LetroHEXAL® 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 act on these isoenzymes.
The metabolism of letrozole has a low affinity for the CYP3A4 isoenzyme, as this isoenzyme has no ability to inhibit letrozole metabolism in normal clinical situations at concentrations 150 times higher than the plasma equilibrium values of letrozole.
Drugs leading to increased serum letrozole concentrations
Inhibitors of the CYP3A4 HCYP2A6 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 during concomitant use of letrozole and potent inhibitors of the CYP3A4 and CYP2A6 isoenzymes. Drugs leading to decreased serum concentrations of letrozole
Inducers of the CYP3A4 and CYP2A6 isoenzymes may increase the metabolism of letrozole, thereby reducing 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 the drug following tamoxifen administration.
Drugs whose serum concentrations are dependent on the administration of letrozole
In vitro, letrozole inhibits the CYP2A6 isoenzyme of cytochrome P450 and slightly the CYP2C19 isoenzyme; the clinical relevance of this effect has not been established. 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). Drugs with a narrow therapeutic index for the CYP2A6 isoenzyme are currently unknown.
When letrozole was 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 prescribed as combination therapy in patients taking letrozole), no clinically significant interactions were observed.