Soforal-LP

Approved Indications:

Ledipasvir + Sofosbuvir is indicated for the treatment of chronic hepatitis C virus (HCV) infection in the following patient groups:

• Adults and pediatric patients ≥3 years of age with genotype 1, 4, 5, or 6 HCV infection, with or without compensated cirrhosis (Child-Pugh A).
• Used in combination with ribavirin in patients with:
• Decompensated cirrhosis (Child-Pugh B or C)
• Post-liver transplantation
• Prior treatment failure with interferon-based regimens

Additional Indications:

• HCV/HIV-1 co-infection
• Patients with mild to moderate renal impairment
• Pediatric HCV patients ≥3 years, including treatment-naïve and treatment-experienced

Formulation:
Fixed-dose oral tablet:

• Ledipasvir 90 mg + Sofosbuvir 400 mg

Route of Administration:
Oral; administer once daily with or without food.

A. Adults

B. Pediatrics (≥3 years)

Weight-based dosing:

Duration: Typically 12 weeks. Use ribavirin if cirrhosis or treatment failure present.

Special Populations:

• Renal impairment: No adjustment needed in mild/moderate renal dysfunction. Use with caution in severe impairment or dialysis.
• Hepatic impairment: No dose adjustment for mild/moderate impairment. Use caution in severe hepatic dysfunction.

Ledipasvir is an NS5A inhibitor that disrupts viral RNA replication and virion assembly. Sofosbuvir is a nucleotide analog NS5B polymerase inhibitor, converted intracellularly to an active triphosphate form that incorporates into HCV RNA, causing chain termination. The combination provides a dual blockade of viral replication pathways, enhancing sustained virologic response (SVR) rates across multiple HCV genotypes.

• Absorption:
• Sofosbuvir: Rapid (Tmax ~0.5–2 hours)
• Ledipasvir: Tmax ~4 hours
• Bioavailability:
• Ledipasvir increases with food
• Sofosbuvir unaffected significantly
• Distribution:
• Ledipasvir: ~99.8% protein-bound
• Sofosbuvir: ~61–65% protein-bound
• Metabolism:
• Sofosbuvir: Hepatically metabolized to active triphosphate form and then to inactive GS-331007
• Ledipasvir: Minimal metabolism
• Excretion:
• Sofosbuvir: Renal (~80%) as GS-331007
• Ledipasvir: Feces (~86%)
• Half-life:
• Sofosbuvir (parent): ~0.4 hours; GS-331007: ~27 hours
• Ledipasvir: ~47 hours

• Pregnancy:
• No assigned FDA pregnancy category under current labeling.
• Animal data show no teratogenicity.
• If used with ribavirin: Contraindicated in pregnancy due to ribavirin's teratogenicity; use effective contraception.
• Lactation:
• Unknown if excreted in human milk.
• Animal studies show excretion into milk.
• Caution is advised when used during breastfeeding, particularly if used with ribavirin.

• Class: Direct-Acting Antiviral (DAA)
• Sub-Class:
• Ledipasvir: NS5A replication complex inhibitor
• Sofosbuvir: NS5B polymerase inhibitor (nucleotide analog)

• Known hypersensitivity to ledipasvir, sofosbuvir, or excipients
• Concomitant use with strong P-glycoprotein inducers (e.g., rifampin, carbamazepine, St. John's Wort)
• Pregnancy (if co-administered with ribavirin)
• Severe renal dysfunction (GFR <30 mL/min/1.73 m²) — use not recommended

• Serious bradycardia risk when co-administered with amiodarone
• HBV reactivation in co-infected patients — test for HBV before starting therapy
• Renal toxicity risk when used with tenofovir-containing regimens — monitor renal function
• Avoid P-gp inducers as they reduce plasma concentration and efficacy
• Monitor liver function and virologic response during treatment

Common (>10%):

• Fatigue
• Headache
• Nausea
• Insomnia
• Diarrhea

Less Common (1–10%):

• Myalgia
• Rash
• Pruritus
• Anemia (especially with ribavirin)
• Elevated bilirubin

Serious:

• Symptomatic bradycardia (with amiodarone)
• Hepatitis B reactivation
• Severe renal impairment in at-risk individuals

Onset:

Adverse effects typically appear during the first 1–4 weeks of therapy and are often self-limiting.

Major Interactions:

• Amiodarone: Life-threatening bradycardia; contraindicated
• P-gp inducers (rifampin, St. John’s Wort, phenytoin): Decreased drug levels; avoid use
• Proton Pump Inhibitors (e.g., omeprazole): May lower ledipasvir levels; space dosing or reduce PPI dose
• Tenofovir (TDF): Increased exposure with potential nephrotoxicity; monitor renal function
• Statins (e.g., rosuvastatin): Risk of myopathy or rhabdomyolysis; monitor CK levels

Enzyme Systems:

• Minimal CYP450 involvement
• Substrates of P-glycoprotein (P-gp) and BCRP transporters

• Shortened 8-week regimen approved for genotype 1, treatment-naïve, non-cirrhotic patients with HCV RNA <6 million IU/mL
• WHO and AASLD-IDSA continue to recommend Ledipasvir + Sofosbuvir as a first-line option for genotypes 1, 4, 5, and 6
• Black box warning added regarding HBV reactivation
• Use in pediatric patients ≥3 years approved with weight-based dosing

• Store at 20°C to 25°C (68°F to 77°F)
• Allowable temperature excursions: 15°C to 30°C
• Protect from light and moisture
• Keep in original container with desiccant
• Do not refrigerate or freeze
• No reconstitution required