Sofovir-C

Approved Indications:

• Chronic Hepatitis C Virus (HCV) Infection:
  Sofosbuvir is indicated for the treatment of chronic HCV infection in adults and pediatric patients (aged ≥3 years), in combination with other antiviral agents, across the following genotypes:
• Genotypes 1, 2, 3, 4, 5, and 6:
  Used in combination with ribavirin, peginterferon alfa, daclatasvir, ledipasvir, or velpatasvir depending on genotype and patient population.
• Patients with or without compensated cirrhosis.
• Patients with decompensated cirrhosis: In combination with ribavirin and/or other DAAs.
• Post-liver transplant recurrence of HCV.

Important Off-Label / Clinically Accepted Uses:

• Coinfection with HIV-1 and HCV: Used with other DAAs in coinfected individuals.
• HCV-associated cryoglobulinemia vasculitis: In some cases, used to treat extrahepatic manifestations.
• Pediatric use in children <3 years old: Under study and occasionally used under compassionate protocols.

Adults (≥18 years):

• Usual Dose: Sofosbuvir 400 mg orally once daily, in combination with other antivirals.
• Treatment Duration: 12–24 weeks depending on genotype, cirrhosis status, and prior treatment history.

Common Regimens:

• Sofosbuvir + Ribavirin: For genotypes 2 and 3 (non-cirrhotic or compensated cirrhosis).
• Sofosbuvir + Ledipasvir: For genotypes 1, 4, 5, or 6.
• Sofosbuvir + Daclatasvir or Velpatasvir: For pan-genotypic treatment.

Pediatric (3 to <18 years):

• <17 kg: Sofosbuvir 150 mg once daily.
• 17–35 kg: Sofosbuvir 200 mg once daily.
• ≥35 kg: Sofosbuvir 400 mg once daily.

Elderly:
No dosage adjustment is necessary; monitor renal and hepatic function.

Renal Impairment:

• No dose adjustment for mild to moderate renal impairment.
• Use with caution or avoid in severe renal impairment (eGFR <30 mL/min/1.73m²) or end-stage renal disease.

Hepatic Impairment:

• No dose adjustment needed in mild, moderate, or decompensated hepatic impairment.
• Use in combination with caution in Child-Pugh Class B or C.

Administration Route:
Oral; take once daily, with or without food.

Sofosbuvir is a nucleotide analog prodrug that, once metabolized intracellularly to its active form (GS-461203), inhibits the NS5B RNA-dependent RNA polymerase, a critical enzyme in the HCV replication cycle. By incorporating into the viral RNA chain, the active metabolite causes premature chain termination, thereby blocking viral RNA synthesis. This mechanism leads to a significant reduction in viral load and ultimately helps achieve sustained virologic response (SVR), equivalent to virologic cure in most patients.

• Absorption: Peak plasma concentration reached in 0.5 to 2 hours.
• Bioavailability: High; not significantly affected by food.
• Distribution: Plasma protein binding ~61–65%.
• Metabolism: Rapid hepatic conversion to the active triphosphate GS-461203; also forms inactive metabolite GS-331007.
• Elimination:
• Active metabolite: Intracellular metabolism.
• Inactive metabolite (GS-331007): Mainly excreted in urine (~80%).
• Half-life:
• Sofosbuvir: ~0.4 hours
• GS-331007: ~27 hours
• Excretion: Renal (urine 80%), feces (14%), exhaled air (2.5%).

• Pregnancy:
  Sofosbuvir alone is not assigned an FDA pregnancy category. However, combinations with ribavirin are contraindicated in pregnancy due to teratogenicity. Women of childbearing potential must use effective contraception during and 6 months after treatment with ribavirin combinations.
• Lactation:
  It is unknown if Sofosbuvir is excreted into human breast milk. Animal studies show drug presence in milk. Due to potential risks, caution is advised when administering to nursing mothers.
• Note: For Sofosbuvir-only regimens, limited human data suggest low risk. For combination regimens (especially with ribavirin), breastfeeding is generally not recommended.

• Primary Class: Direct-Acting Antiviral (DAA)
• Subclass: NS5B Polymerase Inhibitor
• Generation: First-generation nucleotide analog

• Known hypersensitivity to Sofosbuvir or any formulation component
• Co-administration with potent inducers of P-gp (e.g., rifampicin, carbamazepine) which may decrease efficacy
• Use with ribavirin during pregnancy or in male partners of pregnant women

• Severe bradycardia when used with amiodarone and another DAA — avoid this combination.
• Hepatitis B virus (HBV) reactivation: Screen for HBV before initiating treatment.
• Renal dysfunction: Monitor renal function in patients with impaired kidney function.
• Pregnancy risk (with ribavirin): Teratogenic; use contraception.
• Drug resistance: Avoid monotherapy to reduce resistance risk.
• Monitor liver function in decompensated cirrhosis or post-transplant patients.
• Not recommended for patients with severe renal impairment unless benefits outweigh risks.

Common Adverse Effects (≥10%):

• General: Fatigue, headache
• GI: Nausea
• Musculoskeletal: Myalgia, arthralgia

Less Common (1–10%):

• Insomnia
• Rash
• Anemia (particularly with ribavirin)
• Irritability
• Diarrhea

Serious or Rare Adverse Effects (<1%):

• Severe bradycardia (especially with amiodarone)
• Hepatic decompensation (in advanced liver disease)
• Hypersensitivity reactions
• Stevens-Johnson syndrome (extremely rare)

• Strong P-gp Inducers (e.g., rifampicin, St. John's wort): Decrease Sofosbuvir plasma concentration — contraindicated.
• Amiodarone: Risk of life-threatening bradycardia — avoid co-administration.
• Anticonvulsants (e.g., phenytoin, carbamazepine): May reduce Sofosbuvir efficacy.
• Antiretrovirals (e.g., tipranavir/ritonavir): May reduce exposure; monitor effectiveness.
• CYP450: Sofosbuvir is not a CYP450 substrate, inhibitor, or inducer, so interaction via this pathway is minimal.

• WHO & AASLD (2024-2025): Endorsed Sofosbuvir-containing regimens as part of pan-genotypic, interferon-free treatments.
• New Pediatric Approvals: Expanded indication to children as young as 3 years old.
• Combination Therapies: Preferential use of Sofosbuvir + Velpatasvir for simplified, once-daily treatment.
• Amiodarone Warning Reinforced: Black box warning retained due to reports of bradycardia.

• Storage Temperature: 20°C to 30°C (68°F to 86°F)
• Humidity: Store in a dry place with original packaging; protect from moisture.
• Light Protection: Store away from direct sunlight.
• Handling: Keep in a tightly closed container. No refrigeration or reconstitution needed.
• Disposal: Follow standard procedures for pharmaceutical waste.