"SILVER SPRING, MD â€” The US Food and Drug Administration (FDA) is updating labeling information for the hepatitis C antivirals ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and sofosbuvir (Sovaldi, Gilead Sciences) after th"...
Serious Symptomatic Bradycardia When Coadministered With Amiodarone And Another HCV Direct Acting Antiviral
Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with SOVALDI in combination with an investigational agent (NS5A inhibitor) or simeprevir. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (HARVONI (ledipasvir/sofosbuvir)). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.
Coadministration of amiodarone with SOVALDI in combination with another direct acting antiviral (DAA) is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered SOVALDI and another DAA:
- Counsel patients about the risk of serious symptomatic bradycardia
- Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Patients who are taking SOVALDI in combination with another DAA who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.
Due to amiodarone's long half-life, patients discontinuing amiodarone just prior to starting SOVALDI in combination with a DAA should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems [See ADVERSE REACTIONS, DRUG INTERACTIONS].
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 [See CONTRAINDICATIONS]. 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 SOVALDI 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. [See CONTRAINDICATIONS and Use in Specific Populations]. 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 SOVALDI. Rifampin and St. John's wort should not be used with SOVALDI [See DRUG INTERACTIONS].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Ribavirin therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. When SOVALDI is used in combination with peginterferon/ribavirin or ribavirin, patients must be advised of the teratogenic/embryocidal risks of ribavirin and should be advised that extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients both during treatment and for 6 months after the completion of treatment [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Women of childbearing potential and their male partners must use at least two forms of effective contraception during treatment and for 6 months after the treatment has been stopped; routine monthly pregnancy tests must be performed during this time.
Patients should be advised to notify their health care provider immediately in the event of a pregnancy. There is a Ribavirin Pregnancy Registry established to monitor maternal and fetal outcomes of pregnant women exposed to ribavirin. Patients should be encouraged to register by calling 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.
Hepatitis C Virus Transmission
Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken.
Patients should be advised that the recommended regimen for patients with genotype 1 or 4 HCV infection is SOVALDI administered in combination with peginterferon alfa and ribavirin and the recommended regimen for patients with genotype 2 or 3 HCV infection is SOVALDI administered in combination with ribavirin. If peginterferon and/or ribavirin are permanently discontinued, SOVALDI should also be discontinued.
Patients should be advised that the dose of SOVALDI must not be reduced and it should be taken on a regular dosing schedule with or without food. If a patient did not take the SOVALDI at the regular time, it could be taken later in the day. However, no more than 400 mg of SOVALDI should be taken on any calendar day. The patient should resume the regular dosing schedule on the next day.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis and Mutagenesis
Use with Ribavirin and/or Peginterferon alfa: Ribavirin was shown to be genotoxic in several in vitro and in vivo assays. Ribavirin was not oncogenic in a 6-month p53+/-transgenic mouse study or a 2-year carcinogenicity study in rats. See the prescribing information for ribavirin.
Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
Two-year carcinogenicity studies in mice and rats were conducted with sofosbuvir. Mice were administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in females, while rats were administered doses of up to 750 mg/kg/day in males and females. No increase in the incidence of drug-related neoplasms were observed at the highest doses tested in mice and rats, resulting in AUC exposure to the predominant circulating metabolite GS-331007 of approximately 7-and 30-fold (in mice) and 13-and 17-fold (in rats), in males and females respectively, the exposure in humans at the recommended clinical dose.
Impairment of Fertility
Use with Ribavirin and/or Peginterferon alfa: In fertility studies in male animals, ribavirin induced reversible testicular toxicity, while peginterferon alfa may impair fertility in females. Refer to prescribing information for ribavirin and peginterferon alfa for additional information.
Sofosbuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats. At the highest dose tested, AUC exposure to the predominant circulating metabolite GS-331007 was approximately 8-fold the exposure in humans at the recommended clinical dose.
Use In Specific Populations
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 [See WARNINGS AND PRECAUTIONS].
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.
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 [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and ribavirin Package Insert]. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans [See peginterferon alfa Package Insert].
Pregnancy Category B: SOVALDI
There are no adequate and well-controlled studies with SOVALDI in pregnant women.
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.
It is not known whether SOVALDI 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.
Safety and effectiveness of SOVALDI in children less than 18 years of age have not been established.
SOVALDI 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 SOVALDI is warranted in geriatric patients [See CLINICAL PHARMACOLOGY].
No dose adjustment of SOVALDI is required for patients with mild or moderate renal impairment. The safety and efficacy of SOVALDI 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 [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Refer also to ribavirin and peginterferon alfa prescribing information for patients with CrCl < 50 mL/min.
No dose adjustment of SOVALDI is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C) [See CLINICAL PHARMACOLOGY]. Safety and efficacy of SOVALDI have not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation.
Patients With HCV/HIV-1 Co-infection
The safety and efficacy of SOVALDI was assessed in 223 HCV/HIV-1 co-infected subjects [See Clinical Studies]. See DOSAGE AND ADMINISTRATION for dosing recommendations in HCV/HIV-1 co-infected patients. 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 SOVALDI + ribavirin in Phase 3 trials [See ADVERSE REACTIONS].
Patients With Hepatocellular Carcinoma Awaiting Liver Transplantation
SOVALDI 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 SOVALDI 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 SOVALDI 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 SOVALDI 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 SOVALDI 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 SOVALDI and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed in subjects treated with SOVALDI and ribavirin in Phase 3 clinical trials.
Post-Liver Transplant Patients
The safety and efficacy of SOVALDI 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.
Last reviewed on RxList: 4/6/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Sovaldi Information
Report Problems to the Food and Drug Administration
Find out what women really need.