FDA MedWatch: Hepatitis C Treatments Containing Sofosbuvir in Combination With Another Direct Acting Antiviral Drug: Drug Safety Communication - Serious Slowing of Heart Rate When Used With Antiarrhythmic Drug Amiodarone

AUDIENCE: Cardiology, Infectious Disease, Gastroenterology, Pharmacy

ISSUE: FDA is warning that serious slowing of the heart rate can occur when the antiarrhythmic drug amiodarone is taken together with either the hepatitis C drug Harvoni (ledipasvir/sofosbuvir) or with Sovaldi (sofosbuvir) taken in combination with another direct acting antiviral for the treatment of hepatitis C infection. FDA is adding information about serious slowing of the heart rate, known as symptomatic bradycardia, to the Harvoni and Sovaldi labels. FDA is recommending that health care professionals should not prescribe either Harvoni or Sovaldi combined with another direct acting antiviral, such as the investigational drug daclatasvir or Olysio (simeprevir), with amiodarone.

FDA review of submitted postmarketing adverse event reports found that patients can develop a serious and life-threatening symptomatic bradycardia when either Harvoni or Sovaldi combined with another direct-acting antiviral is taken together with amiodarone. The reports included the death of one patient due to cardiac arrest and three patients requiring placement of a pacemaker to regulate their heart rhythms. The other patients recovered after discontinuing either the hepatitis C drugs or amiodarone, or both (see Data Summary). The cause of these events could not be determined. FDA will continue to monitor Harvoni and Sovaldi for risks of serious symptomatic bradycardia and further investigate the reason why the use of amiodarone with these hepatitis C drugs led to the heart-related events.

BACKGROUND: For a Data Summary and additional recommendations for health professionals and patients, see the FDA Drug Safety Communication.

RECOMMENDATION: Health care professionals should not prescribe either Harvoni or Sovaldi combined with another direct-acting antiviral drug with amiodarone. However, in cases where alternative treatment options are unavailable, FDA recommends heart monitoring in an inpatient hospital setting for the first 48 hours. Subsequently, monitoring in a doctor’s office or self-monitoring of the heart rate should be done every day through at least the first 2 weeks of treatment.

Due to the long half-life of amiodarone, patients discontinuing amiodarone just prior to starting Harvoni, or Sovaldi in combination with another direct-acting antiviral, should also undergo similar cardiac monitoring as outlined above.

Patients taking either Harvoni or Sovaldi combined with another direct-acting antiviral drug with amiodarone should seek medical attention right away if they experience signs or symptoms of symptomatic bradycardia such as:

• Near-fainting or fainting
• Dizziness or light-headedness
• Malaise
• Weakness
• Excessive tiredness
• Shortness of breath
• Chest pains
• Confusion or memory problems

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

• Complete and submit the report Online: www.fda.gov/MedWatch/report
• Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Read the MedWatch safety alert, including a link to the FDA Drug Safety Communication, at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm439662.htm

FDA Hepatitis Update - Important safety information: Harvoni , and Sovaldi

IMPORTANT DRUG WARNING

Subject: Serious and Life-Threatening Cases of Symptomatic Bradycardia as well as One Case of Fatal Cardiac Arrest Reported with Coadministration of Amiodarone With Either Harvoni^® (ledipasvir and sofosbuvir fixed-dose combination) or With Sovaldi^® (sofosbuvir) in Combination with Another Direct Acting Antiviral.

On March 20, 2015, FDA approved changes to the Harvoni (ledipasvir/sofosbuvir fixed dose combination) and Sovaldi (sofosbuvir) labels to update the WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and DRUG INTERATIONS sections of the labeling and the patient package insert with information on post-marketing cases of symptomatic bradycardia when co-administered with amiodarone. Additionally, Gilead Sciences has issued a Dear Healthcare Provider letter (below):

Dear Health Care Provider,

The purpose of this letter is to inform you of new important safety information for Harvoni and Sovaldi.

·       Harvoni is indicatedfor the treatment of chronic hepatitis C genotype 1 infection in adults.

·       Sovaldi is indicated for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen.

Serious Risk of Symptomatic Bradycardia With Co-Use of Amiodarone with Either Harvoni or With Sovaldi in Combination with Another Direct Acting Antiviral (DAA)

·       Postmarketing casesof symptomatic bradycardia, as well as one fatal cardiac arrest and cases requiring pacemaker insertion, have been reported in patients taking amiodarone and Harvoni, or amiodarone and Sovaldi in combination with another DAA.

·       Bradycardia was observed within hours to days of starting Harvoni, or Sovaldi in combination with another DAA, but cases have been observed up to 2 weeks after initiating HCV treatment.

·       Risk factors for the development of symptomatic bradycardia in patients receiving amiodarone may include coadministration of a beta blocker, or those with underlying cardiac comorbidities and/or advanced liver disease.

·       Similar cases have not been reported in patients receiving Sovaldi with ribavirin or with pegylated interferon and ribavirin.

Warning and Precaution

Coadministration of amiodarone with either Harvoni or with Sovaldi in combination with another DAA is not recommended.

Further Information

Ninecases of symptomatic bradycardia have been reported during postmarketing in patients receiving amiodarone with either Harvoni, or Sovaldi in combination with another DAA (daclatasvir, an investigational DAA, or Olysio (simeprevir)). Seven patients were also receiving a beta blocker.

·       Sixcases occurred within the first 24 hours and the remaining 3cases occurred within the first 2-12 days following HCV treatment initiation.

·       One case was a fatal cardiac arrest and 3 cases required pacemaker intervention.

·       In 3cases, rechallenge with HCV treatment in the setting of continued amiodarone therapy resulted in recurrence of symptomatic bradycardia.

·       Inone case discontinuation of amiodarone followed by rechallengeof HCV treatment after 8 weeks did not result in recurrent bradycardia.

·       Three of the 9 cases were in patients receiving Harvoni, 5 cases were in patients receiving Sovaldi plus an investigational agent (daclatasvir) and 1 case was in a patient receiving Sovaldi with Olysio (simeprevir).

The mechanism of the potential interaction between amiodarone and Harvoni, or Sovaldi in combination with another DAA is unknown.

Because the number of patients taking amiodarone who have been exposed to Harvoni or Sovaldi in combination with another DAA is unknown, it is not possible to estimate the incidence of occurrence of these events.

Prescriber Action

For patients taking amiodarone who have no other alternative, viable treatment options and who will be co-administered Harvoni, or Sovaldi in combination with 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 Harvoni or 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 Harvoni or Sovaldi in combination with a DAA should also undergo similar cardiac monitoring as outlined above.

Tell your patients if they develop signs or symptoms that might suggest symptomatic bradycardia they should seek medical evaluation immediately. Symptoms may include:

·       Near-fainting or fainting	·       Excessive tiredness
·       Dizziness or lightheadedness	·       Shortness of breath
·       Malaise	·       Chest pains
·       Weakness	·       Confusion or memory problems

Patients should not stop taking any of their medicines without talking to their healthcare provider.

This information is based on currently available data and recommendationsmay change. Additionally, the product labeling will be updated.

Reporting Adverse Events

Please report all adverse events, following or coincident with the use of Harvoni or Sovaldi, to Gilead Global Drug Safety at 1-800-GILEAD-5, option 3; or to FDA's MedWatch program by telephone at 1-800-332-1088; by fax at 1-800-332-0178; via www.FDA.gov/medwatch; or by mail to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857 (use postage-paid FDA Form 3500).

Please refer to the accompanying full prescribing information and approved patient information for a complete description of the risk profile for Harvoni or Sovaldi.

Contact Gilead Medical Information at 1-800-GILEAD-5, option 2 if you have additional questions.

This information is being sent in agreement with the FDA.

Sincerely,

John McHutchison, MD

Executive Vice President, Clinical Research

Gilead Sciences, Inc.