Daclatasvir + Sofosbuvir

Approved Indications:

• Chronic Hepatitis C Virus (HCV) Infection:
• Treatment of chronic HCV genotypes 1, 2, 3, 4, 5, and 6 infections in adults.
• Effective in both treatment-naïve and treatment-experienced patients.
• Indicated for patients with compensated liver disease, including compensated cirrhosis.
• Used in patients co-infected with HIV.
• For treatment of HCV post-liver transplantation.

Clinically Accepted Off-label Uses:

• Use in patients with decompensated cirrhosis (with careful monitoring and adjunctive therapy).
• Treatment of specific populations with renal impairment (dose adjustments or caution advised).
• Occasionally used in pediatric patients under expert guidance (off-label).

Adults:

• Standard Dose:
• Daclatasvir 60 mg once daily plus Sofosbuvir 400 mg once daily, orally.
• Duration:
• Typically 12 weeks; may be extended to 24 weeks in patients with cirrhosis or prior treatment failure.
• Dose adjustments are generally not required for mild to moderate hepatic or renal impairment.

Special Populations:

• Renal Impairment:
• No dose adjustment required for mild to moderate impairment (eGFR ≥30 mL/min).
• Limited data in severe renal impairment or dialysis; caution advised.
• Hepatic Impairment:
• Mild to moderate (Child-Pugh A or B): no dose adjustment needed.
• Severe impairment (Child-Pugh C): safety not well established; use with caution.
• Elderly:
• No specific dose adjustment.
• Pediatrics:
• Not approved; limited data available.

Route of Administration:

• Oral tablets, taken with or without food.

Daclatasvir is a potent inhibitor of the HCV non-structural protein 5A (NS5A), essential for viral RNA replication and assembly of the viral replication complex. By binding to NS5A, it disrupts viral replication and assembly.

Sofosbuvir is a nucleotide analog inhibitor of the HCV NS5B RNA-dependent RNA polymerase, acting as a chain terminator during viral RNA synthesis.

Combined, these drugs provide a highly effective blockade of viral replication by targeting two distinct but complementary steps in the HCV lifecycle, leading to sustained virologic response and viral clearance.

Absorption:

• Both drugs are rapidly absorbed orally; peak plasma levels achieved within 1–4 hours.

Distribution:

• Daclatasvir is highly protein-bound (~99%).
• Sofosbuvir is a prodrug; its active metabolite GS-461203 is intracellular and not measurable in plasma.

Metabolism:

• Daclatasvir is primarily metabolized by CYP3A4.
• Sofosbuvir is metabolized intracellularly to active triphosphate; systemic metabolism involves hydrolysis and renal clearance.

Elimination:

• Daclatasvir is excreted mainly via feces.
• Sofosbuvir metabolites are primarily eliminated renally (~80%).

Half-life:

• Daclatasvir: ~12–15 hours.
• Sofosbuvir: ~0.4 hours (parent drug), active metabolite half-life ~27 hours.

• Pregnancy:
• No established FDA pregnancy category.
• Animal studies show no significant fetal risk at therapeutic doses.
• Use only if potential benefits justify potential risks.
• Effective contraception recommended during therapy.
• Lactation:
• Unknown if excreted in human milk.
• Breastfeeding is generally not recommended during treatment due to limited data.

• Primary Class: Antiviral Agents
• Subclass: Direct-acting antivirals (DAAs) for hepatitis C; NS5A inhibitor + NS5B polymerase inhibitor combination.

• Known hypersensitivity to daclatasvir, sofosbuvir, or excipients.
• Co-administration with strong CYP3A4 inducers (e.g., rifampin, carbamazepine) that reduce daclatasvir levels.
• Use with amiodarone and sofosbuvir due to risk of serious bradycardia (when combined with daclatasvir).
• Severe hepatic impairment without close medical supervision.

• Hepatitis B Reactivation: Monitor patients with current or past HBV infection.
• Cardiac Effects: Serious bradycardia reported with sofosbuvir + amiodarone; caution advised.
• Drug Interactions: Monitor CYP3A4-mediated interactions closely.
• Renal and Hepatic Function: Monitor periodically during therapy.
• Resistance: Potential for resistance if therapy interrupted.

Common Adverse Effects:

• Fatigue
• Headache
• Nausea
• Insomnia
• Diarrhea

Serious and Rare Effects:

• Elevated liver enzymes
• Hypersensitivity reactions (rash, angioedema, anaphylaxis)
• Bradycardia (rare, especially with amiodarone)

• CYP3A4 substrates/inhibitors/inducers: Alter daclatasvir levels.
• P-glycoprotein substrates: Sofosbuvir is a substrate; inducers reduce efficacy.
• Amiodarone + Sofosbuvir: Serious bradycardia risk.
• Avoid St. John’s Wort (CYP3A4 inducer).
• No significant food interactions.

• WHO and EASL endorse daclatasvir + sofosbuvir as a pan-genotypic, effective, and well-tolerated regimen.
• Expanded use in patients with HIV co-infection and compensated cirrhosis.
• Cautions issued regarding concomitant use with amiodarone and strong CYP3A4 inducers.
• Emphasis on screening for HBV reactivation risk.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light; keep in original container.
• No refrigeration or reconstitution required.
• Tablets should be handled with dry hands and stored in a dry place.