Letrozole

Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer. Extended adjuvant treatment of hormone-dependent early invasive breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy for 5 years.

First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer. Advanced breast cancer after relapse or disease progression, in women with natural or artificially induced postmenopausal endocrine status, who have previously been treated with antioestrogens.

Neoadjuvant treatment of postmenopausal women with hormone receptor positive, HER-2 negative breast cancer where chemotherapy is not suitable and immediate surgery not indicated. Efficacy has not been demonstrated in patients with hormone receptor negative breast cancer.

5 mg once daily. In patients with advanced or metastatic breast cancer, treatment with letrozole tablets should continue until tumour progression is evident. In the adjuvant and extended adjuvant setting, treatment with Letrozole tablets should continue for 5 years or until tumour relapse occurs, whichever is first.

In the neoadjuvant setting, treatment with letrozole tablets could be continued for 4 to 8 months in order to establish optimal tumour reduction. If the response is not adequate, treatment with letrozole tablets should be discontinued and surgery scheduled and/or further treatment options discussed with the patient.

Following standard adjuvant tamoxifen therapy, treatment with letrozole tablets should continue for 5 years or until tumour relapse occurs, whichever comes first. In patients with metastatic disease, treatment with letrozole tablets should continue until tumour progression is evident.

1). No dose adjustment is required for elderly patients. Paediatric population Letrozole tablets is not recommended for use in children and adolescents. The safety and efficacy of letrozole tablets in children and adolescents aged up to 17 years have not been established.

Limited data are available and no recommendation on a posology can be made. Renal impairment No dosage adjustment of letrozole tablets is required for patients with renal insufficiency with creatinine clearance ≥10 ml/min. 2). Hepatic impairment No dosage adjustment of letrozole tablets is required for patients with mild to moderate hepatic insufficiency (Child-Pugh grade A or B).

Insufficient data are available for patients with severe hepatic impairment. 2). Method of administration Letrozole tablets should be taken orally and can be taken with or without food. A missed dose should be taken as soon as the patient remembers.

However, if it is almost time for the next dose (within 2 or 3 hours), the missed dose should be skipped, and the patient should go back to her regular dosage schedule. 2).

Summary of the safety profile The frequencies of adverse reactions for letrozole are mainly based on data collected from clinical trials. Up to approximately one third of the patients treated with letrozole in the metastatic settings and approximately 80% of the patients in the adjuvant setting as well as in the extended adjuvant setting experienced adverse reactions.

The majority of the adverse reactions occurred during the first few weeks of treatment. The most frequently reported adverse reactions in clinical studies were hot flushes, hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea.

Important additional adverse reactions that may occur with letrozole are: skeletal events such as osteoporosis and/or bone fractures and cardiovascular events (including cerebrovascular and thromboembolic events). The frequency category for these adverse reactions is described in Table 1.

Tabulated list of adverse reactions The frequencies of adverse reactions for letrozole are mainly based on data collected from clinical trials. The following adverse drug reactions, listed in Table 1, were reported from clinical studies and from post-marketing experience with letrozole tablets.

Table 1 Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥1/100 to <1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Frequency Organ System Very Common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Not known (cannot be estimated from the available data) Infections and infestations Urinary tract infection Neoplasms benign, malignant and unspecified (including cysts and polyps) Tumour pain1 Blood and lymphatic system disorders Leucopenia Immune system disorders Anaphylacti c reactions Metabolism and nutrition disorders Hyperchol esterolaem ia Decreased appetite,app etite increase, Psychiatric disorders Depression Anxiety (including nervousness), irritability Nervous system disorders Headache, dizziness Somnolence, insomnia, memory impairment, dysaesthesia (including paraesthesia, hypoaesthesia), dysgeusia, cerebrovascular accident, carpal tunnel syndrome Eye disorders Cataract, eye irritation, blurred vision Cardiac disorders Palpitations 1 Tachycardia, ischaemic cardiac events (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischaemia) Vascular disorders Hot flushes Hypertensio n Thrombophlebitis (including superficial and deep vein Pulmonary embolism, arterial thrombosis, Frequency Organ System Very Common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Not known (cannot be estimated from the available data) thrombophlebitis), cerebral infarction Respiratory, thoracic and mediastinal disorders Dyspnoea, cough Gastrointestinal disorders Nausea, dyspepsia1, constipation , abdominal pain, diarrhoea, vomiting Dry mouth, stomatitis1 Hepatobiliary disorders Increased hepatic enzymes, hyperbilirubinemia , jaundice.

Hepatitis Skin and subcutaneous tissue disorders Hyperhidr osis, Alopecia, rash (including erythematou s, maculopapu lar, psoriaform, and vesicular rash), dry skin Pruritus, urticaria Angioedem a,Toxic epidermal necrolysis, erythema multiforme Musculoskeletal and connective tissue disorders Arthralgia Myalgia, bone pain1, osteoporosis , bone fractures, arthritis.

Tendonitis Tendon rupture Trigger finger Renal and urinary disorders Pollakiuria Reproductive system and breast disorders Vaginal haemorrhag e Vaginal discharge, vulvovaginal dryness, breast pain General disorders and administration site conditions Fatigue (including asthenia, malaise), Peripheral oedema, chest pain.

General oedema, pyrexia, mucosal dryness, thirst Investigations Weight Weight loss Frequency Organ System Very Common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Not known (cannot be estimated from the available data) increase 1 Adverse drug reactions reported only in the metastatic setting Some adverse reactions have been reported with notably different frequencies in the adjuvant treatment setting.

9% Note: “During treatment” includes 30 days after last dose. “Any time” includes follow-up period after completion or discontinuation of study treatment. Differences were based on risk ratios and 95% confidence intervals. 7%** * Significantly less than with letrozole monotherapy ** Significantly more than with letrozole monotherapy Note: Reporting period is during treatment or within 30 days of stopping treatment Description of selected adverse reactions Cardiac adverse reactions In the adjuvant setting, in addition to the data presented in Table 2, the […]

6).

M-LETROZOLE (letrozole) film-coated tablets is indicated for: • The adjuvant treatment of postmenopausal women with hormone receptor-positive invasive early breast cancer. Clinical effectiveness is based on superior Disease-Free Survival (DFS) compared to tamoxifen.

Overall survival was not significantly different between the two treatments (see 14 CLINICAL TRIALS). • The extended adjuvant treatment of hormone receptor positive invasive early breast cancer in postmenopausal women who have received approximately 5 years of prior standard adjuvant tamoxifen therapy.

Clinical effectiveness is based on superior Disease-Free Survival (DFS) compared to placebo in the overall study population, at a median follow-up of 28 months. However, overall survival was not significantly different between the two treatments for the overall population and an increase in deaths was seen in node-negative patients in the letrozole arm versus the placebo arm (see 7 WARNINGS AND PRECAUTIONS and 14 CLINICAL TRIALS).

• First-line therapy in postmenopausal women with advanced breast cancer. • The hormonal treatment of advanced/metastatic breast cancer after relapse or disease progression, in women with natural or artificially-induced postmenopausal endocrine status, who have previously been treated with anti-estrogens.

M-LETROZOLE is not indicated in hormone-receptor negative disease. Men Use of letrozole in men with breast cancer has not been studied (See 7 WARNINGS AND PRECAUTIONS: Reproductive Health: Female and Male Potential). 1 Pediatrics Pediatrics (< 18 years of age): M-LETROZOLE is contraindicated in children and adolescents.

The safety and efficacy of letrozole in children and adolescents (under 18 years of age) have not been established. 2 Geriatrics Geriatrics (≥ 65 years of age): No age-related pharmacokinetic effects were observed with the use of letrozole.

4 Geriatrics).

5 mg tablet once daily. In the adjuvant setting, the intended duration of treatment is 5 years. In the extended adjuvant setting, treatment with M-LETROZOLE is intended for 5 years and should be initiated within 3 months of completion of approximately 5 years of prior standard adjuvant tamoxifen therapy.

In the first- and second-line advanced breast cancer settings, M-LETROZOLE treatment should continue until further tumour progression is evident.

Special populations Hepatic impairment:

No dose adjustment of M-LETROZOLE is required for patients with mild to moderate hepatic impairment (Child-Pugh score A or B). Insufficient data are available to recommend a dose adjustment in breast cancer patients with severe hepatic impairment (Child-Pugh C).

However, since letrozole elimination depends mainly on intrinsic metabolic clearance, caution is recommended. 3 Pharmacokinetics).

Renal impairment:

No dosage adjustment is required for patients with renal impairment with a creatinine clearance (CLcr) ≥10 mL/min. 3 Pharmacokinetics).

Pediatrics (< 18 years of age):

Letrozole is contraindicated in children and adolescents. The safety and efficacy of letrozole in children and adolescents (under 18 years of age) have not been established.

Geriatrics ( 65 years of age):

No dose adjustment is required for elderly patients. 3 Pharmacokinetics, Absorption). 5 Missed Dose The missed dose should be taken as soon as the patient remembers. However, if it is almost time for the next dose, the missed dose should be skipped, and the patient should go back to the regular dosage schedule.

3 Pharmacokinetics).

). 1% vs. 4%, respectively. A significantly higher incidence of events was seen for letrozole vs. 8% vs. 2% vs. 0%). 8% vs. 5% vs. 4% vs. 4% vs. 2% vs. 2% respectively). 3 % vs. 3%, respectively (a non- significant difference). 80). 1%) than with tamoxifen.

37). 67). 53) (see 8 ADVERSE REACTIONS). 0%)], but the difference was not statistically significant. Of the 19 deaths attributed to a cardiovascular cause in the placebo arm, 12 occurred in the group of 1026 patients who did not switch to letrozole after study unblinding, and 7 occurred in the group of 1551 patients who switched to letrozole.

A total of 7 patients died from a stroke – 6 in the letrozole arm and 1 after switching from placebo to letrozole after study unblinding. Driving and operating machinery No studies on the effects of letrozole on the ability to drive and use machines have been performed.

PrM-LETROZOLE (letrozole), tablets Page 8 of 57 However, since fatigue, dizziness, and uncommonly somnolence have been observed with the use of letrozole, caution is advised when driving or operating machinery while such symptoms persist.

Endocrine and Metabolism Hyperlipidemia:

The use of aromatase inhibitors, including M-LETROZOLE, may increase lipid levels. 6% of patients treated with tamoxifen. In a smaller study (D2407) comparing 2 years of adjuvant treatment with letrozole or tamoxifen, significant differences were observed between treatments at all time-points in total cholesterol, LDL cholesterol and the HDL: LDL ratio in favour of tamoxifen.

Clinically relevant changes in total cholesterol at 2 years occurred significantly more often for patients treated with letrozole (17%) than with tamoxifen (5%). Monitoring of serum cholesterol is advised for patients treated with M-LETROZOLE.

(see also 8 ADVERSE REACTIONS, 10 CLINICAL PHARMACOLOGY, 14 CLINICAL TRIALS).

Monitoring and Laboratory Tests Plasma Lipids:

Women should have their cholesterol levels assessed and managed according to current clinical practice and guidelines (see 7 WARNINGS & PRECAUTIONS- Endocrine and Metabolism).

Bone Mineral Density:

Monitoring of overall bone health is recommended during treatment with M- LETROZOLE. (See 7 WARNINGS & PRECAUTIONS- Musculoskeletal). In patients whose menopausal status is unclear or who become amenorrheic after chemotherapy, luteinising hormone (LH), follicle- stimulating hormone (FSH) and/or estradiol levels should be measured before initiating treatment with M-LETROZOLE and regularly during the first 6 months of treatment.

Musculoskeletal Bone Mineral Density:

The use of estrogen lowering agents, including M-LETROZOLE, may cause a reduction in bone mineral density (BMD) with a possible consequent increased risk of osteoporosis and fracture. 7%). 2%). 4%). Similarly, significantly more patients receiving letrozole […]

M-LETROZOLE is contraindicated in: • Patients who are hypersensitive to letrozole, other aromatase inhibitors, or to any ingredient in the formulation or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

PrM-LETROZOLE (letrozole), tablets Page 5 of 57 • Premenopausal women (see 7 WARNINGS AND PRECAUTIONS). 1 Pregnant Women). 2 Breast-feeding). • Children or adolescents under 18 years of age.

1 Adjuvant Treatment of Early Breast Cancer Letrozole tablets are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. 2 Extended Adjuvant Treatment of Early Breast Cancer Letrozole tablets are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy.

3) ]. 3 First and Second-Line Treatment of Advanced Breast Cancer Letrozole tablets are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer.

5) ].

5 mg tablet administered once a day, without regard to meals. 2 Use in Adjuvant Treatment of Early Breast Cancer In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. In both the adjuvant study and the postapproval adjuvant study, median treatment duration was 5 years.

1) ]. 3 Use in Extended Adjuvant Treatment of Early Breast Cancer In the extended adjuvant setting, the optimal treatment duration with letrozole tablets 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 for letrozole was 60 months.

5 years of extended adjuvant treatment. 2) ]. 5) ]. 5 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.

3) ]. 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. 3) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. 4) ] The most common adverse reactions (greater than 20%) were hot flashes, arthralgia; flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain; and musculoskeletal (6) .

gov/medwatch . 1 Clinical Trials Experience 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 In study, BIG 1-98, the median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 96 months for patients receiving letrozole and tamoxifen.

Certain adverse reactions were prospectively specified for analysis (see Table 1), 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.

0. Table 1 describes adverse reactions (Grades 1 to 4 and Grades 3 to 4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population). e. e. during treatment + 30 days after discontinuation of treatment) for letrozole and tamoxifen (range up to 68 months) 3 Excluding women who had undergone hysterectomy before study entry TIA = Transient ischemic attack Note: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and second primary malignancies were collected life-long.

All of these events were assumed to be of CTC Grade 3 to 5 and were not individually graded. 4%) (letrozole vs tamoxifen respectively). 8%) (letrozole vs tamoxifen respectively). 4%) regarding fractures. 4%) (tamoxifen vs letrozole, respectively).

0001). 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 safety trial in 263 postmenopausal 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.

In another postapproval randomized, multicenter, open label, study of letrozole vs anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor and node positive breast cancer (FACE, NCT00248170), the median duration of treatment was 60 months for both treatment arms.

Table 2 describes adverse reactions (Grades 1 to 4 and Grades 3 to 4) irrespective of relationship to study treatment in the adjuvant study (safety population). 3) The following adverse reactions were also identified in less than 5% of the 2049 patients treated with letrozole and not included in the table: fall, vertigo, hyperbilirubinemia, jaundice, and chest pain.

Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months In study MA-17, 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 3 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment. 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.

5% (142). 5% (141). 7% of the patients who received placebo. 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.

1) ] Lipid Substudy: 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.

2) ]. Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months The extended adjuvant treatment trial (MA-17) was unblinded early [ see Adverse Reactions (6) ]. At the updated (final analysis), overall the side effects seen were consistent to those seen at a median treatment duration of 24 months.

4%). 8% for placebo. 8% for placebo. 0% for placebo. 8% for placebo.

Lipid substudy :

In the extended adjuvant setting (MA-17), 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. 2) ]. First-Line Treatment of Advanced Breast Cancer In study P025 a total of 455 patients were treated for a median time of exposure of 11 months in the letrozole arm (median 6 months in the tamoxifen arm).

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.

5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 4 . 5 mg (N = 455) % Tamoxifen 20 mg (N = 455) % General Disorders Fatigue 13 13 Chest Pain 8 9 Edema Peripheral 5 6 Pain NOS 5 7 Weakness 6 4 Investigations Weight Decreased 7 5 Vascular Disorders Hot Flushes 19 16 Hypertension 8 4 Gastrointestinal Disorders Nausea 17 17 Constipation 10 11 Diarrhea 8 4 Vomiting 7 8 Infections/Infestations Influenza 6 4 Urinary Tract Infection NOS 6 3 Injury, Poisoning and Procedural Complications Post-Mastectomy Lymphedema 7 7 Metabolism and Nutrition Disorders Anorexia 4 6 Musculoskeletal and Connective Tissue Disorders Bone Pain 22 21 Back Pain 18 19 Arthralgia 16 15 Pain in Limb 10 8 Nervous System Disorders Headache NOS 8 7 Psychiatric Disorders Insomnia 7 4 Reproductive System and Breast Disorders Breast Pain 7 7 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 18 17 Cough 13 13 Chest Wall Pain 6 6 Other less frequent (less than or equal to 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. 9%) on megestrol acetate. 7%). 2%) on letrozole than on megestrol acetate. 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.

5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials AR/BC2 and AR/BC3 are shown in Table 5 . 5 mg (N = 380) % Megestrol Acetate 160 mg (N = 189) % Aminoglutethimide 500 mg (N = 178) % Body as a Whole Chest Pain 6 3 7 3 Peripheral Edema 1 5 5 8 3 Asthenia 4 5 4 5 Weight Increase 2 2 9 3 Cardiovascular Hypertension 5 7 5 6 Digestive System Nausea 13 15 9 14 Vomiting 7 7 5 9 Constipation 6 7 9 7 Diarrhea 6 5 3 4 Pain-Abdominal 6 5 9 8 Anorexia 5 3 5 5 Dyspepsia 3 4 6 5 Infections/Infestations Viral Infection 6 5 6 3 Lab Abnormality Hypercholesterolemia 3 3 0 6 Musculoskeletal System Musculoskeletal 2 21 22 30 14 Arthralgia 8 8 8 3 Nervous System Headache 9 12 9 7 Somnolence 3 2 2 9 Dizziness 3 5 7 3 Respiratory System Dyspnea 7 9 16 5 Coughing 6 5 7 5 Skin and Appendages Hot Flushes 6 5 4 3 Rash 3 5 4 3 12 Pruritus 1 2 5 3 1 Includes peripheral edema, leg edema, dependent edema, edema 2 Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain 3 Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash Other less frequent (less than 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 postmarketing 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.

2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of letrozole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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1) ]. Known hypersensitivity to the active substance, or to any of the excipients [ see Adverse Reactions (6) ]. Pregnancy (4) Known hypersensitivity to the active substance, or to any of the excipients (4)