sovihep D is also used to associated treatment for these conditions: Chronic Hepatitis C Genotype 1, Chronic Hepatitis C Virus (HCV) Infection, Chronic hepatitis C genotype 2, Chronic hepatitis C genotype 3Chronic Hepatitis C Genotype 1, Chronic hepatitis C genotype 2, Chronic hepatitis C genotype 3, Chronic hepatitis C genotype 4, Chronic hepatitis C genotype 5, Genotype 6 chronic hepatitis C infection

How Sovihep D works

NS5A is a viral nonstructural phospoprotein that is part of a functional replication complex in charge of viral RNA genome amplification on endoplasmic reticulum membranes. It has the ability to bind to HCV RNA. It is shown to have two distinct functions in HCV RNA replication based on phosphorylated states. Maintaining the HCV replication complex is mediated by the cis-acting function of basally phosphorylated NS5A and the trans-acting function of hyperphosphorylated NS5A modulates HCV assembly and infectious particle formation . Daclatasvir is shown to disrupt hyperphosphorylated NS5A proteins thus interfere with the function of new HCV replication complexes. It is also reported that daclatasvir also blocks both intracellular viral RNA synthesis and virion assembly/secretion in vivo .

Sofosbuvir is nucleotide analog inhibitor, which specifically inhibits HCV NS5B (non-structural protein 5B) RNA-dependent RNA polymerase. Following intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), sofosbuvir incorporates into HCV RNA by the NS5B polymerase and acts as a chain terminator . More specifically, Sofosbuvir prevents HCV viral replication by binding to the two Mg2+ ions present in HCV NS5B polymerase's GDD active site motif and preventing further replication of HCV genetic material .

Dosage

Sovihep D dosage

The recommended dose of Daclatasvir is 60 mg once daily, to be taken orally with or without meals. Daclatasvir must be administered in combination with other medicinal products.HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C without cirrhosis, including treatment-naïve patients and patients who failed on a treatment based on Peginterferon alfa & Ribavirin

• All genotypes: Daclatasvir + Sofosbuvir for 12 weeks

HCV-monoinfected or HCV/HIV coinfected patients with chronic hepatitis C with compensated (Child-Pugh A) cirrhosis, including treatment-naïve patients and patients who failed on a treatment based on Peginterferon alfa & Ribavirin

• Genotype 1,4,5,6: Daclatasvir + Sofosbuvir for 24 weeks or Daclatasvir + Sofosbuvir + Ribavirin for 12 weeks
• Genotype 2: Daclatasvir + Sofosbuvir for 12 weeks
• Genotype 3: Daclatasvir + Sofosbuvir + Ribavirin for 24 week

The dose of Ribavirin, when combined with Daclatasvir, is weight-based (1000 or 1200 mg in patients <75 kg or ≥75 kg, respectively).

One 400 mg tablet taken once daily with or without food. Should be used in combination with Ribavirin or in combination with Pegylated Interferon and Ribavirin for the treatment of CHC.

Recommended combination therapy: (HCV Mono-infected and HCV/HIV-1 Co-infected)-

• Genotype 1 or 4: Sofosbuvir + Peginterferon alfa + Ribavirin for 12 weeks
• Genotype 2: Sofosbuvir + Ribavirin for 12 weeks
• Genotype 3: Sofosbuvir + Ribavirin for 24 weeks

Sofosbuvir in combination with Ribavirin for 24 weeks can be considered for CHC patients with genotype 1 infection who are Interferon ineligible

Should be used in combination with Ribavirin for treatment of CHC in patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation whichever occurs first

A dose recommendation cannot be made for patients with severe renal impairment or end stage renal disease

Side Effects

Daclatasvir in combination with Sofosbuvir: Fatigue, headache, nausea. Daclatasvir in combination with Peginterferon alfa and Ribavirin: The most frequently reported adverse reactions were fatigue, headache, pruritus, insomnia, influenza-like illness, dry skin, nausea, decreased appetite, alopecia, rash, asthenia, irritability, myalgia, anaemia, pyrexia, cough, dyspnoea, neutropenia, diarrhoea and arthralgia.

The most common adverse events observed with Sofosbuvir in combination with ribavirin were fatigue and headache.

The most common adverse events for Sofosbuvir, peginterferon alfa and Ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

The following ADRs occured in <1% of subjects receiving Sofosbuvir in combination regimen.

Hematologic effects: pancytopenia (particularly in subjects receiving concomitant Pegylated Interferon).

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

Toxicity

The most common adverse effects experienced in patients undergoing daclatasvir and sofosbuvir therapy include headache, fatigue, nausea and diarrhea. Similar side effects are seen when ribavirin is added, in addition to rash, insomnia, anemia, dizziness and somnolence. There are postmarketing cases that link serious symptomatic bradycardia with Daklinza when used in conjunction with sofosbuvir and amiodarone. Coadministration of these three drugs is not recommended unless there are no other alternatives.

Sofosbuvir, as a single agent, has very mild toxicity. The most common adverse reactions are headache and fatigue. The FDA Label currently warns of a risk of symptomatic bradycardia when Epclusa is used in combination with amiodarone .

Precaution

Bradycardia with Sofobuvir and Amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone with Sofosbuvir in combination with Daclatasvir, particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease. Coadministration of amiodarone with Sofobuvir in combination with Daclatasvir is not recommended.

Daclatasvir must not be administered as monotherapy. Daclatasvir must be administered in combination with other medicinal products for the treatment of chronic HCV infection

Bradycardia with amiodarone co-administration: Serious symptomatic bradycardia may occur in patients taking amiodarone and Sofosbuvir in combination with another direct acting antiviral (DAA), particularly in patients also receiving beta blockers, or those with underlying cardiac comorbidities and/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.

Interaction

Strong or moderate CYP3A4 or P-gp inducers (eg, phenytoin, carbamazepine, phenobarbital, rifampicin, systemic dexamethasone. Strong CYP3A4 inhibitors (eg, boceprevir, telaprevir, HIV protease inhibitors, cobicistat, macrolides, azole antifungals, calcium channel blockers). NNRTIs, dabigatran, digoxin, oral contraceptives, statins, amiodarone

Reduced therapeutic effect with drugs that are potent P-gp inducers in the intestine (eg rifampicin, St. John's wort, carbamazepine & phenytoin), modafinil, phenobarb/ oxcarbazepine, rifabutin/ rifapentine. P-gp &/or BCRP inhibitors. May result in serious symptomatic bradycardia when co-administered with amiodarone in combination with another direct acting antiviral.

Volume of Distribution

The approximate volume of distribution of daclatasvir is 47 L in patients who was orally administered 60 mg tablet followed by 100 µg [13C,15N]-daclatasvir intravenously.

The volume of distribution for sofosbuvir has yet to be determined .

Elimination Route

Studies demonstrated that peak plasma concentrations typically occurred within 2 hours after administration of multiple oral doses ranging from 1 - 100 mg once daily. Steady state is reached after approximately 4 days of once-daily daclatasvir administration. The absolute bioavailability of the tablet formulation is 67%.

When given orally, sofosbuvir reaches its maximum plasma concentration in about 0.5 to 2 hours with a maximal concentration (Cmax) of 567 ng/mL .

Half Life

Following multiple dose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours.

Sofosbuvir has a terminal half life of 0.4 hours .

Clearance

In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg radiolabeled daclatasvir intravenously, the total clearance was 4.2 L/h.

The clearance of sofosbuvir has yet to be determined .

Elimination Route

Approximately 88% of total dose of daclatasvir is eliminated into bile and feces in which 53% remains as unchanged form, while 6.6% of the total dose is eliminated primarily unchanged in the urine.

Sofosbuvir is eliminated by three routes: urine ( 80%), feces (14%), and respiration (2.5%); however, elimination through the kidneys is the major route .

Pregnancy & Breastfeeding use

Daclatasvir should not be used during pregnancy or in women of childbearing potential not using contraception. Use of highly effective contraception should be continued for 5 weeks after completion of Daclatasvir therapy. It is not known whether daclatasvir is excreted in human milk.

Pregnancy Category- B. Ribavirin may cause birth defects and fetal death and animal studies have shown interferons have abortifacient effects; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to initiating therapy, use at least 2 effective methods of contraception and have monthly pregnancy tests.

Lactation: Unknown if distributed in human breast milk; take into account the importance of therapy to the mother when administered combination with ribavirin and/or peg-interferon alfa; because of the potential for adverse reaction, breastfeeding is not recommended

Contraindication

Strong inducers of CYP3A, including phenytoin, carbamazepine, rifampicin, and St. John’s wort Hypersensitivity to the active substance or to any of the excipients

When Sofosbivur is used in combination with Ribavirin or Peginterferon alfa/ Ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Sofosbuvir combination treatment with Ribavirin or Peginterferon alfa/Ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant, because of the risks for birth defects and fetal death associated with Ribavirin.

Special Warning

Geriatric Use: No dose adjustment of Sofosbuvir is warranted in geriatric patients.

Acute Overdose

The highest dose of Sofosbuvir is a single dose of Sofosbuvir 1200 mg. No specific antidote is available for overdose treatment. 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 Condition

Keep out of the reach of children. Keep in a cool & dry place. Protect from light.

Innovators Monograph

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