Clarithromycin Should Not Be Combined With Statins Co-prescribing clarithromycin (or erythromycin) with statins metabolized by cytochrome P450 isoform 3A4 in older adults increases the risk of statin toxicity in those taking it, according to a population-based cohort study. On June 17, 2013, the Annals of Internal Medicine published online the results of the study by Dr. Amity M. Patel, from the London Renal Clinical Research Unit, London Health Sciences Centre, Ontario, Canada, and colleagues. On the same day, Dr. Paul Thompson from Hartford Hospital in Hartford, Connecticut, USA, told Medscape Medical News that “although the absolute increase in risk is small, one should be cautious when prescribing “xyzomycin”-type drugs to someone who is on statins. cautious.” Dr. Thompson is chief of cardiology at Hartford Hospital and was not involved in the study. Background and Overview: Statins are used primarily for the prevention and treatment of dyslipidemia and cardiovascular disease, and are prescribed to millions of people each year. Despite their generally favorable safety profile, the U.S. Food and Drug Administration has issued warnings about potential interactions between commonly used statins and antiviral drugs used in the treatment of HIV infection and hepatitis. In addition, unlike azithromycin, clarithromycin and erythromycin inhibit CYP3A4, and this inhibition can lead to increased blood levels of those statins metabolized by CYP3A4. Statins are the most prescribed class of drugs in North America, and it is still common for them to be co-prescribed with macrolide antibiotics,” study co-author Dr. Amity X. Garg, also of the London Health Sciences Centre, said in a news release. And the clinical, and its population-based consequences of the effects of potential drug interactions between such combinations remain unclear.” It was to deepen their understanding of this issue that they conducted the study. The primary subjects of the study were: continuous statin users in Ontario who were over the age of 65 between 2003 and 2010. The researchers assessed the incidence of statin toxicity in these individuals in combination with clarithromycin (n=72591), or erythromycin (N=3267), and compared them to statin users who were co-treated with azithromycin (N=68478). The primary endpoint of the study was: the status of hospitalization for rhabdomyolysis within 30 days after application of antibiotic prescription in the above study subjects. The study revealed that: the most commonly prescribed statin in the study was atorvastatin (73% of the cases), followed by simvastatin and lovastatin. Compared with azithromycin, the combination of clarithromycin or erythromycin with statins was associated with its higher risk of hospitalization for rhabdomyolysis. Its absolute risk increase was 0.02% and its relative risk (RR) was 2.17 In addition, those who combined clarithromycin or erythromycin with azithromycin had an increased risk of acute kidney injury and their all-cause mortality compared with azithromycin. Limitations of the study and its significance Dr. Thompson said, “The main strength of the study is its size; the main weakness is that the control group for the study was azithromycin, which means that the investigators presumed that the increased risk of medication use was due to altered CYP metabolism. Therefore, the study should have had a non-drug control group.” Other shortcomings of the study, as acknowledged by the study authors, include (i) the study design was observational; (ii) the results may not be applicable to non-elderly individuals; (iii) no meaningful assessment of the interaction of the subject individuals with each statin metabolized by CYP3A4 was made; and (iv) the study may have underestimated the absolute increase in the risk of rhabdomyolysis due to the poor sensitivity of diagnostic indicators, among others. Dr. Patel, lead author of the study, said, “Although this type of hospitalization due to drug-drug interactions, which occurs in hundreds of cases in Ontario alone, is preventable. Our findings provide important safety information for these commonly prescribed medications…, i.e., when prescribing clarithromycin or erythromycin for users of the statins mentioned above, appropriate precautions should be considered, such as discontinuing the statin during antibiotic therapy, increased monitoring of the user for adverse events, or the use of antibiotics that do not interact with these statins .” The study’s authors recommend that: computer software and free online drug interaction programs should be used to increase the overall safety of medication use in older adults on polypharmacy; and that early prevention of adverse drug-drug interactions should be achieved through multidisciplinary collaboration. Dr. Thompson, on the other hand, believes that more studies should be conducted to validate the results of the above studies”. Summary In response to the above studies, while no one would deny the tremendous health benefits of statins, the fact that such drugs are used on such a large scale in the population demands that prescribers should be especially cautious when adding new medications to their patients’ regimens. Although the U.S. Drug Enforcement Administration issued the first pharmacovigilance warning about statin use 10 years ago; and the American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute jointly issued a clinical advisory statement on the subject, the phenomenon of co-prescribing of statins with clarithromycin (or erythromycin) has persisted to this day, which can’t help but be disappointing. The fact that this study shows a decline in said co-prescribing over time is somewhat reassuring.