LETROZOLE Drug Interactions: What You Need to Know

INTERACTIONS Tamoxifen Coadministration of letrozole tablets and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average (study P015). Clinical experience in the second-line breast cancer trials (AR/BC2 and AR/BC3) indicates that the therapeutic effect of letrozole tablets therapy is not impaired if letrozole tablets is administered immediately after tamoxifen. Cimetidine A pharmacokinetic interaction study with cimetidine (study P0004) showed no clinically significant effect on letrozole pharmacokinetics. Warfarin An interaction study (P017) with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics. Other anticancer agents There is no clinical experience to date on the use of letrozole tablets in combination with other anticancer agents.

Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations ( 8.1 )] . Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations ( 8.1 )] . Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations ( 8.1 )] . Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations ( 8.1 )] . Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions ( 6 )] . Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions ( 6 )] . Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions ( 6 )] . Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions ( 6 )] . Pregnancy ( 4 ) Known hypersensitivity to the active substance, or to any of the excipients ( 4 )

AND PRECAUTIONS This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Decreases in bone mineral density may occur. Consider bone mineral density monitoring (5.1) Increases in total cholesterol may occur. Consider cholesterol monitoring. (5.2) Fatigue, dizziness and somnolence may occur. Exercise caution when operating machinery (5.4) Embryo-Fetal toxicity: Can cause fetal harm when administered to pregnant women. Obtain a pregnancy test in females of reproductive potential. Advise females of reproductive potential to use effective contraception (5.6 , 8.1 , 8.3)

5.1 Bone Effects Use of letrozole may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a safety study to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2 to L4) BMD of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) ( P < 0.0001) [ see Adverse Reactions (6) ]. Updated results from the BMD substudy (MA-17B) in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [ see Adverse Reactions (6) ]. In the adjuvant trial (BIG 1-98) the incidence of bone fractures at any time after randomization was 14.7% for letrozole and 11.4% for tamoxifen at a median follow-up of 96 months. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [ see Adverse Reactions (6) ]. In the extended adjuvant trial (MA-17), the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo at a median follow-up of 62 months. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [ see Adverse Reactions (6) ].

5.2 Cholesterol Consideration should be given to monitoring serum cholesterol. In the adjuvant trial (BIG 1-98), hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients.

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3 to 4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of greater than or equal to 1.5 x upper limit of normal (ULN) in total cholesterol (generally nonfasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., less than = 1.5 x ULN) in 155/1843 (8.4%) patients on letrozole vs 71/1840 (3.9%) patients on tamoxifen Lipid lowering medications were required for 29% of patients on letrozole and 20% on tamoxifen [ see Adverse Reactions (6) ].

5.3 Hepatic Impairment Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole tablets experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function [ see Clinical Pharmacology (12.3) ]. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined [ see Dosage and Administration (2.5) ].

5.4 Fatigue and Dizziness Because fatigue, dizziness, and somnolence have been reported with the use of letrozole, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole use.

5.5 Laboratory Test Abnormalities No dose-related effect of letrozole on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving letrozole 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not was infrequent.

5.6 Embryo-Fetal Toxicity Based on postmarketing reports, findings from animal studies and the mechanism of action, letrozole can cause fetal harm and is contraindicated for use in pregnant women. In postmarketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects. Letrozole caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MHRD) on a mg/m 2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with letrozole and for at least 3 weeks after the last dose [ see Adverse Reactions (6.2) , Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ].

5.7 Risk of Allergic Reactions due to Tartrazine This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.