SOVALDI™ (sofosbuvir) tablets

The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45.

INDICATIONS AND USAGE:
SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.

SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection.

The following points should be considered when initiating treatment with SOVALDI:

• Monotherapy of SOVALDI is not recommended for treatment of CHC.
• Treatment regimen and duration are dependent on both viral genotype and patient population.
• Treatment response varies based on baseline host and viral factors.

 USE IN SPECIFIC POPULATIONS
Patients with HCV/HIV-1 co-infection: Safety and efficacy have been studied.
Patients with hepatocellular carcinoma awaiting liver transplantation: Safety and efficacy have been studied.

Because ribavirin may cause birth defects and fetal death, SOVALDI in combination with peginterferon alfa/ribavirin or ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant.

1. Pregnancy: Ribavirin may cause birth defects and fetal death and animal studies have shown interferons have abortifacient effects; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to initiating therapy, use at least 2 effective non-hormonal methods of contraception and have monthly pregnancy tests.
2. Drug interactions: Drugs that are potent intestinal P-gp inducers (e.g., rifampin, St. John's wort) may alter the concentrations of sofosbuvir. Consult the full prescribing information prior to use for potential drug-drug interactions.

• The most common adverse events (incidence greater than or equal to 20%, all grades) observed with SOVALDI in combination with ribavirin were fatigue and headache. The most common adverse events observed with SOVALDI in combination with peginterferon alfa and ribavirin were fatigue, headache, nausea, insomnia and anemia.

See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide.

SOVALDI should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of CHC in adults. The recommended regimen and treatment duration for SOVALDI combination therapy is provided in Table 1.

Table 1 Recommended Regimens and Treatment Duration for SOVALDI Combination Therapy in HCV Mono-infected and HCV/HIV-1 Co-infected Patients.

*See peginterferon alfa prescribing information for dosing recommendation for patients with genotype 1 or 4 CHC.
†Dose of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily dose of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤ 50 mL/min) require ribavirin dose reduction; refer to ribavirin prescribing information.

Patients with genotype 1 or 4 CHC SOVALDI + peginterferon alfa* + ribavirin† 12 weeks
Patients with genotype 2 CHC SOVALDI + ribavirin† 12 weeks
Patients with genotype 3 CHC SOVALDI + ribavirin† 24 weeks

SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen [See Use in Specific Populations and Clinical Studies  - package insert]. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient.

Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation
SOVALDI in combination with ribavirin is recommended for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection.

Dose Modification
Dose reduction of SOVALDI is not recommended.

Genotype 1 and 4:
If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose.

Genotype 2 and 3:
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status.

Table 2 Ribavirin Dose Modification Guideline for Coadministration with SOVALDI

Discontinuation of Dosing
If the other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued.

Severe Renal Impairment and End Stage Renal Disease
No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite