Zofomune

Uses

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

Zofomune 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 3

How Zofomune 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 . Zofomune 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 .

Dosage

Zofomune dosage

The recommended dose of Zofomune is 60 mg once daily, to be taken orally with or without meals. Zofomune 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: Zofomune + 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: Zofomune + Sofosbuvir for 24 weeks or Zofomune + Sofosbuvir + Ribavirin for 12 weeks
• Genotype 2: Zofomune + Sofosbuvir for 12 weeks
• Genotype 3: Zofomune + Sofosbuvir + Ribavirin for 24 week

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

Side Effects

Zofomune in combination with Sofosbuvir: Fatigue, headache, nausea. Zofomune 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.

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.

Precaution

Bradycardia with Sofobuvir and Amiodarone coadministration: Serious symptomatic bradycardia may occur in patients taking amiodarone with Sofosbuvir in combination with Zofomune, 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 Zofomune is not recommended.

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

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

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of daclatasvir, which may increase its serum concentration. Dose changes may be necessary.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of daclatasvir and may reduce its serum concentration. Co-administration of daclatasvir with St. John's Wort is contraindicated.
• Take with or without food. Zofomune AUC and Cmax are slightly reduced when administered with food.

Zofomune Drug Interaction

Moderate: diltiazemUnknown: aspirin, charcoal, aspirin, sulfamethoxazole / trimethoprim, diphenhydramine, celecoxib, sulfamethoxazole / trimethoprim, ubiquinone, copper gluconate, secukinumab, losartan, glucose, betamethasone topical, carbonyl iron, omega-3 polyunsaturated fatty acids, metoprolol, metoprolol, acetaminophen, valproic acid

Zofomune Disease Interaction

Major: cirrhosis

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.

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%.

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.

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.

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.

Pregnancy & Breastfeeding use

Zofomune 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 Zofomune therapy. It is not known whether daclatasvir is excreted in human milk.

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

Innovators Monograph

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