Rhabdomyolysis a result of azithromycin and statins: an unrecognized interaction

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rhabdomyolysis is a serious but rare adverse effect of statins. • The mechanism of rhabdomyolysis with statins is poorly defined, but the occurrence is known to increase with dose/ concentration. • Some macrolides are known to interact with statins; however, azithromycin has not been described to interact with statins with the exception of two literature case reports. WHAT THIS STUDY ADDS • A case series in the World Health Organization Adverse Drug Reaction (WHO‐ADR) database was suggestive of a possible drug interaction between statins and azithromycin with rhabdomyolysis. • A disproportionality measure, Omega, was shown to identify previously not recognized suspected drug interactions within the WHO‐ADR dataset. AIMS In a systematic screening of the World Health Organization Adverse Drug Reaction database, VigiBase, in July 2008, a measure of association used to detect interactions (Omega) highlighted azithromycin with the individual statins atorvastatin, lovastatin and simvastatin and rhabdomyolysis. The aim was to examine all reports including rhabdomyolysis‐azithromycin and statins in VigiBase to assess if the data were suggestive of an interaction. METHODS The individual case reports in VigiBase and the original files were reviewed. In order to investigate the reporting over time for rhabdomyolysis with azithromycin and statins to VigiBase, Omega values were generated retrospectively. RESULTS The reporting over time showed that rhabdomyolysis under concomitant use of azithromycin and statins was reported more often than expected from 2000 and onwards in Vigibase. After exclusion of possible duplicates and follow‐up reports, 53 cases from five countries remained. Rhabdomyolysis occurred shortly after initiation of azithromycin in 23% of cases. In 11 patients an interaction had been suggested by the reporter. With the exception of one patient, the statin doses reported were within the recommended daily doses. CONCLUSIONS Case reports in VigiBase are suggestive that interactions between azithromycin and statins resulting in rhabdomyolysis may occur. This analysis showed the potential of the newly developed disproportionality measure, Omega, which can help to identify drug interactions in VigiBase in the future. The results also showed that reviewing spontaneous reports can add information to drug interactions not established previously.

Prescribing azithromycin

“…[23][24][25][26][27][28][29] Due to its long half-life, interactions may continue for several days after it has been stopped. 10 Box Clinically significant interactions of azithromycin • Azithromycin should be used with great caution if co-administered with other drugs that prolong the QT interval.…”

A Review of Pharmacovigilance

“…Rhabdomyolysis is a serious but uncommon adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). However, there have been reports of rhabdomyolysis occurring as a result of the interaction between azithromycin and various statins (32).…”

Drug interactions with statins

“…-The macrolide antibiotics erythromycin, clarithromycin, troleandomycin, and telithromycin have been mentioned as potential interacting agents with statins in standard drug references (32) because they are cleared through the same metabolic pathway, regulated by CYP3A4. Even though the newer macrolide azithromycin has not been suggested to cause clinically significant interactions with agents metabolized through the cytochrome P450 enzyme system (33)(34)(35), there are certain case reports suggesting an interaction between azithromycin and statins (36)(37)(38).…”