Sofosbuvir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
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Overview
Sofosbuvir is an antiviral that is FDA approved for the treatment of chronic hepatitis C (CHC) infection. Common adverse reactions include diarrhea, anemia, headache, insomnia, fatigue.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
The recommended dose of sofosbuvir is one 400 mg tablet, taken orally, once daily with or without food.
Sofosbuvir 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 sofosbuvir combination therapy is provided in the table below.
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 (8.8) and Clinical Studies (14.4)]. 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
Sofosbuvir 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 [See Use in Specific Populations (8.9)].
Dose Modification
Dose reduction of sofosbuvir 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.
Discontinuation of Dosing
If the other agents used in combination with sofosbuvir are permanently discontinued, sofosbuvir 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 [See Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sofosbuvir in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sofosbuvir in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sofosbuvir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sofosbuvir in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sofosbuvir in pediatric patients.
Contraindications
- When sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.
- Sofosbuvir combination treatment with ribavirin or peginterferon alfa/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.
Warnings
Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin
Ribavirin may cause birth defects and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient effects. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.
When sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. There are no data on the effectiveness of systemic hormonal contraceptives in women taking sofosbuvir, therefore, two non-hormonal methods of contraception should be used during treatment with sofosbuvir and concomitant ribavirin. Refer also to the prescribing information for ribavirin.
Use with Potent P-gp Inducers
Drugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John's wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of sofosbuvir. Rifampin and St. John's wort should not be used with sofosbuvir.
Adverse Reactions
Clinical Trials Experience
Sofosbuvir should be administered with ribavirin or peginterferon alfa/ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety assessment of sofosbuvir is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received sofosbuvir + ribavirin (RBV) combination therapy for 12 weeks, 98 subjects who received sofosbuvir + ribavirin combination therapy for 16 weeks, 250 subjects who received sofosbuvir + ribavirin combination therapy for 24 weeks, 327 subjects who received sofosbuvir + peginterferon (Peg-IFN) alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks and 71 subjects who received placebo (PBO) for 12 weeks.
The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving sofosbuvir + ribavirin for 12 weeks, <1% for subjects receiving sofosbuvir + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks.
Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.
The most common adverse events (≥ 20%) for sofosbuvir + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for sofosbuvir + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.
With the exception of anemia and neutropenia, the majority of events presented in Table 3 occurred at severity of grade 1 in sofosbuvir-containing regimens.
Less Common Adverse Reactions Reported in Clinical Trials (<1%)
The following ADRs occurred in <1% of subjects receiving sofosbuvir in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.
- Hematologic Effects: Pancytopenia (particularly in subjects receiving concomitant pegylated interferon).
- Psychiatric Disorders: Severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide.
Laboratory Abnormalities
Changes in selected hematological parameters are described in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.
Bilirubin Elevations
Total bilirubin elevation of more than 2.5×ULN was observed in none of the subjects in the sofosbuvir + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir + ribavirin 12 weeks and sofosbuvir + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations.
Creatine Kinase Elevations
Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10×ULN was observed in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir + peginterferon alfa + ribavirin 12 weeks and sofosbuvir + ribavirin 12 weeks groups, respectively.
Lipase Elevations
Isolated, asymptomatic lipase elevation of greater than 3×ULN was observed in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively.
Postmarketing Experience
There is limited information regarding Sofosbuvir Postmarketing Experience in the drug label.
Drug Interactions
Potential for Drug Interactions
After oral administration, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of sofosbuvir and thus should not be used with sofosbuvir. Coadministration of sofosbuvir with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, sofosbuvir may be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters.
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs.
Potentially Significant Drug Interactions
Drug interaction information for sofosbuvir with potential concomitant drugs is summarized in the table below. The drug interactions described are based on potential drug interactions that may occur with sofosbuvir. The table is not all-inclusive.
Drugs without Clinically Significant Interactions with Sofosbuvir
In addition to the drugs included in the table above, the interaction between sofosbuvir and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine,tacrolimus, or tenofovir disoproxil fumarate.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): B There are no adequate and well-controlled studies with sofosbuvir in pregnant women.
Animal Data
- No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 5- to 10-fold and 12- to 28-fold the exposure in humans at the recommended clinical dose, respectively.
Pregnancy Category X: Use with Ribavirin or Peginterferon Alfa/Ribavirin
- Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using two forms of effective contraception during treatment with ribavirin and for 6 months after treatment has concluded. There are no data on the effectiveness of systemic hormonal contraceptives in women taking sofosbuvir. Therefore, two effective non-hormonal methods of contraception should be used during treatment with sofosbuvir and concomitant ribavirin.
- In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263.
Animal Data
- Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sofosbuvir in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Sofosbuvir during labor and delivery.
Nursing Mothers
It is not known whether sofosbuvir and its metabolites are present in human breast milk. The predominant circulating metabolite GS-331007 was the primary component observed in the milk of lactating rats, without effect on nursing pups. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with ribavirin-containing regimens, taking into account the importance of the therapy to the mother. See also the prescribing information for ribavirin.
Pediatric Use
Safety and effectiveness of sofosbuvir in children less than 18 years of age have not been established.
Geriatic Use
Sofosbuvir was administered to 90 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups. No dose adjustment of sofosbuvir is warranted in geriatric patients
Gender
There is no FDA guidance on the use of Sofosbuvir with respect to specific gender populations.
Race
There is no FDA guidance on the use of Sofosbuvir with respect to specific racial populations.
Renal Impairment
No dose adjustment of sofosbuvir is required for patients with mild or moderate renal impairment. The safety and efficacy of sofosbuvir have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. No dose recommendation can be given for patients with severe renal impairment or ESRD. Refer also to ribavirin and peginterferon alfa prescribing information for patients with CrCl <50 mL/min.
Hepatic Impairment
No dose adjustment of sofosbuvir is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C). Safety and efficacy of sofosbuvir have not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sofosbuvir in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Sofosbuvir in patients who are immunocompromised.
Others
Patients with HCV/HIV-1 Co-infection
The safety and efficacy of sofosbuvir was assessed in 223 HCV/HIV-1 co-infected subjects. The safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving sofosbuvir + ribavirin in Phase 3 trials.
Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation
Sofosbuvir was studied in HCV-infected subjects with hepatocellular carcinoma prior to undergoing liver transplantation in an open-label clinical trial evaluating the safety and efficacy of sofosbuvir and ribavirin administered pre-transplant to prevent post-transplant HCV reinfection. The primary endpoint of the trial was post-transplant virologic response (pTVR) defined as HCV RNA < lower limit of quantification (LLOQ) at 12 weeks post-transplant. HCV-infected subjects, regardless of genotype, with hepatocellular carcinoma (HCC) meeting the MILAN criteria (defined as the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter in patients with multiple tumors and no extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor) received 400 mg sofosbuvir and weight-based 1000–1200 mg ribavirin daily for 24–48 weeks or until the time of liver transplantation, whichever occurred first. An interim analysis was conducted on 61 subjects who received sofosbuvir and ribavirin; 45 subjects had HCV genotype 1; 44 subjects had a baseline CPT score less than 7 and all subjects had a baseline unadjusted MELD score ≤14. Of these 61 subjects, 41 subjects underwent liver transplantation following up to 48 weeks of treatment with sofosbuvir and ribavirin; 37 had HCV RNA < LLOQ at the time of transplantation. Of the 37 subjects, the post-transplant virologic response (pTVR) rate is 64% (23/36) in the 36 evaluable subjects who have reached the 12 week post-transplant time point. The safety profile of sofosbuvir and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed in subjects treated with sofosbuvir and ribavirin in Phase 3 clinical trials.
Post-Liver Transplant Patients
The safety and efficacy of sofosbuvir have not been established in post-liver transplant patients.
CHC Patients with Genotype 5 or 6 HCV Infection
Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing recommendations.
Administration and Monitoring
Administration
(Oral/Intravenous/etc)
Monitoring
Condition 1
(Description regarding monitoring, from Warnings section)
Condition 2
(Description regarding monitoring, from Warnings section)
Condition 3
(Description regarding monitoring, from Warnings section)
IV Compatibility
Solution
Compatible
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Not Tested
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Variable
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Incompatible
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Y-Site
Compatible
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Not Tested
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Variable
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Incompatible
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Admixture
Compatible
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Not Tested
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Variable
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Incompatible
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Syringe
Compatible
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Not Tested
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Variable
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Incompatible
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TPN/TNA
Compatible
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Not Tested
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Variable
- Solution 1
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Incompatible
- Solution 1
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- Solution 3
Overdosage
Acute Overdose
Signs and Symptoms
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Management
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Chronic Overdose
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Pharmacology
Sofosbuvir
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Storage
There is limited information regarding Sofosbuvir Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
(Patient Counseling Information)
Precautions with Alcohol
Alcohol-Sofosbuvir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Sofosbuvir Brand Names in the drug label.
Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
Drug Shortage Status
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References
The contents of this FDA label are provided by the National Library of Medicine.