Letero

Letero

letrozole

Manufacturer:

Hetero Labs

Distributor:

Camber
Full Prescribing Info
Contents
Letrozole.
Description
Each film coated tablet contains: 2.5 mg of Letrozole.
Letrozole tablets for oral administration contain 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-1ylmethylene)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 is available as 2.5 mg tablets for oral administration.
Inactive Ingredients: Lactose monohydrate, Povidone, Croscarmellose sodium, Silica colloidal anhydrous, Magnesium stearate and Opadry yellow 03B824011.
Action
Pharmacology: 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 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 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 was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.
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 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.
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: Absorption and Distribution: 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 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 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 GYP 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.
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.
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 bilirubins about 2-11 times ULN 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 (see Dosage & Administration).
Indications/Uses
Adjuvant Treatment of Early Breast Cancer: Letrozole is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
Extended Adjuvant Treatment of Early Breast Cancer: Letrozole 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 in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with Letrozole for a median of 60 months.
First and Second-Line Treatment of Advanced Breast Cancer: Letrozole is indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
Dosage/Direction for Use
Recommended Dose: The recommended dose of Letrozole is one 2.5 mg tablet administered once a day, without regard to meals.
Use in Adjuvant Treatment of Early Breast Cancer: In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy.
Use in Extended Adjuvant Treatment of Early Breast Cancer: 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. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58% of patients completed least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse.
Use in First and Second-Line Treatment of Advanced Breast Cancer: In patients with advanced disease, treatment with Letrozole should continue until tumor progression is evident.
Use in Hepatic Impairment: No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although Letrozole blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of Letrozole in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% (see Precautions). 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.
Use in Renal Impairment: No dosage adjustment is required for patients with renal impairment if creatinine clearance is ≥10 mL/min (see Pharmacology under Actions).
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 reactions 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 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.
Contraindications
Letrozole may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole is contraindicated in women who are or may become pregnant. If Letrozole is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus (see Use in Pregnancy & Lactation).
Special Precautions
Bone Effects: Use of Letrozole may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a substudy to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2-L4) bone mineral density (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 (difference = 4.4%) (P<0.0001) (see Adverse Reactions). 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 (see Adverse Reactions).
In the adjuvant trial the incidence of bone fractures at any time after randomization was 13.8% for letrozole and 10.5% for tamoxifen. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen (see Adverse Reactions). 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. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo (see Adverse Reactions).
Cholesterol: 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. CTC 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 ≥1.5 X ULN in total cholesterol (generally non-fasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., <=1.5 X ULN) in 151/1843 (8.2%) on letrozole vs 57/1840 (3.2%). Lipid lowering medications were required for 25% of patients on letrozole and 16% on tamoxifen (see Adverse Reactions).
Hepatic Impairment: 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. The effect of hepatic impairment on Letrozole exposure in cancer patients with elevated bilirubin levels has not been determined (see Dosage & Administration).
Fatigue and Dizziness: Because fatigue, dizziness, and somnolence have been reported with the use of Letrozole, caution is advised when driving or using machinery until it is known how the patient reacts to Letrozole use.
Laboratory Test Abnormalities: 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 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.
Use in Children: The safety and effectiveness in pediatric patients have not been established.
Use in 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 older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, 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
Use in Pregnancy: Pregnancy Category X (see Contraindications).
Letrozole may cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. Letrozole is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Letrozole caused adverse pregnancy outcomes, including congenital malformations, in rats and rabbits at doses much smaller than the daily maximum recommended human dose (MRHD) on a mg/m2 basis. Effects included increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems. Animal data and letrozole's mechanism of action raise concerns that letrozole could be a human teratogen as well.
Reproduction studies in rats showed embryo and fetal toxicity at letrozole doses during organogenesis equal to or greater than 1/100 the daily maximum recommended human dose (MHRD) (mg/m2 basis). Adverse effects included: intrauterine mortality; increased resorptions and 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 doses 1/10 the daily MHRD (mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion. In rabbits, letrozole caused embryo and fetal toxicity at doses about 1/100,000 and 1/10,000 the daily MHRD respectively (mg/m2 basis). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.
Physicians should discuss the need for adequate contraception with women who are recently menopausal. Contraception should be used until postmenopausal status is clinically well established.
Use in Lactation: It is not known if letrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from letrozole, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
The most serious adverse reactions from the use of Letrozole are: Bone effects (see Precautions), and Increases in cholesterol (see Precautions).
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adjuvant Treatment of Early Breast Cancer: The median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 73 months for patients receiving Letrozole and tamoxifen.
Certain adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs.
Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients reporting 1 or more AE) were Grade 1 or Grade 2 applying the Common Toxicity Criteria Version 2.0/Common Terminology Criteria for Adverse Events, version 3.0. Table 1 describes adverse reactions (Grades 1-4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population). (See Table 1.)

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When considering all grades during study treatment, a higher incidence of events was seen for Letrozole regarding fractures (10.1 % vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (Letrozole vs tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs 3.6%), endometrial hyperplasia/cancer (0.3% vs 2.9%), and endometrial proliferation disorders (0.3% vs 1.8%) (Letrozole vs tamoxifen respectively).
At a median follow up of 73 months, a higher incidence of events was seen for Letrozole (13.8%) than for tamoxifen (10.5%) regarding fractures. A higher incidence was seen for tamoxifen compared to Letrozole regarding thromboembolic events (4.5% vs 2.9%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Letrozole, respectively).
Bone Study: Results of a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) bone mineral density (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 (difference = 4.4%) (P>0.0001). No patients with a normal BMD at baseline became osteoporotic over the 2 years and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review). The results for total hip BMD were similar, although the differences between the two treatments were less pronounced. During the 2 year period, fractures were reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients (6%) in the tamoxifen arm.
Lipid Study: In a phase 3 safety trial in 262 post menopausal women with resected receptor positive early breast cancer at 24 months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of patients on letrozole had at least one total cholesterol value of a higher CTCAE grade than at baseline compared with 4% of patients on tamoxifen.
Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months: 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.
Table 2 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse reactions 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 reactions that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia. (See Table 2.)

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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.
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).
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.
Bone Sub-study: See Precautions.
Lipid Sub-study: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Letrozole and placebo in total cholesterol or in any lipid fraction at any time over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed (see Warnings and Precautions).
Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months: The extended adjuvant treatment trial was unblinded early (see Adverse Reactions). At the updated (final analysis), overall the side effects seen were consistent to those seen at a median treatment duration of 24 months.
During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) a higher rate of fractures was observed for Letrozole (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (Letrozole 12.2% vs placebo 6.4%).
Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of new fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo.
During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) the incidence of cardiovascular events was 9.8% for Letrozole and 7.0% for placebo.
Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of cardiovascular disease at any time after randomization was 14.4% for letrozole and 9.8% for placebo.
Lipid sub-study: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Letrozole and placebo in total cholesterol or in any lipid fraction over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed (see Precautions).
First-Line Treatment of Advanced Breast Cancer: A total of 455 patients were treated for a median time of exposure of 11 months. The incidence of adverse reactions was similar for Letrozole and tamoxifen. The most frequently reported adverse reactions were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea. Discontinuations for adverse reactions other than progression of tumor occurred in 10/455 (2%) of patients on Letrozole and in 15/455 (3%) of patients on tamoxifen.
Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Letrozole 2.5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 3. (See Table 3.)

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Other less frequent (≤2%) adverse reactions 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 Treatment of Advanced Breast Cancer: Study discontinuations in the megestrol acetate comparison study for adverse reactions other than progression of tumor were 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 reactions revealed no significant differences between the high and low dose Letrozole groups in either study. Most of the adverse reactions 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.
Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Letrozole 0.5 mg, Letrozole 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials are shown in Table 4. (See Table 4.)

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Other less frequent (<5%) adverse reactions 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 and Second-Line Treatment of Advanced Breast Cancer: In the combined analysis of the first- and second-line metastatic trials and post-marketing experiences other adverse reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypesthesia/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.
Postmarketing Experience: Cases of blurred vision, increased hepatic enzymes, angioedema, anaphylactic reactions, toxic epidermal necrolysis, erythema multiforme, and hepatitis have been reported.
Drug Interactions
Tamoxifen: Coadministration of Letrozole 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 therapy is not impaired if Letrozole is administered immediately after tamoxifen.
Cimetidine: A pharmacokinetic interaction study with cimetidine showed no clinically significant effect on letrozole pharmacokinetics.
Warfarin: 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 in combination with other anticancer agents.
Storage
Store at temperatures not exceeding 30°C.
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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