Idelara

Idelara

letrozole

Manufacturer:

Craveri

Distributor:

Apolloplus Capital

Marketer:

Bioprofarma Bago
Full Prescribing Info
Contents
Letrozole.
Description
Each film-coated tablet contains: See Table 1.

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Action
Pharmacotherapeutic Group: Aromatase inhibitor. ATC Code: L02B G04.
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 (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). The 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 non-steroidal 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 in 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 steroideogenesis 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 corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.
Pharmacodynamics: In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg 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 0.5 mg 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 0.5 mg or higher.
Letrozole is highly specific in inhibiting aromatase activity.
There is no impairment of adrenal steroideogenesis. 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 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 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 were thyroid function as evaluated by 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 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, 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 letrozole clearance. Of the substance 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 isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP2A6 and moderately inhibited CYP2C19.
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 impairment: 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 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 0.5 mg letrozole, renal impairment (calculated creatinine clearance: 20-50 mL/min) did not affect steady-state plasma letrozole concentrations.
Hepatic impairment: In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean 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.
In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubin about 2-11 times UNL with minimal to severe ascites) had two-fold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug.
Carcinogenesis, Mutagenesis, Impairment of Fertility: A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma ABC0-12hs levels in mice at 60 mg/kg/day were 55 times higher than the ABC0-24hs level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on an mg/m2 basis) for up to years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma ABC0-24hs levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose.
Letrozole was not mutagenic in in vitro test (Ames and E. coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats).
Studies to investigate the effect of letrozole on fertility have not been conducted; however, repeated dosing caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (about one, 0.4 and 0.4 the daily maximum recommended human dose on a mg/m2 basis, respectively).
Indications/Uses
Letrozole (Idelara) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
Letrozole (Idelara) is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy.
Letrozole (Idelara) is indicated for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer.
Letrozole (Idelara) is 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 (Idelara) is one 2.5 mg tablet administered once a day, without regard to meals. In patients with advanced disease, treatment with Letrozole (Idelara) should continue until tumor progression is evident.
In the extended adjuvant setting, the optimal treatment duration with letrozole 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 have been treated for 5 years. Treatment should be discontinued at relapse.
No dose adjustment is required for elderly patients. Patients treated with letrozole 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: No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although letrozole blood concentrations were modestly increased. The dose of letrozole in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50%. The recommended dose of letrozole for such 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 determined.
Overdosage
Isolated cases of letrozole 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 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 2,000 mg/kg (about 4.000 to 8.000 times the daily maximum recommended human dose on an 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 an mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias.
Contraindications
Letrozole (Idelara) is contraindicated in those patients with a known hypersensitivity to the drug or non medical ingredients.
It is also contraindicated in premenopausal endocrine status.
Warnings
Pregnancy: Letrozole may cause fetal harm when administered to a pregnant woman. Reproduction studies in rats at doses equal 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 or organogenesis, have shown that letrozole is embrotoxic and fetotoxic, as indicated by intrauterine mortality, increased post implantation loss, decreased numbers of live fetuses and incomplete ossifications of frontal skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg doses (about 1/10 the daily maximum recommended human dose on an mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion.
Letrozole is embriotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg respectively (about 1/100.000 and 1/10.000 the daily maximum recommended human dose on an 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 apprised of the potential hazard to the fetus and potential risk for loss of the pregnancy.
The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who recently became postmenopausal, until their post menopausal status is fully established.
Special Precautions
Since fatigue and dizziness have been observed with the use of letrozole and somnolence was uncommonly reported, caution is advised when driving or using machinery.
Laboratory tests: No dose-related effect of letrozole on any hematological or clinical chemistry parameter was 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 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% of 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.
Bone effects: In the extended adjuvant setting, preliminary results (median duration of follow-up was 20 months) from the bone sub-study (calcium 500 mg and vitamin D 400 IU per day mandatory; bisphosphonates not allowed) demonstrated that at 2 years the mean decrease compared to baseline in hip BMD in letrozole patients was 3% vs. 0.4% for placebo (P=0.048). The mean decrease from baseline BMD results for the lumbar spine at 2 years was letrozole 4.6% decrease and placebo 2.2% (P=0.069).
Consideration should be given to monitoring BMD.
Use in Children: The safety and effectiveness in pediatric patients have not been established.
Use in the Elderly: The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years.
About 1/3 of the patients were ≥70 years old. In the first-line study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients <70.
For the extended adjuvant setting, more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these groups, but greater sensitivity of some older individuals cannot be ruled out.
In the adjuvant setting, more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation.
However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.
Use In Pregnancy & Lactation
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.
Adverse Reactions
Letrozole was generally well tolerated across all studies 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.
Adjuvant treatment of early breast cancer in postmenopausal women: The median duration of adjuvant treatment was 24 months and the median duration of follow-up for safety was 26 months for patients receiving letrozole and tamoxifen.
Certain adverse events were prospectively specified for analysis, based on the known pharmacological properties and side effect profiles of the two drugs.
Adverse events were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse events reported (82%) were Grade 1 and Grade 2 applying the Common Toxicity Criteria Version 2.0. (See Table 2.)

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When considering all grades, a higher incidence of events were seen for letrozole regarding fractures (5.7% vs. 4), myocardial infarctions (0.6% vs. 0.4%), and arthralgia (21.2% vs. 13.5%) (letrozole vs. tamoxifen, respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (1.2% vs. 2.8%), endometrial cancer (0.2% vs. 0.4%), and endometrial proliferative disorders (0.3% vs. 1.8%) (letrozole vs. tamoxifen, respectively).
Extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy: The median duration of extended adjuvant treatment was 24 months and the median duration of follow-up for safety was 28 months for patients receiving letrozole and placebo.
Most adverse events reported were Grade 1 and Grade 2 based on the Common Toxicity Criteria version 2.0. In the extended adjuvant setting, the reported drug-related adverse events that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia. (See Table 3.)

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The duration of follow-up for both the main clinical study and the bone study were insufficient to assess fracture risk associated with long-term use of letrozole. Based on a median follow-up of patients for 28 months, the incidence of clinical fractures from the core randomized study in patients who received letrozole was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received letrozole 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received letrozole and 18.7% of the patients who received placebo.
Preliminary results (median duration of follow-up was 20 months) from the bone sub-study (calcium 500 mg and vitamin D 400 IU per day mandatory; bisphosphonates not allowed) demonstrated that at 2 years the mean decrease compared to baseline in hip BMD in letrozole patients was 3% vs. 0.4% for placebo. The mean decrease from baseline BMD results for the lumbar spine at 2 years was letrozole 4.6% decrease and placebo 2.2%. The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients who received letrozole 6.8% (175) and placebo 6.5% (167).
Preliminary results from the lipid sub-study did not show significant differences between the letrozole and placebo groups. The HDL:LDL ratio decreased after the first 6 months of therapy but the decrease was similar in both groups and no statistically significant differences were detected.
A patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains.
First-Line Breast Cancer: A total of 455 patients were treated for a median time of exposure of 11 months. The incidence of adverse experiences was similar for letrozole and tamoxifen. The most frequently reported adverse experiences were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea. Discontinuations for adverse experiences other than progression of tumor occurred in 10/455 (2%) of patients on letrozole and in 15/455 (3%) of patients on tamoxifen. (See Table 4.)

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Other less frequent (≤2%) adverse experiences considered consequential for 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: Letrozole 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 5/188 (2.7%) on letrozole 0.5 mg, in 4/174 (2.3%) on letrozole 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both letrozole doses than on the megestrol acetate arm (0.6% vs. 4.7%). There was also less vaginal bleeding (0.3% vs. 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%) on 0.5 mg letrozole, 7/185 (3.8%) on 2.5 mg letrozole, and 7/178 (3.9%) of patients on aminoglutethimide.
Comparisons of the incidence of adverse events revealed no significant differences between the high and low dose letrozole groups in either study.
Most of the adverse events observed in all treatment groups were mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the patient's metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness. (See Table 5.)

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Other less frequent (<5%) adverse experiences considered consequential and reported in at least 3 patients treated with letrozole, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo.
First-line and second-line breast cancer: In the combined analysis of the first- and second-line metastatic trials and post-marketing experiences other adverse events that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypoesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, nervousness, urticaria, increased urinary frequency, leukopenia, stomatitis cancer pain, pyrexia, vaginal discharge, appetite increase, dryness of skin and mucosa (including dry mouth), and disturbances of taste and thirst.
Phase IV experiences: Cases of blurred vision, increased hepatic enzymes, angioedema and anaphylactic reactions have been reported.
Storage
Store at temperatures not exceeding 30°C. Protect from light and moisture.
ATC Classification
L02BG04 - letrozole ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.
Presentation/Packing
FC tab 2.5 mg x 30's.
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