Sofosbuvir - Drug Monograph

Introduction

Sofosbuvir is a revolutionary direct-acting antiviral agent that has transformed the treatment landscape for chronic hepatitis C virus (HCV) infection. As a nucleotide analog NS5B polymerase inhibitor, it represents a cornerstone of modern interferon-free regimens with unprecedented cure rates. Approved by the FDA in 2013, sofosbuvir-based therapies have dramatically improved outcomes for patients with HCV across all genotypes.

Mechanism of Action

Sofosbuvir is a prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203). This active metabolite incorporates into HCV RNA by the NS5B RNA-dependent RNA polymerase, acting as a chain terminator. By inhibiting viral replication through this mechanism, sofosbuvir effectively suppresses HCV replication without significant effects on human DNA or RNA polymerases.

Indications

Sofosbuvir is indicated for the treatment of chronic hepatitis C virus infection in adults, in combination with other antiviral agents. Specific FDA-approved regimens include:

• Genotypes 1, 4, 5, and 6: Sofosbuvir/velpatasvir
• Genotype 2: Sofosbuvir/velpatasvir or sofosbuvir with ribavirin
• Genotype 3: Sofosbuvir/velpatasvir or sofosbuvir with ribavirin
• All genotypes in patients with decompensated cirrhosis: Sofosbuvir/velpatasvir with ribavirin

Dosage and Administration

• Renal impairment: No dosage adjustment needed in mild to moderate impairment; use not recommended in severe renal impairment (eGFR <30 mL/min)
• Hepatic impairment: No dosage adjustment needed
• Elderly: No dosage adjustment needed
• Pediatric: Safety and efficacy not established in children <3 years

Pharmacokinetics

Contraindications

• Hypersensitivity to sofosbuvir or any component of the formulation
• Concomitant use with strong P-gp inducers (e.g., rifampin, St. John's wort)
• Use with amiodarone due to risk of serious symptomatic bradycardia

Warnings and Precautions

• Hepatitis B virus reactivation reported in HCV/HBV coinfected patients
• Use in pregnancy: No human data; weigh potential benefits against risks
• Lactation: Unknown if excreted in human milk; consider risk/benefit
• Monitoring required when used with certain antiretroviral regimens

Drug Interactions

• P-gp inducers: Decreased sofosbuvir concentrations (avoid coadministration)
• P-gp inhibitors: May increase sofosbuvir concentrations (monitor)
• Antacids: Separate administration by 4 hours
• H2-receptor antagonists: Separate administration by 12 hours
• Proton pump inhibitors: Avoid concomitant use if possible

Adverse Effects

Monitoring Parameters

• HCV RNA levels at baseline, during treatment, and post-treatment
• Liver function tests (ALT, AST, bilirubin)
• Renal function (serum creatinine, eGFR)
• Complete blood count
• Cardiac monitoring if co-administered with amiodarone
• HBV screening before initiation of therapy

Patient Education

• Take exactly as prescribed, once daily with or without food
• Do not stop treatment early even if feeling better
• Report any cardiac symptoms (dizziness, lightheadedness, fainting) immediately
• Use effective contraception during treatment
• Inform all healthcare providers about sofosbuvir use
• Keep all follow-up appointments for monitoring
• Avoid missing doses; if missed, take as soon as remembered unless close to next dose

References

1. American Association for the Study of Liver Diseases/Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. 2023. 2. Gilead Sciences. Sovaldi (sofosbuvir) prescribing information. 2022. 3. Lawitz E, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887. 4. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C. J Hepatol. 2023. 5. FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments. 2015.