A population-based analysis of the risk of drug interaction between clarithromycin and statins for hospitalisation or death

Background Clarithromycin, known as a potent inhibitor of the cytochrome P450 isoenzyme CYP3A, may increase the plasma concentration of statins metabolized by this pathway; therefore, increase the risk of interaction with statins in reference to pharmacokinetic studies. This study aimed to characterize whether the concomitant use of a statin with clarithromycin is associated with serious outcomes among adult persons. Methods Health claims data of adult persons in the Regional Sickness Fund of Burgenland, Austria, who filled a prescription for clarithromycin between July 1, 2009 and June 30, 2012 were reviewed retrospectively. We assumed that the risk of hospitalisation increases acutely with the indication for taking an antibiotic, whereas statin use can be considered a chronic exposure with a low constant effect on hospitalisation. When defining the population as persons taking clarithromycin and the use of statins as the exposure we could achieve a comparable effect in both groups from the acute condition on hospitalisation. Therefore, we defined exposed patients as those who had overlapping treatment with a statin and unexposed controls as those who had filled a prescription for clarithromycin without concomitant statin therapy. Outcome was defined as a composite of hospital admission or death within 30 days after starting clarithromycin. We used generalised linear regression to model an association between outcome and exposure to statins. Results Among 28,484 prescriptions of clarithromycin, 2317 persons were co-exposed to statins. Co-administration of CYP3A4 metabolized statins and clarithromycin was associated with a 2.11 fold increased risk of death or hospitalisation (95 % confidence interval [CI]: 1.79–2.48). This effect was explained by age, evidence of cardiovascular disease, diabetes mellitus and utilization of other antibiotics (multivariable adjusted risk ratio: 1.02, 95 % CI: 0.85–1.22). The sensitivity analyses did not change the significance of effect. Conclusions The risk for hospitalisation or death in persons receiving clarithromycin increases with age and cardiovascular disease but is not causally associated with statin-clarithromycine co-administration. Electronic supplementary material The online version of this article (doi:10.1186/s12944-015-0134-y) contains supplementary material, which is available to authorized users.

* The list is adopted from the table of interaction in medis (Medikamenten-Informations-Systems) for clarithromycin and clarithromycin package insert. ¶ The interaction is not addressed in medis but in clarithromycin product information.
1 "Cholestrol-Synthese-Hemmer", albeit excluding fluvastatin and rosuvastatin which are not dependent on CYP3A metabolism. 4 fentanyl and its derivatives 5 H1-antihistamines (second-generation) 6 Phosphodiesterase-5 inhibitors 7 Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold (Ivacaftor product information). AUC increase by clarithromycin is predicted 4.35 fold by using method presented by Hisaka 2009. 8 Co-administration of brentuximab vedotin, primarily metabolized by CYP3A, with ketoconazole increased exposure to brentuximab vedotin by approximately 34% (ADCETRIS TM (brentuximab vedotin) product information). AUC increase by clarithromycin is predicted 1.28 fold by using method presented by Hisaka 2009. 9 Co-administration of single doses of the P-gp inhibitor cyclosporine A and DIFICLIR in healthy volunteers, resulted in a 4-and 2-fold increase in fidaxomicin Cmax and AUC, respectively and in a 9.5 and 4-fold increase in Cmax and AUC, respectively, of the main active metabolite OP-1118. As the clinical relevance of this increase in exposure is unclear, co-administration of potent inhibitors of P-gp, such as cyclosporine, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone are not recommended (DIFICLIR®(fidaxomicin tablet) product information). 10 The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole 200 mg twice daily for four days, compared to receiving ruxolitinib alone in healthy subjects (JAKAFI™ (ruxolitinib) product information). AUC increase by clarithromycin is predicted 1.69 fold by using method presented by Hisaka 2009.  * The list is adopted from the table of interaction in medis (Medikamenten-Informations-Systems) for simvastatin and simvastatin package insert. ¶ The interaction is not addressed in medis but in simvastatin product information.
1 Azole-antifungals 2 When single 40-mg doses of simvastatin, substrates of CYP3A4, was given to healthy adult volunteers who had received nefazodone 200 mg BID for 6 days, approximately 20-fold increases in plasma concentrations of simvastatin and simvastatin acid were seen (SERZONE® (nefazodone) product information)
2 Cholestyramine is a strongly basic "ion-exchange resin". An in vivo animal experiment demonstrated a significant reduction (about 50% with AUC) in the concentration of active hydroxy acid form of simvastatin in plasma following the co-administration of simvastatin (500 mg/kg p.o.) and cholestyramine (600 mg/kg p.o.), compared with the administration of simvastatin alone (Nakai 1996). Nicotinic acid and derivatives

C04AC
Vitamin K antagonists B01AA * The list is adopted from the table of interaction in medis (Medikamenten-Informations-Systems) for rosuvastatin and rosuvastatin package insert. ¶ The interaction is not addressed in medis but in rosuvastatin product information.
1 Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4). Concomitant administration of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted in a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected (Summary of Product Characteristics (SmPC) presented by EMEA for rosuvastatin). 2 Dronedarone (400 mg BID) plus rosuvastatin (10 mg) increased area under the serum concentration-time curve (AUC) of rosuvastatin by 1.4 fold (CRESTOR®(rosuvastatin calcium) product information). 3 Ezetimibe (10 mg QD, 14 days) plus rosuvastatin (10 mg QD, 14 days) increased area under the serum concentration-time curve (AUC) of rosuvastatin by 1.2 fold (CRESTOR®(rosuvastatin calcium) product information).