1) DRAP is warning the public and healthcare providers about the risk of fatal irregular heart rhythms with the antibiotic azithromycin. 2) A study found an increased risk of cardiovascular death among patients treated with a 5-day course of azithromycin compared to other antibiotics or no drug. 3) DRAP is requiring label changes and updates for azithromycin to describe this risk of QT interval prolongation and potential fatal heart rhythm abnormalities.

1. PTPS-DSA-02-2013
Drug Safety Alert
Azithromycin
(Risk of fatal irregular heart rhythm)
Ref: US-FDA
Roohi Bano Obaid, Deputy Director,
Drugs Regulatory Authority of Pakistan
For Policy, Training and Pharmacy Services
September 2013

2. Roohi Bano Obaid, Deputy Director, DRAP, September 09th 2013 Page 2 of 6
AZITHROMYCIN
AZITHROMYCIN
DRAP requires label changes to warn of risk for potentially fatal heart rhythm
from antibacterial Azithromycin.
DRAP is warning the public (Patients and Health Care Providers) that Azithromycin (all brands
registered in Pakistan) can cause abnormal changes in the electrical activity of the heart that may
lead to a potentially fatal irregular heart rhythm. Patients at particular risk for developing this
condition include those with known risk factors such as existing QT interval prolongation, low
blood levels of potassium or magnesium, a slower than normal heart rate, or use of certain drugs
used to treat abnormal heart rhythms, or arrhythmias. This public announcement is a result of
US-FDA review of a study by medical researchers as well as another study by a manufacturer of
the drug that assessed the potential for Azithromycin to cause abnormal changes in the electrical
activity of the heart.
Hence, DRAP requires from manufacturers of azithromycin that the Drug Labels (and all other
literature designed to promote the drug) of Azithromycin, an antibacterial drug be strengthened
and updated to better describe the risk of QT interval prolongation and torsades de pointes, a
specific, rare (potentially fatal) heart rhythm abnormality. Information must also be added
regarding the results of a clinical QT study which showed that Azithromycin can prolong the
QTc interval. (see Data Summary)
Health care professionals should consider the risk of fatal heart rhythms with azithromycin
when considering treatment options for patients who are already at risk for cardiovascular
events (see Additional Information for Health Care Professionals below). US-FDA notes
that the potential risk of QT prolongation with azithromycin should be placed in
appropriate context when choosing an antibacterial drug: Alternative drugs in the
macrolide class, or non-macrolides such as the fluoroquinolones, also have the potential for
QT prolongation or other significant side effects that should be considered when choosing
an antibacterial drug.

3. Roohi Bano Obaid, Deputy Director, DRAP, September 09th 2013 Page 3 of 6
AZITHROMYCIN
Report of US-FDA: On May 17, 2012, FDA referred about a New England Journal of
Medicine (NEJM) study that compared the risks of cardiovascular death in patients treated with
the antibacterial drugs azithromycin, amoxicillin, ciprofloxacin and levofloxacin or no
antibacterial drug.A
The study reported an increase in cardiovascular deaths, and in the risk
of death from any cause, in persons treated with a 5-day course of azithromycin compared
to persons treated with amoxicillin, ciprofloxacin, or no drug. The risks of cardiovascular
death associated with levofloxacin treatment were similar to those associated with azithromycin
treatment. Azithromycin was the only macrolide examined in the published study; the study did
not address other macrolide antibacterial drugs, such as clarithromycin (Biaxin) and
erythromycin, regarding the potential for cardiovascular death.
In 2011, approximately 40.3 million individuals in the U.S. received an outpatient prescription
for the macrolide azithromycin.B
In 2011, US-FDA reviewed macrolide drug labeling
information related to QT interval prolongation and TdP. The WARNINGS AND
PRECAUTIONS section of the drug label of azithromycin extended release for oral suspension
was revised in March 2012 to include new information regarding risk for QT interval
prolongation, which appears to be low. The drug labels for clarithromycin and erythromycin also
contain information about QT interval prolongation in the WARNINGS section. US-FDA is in
the process of updating risk information in the drug labels for additional macrolide antibacterial
drugs.
DRAP will continue to update health care professionals and the public with any relevant
information that becomes available about azithromycin and the risk of abnormal heart rhythms.
FACTS ON AZITHROMYCIN
Azithromycin belongs to a class of antibacterial drugs called macrolides, which have been
associated with cardiovascular effects; specifically, prolongation of the QT interval. Prolongation
of the QT interval can lead to torsades de pointes (TdP), an abnormal heart rhythm, which can be
fatal.
Azithromycin is marketed under the various brand names registered in the name of different
companies in Pakistan.

4. Roohi Bano Obaid, Deputy Director, DRAP, September 09th 2013 Page 4 of 6
AZITHROMYCIN
Approved indications for azithromycin include:
• Acute bacterial exacerbations of chronic obstructive pulmonary disease
• Acute bacterial sinusitis
• Community-acquired pneumonia
• Pharyngitis/tonsillitis
• Uncomplicated skin and skin structure infections
• Urethritis and cervicitis
• Genital ulcer disease
Additional Information for Patients
• Do not stop taking azithromycin without talking to your Doctor / Pharmacist (Health
Care Provider).
• Discuss any questions or concerns about azithromycin or other antibacterial drugs with
your Doctor / Pharmacist (Health Care Provider).
• Seek immediate care if you experience an irregular heartbeat, shortness of breath,
dizziness, or fainting while taking azithromycin.
• Report any side effects you experience to your Doctor / Pharmacist (Health Care
Provider) and DRAP.
• Carefully read the updated information that comes with your azithromycin/ macrolide
class drugs prescription.
Additional Information for Doctor / Pharmacist (Health Care Provider)
• Doctor / Pharmacist (Health Care Provider) should consider the risk of torsades de
pointes and fatal arrhythmia when considering treatment options with azithromycin or
alternative antibacterial drugs. Groups at higher risk include:

5. Roohi Bano Obaid, Deputy Director, DRAP, September 09th 2013 Page 5 of 6
AZITHROMYCIN
 Patients with known prolongation of the QT interval, a history of torsades de
pointes, congenital long QT syndrome, brady-arrhythmias, or uncompensated
heart failure
 Patients on drugs known to prolong the QT interval
 Patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia
or hypomagnesemia, clinically significant bradycardia, and in patients receiving
Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol)
antiarrhythmic agents.
• Elderly patients and patients with cardiac disease may be more susceptible to the effects
of arrhythmogenic drugs on the QT interval.
• The potential risk of QT prolongation should be placed in appropriate context when
choosing an antibacterial drug: Alternative drugs in the macrolide or fluoroquinolone
drug classes also have the potential for QT prolongation or other significant side effects
that should be considered when choosing an antibacterial drug.
• Make sure patients know to contact you if they experience an irregular heartbeat,
shortness of breath, dizziness, or fainting while taking azithromycin.
• If the patient develops such symptoms, the azithromycin should be stopped and an
alternative antibacterial drug should be used, unless the benefit of continued treatment
with azithromycin outweighs the risk.
• Make sure your patients receive the updated information with every prescription.
• Report adverse events involving azithromycin to DRAP.
Data Summary
The study published in NEJM suggested a higher risk of cardiovascular deaths and deaths from
any cause in persons treated with a 5-day course of azithromycin compared to persons treated
with amoxicillin, ciprofloxacin, or no drug.A

6. Roohi Bano Obaid, Deputy Director, DRAP, September 09th 2013 Page 6 of 6
AZITHROMYCIN
The study has important limitations. First, patients were not randomized to the antibacterial
drugs studied, so patients who received different drugs might have differed in ways that could
have biased the results. Second, the study only examined antibacterial drugs used in an outpatient
setting, so it is likely that few patients were being treated for severe or life-threatening infections.
Third, cardiovascular deaths were determined using death certificates rather than full medical
records. Fourth, there were also some limitations to the statistical methods used.
On balance, however, the study was methodologically sound and supports the validity of the
overall finding. The estimated excess risk of cardiovascular death compared with amoxicillin
varied considerably with the patients’ baseline cardiovascular risk, from roughly 1 in 111,000
among healthier patients to 1 in 4,100 among high-risk patients. The duration of the elevated risk
of all-cause mortality and of cardiovascular death corresponded to the duration of azithromycin
therapy. The increase in total deaths was due to cardiovascular deaths and not due to an increase
in deaths from other causes. The excess risk of cardiovascular death, especially of sudden death,
is consistent with arrhythmias from drug-related QT prolongation.
Leading Regulatory Agency evaluated the results of a clinical QT study of the manufacturer
assessing the effects of azithromycin on the QT interval in adults, which indicates the
prolongation of QTc interval associated with azithromycin. Information regarding the results of
the QT study has been added to the azithromycin drug label in parent country of drug origin.
References:
A. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N
Engl J Med 2012;366:1881-1890.http://www.nejm.org/doi/full/10.1056/NEJMoa1003833
B. Source: IMS Health Vector One National Total Patient Tracker.
C. US-FDA