Pharmaceutical Approval Update
Letrozole (Femara drug)
Manufacturer: Novartis, Inc., East Hanover, NJ Indication: Originally approved for the treatment of postmenopausal women with hormone-sensitive early breast cancer, letrozole can now be used immediately after surgery (in the adjuvant setting) to prevent cancer recurrence.
Drug Class: Letrozole is an aromatase inhibitor that blocks the enzyme aromatase from converting androgen to estrogen. This action causes reduced estrogen levels in the bloodstream, prevents estrogen from reaching estrogen receptors, and blocks the growth of cancer cells. Estrogen is thus prevented from stimulating the growth of hormone receptor-positive breast cancer. In postmenopausal women, most of the body’s estrogen is made from another hormone, androgen.
Uniqueness of Drug: The phase 3 Breast International Group (BIG 1-98) trial compared the effectiveness and tolera-bility of letrozole and tamoxifen tablet citrate (canadian Nolvadex, Astra-Zeneca) when used as initial therapy after surgery for this population of women. Letrozole reduced the risk of breast cancer recurrence by an additional 21% (P = .002) over the reduction offered by generic tamoxifen. Patients taking letrozole also showed a 27% reduction in the risk of metastasis (P = .0012).
Letrozole demonstrated its greatest benefit in two groups of women at increased risk of recurrence. Letrozole therapy reduced this risk by 29% in women whose breast cancer had already spread to the lymph nodes at the time of diagnosis and by 30% in women who had undergone chemotherapy. In these high-risk subgroups, letrozole reduced the risk of metastasis by 33% and 31%, respectively.
Warnings: Letrozole may cause fetal harm when administered to pregnant women. At doses equal to or greater than 0.003 mg/kg (about 1/100 of the daily maximum recommended human dose), when administered to rats during the period of organogenesis, generic letrozole was toxic, as indicated by intrauterine mortality, increased resorption, increased post-implantation loss, decreased numbers of live fetuses; it also resulted in fetal anomalies.
Letrozole is also teratogenic in rats. A 0.03-mg/kg dose (about 1/10 the daily maximum recommended human dose) caused a domed head and cervical/centrum vertebral fusion in the fetus.
Letrozole was toxic to rabbit embryos at doses equal to or greater than 0.002 mg/kg and was toxic to rabbit fetuses when administered at a dosage of 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose). Fetal anomalies included incomplete ossification of the skull, sternebrae, forelegs, and hindlegs.
Precautions: Fatigue and dizziness have been observed with the use of letrozole tablets. Somnolence was not commonly reported, but caution is advised for patients who drive or use machinery.
Laboratory Tests: No dose-related effects on any hematological or clinical chemistry parameters were 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 50% of those affected. Two patients who were using letrozole developed thrombocytopenia; this relationship to the study drug was unclear.
Few patients with abnormal laboratory findings, whether or not these were related to the study treatment, withdrew from the trial.
Increases in alanine and aspartate transaminases (ALT, AST) and gamma-glutamyl-transferase (GGT) at or above five times the upper limit of normal (ULN) and of bilirubin at or equal to 1.5 times the ULN were most often associated with metastatic disease in the liver. About 3% of study participants receiving the study drug had abnormalities in liver chemistries not associated with documented metastases; these abnormalities may have been related to drug therapy.
By contrast, about 8% of patients receiving megestrol acetate (Megace, Bristol-Myers Squibb) and 10% of patients treated with aminoglutethimide (Cytadren, Novartis) had abnormalities in liver chemistries that were not associated with documented liver metastases.
Drug Interactions: In studies of cimetidine (Tagamet, GlaxoSmithKline) and warfarin (Coumadin, Bristol-Myers Squibb), the coadministration of letrozole with these drugs did not result in clinically significant drug interactions.
The administration of letrozole and tamoxifen 20 mg daily resulted in reduced letrozole plasma levels by 38% on average. No data are yet available to document the use of letrozole in combination with other anticancer agents.
Hepatic Insufficiency: Patients with cirrhosis and severe hepatic dysfunction who received letrozole canadian at a dose of 2.5 mg experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function. Therefore, a lower dose is recommended for these patients. The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined.
Dosage and Administration:
Adults and Elderly Patients: The recommended dose is one 2.5-mg letrozole tablet once a day, without regard to meals. Treatment should continue until tumor progression is evident. No dose adjustment is required for older adults. Patients taking letrozole do not require glucocorticoid or mineralocorticoid replacement therapy.
Renal Impairment: No dosage adjustment is required for patients with renal impairment if the creatinine clearance is 10 ml/minute or more.
Hepatic Impairment: No dosage adjustment is recommended for patients with mild-to-moderate hepatic impairment, although letrozole blood concentrations were modestly increased in the subjects with moderate hepatic impairment caused by cirrhosis. The dose of letrozole in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50%. The recommended dose of letrozole tablets for these patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been established.
Commentary: Women who have gone through menopause now have another option for treating early-stage breast cancer and staving off recurrences. Letrozole fared better than tamoxifen, the long-favored treatment, in women of all ages. It is free of the more worrisome adverse effects of tamoxifen, such as endometrial cancer and potentially fatal blood clots. However, letrozole and other aromatase inhibitors are not without problems. Women receiving letrozole were more likely to experience osteoporosis and higher cholesterol levels.
Letrozole is the only agent in its class approved for use as an initial treatment immediately after surgery for hormone-sensitive early breast cancer and following the completion of five years of tamoxifen therapy.