'Modest' Increased Adverse-Event Risk With Clarithromycin Plus Some Statins

December 29, 2014

LONDON, ON – Combining a statin not metabolized by cytochrome P450 3A4 (CYP3A4) with the antibiotic clarithromycin is associated with an increased risk of adverse events, according to the results of a new analysis. Individuals taking rosuvastatin (Crestor, AstraZeneca), pravastatin, or fluvastatin with clarithromycin had a 65% increased risk of hospitalization for acute kidney injury, a more than twofold increased risk of hyperkalemia, and a 43% increased risk of all-cause mortality compared with individuals taking non-CYP3A4-metabolized statins and azithromycin[1].

The absolute increase in the risk of adverse events was small—less than 1%. Still, researchers say the "modest increase" in the number of deaths and hospital admissions among the older adults studied may reflect statin toxicity.

"The population impact of this preventable drug–drug interaction can be considered in the context of the high frequency of clarithromycin and statin co-prescription," write Dr Daniel Li (University of Western Ontario, London) and colleagues December 22, 2014 in CMAJ. In Canada, rosuvastatin was the second most commonly prescribed drug in 2010.

Co-Prescription of Clarithromycin and Rosuvastatin

In their report, the researchers explain that clarithromycin is an antibiotic that can inhibit organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3). "Several haplotypes of commonly occurring genetic polymorphisms in the liver-specific OATP1B1 were associated with increased concentrations of rosuvastatin and pravastatin," they note.

In total, 51 523 individuals were prescribed clarithromycin and 52 518 were prescribed azithromycin, an antibiotic that does not inhibit CYP3A4, OATP1B1, or OATP1B3. Regarding statin therapy, 76% were treated with rosuvastatin, 21% with pravastatin, and 3% with fluvastatin.

30-Day Adverse-Event Outcomes

Outcome Number of events, clarithromycin) Number of events, azithromycin Absolute risk difference, % Adjusted relative-risk (95% CI)
Hospitalization for rhabdomyolysis 13 6 0.02 2.27 (0.86–5.96)
Hospitalization for acute kidney injury 175 122 0.11 1.65 (1.31–2.09)
Hospitalization for hyperkalemia 33 18 0.03 2.17 (1.22–3.86)
All-cause mortality 200 155 0.09 1.43 (1.15–1.76)

Li et al's finding of increased risk with rosuvastatin, pravastatin, and fluvastatin when taken with clarithromycin can't be explained by the inhibition of CYP3A4, as the drugs are not metabolized by this pathway. "A growing body of evidence highlights the role of transporter-mediated mechanisms in such interactions, notably the inhibition of human OATPs," they write.

The US Food and Drug Administration recommends the use of non-CYP3A4-metabolized statins in patients taking drugs that inhibit CYP3A4. However, "unintended adverse events may still occur, possibly because of additional mechanisms of drug interactions independent of the CYP3A4 pathway," say Li and colleagues. "To prevent toxicity, the use of azithro­mycin or another antibiotic that does not interact with statins can be considered."

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