Drug Safety Alert 2 Azithromycin

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

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.


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.


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:


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


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

Leadership & Management

Drug Safety Alert 2 Azithromycin