Letov 2.5

Each film-coated tablet contains: Letrozole 2.5 mg.
Letrozole tablets (Letov) for oral administration contains 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4, 4'-(1H-1, 2, 4-Triazol-1-ylmethylene)dibenzonitrile, Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31, empirical formula C₁₇H₁₁N₅, and a melting range of 184°C-185°C.
Letrozole tablets are available as 2.5 mg tablets for oral administration.

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 (i.e., 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 androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum Luteinizing Hormone (LH), and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum Follicle Stimulating Hormone (FSH). Letrozole selectively inhibits gonadal steroidogenesis 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 biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticoid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.
Pharmacodynamics: In postmenopausal patients with advanced breast cancer, daily doses of 100 mcg to 5 mg Letrozole suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75%-95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 500 mcg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 500 mcg or higher. 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, Adrenocorticotropic Hormone (ACTH) or in plasma renin activity among postmenopausal patients treated with a daily dose of Letrozole 100 mcg to 5 mg. The Adrenocorticotropic Hormone (ACTH) stimulation test performed after 6 and 12 weeks of treatment with daily doses of 100 mcg, 250 mcg, 500 mcg, 1 mg, 2.5 mg 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 100 mcg, 500 mcg and 2.5 mg single doses of Letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 100 mcg 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 Thyroid-Stimulating Hormone (TSH) levels, T3 uptake, and T4 levels.
Pharmacokinetics: 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. About 90% of 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 the concentrations measured after a single dose, indicating 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'-methanol bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of 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 unchangeable letrozole. In human microsomes with specific Cytochrome P450 (CYP) isozyme activity, CYP 3A4 metabolized letrozole to the carbinol 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.
Special Populations: Pediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to >80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.
Renal Insufficiency: In a study of volunteers with varying renal function (24-hour creatinine clearance: 9-116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of letrozole tablets was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5 mg Letrozole and half 500 mcg Letrozole, renal impairment (calculated creatinine clearance: 20-50 mL/min) did not affect steady-state plasma letrozole concentration.
Hepatic Insufficiency: In a study of subjects with varying degrees of non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean Area Under the Curve (AUC) values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. Patients with severe hepatic impairment (Child-Pugh classification C) have not been studied.

a.) Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
b.) Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy.
c.) First and second line treatment of postmenopausal women hormone-receptor positive or unknown advanced breast cancer.

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 to 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.

Isolated cases of letrozole tablets overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse events were reported in these cases, because of the limited data available, no firm recommendations for the treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. 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 2 g/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.

Letrozole Tablets is contraindicated in patients with known hypersensitivity to Letrozole or any of its excipients.

Laboratory Tests: 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. Increase in Serum glutamic-oxaloacetic transaminase (SGOT), Serum glutamic pyruvic transaminase (SGPT), and gamma Glutamyl transpeptidase (GT) ≥5 times the upper limit of normal (ULN) and of bilirubin ≥1.5 times the ULN were most often associated with metastic disease in the liver. About 3% of study participants receiving Letrozole Tablets had abnormalities in liver chemistries not associated with documented metastases; these abnormalities may have been related to study drug therapy.
Use in Children: The safety and effectiveness in pediatric patients have not been established.

Use in Pregnancy: Letrozole may cause fatal harm when administered to pregnant women. Studies in rats at doses equal to or greater than 3 mcg/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 numbers 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 30 mcg/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 2 mcg/kg and fetotoxic when administered to rabbits at 20 mcg/kg (about 1/100,000 and 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 tablets is indicated for post-menopausal women. If there is exposure to letrozole during pregnancy, the patient should be apprised of the potential of the potential hazard to the fetus and potential risk for loss of the pregnancy.
Use in Lactation: 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.

Letrozole tablet was generally well tolerated across all studies as first-line and second-line treatment for breast cancer and adverse reaction rates were similar in both settings.
Adjuvant Treatment of Early Breast Cancer: Adverse reactions are mentioned as follows: Hypercholesterolemia, Hot Flashes/Flushes, Arthralgia/Arthritis, Night Sweats, Bone Fractures, Weight Increase, Nausea, Bone Fractures, Fatigue (Lethargy, Malaise, Asthenia), Myalgia, Edema, Weight Decrease, Vaginal Bleeding, Back Pain, Osteoporosis NOS, Bone Pain, Depression, Vaginal Irritation, Headache, Pain in extremity, Osteopenia, Dizziness/Light-Headedness, Alopecia, Vomiting, Cataract, Constipation, Breast pain, Anorexia, Endometrial Hyperplasia/Cancer, Endometrial Proliferation Disorders, Endometrial Hyperplasia/Cancer, Other Endometrial Disorders, Myocardial Infarction, Myocardial Ischemia, Cerebrovascular Accident, Angina, Thromboembolic Event, Other Cardiovascular, Second Malignancies.
Extended Adjuvant Treatment of Early Breast Cancer: Adverse reactions are seen in the following table: See Table 1.

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First-line breast cancer: The most frequently reported adverse experiences were bone pain, hot flushes, back pain, nausea, arthralgia, dyspnea. Adverse events with Letrozole Tablets 2.5 mg are shown in the following table: See Table 2.

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Other less frequent (<2%) adverse experiences considered consequential for both treatment groups, included peripheral thromboembolic events, cardiovascular events, and cerebrovascular events. Peripheral thromboembolic events included venous thrombosis, thrombophlebitis, portal vein thrombosis and pulmonary embolism. Cardiovascular events included angina, myocardial infarction, myocardial ischemia, and coronary heart disease. Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic strokes and development of hemiparesis.
Second-line breast cancer: Adverse reactions are shown in the following table: See Table 3.

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Clinical interaction studies with cimetidine and warfarin indicated that the coadministration of Letrozole tablets with these drugs does not result in clinically-significant drug interactions. There is no clinical experience to date on the use of Letrozole tablets in combination with other anticancer agents.

Store at temperatures not exceeding 30°C.

Cancer Hormone Therapy

L02BG04 - letrozole ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.

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