Letoripe

Letoripe

letrozole

Manufacturer:

Ambica

Distributor:

Zuellig

Marketer:

Multicare
Full Prescribing Info
Contents
Letrozole.
Description
Each tablet contains: Letrozole USP 2.5 mg.
Action
Pharmacology: Mechanism of action: The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (ie. Estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy or inhibit estrogen effects antiestrogens and progestational agents) these interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.
In postmenopausal women estrogens are mainly derived from the action of the aromatase enzyme which converts adrenal endrogens primarily androstenedione and testosterone 0 to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in cancer tissues itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non steroidal competitive inhibitor of the aromatase enzyme system, it inhibits the conversion of androgens to estrogens. In adult non tumor and tumor bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH and causing the regression of estrogen dependent tumors. In contrast with ovariectomy treatment with letrozole does not lead to an increase in serum. FSH. Letrozole selectively inhibits gonadal steroidgenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme resulting in a reduction of estrogen bio synthesis of the tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis or synthesis of thyroid hormones.
Pharmacokinetics: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolised slowly to an inactive metabolite whose glucuronide conjugate is excreted renally representing the major clearance pathway. About 90% of the radiolabeled letrozole is recovered in urine. Letrozole's terminal elimination half life is about 2 days and steady state plasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady state are 1.5 to 2 times higher than predicted from then concentrations measured after a single dose indicating a slight non-linearity in the pharmacokinetics of Letrozole upon daily administration of 2.5 mg . These steady state levels are maintained over extended periods however and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).
Metabolism and Excretion: Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'-methanolbisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole.
In human microsomes with specific CYP isozymes activity, CYP 3A4 metabolized letrozole to the carbotinol metabolite while CYP 2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP 2A6 and moderately inhibited CYP 2C19.
Indications/Uses
Letrozole tablets are indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
Dosage/Direction for Use
Adult and Elderly Patients: The recommended dose of Letrozole tablets is one 2.5 mg tablet administered once a day, without regard to meals. Treatment with Letrozole tablets should continue until tumor progression is evident. No dose adjustment is required for elderly patients. Patients treated with Letrozole tablets do not require glucocorticoid or mineralocorticoid replacement therapy.
Renal Impairment: No dosage adjustment is required for patients with renal impairment if creatinine clearance is >10 mL/min.
Hepatic Impairment: Although letrozole blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis, no dosage adjustment is recommended for patients with mild-to-moderate hepatic impairment. Patients with severe impairment of liver function have not been studied. Because letrozole is eliminated almost exclusively by hepatic metabolism, patients with severe impairment of liver function should be dosed with caution.
Overdosage
No experience with Letrozole tablets overdose has been reported. In single dose studies the highest dose used was 30 mg, which was well tolerated; in multiple dose trials, the largest dose of 10 mg was well tolerated.
Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2000 mg/kg (about 4000 to 8000 times the daily maximum recommended human dose on a mg/m2 basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias. There is no experience in humans with an overdose of Letrozole tablets, so firm recommendations for treatment are not possible. Emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs is appropriate.
Contraindications
Letrozole tablets is contraindicated in patients with known hypersensitivity to Letrozole tablets or any of its excipients.
Warnings
Use in Pregnancy: Pregnancy Category D. Letrozole may cause fetal harm when administered to pregnant women. Studies in rats at doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased postimplantation loss, decreased number of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion.
Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 & 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore-and hindlegs.
There are no studies in pregnant women. Letrozole is indicated for postmenopausal women. If there is exposure to letrozole during pregnancy, the patient should be appraised of the potential hazard to the fetus and potential risk for loss of the pregnancy.
Special Precautions
Laboratory Tests: 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 tablets 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. Increases in SGOT, SGPT, and gamma GT ≥5 times the upper limit of normal (ULN) and of bilirubin ≥1.5 times the ULN were most often associated with metastatic disease in the liver. About 3% study participants receiving Letrozole had abnormalities in liver chemistries not associated with documented metastases; these abnormalities may have been related to study drug therapy. In the megestrol acetate comparative study about 8% of patients treated with megestrol acetate had abnormalities in liver chemistries that were not associated with documented liver metastases; in the aminoglutethimide study about 10% of aminoglutethimide-treated patients had abnormalities in liver chemistries not associated with hepatic metastases.
Use in Children: The safety and effectiveness in pediatric patients have not been established.
Use in Elderly: The mean age of patients in the two randomized trials, that compared Letrozole tablets (0.5 mg and 2.5 mg) to megestrol acetate and to aminoglutethimide, was 64 years. Thirty percent of patients were >70 years old. The proportion of patients responding to each dose of Letrozole was similar for women >70 years old and <70 years old.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy Category D. Letrozole may cause fetal harm when administered to pregnant women. Studies in rats at doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased postimplantation loss, decreased number of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion.
Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 & 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore-and hindlegs.
There are no studies in pregnant women. Letrozole is indicated for postmenopausal women. If there is exposure to letrozole during pregnancy, the patient should be appraised of the potential hazard to the fetus and potential risk for loss of the pregnancy.
Nursing Mothers: It is not known if letrozole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when letrozole is administered to a nursing woman.
Adverse Reactions
Letrozole tablets was generally well tolerated in two controlled clinical trials.
Study discontinuations in the megestrol acetate comparison study for adverse events other than progression of tumor occurred in 5/188 (2.7%) of patients on Letrozole tablets 0.5 mg, in 4/174 (2.3%) of the patients on Letrozole tablets 2.5 mg, and in 15/190 (7.9%) of patients on megestrol acetate. There were fewer thromboembolic events at both Letrozole tablets doses than on the megestrol acetate arm (2 of 362 patients or 0.6% vs. 9 of 190 patients or 4.7%). There was also less vaginal bleeding (1 of 362 patients or 0.3% vs. 6 of 190 patients or 3.2%) on letrozole than on megestrol acetate. In the aminoglutethimide comparison study discontinuations for reasons other than progression occurred in 6/193 (3.1%) of patients on 0.5 mg Letrozole tablets, 7/185 (3.8%) of patients on 2.5 mg Letrozole tablets, and 7/178 (3.9%) of patients on aminoglutethimide.
Other less frequent (<5%) adverse experiences considered consequential and reported in at least 3 patients treated with Letrozole tablets included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo.
Drug Interactions
Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of Letrozole with these drugs does not result in clinically-significant drug interactions.
There is no clinical experience to date on the use of Letrozole in combination with other anti-cancer agents.
Storage
Store at temperatures not exceeding 25°C. Protect from light and moisture.
MIMS Class
Cancer Hormone Therapy
ATC Classification
L02BG04 - letrozole ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.
Presentation/Packing
Tab 2.5 mg x 30's.
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