Letoripe

Each tablet contains: Letrozole USP 2.5 mg.
A film coated, orange colour, biconvex round shaped tablet both side plain. Letrozole tablets for oral administration contains letrozole, a non-steroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene) dibenzonitrile.
It has a molecular weight of 285.31 and empirical formula C₁₇H₁₁N₅.
Excipients/Inactive Ingredients: Colour: Iron oxide Yellow, Sunset Yellow Lake and Titanium Dioxide.

Pharmacology: Mechanism of Action: 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 LH and causing the regression of estrogen dependent tumors. In contrast to ovariectomy, treatment with Letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
Pharmacodynamics: 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 tissues itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
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 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 metabolized 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 the 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, 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 pharmaceutically inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of Letrozole clearance, of the radio label covered 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 enzymes activity, CYP 3A4 metabolized Letrozole to the carbotinol metabolite while CYP 2A6 formed both the metabolite and its ketoanalogue. In human liver microsomes, Letrozole strongly inhibited CYP 2A6 and moderately inhibited CYP 2C19.
Toxicology: Preclinical safety data: In a variety of preclinical safety studies conducted in standard animal species, there was no evidence of systemic or target organ toxicity. Letrozole showed a low degree of acute toxicity in rodents exposed up to 2000 mg/kg. In dogs, Letrozole caused signs of moderate toxicity at 100 mg/kg.
In repeated-dose toxicity studies in rats and dogs up to 12 months, the main findings observed can be attributed to the pharmacological action of the compound. The no-adverse-effect level was 0.3 mg/kg in both species.
Both in vitro and in vivo investigations of Letrozole's mutagenic potential revealed no indications of any genotoxicity.
In a 104-week rat carcinogenicity study, no treatment-related tumours were noted in male rats. In female rats, a reduced incidence of benign and malignant mammary tumours at all the doses of Letrozole was found.
Letrozole was embryotoxic and foetotoxic in pregnant rats and rabbits following oral administration at clinically relevant doses. In rats that had live foetuses, there was an increase in the incidence of foetal malformations including domed head and cervical/centrum vertebral fusion. An increased incidence of foetal malformations was not seen in the rabbit. It is not known whether this was an indirect consequence of the pharmacological properties (inhibition of oestrogen biosynthesis) or a direct drug effect.
Preclinical observations were confined to those associated with the recognized pharmacological action, which is the only safety concern for human use derived from animal studies.

Letrozole tablet is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
The effectiveness of Letrozole tablet in early breast cancer is based on an analysis of disease-free survival in patients treated for a median of 24 months and followed for a median of 26 months. Follow up analyses will determine long-term outcomes for both safety and efficacy.
Letrozole tablet is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy.
The effectiveness of Letrozole tablet in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated for a median of 24 months.
Further data will be required to determine long-term outcome.
Letrozole tablet is indicated for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Letrozole tablet is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Adult and Elderly Patients: The recommended dose of Letrozole tablet is one 2.5 mg tablet administered once a day, without regard to meals. In patients with advanced disease, treatment with Letrozole tablet should continue until tumor progression is evident.
In the extended adjuvant setting, the optimal treatment duration with Letrozole tablet is not known. The planned duration of treatment in the study was 5 years. However, at the time of the analysis, the median treatment duration was 24 months, 25% of patients were treated for at least 3 years and less than 1% of patients were treated for the planned duration of 5 years. The median duration of follow-up was 28 months. Treatment should be discontinued at tumor relapse.
In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study is 5 years. However, at the time of analysis, the median duration of treatment was 24 months, median duration of follow-up was 26 months, and 16% of the patients had been treated for 5 years. Treatment should be discontinued at relapse.
Renal Impairment: No dosage adjustment is required for patients with renal impairment if creatinine clearance is 10 mL/min.
Hepatic Treatment: No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of Letrozole tablet in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50%. The recommended dose of Letrozole tablet for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

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.
There is no experience in humans with an overdose of Letrozole tablet, so firm recommendations for treatment are not possible. Emesis could be induced if the patients is alert. In general, supportive care and frequent monitoring of vital signs is appropriate.
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 2 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 the single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily 2 maximum recommended human dose on a mg/m² basis); death was preceded by depressed blood pressure and arrhythmias.

Letrozole tablet is contraindicated in patients with known hypersensitivity to Letrozole tablet or any of its excipients.
Letrozole tablet is contraindicated in women of premenopausal endocrine status.

Bone Effects: Letrozole may cause decrease in bone mineral density (BMD).
Cholesterol: Consideration should be given to monitoring serum cholesterol.
Hepatic treatment: Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Letrozole experienced approximately twice the exposure to Letrozole as healthy volunteers with normal liver function. Therefore, a dose reduction is recommended for this patient population.
Fatigue and Dizziness: Because fatigue, dizziness, and somnolence have been reported, caution is advised when driving or using machinery.
Use in Pregnancy: 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 post implantation 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 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 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 hind legs.
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.

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 tablet 2.5 mg. This depression was transient in about half of those affected. 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.
Effects on ability to drive and use machine: Letrozole tablet has minor influence on the ability to drive and use machines. Since fatigue and dizziness have been observed with the use of letrozole tablet and somnolence has been reported uncommonly, caution is advised when driving or using machines.
Use in Children: The safety and effectiveness in pediatric patients have not been established.
Use in the Elderly: The mean age of patients in the two randomized trials, that compared Letrozole tablet (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.

Pregnancy: Pregnancy Category D.
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.

Letrozole tablet was generally well tolerated in two controlled clinical trials. Study discontinuations in the megestrol acetate comparisons study for adverse events other than progression of tumor occurred in 5/188 (2.7%) of patients on Letrozole tablet 0.5 mg, in 4/174 (2.3%) of the patients on Letrozole tablet 2.5 mg, and in 15/190 (7.9%) of patients on megestrol acetate. There were fewer thromboembolic events at both Letrozole tablet 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 loss in 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 tablet, and 7/185 (3.8%) of patients on 2.5 mg Letrozole tablet, 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 tablet included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating, and vertigo.
Undesirable Effects: Letrozole tablet was generally well tolerated across in first-line and second-line metastatic breast cancer, adjuvant treatment, as well as extended adjuvant treatment in women who have received prior adjuvant tamoxifen treatment. Generally, the observed adverse reactions are mild or moderate in nature. Hot flashes, arthralgia, night sweats, weight increase, nausea, fatigue, edema, headache, vomiting, dizziness, constipation, vaginal irritation, osteoporosis, angina.
Undesirable effects with Letrozole tablet included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating, and vertigo.

Clinical interaction studies with cimetidine and warfarin indicated that the co-administration 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.

Special precautions for disposal and other handling: No special requirements for disposal.

Store at temperatures not exceeding 30°C. Protect from light and moisture.

Cancer Hormone Therapy

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

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