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
The purpose of this
letter is to inform you of new important
safety information for Harvoni and Sovaldi.
for the treatment of chronic hepatitis
C genotype 1 infection in adults.
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)
of 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.
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.
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.
cases have not been reported in patients receiving Sovaldi with ribavirin or
with pegylated interferon and ribavirin.
Warning and Precaution
amiodarone with either Harvoni or with Sovaldi in combination with another DAA
is not recommended.
cases 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.
cases occurred within the first 24 hours and the remaining 3
cases occurred within the first
2-12 days following HCV treatment initiation.
one case discontinuation of amiodarone followed by rechallenge
of HCV treatment after 8 weeks did not result in recurrent bradycardia.
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.
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:
patients about the risk of serious symptomatic
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:
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 recommendations
may change. Additionally, the product labeling will be
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).
refer to the accompanying full prescribing information and approved patient
information for a complete description of the risk profile for Harvoni or
Contact Gilead Medical Information at 1-800-GILEAD-5, option 2 if you
have additional questions.
information is being sent in agreement with the FDA.
Executive Vice President, Clinical Research
Labels: adverse events, Amiodarone, Harvoni, Sovaldi, Warnings