Letrozol-ratiopharm® 2,5 mg

Description

Drug interactions

Letrozole is mainly metabolised in the liver with the CYP3A4 and CYP2A6 isoenzymes of cytochrome P450. Systemic elimination of letrozole may be influenced by medicinal preparations that interact with these isoenzymes.

The metabolism of letrozole has a low affinity for the CYP3A4 isoenzyme, as this isoenzyme is unable to inhibit the metabolism of letrozole under normal clinical conditions at concentrations 150 times higher than the equilibrium values of letrozole in plasma.

Inhibitors of the CYP3A4 and CYP2A6 isoenzymes are able to reduce the metabolism of letrozole, thereby increasing its serum concentration. Concomitant use of potent inhibitors of these isoenzymes (for the CYP3A4 isoenzyme, such inhibitors are e.g. ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin; for the CYP2A6 isoenzyme, methoxsalen) may lead to increased exposure to letrozole. Caution should be exercised when using letrozole concomitantly with potent inhibitors of CYP3A4 and CYP2A6 isoenzymes.

Inducers of the CYP3A4 and CYP2A6 isoenzymes may increase the metabolism of letrozole, thereby decreasing its serum concentrations. Concomitant use of inducers of these isoenzymes (for the CYP3A4 isoenzyme, such inducers are e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, St. John’s Wort) may lead to decreased exposure to letrozole; for the CYP2A6 isoenzyme, the inducers are not known.

Concomitant use of letrozole (at a dose of 2.5 mg) and tamoxifen at a dose of 20 mg/day leads to an average 38% reduction in serum letrozole concentrations. There are no clinical data on the effect on efficacy and safety of letrozole following tamoxifen administration.

In vitro, letrozole inhibits the CYP2A6 isoenzyme of cytochrome P450 and to a minor extent the CYP2C19 isoenzyme. Caution should be exercised during concomitant use of letrozole and drugs with a narrow therapeutic index, whose excretion depends mainly on the CYP2C19 isoenzyme (e.g. phenytoin, clopidogrel).

When letrozole is co-administered with cimetidine (a known non-specific inhibitor of the CYP2C19 and CYP3A4 isoenzymes) and warfarin (a sensitive substrate of the CYP2C9 isoenzyme with a narrow therapeutic index, which is often co-administered with letrozole), no clinically relevant interactions are observed.