June 29, 2016
Recommended Topic Related To:

Sovaldi

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Sovaldi

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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].

Risk Of Reduced Therapeutic Effect Due To Use With P-gp Inducers

Drugs that are 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. The use of rifampin and St. John's wort with SOVALDI is not recommended [see DRUG INTERACTIONS].

Risks Associated With Combination Treatment

Because SOVALDI is used in combination with other antiviral drugs for treatment of HCV infection, consult the prescribing information for these drugs used in combination with SOVALDI. Warnings and Precautions related to these drugs also apply to their use in SOVALDI combination treatment.

Related Products Not Recommended

The use of SOVALDI with other products containing sofosbuvir is not recommended.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Serious Symptomatic Bradycardia When Coadministered with Amiodarone and Another HCV Direct Acting Antiviral

Advise patients to seek medical evaluation immediately for symptoms of bradycardia such as near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and DRUG INTERACTIONS].

Pregnancy

Advise patients to avoid pregnancy during combination treatment with SOVALDI and ribavirin or SOVALDI and peginterferon and ribavirin. Inform patients to notify their health care provider immediately in the event of a pregnancy [see Use In Specific Populations].

Drug Interactions

Advise patients that SOVALDI may interact with some drugs; therefore, patients should be advised to report the use of any prescription, non-prescription medication or herbal products to their healthcare provider [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Hepatitis C Virus Transmission

Inform patients 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.

Important Information on Co-Administration with Ribavirin or Peginterferon and Ribavirin

Advise patients 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis and Mutagenesis

Use with Ribavirin and/or Peginterferon alfa: Refer to prescribing information for ribavirin and/or peginterferon alfa for information on carcinogenesis and mutagenesis.

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: Refer to prescribing information for ribavirin and/or peginterferon for information on impairment of fertility.

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

Pregnancy Category B

There are no adequate and well-controlled studies with SOVALDI in pregnant women. Because animal reproduction studies are not always predictive of human response, SOVALDI should be used during pregnancy only if the potential for benefit justifies the potential risk to the fetus.

If SOVALDI is administered with ribavirin or peginterferon and ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin and/or peginterferon prescribing information for more information on use in males and females of child-bearing potential.

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.

Nursing Mothers

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. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SOVALDI and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

If SOVALDI is administered in a regimen containing ribavirin, the information for ribavirin with regard to nursing mothers also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use in nursing mothers.

Pediatric Use

Safety and effectiveness of SOVALDI in children less than 18 years of age have not been established.

Geriatric Use

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 dosage adjustment of SOVALDI is warranted in geriatric patients [see CLINICAL PHARMACOLOGY].

Renal Impairment

No dosage 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 less than 30 mL/min/1.73m²) or ESRD requiring hemodialysis. No dosage 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 less than 50 mL/min.

Hepatic Impairment

No dosage 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 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 less than 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 up to 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 less than 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.

Patients With Genotype 5 Or 6 HCV Infection

Available data on subjects with genotype 5 or 6 HCV infection are insufficient for dosing recommendations.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/31/2016

Warnings
Precautions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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