Azithromycin and potential risk of QT prolongation

Two recent research studies have strengthened the evidence regarding the potential risk of QT prolongation associated with the use of azithromycin. In the light of this latest data, healthcare professionals are advised to be aware of the risk of Torsades de Pointes and fatal arrhythmia when considering azithromycin as a treatment option for patients who are at risk for cardiovascular events. These patient groups include¹:

• Patients with known prolongation of the QT interval, a history of Torsades de Pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure

• Patients on drugs known to prolong the QT interval

• Patients with ongoing proarrhythmic conditions such as uncorrected hypokalaemia or hypomagnesaemia, clinically significant bradycardia, and patients receiving Class IA (quinidine, procainamide) or Class III (amiodarone, sotalol) antiarrhythmic agents.

• Elderly patients and patients with cardiac disease who may be more susceptible to the effects of arrhythmogenic drugs on the QT interval

Background

Azithromycin is an azalide, a subclass of macrolide antibiotics derived from erythromycin that is widely used both orally and intravenously for the treatment of upper and lower respiratory tract infections and other infections involving susceptible organisms. There are currently 17 registered azithromycin-containing products in Singapore, including the Zithromax^TM range of products (Pfizer Pte Ltd), Zmax^TM (Pfizer Pte Ltd) and 11 other generic products.

Although closely related macrolide drugs such as erythromycin and clarithromycin are known to increase the risk of serious ventricular arrhythmias and are associated with an increased risk of sudden cardiac death, azithromycin has previously been reported to be better tolerated than other macrolides, and has minimal side effects.² However, within the last year, two research studies have provided evidence on the risk of QT prolongation associated with azithromycin.

Publication in New England Journal of Medicine (NEJM)

One of the studies published in the NEJM³ in May 2012 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. There were some limitations to this study, such as potential bias due lack of randomisation to the antibacterial drugs, outpatient setting investigation where it is likely that few patients were treated for severe or life-threatening infections, and the method of determination of cardiovascular deaths through death certificates instead of full medical records. Despite these, the study was noted to be methodologically sound and supportive of the validity of the overall findings.

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 determined to be attributed to cardiovascular deaths and not from other causes. The excess risk of cardiovascular death, especially of sudden death, was consistent with arrhythmias from drug-related QT prolongation.

Clinical QT study conducted by manufacturer

The manufacturer of azithromycin also conducted a randomised, placebo-controlled parallel trial to assess the effects of azithromycin on the QT interval in 116 healthy adults.¹ These subjects received either chloroquine (1000mg) alone or in combination with azithromycin (500mg, 1000mg, and 1500mg once daily). Co-administration of azithromycin increased the QTc* interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF** were 5ms (10), 7ms (12) and 9ms (14) with the co-administration of 500mg, 1000mg and 1500mg azithromycin, respectively.

_{*As the QT interval has an inverse relationship to heart rate, the measured QT interval is routinely corrected by means of various formulae to a value known as the QTc interval which is less dependent on the heart rate}

_{** the maximum mean difference in QT duration corrected for heart rate by the Fridericia's Formula}

Actions taken by US Food and Drug Administration (FDA)

The US FDA has updated the azithromycin US package inserts to strengthen the Warnings and Precautions section with information related to the risk of QT interval prolongation and Torsades de Pointes.⁴ Information regarding the results of the clinical QT study which showed that azithromycin can prolong the QTc interval has also been added.

Local Situation

From 1996 to-date, HSA has received 181 ADR reports associated with the use of azithromycin. Of these reports, there was one case of QT prolongation in a 75-year-old patient with positive rechallenge. There was also one reported case of palpitations in a 38-year-old patient.

HSA's action and advisory

HSA is currently working with the relevant product licence holders to update the package inserts of all azithromycin products to strengthen the warnings regarding the risk of abnormal cardiac rhythms.

Apart from azithromycin, other macrolides such as erythromycin and clarithromycin or non-macrolides such as the fluoroquinolones, are known to have the potential for QT prolongation or other significant side effects. Healthcare professionals are advised to take into consideration these factors when prescribing antibacterial treatment for their patients. Healthcare professionals are also encouraged to report all suspected adverse reactions associated with azithromycin to the Vigilance Branch of HSA.

References

Zithromax® US package insert. Revised January 2013

2. http://www.actabiomedica.it/data/2006/1_2006/russo.pdf

3. N Engl J Med 2012; 366: 1881-90

4. http://www.fda.gov/drugs/drugsafety/ucm341822.htm