Letrzole is an aromatase inhibitor which is used in the treatment of hormonally-responsive breast cancer after surgery. letrozole lowers estrogen levels in postmenopausal women, which may slow the growth of certain types of breast tumors that need estrogen to grow in the body.
Letrozole is highly specific in inhibiting aromatase activity.
There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of Letrozole tablets 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of Letrozole tablets or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by Letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.
Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway.
indications and usage:
Adjuvant Treatment of Early Breast Cancer:
Letrozole tablets are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
Extended Adjuvant Treatment of Early Breast Cancer:
Letrozole tablets are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy.
First and Second-Line Treatment of Advanced Breast Cancer:
Letrozole tablets are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer.
dosage and administration:
Letrozole should be taken orally and can be taken with or without food.
A missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next dose (within 2 or 3 hours), the missed dose should be skipped, and the patient should go back to her regular dosage schedule. Doses should not be doubled because with daily doses over the 2.5 mg recommended dose, over-proportionality in systemic exposure was observed (see section 5.2).
• Hypersensitivity to the active substance or to any of the excipients
• Premenopausal endocrine status
warnings and precautions:
Use of Letrozole tablets 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, 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. Updated results from the BMD substudy 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.
In the adjuvant trial 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. In the extended adjuvant trial, 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.
Consideration should be given to monitoring serum cholesterol. In the adjuvant trial, hypercholesterolemia was reported in 52.3% of Letrozole patients and 28.6% of tamoxifen patients. Grade 3-4 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 × upper limit of normal in total cholesterol was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range 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.
Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Letrozole tablets experienced approximately twice the exposure to Letrozole tablets as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on Letrozole tablets exposure in cancer patients with elevated bilirubin levels has not been determined.
Fatigue and Dizziness
Because fatigue, dizziness, and somnolence have been reported with the use of Letrozole tablets, caution is advised when driving or using machinery until it is known how the patient reacts to Letrozole tablets use.
Laboratory Test Abnormalities
No dose-related effect of Letrozole tablets 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 tablets 2.5 mg. This depression was transient in about half of those affected. Two patients on Letrozole tablets developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not was infrequent.
Based on post-marketing reports, findings from animal studies and the mechanism of action, Letrozole tablets can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of Letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with Letrozole tablets and for at least 3 weeks after the last dose.
Coadministration of Letrozole tablets and tamoxifen 20 mg daily resulted in a reduction of Letrozole plasma levels of 38% on average. Clinical experience in the second-line breast cancer trials indicates that the therapeutic effect of Letrozole tablets therapy is not impaired if Letrozole tablets are administered immediately after tamoxifen.
A pharmacokinetic interaction study with cimetidine showed no clinically significant effect on Letrozole pharmacokinetics.
An interaction study 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 and lactation:
Based on post-marketing reports, findings from animal studies and the mechanism of action, Letrozole tablets can cause fetal harm and are contraindicated for use in pregnant women. In post-marketing reports, use of Letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk.
In animal reproduction studies, administration of Letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose on a mg/m² basis .
It is not known if Letrozole is present in human milk. There are no data on the effects of Letrozole on the breastfed infant or milk production. Exposure of lactating rats to Letrozole was associated with impaired reproductive performance of the male offspring. Because of the potential for serious adverse reactions in breastfed infants from Letrozole, advise lactating women not to breastfeed while taking Letrozole and for at least 3 weeks after the last dose.
Bone effects：Use of Letrozole tablets may cause decreases in bone mineral density .
Increases in cholesterol：should be given to monitoring serum cholesterol
Fatigue and Dizziness：Because fatigue, dizziness, and somnolence have been reported with the use of Letrozole tablets, caution is advised when driving or using machinery until it is known how the patient reacts to Letrozole tablets use.
There have been no reports of acute overdosage with anabolics.
Store in cool dry place below 30℃. Protect from light.