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AZITHROMYCIN AND THE RISK OF CARDIOVASCULAR DEATH 

Helping to achieve safe 

medication use

ISSUE 8 VOLUME 2 SEPTEMBER 2012

 AZITHROMYCIN AND RISK OF

CARDIOVASCULAR DEATH

............................... 1-2

 MEDICATION SAFETY NEWS 

FROM THE VA NATIONAL

PHARMACY BENEFITS 

MANAGEMENT SERVICES 

[PBM] AND THE FOOD AND

DRUG ADMINISTRATION

[FDA]........................ 2

 IDENTIFYING POTENTIALLY

PREVENTABLE ADVERSE

DRUG REACTIONS IN THE

VA ADVERSE DRUG EVENT

REPORTING SYSTEM [VA

ADERS] ..................... 3Medication

Macrolide antibiotics have well-known proarrhythmic properties. There is now growing evidence in the published literature 

as well as from cases reported to FDA’s Adverse Event Reporting System (AERS) that azithromycin, a broad-spectrum macrolide antibiotic, increases the risk of QT-interval prolongation, 

torsades de pointes, polymorphic ventricular tachycardia, as well 

as sudden cardiac death. 

The increase in reports of azithromycin-induced ventricular arrhythmias and abrupt fatal effects was recently reported in the 

New England Journal of Medicine. The investigators conducted 

a retrospective review of cardiac deaths related to the use of a 

five day course of azithromycin. The cohort included Medicaid 

patients receiving a prescription for azithromycin during any 

time between 1992 and 2006, of which approximately 80% consisted of women with a mean age of 49 years. Subjects who 

received azithromycin (347,795 prescriptions) were propensityscore-matched to a control group receiving no antibiotics 

(1,391,180 matched treatment periods) to take into account comorbid and cardiovascular conditions in addition to behavioral 

risk factors that may influence cardiovascular disease (i.e., 

smoking, diet, weight, sedentary lifestyle). Furthermore, the 

study included a second control group of patients with prescriptions for either amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions) in order to reduce any confounding by the types of infections being treated due to similar indications for use. The study 

analyzed cumulative incidence, or risk, of cardiovascular death, 

as well as death from any cause, during a course of antibiotic 

therapy, defined as a 5-day treatment duration generally recommended with azithromycin use and a 10-day treatment schedule 

routinely prescribed with the comparator antibiotics. 

Results showed a significant increase in the risk of cardiovascular death with a 5-day course of azithromycin when compared to 

the first 5 days of a 10-day course of either amoxicillin (hazard 

ratio, 2.49; 95% confidence interval, 1.38 to 4.50; p=0.002) or 

ciprofloxacin (hazard ratio, 3.49; 95% confidence interval, 1.32 

to 9.26; p=0.01), but no significant difference from that with 

levofloxacin (hazard ratio, 1.27; 95% confidence interval, 0.66 

to 2.47; p=0.48). Azithromycin was associated with 29 cardiovascular deaths during the 5-day treatment period (85.2 per 1 

million courses), of which 22 (64.6 per 1 million courses) 

(continued on page 2)

EDITOR-IN-CHIEF | Marie Sales, Pharm.D.

VA Pharmacy Benefits Management Services [PBM] & Center for Medication Safety [VA MedSAFE]

1st Avenue—1 Block North of Cermak Road | Building 37; Room 139 | Hines, Illinois | 60141

www.pbm.va.gov

safety in seconds

A M ONT H L Y P U B LI C AT IO N FRO M V A M E D S AF E: 

V A ’S CO M P R EH E N SI V E P H A R M ACO V IG IL A NC E C E NT E R
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NEWS YOU CAN USE

FROM THE FOOD AND DRUG ADMINISTRATION (FDA)

CARDIOLOGY

FDA recommends against use of Revatio in children with pulmonary hypertension

8/30/2012 

Sildenafil (Revatio®) received FDA approval for improving exercise ability and delaying clinical progression of pulmonary arterial hypertension in adults classified as WHO Group I. Off-label use has occurred in the pediatric population. However, results from a recent 

long-term, randomized, double-blind, multi-center, placebo-controlled, parallel group, dose-ranging clinical trial in 234 pediatric patients 

(aged 1-17 years) showed: 

Higher risk of death in children associated with high doses compared to low doses; and

No improvement in exercise ability in children with lower doses.

Therefore, FDA does not recommend use of sildenafil (Revatio®) in children, and new product labeling will reflect this warning. FDA 

believes that the direct dose-related effect on mortality does not apply to sildenafil marketed as Viagra® used to treat erectile dysfunction 

due to differences in population and dosing.

PAIN MANAGEMENT

Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death

8/15/2012 

Genetic variations in DNA result in different cytochrome P450 2D6 enzyme activity that may lead to quicker metabolism of codeine into 

morphine leading to life-threatening levels in the body and the potential for toxicity, including respiratory depression or death. Certain 

racial/ethnic populations express this “ultra-high metabolizer” genotype more than others, with ranges from as low as 1% in people of 

Northern European decent to up to almost 30% in those with African/Ethiopian backgrounds. Three pediatric deaths and one case of severe respiratory depression occurred in children found to have the “ultra-high metabolizer” genotype. These children, ranging from ages 

2-5 years, received usual doses of codeine products for analgesia after undergoing tonsillectomy and/or adenoidectomy for obstructive 

sleep apnea. FDA recommends to:

Consider alternative analgesic agents for children post-tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome due to already compromised breathing status; and

If codeine-containing products are clinically indicated, use the lowest dose in the shortest time on an “as needed” basis (not 

scheduled or administered more than 6 times a day).

Helping to achieve safe medication use

AZITHROMYCIN AND RISK OF CARDIOVASCULAR DEATH

comprised sudden cardiac deaths. An estimated 47 additional cardiovascular deaths per 1-million 5-day courses with azithromycin in 

comparison to amoxicillin were derived from study data. Moreover, a 5-day course of azithromycin maintained a significant increase in the risk of death from any cause compared to the first 5 

days of a course of amoxicillin (hazard ratio, 2.02; 95% confidence 

interval 1.24 to 3.30; p=0.005), but not with ciprofloxacin (hazard 

ratio, 1.75; 95% confidence interval, 0.91 to 3.37; p=0.09) or 

levofloxacin (hazard ratio, 1.07; 95% confidence interval, 0.61 to 

1.85; p=0.82). When compared to a matched period of no antibiotic 

treatment, 5-days of azithromycin therapy increased the risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval, 1.79 

to 4.63; p<0.001) and death from any cause (hazard ratio, 1.85; 

95% confidence interval 1.25 to 2.75; p=0.002). 

Since azithromycin is commonly used in VA, awareness of this 

safety concern can help providers to recognize veteran patients potentially at risk for developing an adverse cardiac event with 

azithromycin and to weigh the risks versus benefits when considering antibiotic therapy. Although the Medicaid cohort mostly 

consisted of young, female patients, one cannot preclude similar 

adverse events from occurring in an elderly and mainly male population with multiple co-morbidities. High-risk patients with a predisposition to cardiac adverse events may warrant use of alterative 

antimicrobial agents or class of agents. Providers should continue 

to report any adverse reactions with the use of azithromycin by entering the information into CPRS’ Allergies/ Adverse Reactions 

field and/or via local reporting mechanisms. Adverse events should 

also be reported, as appropriate, to the VA ADERS program and 

FDA MedWatch (1-800-FDA-1088, fax 1-800-FDA 0178, online at 

https://www.accessdata.fda.gov/scripts/medwatch/medwatchonline.htm, or by mail).

REFERENCE:

Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the Risk of Cardiovascular Death. N Eng J Med 2012; 366:1881-90.

Contributed by:

Cedric Salone, Pharm.D., MPH, PGY-2 Resident; and

Courtney Smith, Pharm.D., PGY-2 Resident

(continued from page 1)
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Getting the most from our 

safety surveillance

IDENTIFYING POTENTIALLY PREVENTABLE ADVERSE DRUG 

REACTIONS IN THE VA ADVERSE DRUG EVENT REPORTING SYSTEM 

(VA ADERS)

EXAMPLE OF 

POTENTIALLY 

PREVENTABLE ADR 

REPORTED TO 

VA ADERS

Patient presents to the emergency 

room with confusion, difficulty ambulating, and falling. Active medications include simvastatin 10mg 

at bedtime (reported as the primary 

suspect medication) and gemfibrozil 600mg twice daily (reported as 

the secondary suspect medication), in addition to niacin (SloNiacin) 500mg twice daily, morphine sulfate (MS Contin) 15 mg 

twice daily, and acetaminophen/

hydrocodone 5/500 mg every 6 

hours as needed. Labs consist of 

BUN 70, SCr 4.9, SGOT 384, SGPT 

95, and CPK 12,840. Patient was 

admitted for intravenous hydration 

in addition to discontinuation of 

simvastatin, gemfibrozil, and niacin 

due to diagnosis of rhabdomyolysis. Symptoms resolved and the 

patient was discharged. Subsequent medical record review revealed a previous hospital admission for the patient in 2010 for 

rhabdomyolysis, confusion, and 

weakness with primary suspect 

medication simvastatin 20 mg at 

bedtime and secondary suspect 

medication gemfibrozil 600 mg 

twice daily.

Preventability questions were answered as follows in Table 2. Answers that signify potential preventability include: #5 = YES, #6 = 

YES. The assessment revealed 

that use of alternative agents may 

have helped to avoid this adverse 

event due to the drug-drug interaction between concomitant use of 

simvastatin and gemfibrozil that 

may have led to the rhabdomyolysis.

Adverse drug events (ADEs) entered into 

the VA Adverse Drug Event Reporting 

System (VA ADERS) may be evaluated 

for elements that signal potential preventability. VA ADERS poses preventability 

questions with each adverse drug reaction 

entered to focus on factors involved with 

the ADE as well as potential steps that may 

have circumvented the event (Table 1). 

While individual assessment of each question can denote potential preventability, the 

overall determination of preventability for 

the event should derive from the collective 

answers to the series of questions as well 

as from any changes in pharmacotherapy 

based on the patient’s clinical presentation 

that could have prevented the event. For 

example, Questions 1-4 suggests potential 

preventability when answered “NO”. A 

“NO” answer to Question 1 indicates an 

inappropriate drug choice and that a therapeutic alternative may less likely lead to an 

adverse outcome if selected. Furthermore, 

Questions 5-9 imply potential preventability when answered “YES”. A “YES” answer to Question 5 would necessitate a 

critical comparison to all questions to ascertain the appropriateness of this agent 

given the history of allergy or previous 

adverse reaction.

Answering these preventability questions 

can help minimize the recurrence of harm 

by uncovering areas of the medication use 

process that need additional regulation or 

system improvements to enhance the procedures involved in drug selection, monitoring, administration, or adherence. Sharing data from preventability analyses via 

provider and staff education can increase 

awareness of potential weaknesses in the 

medication process locally as well as nationally for targeted intervention. An example of consequent process improvements includes the development of prescribing alerts based on dose, drug-drug 

interactions, and previous ADEs that provide a “flag” associating potential risk with 

a particular order. Process improvements 

like this may have national applications 

depending on patterns of care across the 

VA system. However, not all risk can be 

eliminated, and in the case of a nonpreventable adverse drug reaction, unwanted adverse effects may still occur. 

Nevertheless, having a system in place to 

detect potentially preventable ADEs can 

help optimize safe and appropriate medication use while reducing the morbidity and 

mortality associated with adverse events.

REFERENCES

1. Winterstein AG, Hatton RC, Gonzalez-Rothi R, et al. 

Identifying clinically significant preventable adverse drug 

events through a hosptial’s database of adverse drug reaction 

reports. Am J Health-Syst Pharm. 2002; 59:1742-9.

Contributed by:

Von Moore, Pharm.D.