Letrozole Sandoz Drug Interactions

Letrozole is mainly metabolized in the liver and the cytochrome P450 enzymes CYP3A4 and CYP2A6 mediate the metabolic clearance of letrozole. Therefore, the systemic elimination of letrozole may be influenced by drugs known to affect the CYP3A4 and CYP2A6.
Drugs that may increase Letrozole serum concentrations: Inhibitors of CYP3A4 and CYP2A6 activities could decrease the metabolism of letrozole and thereby increase plasma concentrations of letrozole. The concomitant administration of medications that strongly inhibit these enzymes (strong CYP3A4 inhibitors: including but not limited to ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin; CYP2A6 (e.g. methoxsalen) may increase exposure to letrozole. Therefore caution is recommended in patients for whom strong CYP3A4 and CYP2A6 inhibitors are indicated.
Drugs that may decrease Letrozole serum concentrations: Inducers of CYP3A4 activity could increase the metabolism of letrozole and thereby decrease plasma concentrations of letrozole. The concomitant administration of medications that induce CYP3A4 (e.g. phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's Wort) may reduce exposure to letrozole. Therefore caution is recommended in patients for whom strong CYP3A4 inducers are indicated. No drug inducer is known for CYP2A6.
Co-administration of letrozole (2.5mg) and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels by 38% on average. There is limited clinical experience to date on the use of letrozole in combination with other anti-cancer agents other than tamoxifen.
Drugs that may have their systemic serum concentrations altered by Letrozole: In vitro, letrozole inhibits the cytochrome P450 isoenzymes CYP2A6 and, moderately, CYP2C19, but the clinical relevance is unknown. Caution is therefore indicated when giving letrozole concomitantly with medicinal products whose elimination is mainly dependent on CYP2C19 and whose therapeutic index is narrow (e.g. phenytoin, clopidrogel). No substrate with a narrow therapeutic index is known for CYP2A6.
Clinical interaction studies with cimetidine (a known non-specific inhibitor of CYP2C19 and CYP3A4 and warfarin (sensitive substrate for CYP2C9 with a narrow therapeutic window and commonly used as co-medication in the target population of letrozole) indicated that the coadministration of letrozole with these drugs does not result in clinically significant drug interactions.
A review of the clinical trial database indicated no evidence of other clinically relevant interaction with other commonly prescribed drugs.