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FDA Warns of Heart Risk When Combining Amiodarone with Sovaldi or Harvoni

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The new oral hepatitis C drug sofosbuvir, either in the sofosbuvir/ ledipasvir coformulation (Harvoni) or with other direct-acting antivirals, should not be taken with the anti-arrhythmic medication amiodarone, the U.S. Food and Drug Association (FDA) and Gilead Sciences warned after several patients developed decreased heart rate (bradycardia) and 1 had a fatal heart attack when they combined these drugs.

Slow heart rate has been reported in 9 patients taking amiodarone while receiving sofosbuvir-based hepatitis C treatment, including 3 who required a pacemaker and 1 who experienced a fatal cardiac arrest. Of these, 3 were using the Harvoni coformulation, 5 were taking sofosbuvir plus Bristol-Myers Squibb's daclatasvir (Daklinza), and 1 was taking sofosbuvir plus Janssen's simeprevir (Olysio).

While the FDA advises against using amiodaronewith sofosbuvir-based therapy, hepatitis C patients who require amiodarone and have no other available treatment options should be monitored as inpatients for 48 hours after starting sofosbuvir and then followed with daily outpatient or self-monitoring for at least 2 weeks.

"The mechanism of the potential interaction between amiodarone and Harvoni, or Sovaldi in combination with another DAA (direct antiviral agent) is unknown," the Gilead letter stated.

Below is an edited excerpt from an FDA drug safety announcement describing the adverse events and label changes in more detail.

FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni or Sovaldi) in combination with another Direct Acting Antiviral drug

March 24, 2015 -- The U.S. Food and Drug Administration (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. We are adding information about serious slowing of the heart rate, known as symptomatic bradycardia, to the Harvoni and Sovaldi labels. We are 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. Patients should not stop taking any of their medicines without first talking to their health care professionals.

Harvoni and Sovaldi are used to treat chronic hepatitis C, a viral infection that can last a lifetime and lead to serious liver problems, including cirrhosis or liver cancer. These drugs reduce the amount of hepatitis C virus in the body by preventing the virus from multiplying within the body.

Our review of submitted post-marketing 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. Information about this serious risk of bradycardia has been added to the Warnings and Precautions, Drug Interactions, and Postmarketing Experience sections of the drug labels for Harvoni and Sovaldi. We 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.

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, we recommend 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.

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

We urge health care professionals and patients to report side effects involving Harvoni, Sovaldi, or amiodarone to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of the page.

Facts about Harvoni and Sovaldi

More Info for Patients

More Info for Health Care Professionals

Data Summary

FDA reviewed post-marketing reports of bradycardia submitted by the manufacturer Gilead Sciences and from the FDA Adverse Event Reporting System (FAERS) database. Reports included the use of amiodarone with either Harvoni (ledipasvir/sofosbuvir) or Sovaldi (sofosbuvir) in combination with other direct-acting antivirals, such as investigational drug daclatasvir or Olysio (simeprevir). Based on the reports, the concomitant administration of amiodarone with Harvoni, or with Sovaldi in combination with another direct-acting antiviral, may result in a severe or life-threatening bradycardia.

The postmarketing reports of serious symptomatic bradycardia are difficult to interpret because they occurred in patients with underlying cardiac disease, concomitant beta blocker therapy, and/or advanced liver disease. However, the following characteristics of these postmarketing cases suggest a causal association:

  • Short time to symptom onset from starting either Harvoni or Sovaldi in combination with other direct-acting antivirals;
  • Resolution of symptoms upon dechallenge;
  • Recurrence of symptoms upon rechallenge.

The mechanism of these events due to the coadministration of amiodarone with either Harvoni or with Sovaldi in combination with another direct-acting antiviral is unknown.

Nine patients receiving amiodarone reported symptomatic bradycardia during treatment with either Harvoni or with Sovaldi in combination with another direct-acting antiviral, such as daclatasvir, an investigational direct acting antiviral, or Olysio (simeprevir). Seven of the 9 patients were also receiving a beta blocker.

Six of the 9 patients experienced symptomatic bradycardia within the first 24 hours, and the remaining 3 patients experienced it within the first 2 to 12 days following hepatitis C treatment initiation. One patient had a fatal outcome due to cardiac arrest, and 3 patients required pacemaker intervention.

In 3 of the patients, rechallenge with hepatitis C treatment in the setting of continued amiodarone therapy resulted in recurrence of symptomatic bradycardia. In one patient, discontinuation of amiodarone followed by rechallenge with hepatitis C treatment after 8 weeks did not result in recurrent bradycardia.

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The updated product label information will be posted soon on the DailyMed website.

Gilead's Dear Health Care provider letter is available online.

3/25/15

Sources

U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni or Sovaldi) in combination with another Direct Acting Antiviral drug. Safety announcement. March 24, 2015.

R Klein, K Struble, and S Morin, U.S. Food and Drug Administration. FDA Hepatitis Update -- Important Safety Information: Harvoni and Sovaldi. FDA bulletin. March 21, 2015.

Gilead Sciences. 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. Dear Health Care Provider letter. March 20, 2015.