Sofgen

Sofgen is a prodrug nucleotide analog used as part of combination therapy to treat hepatitis C virus (HCV) infection or to treat co-infection of HIV and HCV. After metabolism to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate (also known as GS-461203), the triphosphate serves as a defective substrate for the NS5B protein, an RNA-dependent RNA polymerase required for replication of viral RNA. Sofgen and other nucleotide inhibitors of the HCV RNA polymerase exhibit a very high barrier to resistance development. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid resistance development has proved to be an important cause of therapeutic failure. More recently, Sofgen has become available as a fixed dose drug combination product with levipasvir (tradename Harvoni) used for the treatment of chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). Approved in October 2014 by the FDA, ledipasvir and Sofgen are direct-acting antiviral agents indicated for the treatment of HCV genotype 1 with or without cirrhosis. HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States affecting 72% of all chronic HCV patients. Prior to development of this drug, the main treatment available was weekly injections of pegylated interferon with weight-based ribavirin over 48 weeks, which achieved a sustained virological response (SVR) of 45-50% and had multiple unpleasant side effects. When combined together, ledipasvir and Sofgen have been shown to have a SVR between 93 and 100% after 12 weeks of treatment. Its use has also proven successful in the treatment of HCV in patients co-infected with HIV.

Treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.

Sofgen 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 Sofgen: Monotherapy 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.

Sofgen (Sofgen) is an antiviral medication that prevents hepatitis C virus (HCV) from multiplying in your body.

Sofgen is used in combination with other medications to treat hepatitis C in adults. Sofgen is sometimes used in people who also have HIV, or people who have liver cancer and are going to have a liver transplant. This medicine is not a treatment for HIV or AIDS.

Sofgen must be given in combination with other antiviral medications and should not be used alone. Sofgen is usually given with ribavirin (Copegus, Rebetol, Ribasphere, RibaTab) with or without peginterferon alfa (Pegasys, PegIntron).

Sofgen is also used together with Daklinza (daclatasvir) to treat hepatitis C genotype 3 infection in adults.

Recommended Dosage

The recommended dosage of Sofgen is one 400 mg tablet, taken orally, once daily with or without food.

Administer Sofgen in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of HCV. The recommended treatment regimen and duration for Sofgen combination therapy is provided in Table 1.

For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.

Table 1 : Recommended Treatment Regimens and Duration

Patients with Genotype 1 HCV Who are Ineligible to Receive an Interferon-Based Regimen

Sofgen in combination with ribavirin for 24 weeks can be considered as a therapeutic option for patients with genotype 1 infection who are ineligible to receive an interferon-based regimen. 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

Administer Sofgen in combination with ribavirin for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection.

Dosage Modification

Dosage reduction of Sofgen is not recommended.

If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dosage should be reduced or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. 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 dosage.

Discontinuation Of Dosing

If the other agents used in combination with Sofgen are permanently discontinued, Sofgen should also be discontinued.

Severe Renal Impairment And End Stage Renal Disease

No dosage recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73m²) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant Sofgen metabolite.

How supplied

Dosage Forms And Strengths

Sofgen is available as a yellow-colored, capsule-shaped, film-coated tablet debossed with “GSI” on one side and “7977” on the other side. Each tablet contains 400 mg Sofgen.

Storage And Handling

Sofgen tablets are yellow, capsule-shaped, film-coated tablets containing 400 mg Sofgen debossed with “GSI” on one side and “7977” on the other side. Each bottle contains 28 tablets (NDC 61958-1501-1), a silica gel desiccant and polyester coil with a child-resistant closure.

Store at room temperature below 30 °C (86 °F).

• Dispense only in original container
• Do not use if seal over bottle opening is broken or missing

Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404. Issued: August 2015

See also:
What is the most important information I should know about Sofgen?

When Sofgen is used in combination with ribavirin or peginterferon-α/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon-α and ribavirin for a list of their contraindications.

Sofgen combination treatment with ribavirin or peginterferon-α/ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin.

Use Sofgen as directed by your doctor. Check the label on the medicine for exact dosing instructions. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Sofgen. Talk to your pharmacist if you have questions about this information.
• Sofgen must be taken with either ribavirin or peginterferon alfa and ribavirin, which come with their own Medication Guides. Be sure to read those Medication Guides each time you get them filled.
• Take Sofgen by mouth with or without food.
• Sofgen works best if it is taken at the same time each day.
• Continue to take Sofgen even if you feel well. Do not miss any doses.
• If you miss a dose of Sofgen, take it as soon as you remember the same day and go back to your regular dosing schedule. Do not take more than 1 dose of Sofgen in the same day. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Sofgen.

Use: Labeled Indications

Chronic hepatitis C: Treatment of genotype 1, 2, 3, or 4 chronic hepatitis C virus (HCV) infection in adults and genotype 2 or 3 chronic HCV infection in pediatric patients ≥3 years of age, without cirrhosis or with compensated cirrhosis, as a component of a combination antiviral treatment regimen.

Off Label Uses

Chronic hepatitis C, genotype 1, 2, 3, or 4 (decompensated cirrhosis)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, Sofgen, in combination with daclatasvir with or without ribavirin, is effective and recommended for treatment of hepatitis C virus genotype 1, 2, 3, or 4 infection in patients with decompensated cirrhosis. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C, genotype 1, 2, 3, 4, 5, or 6 (liver transplant recipients)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, Sofgen, in combination with daclatasvir and ribavirin, is an effective and recommended regimen for treatment of hepatitis C virus genotype 2, 3 infection in liver transplant recipients with or without cirrhosis (including decompensated cirrhosis) and recommended alternative regimen for treatment of genotype 5 or 6 in patients without cirrhosis or with compensated cirrhosis. Sofgen, in combination with daclatasvir and ribavirin or simeprevir with or without ribavirin, is an effective and recommended alternative regimen for treatment of hepatitis C virus genotype 1 or 4 infection in liver transplant recipients without cirrhosis or with compensated cirrhosis. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Chronic hepatitis C, genotype 2, 3, 5, or 6 (renal transplant recipients)

Based on the AASLD/IDSA Recommendations for Testing, Managing, and Treating Hepatitis C guidelines, Sofgen, in combination with daclatasvir and ribavirin, is an effective and recommended alternative regimen for treatment of hepatitis C virus genotype 2, 3, 5, or 6 infection in renal transplant recipients without cirrhosis or with compensated cirrhosis. Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

See also:
What other drugs will affect Sofgen?

Sofgen is a nucleotide prodrug. After oral administration of Sofgen, Sofgen is rapidly absorbed and subject to extensive first‑pass hepatic and intestinal metabolism. Intracellular hydrolytic prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS‑331007 that accounts for >90% of drug‑related material systemic exposure is formed through pathways sequential and parallel to formation of active metabolite. The parent Sofgen accounts for approximately 4% of drug‑related material systemic exposure. In clinical pharmacology studies, both Sofgen and GS‑331007 were monitored for purposes of pharmacokinetic analyses.

Sofgen is a substrate of drug transporter P‑gp and breast cancer resistance protein (BCRP) while GS‑331007 is not. Medicinal products that are potent P‑gp inducers in the intestine (e.g. rifampicin, St. John's wort, carbamazepine and phenytoin) may decrease Sofgen plasma concentration leading to reduced therapeutic effect of Sofgen and thus should not be used with Sofgen. Co‑administration of Sofgen with medicinal products that inhibit P‑gp and/or BCRP may increase Sofgen plasma concentration without increasing GS‑331007 plasma concentration, thus Sofgen may be co‑administered with P‑gp and/or BCRP inhibitors. Sofgen and GS‑331007 are not inhibitors of P‑gp and BCRP and thus are not expected to increase exposures of medicinal products that are substrates of these transporters.

The intracellular metabolic activation pathway of Sofgen is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant medicinal products.

Other Interactions: Drug interaction information for Sofgen with potential concomitant medicinal products is summarised in Table 21 (where 90% confidence interval of the geometric least‑squares mean ratio were within "↔", extended above "↑", or extended below "↓" the predetermined equivalence boundaries). The table is not all‑inclusive.

Medicinal products that are potent P‑gp inducers in the intestine (rifampicin, St. John's wort, carbamazepine and phenytoin) may significantly decrease Sofgen plasma concentration leading to reduced therapeutic effect. For this reason, Sofgen should not be co‑administered with known inducers of P‑gp.

See also:
What are the possible side effects of Sofgen?

Summary of the Safety Profile: During treatment with Sofgen in combination with ribavirin or with peginterferon alfa and ribavirin, the most frequently reported adverse drug reactions were consistent with the expected safety profile of ribavirin and peginterferon alfa treatment, without increasing the frequency or severity of the expected adverse drug reactions.

Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both controlled and uncontrolled).

The proportion of subjects who permanently discontinued treatment due to adverse reactions was 1.4% for subjects receiving placebo, 0.5% for subjects receiving Sofgen + ribavirin for 12 weeks, 0% for subjects receiving Sofgen + ribavirin for 16 weeks, 11.1% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2.4% for subjects receiving Sofgen + peginterferon alfa + ribavirin for 12 weeks.

Tabulated Summary of Adverse Reactions: Sofgen has mainly been studied in combination with ribavirin, with or without peginterferon alfa. In this context, no adverse drug reactions specific to Sofgen have been identified. The most common adverse drug reactions occurring in subjects receiving Sofgen and ribavirin or Sofgen, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia.

The following adverse drug reactions have been identified with Sofgen in combination with ribavirin or in combination with peginterferon alfa and ribavirin. The adverse reactions are listed below by body system/organ class and frequency. Frequencies are defined as follows: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000).

Other Special Populations: Human Immunodeficiency Virus/Hepatitis C Virus (HIV/HCV) Co‑Infection: The safety profile of Sofgen and ribavirin in HCV/HIV co‑infected subjects was similar to that observed in mono‑infected HCV subjects treated with Sofgen and ribavirin in Phase 3 clinical studies.

Patients Awaiting Liver Transplantation: The safety profile of Sofgen and ribavirin in HCV infected subjects prior to liver transplantation was similar to that observed in subjects treated with Sofgen and ribavirin in Phase 3 clinical studies.

Description of Selected Adverse Reactions: Cardiac Arrhythmias: Cases of severe bradycardia and heart block have been observed when Sofgen is used in combination with daclatasvir and concomitant amiodarone and/or other drugs that lower heart rate.

Reporting of Suspected Adverse Reactions: It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.