NRA-LETROZOLE

and 10 CLINICAL PHARMACOLOGY). 7. Drug-Laboratory Test Interactions No clinically significant changes in the results of clinical laboratory tests have been observed. 10. 1. Mechanism of Action NRA-LETROZOLE tablets (letrozole) are a potent and highly specific non-steroidal aromatase inhibitor.

It 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. 2. Pharmacodynamics NRA-LETROZOLE exerts its anti-tumour effect by depriving estrogen-dependent breast cancer cells of one of their growth stimuli.

In postmenopausal women, estrogens are derived mainly from the action of the aromatase enzyme, which converts adrenal androgens - primarily androstenedione and testosterone - to estrone (E1) and estradiol (E2). The suppression of estrogen biosynthesis in peripheral tissues and the malignant tissue can be achieved by specifically inhibiting the aromatase enzyme.

5 mg letrozole suppressed serum estrone by 75-78% and estradiol by 78% from baseline. Maximum suppression is achieved in 48-78 hours. 1 to 5 mg suppress estradiol, estrone and estrone sulphate plasma levels by 75-95% from baseline in all patients treated.

5 mg doses and higher, many plasma levels of estrone and estrone sulphate are below the limit of detection of the assays, indicating that higher estrogen suppression is achieved with these doses. Estrogen suppression was maintained throughout treatment in all patients.

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenalsteroidogenesis has not been observed. 1 to 5 mg letrozole daily. 1 to 5 mg letrozole did not indicate any attenuation of aldosterone or cortisol production.

Thus, glucocorticoid or mineralocorticoid supplementation is not required. 1 to 5mg. These results indicate that accumulation of androgenic precursors does not occur. Plasma levels of LH and FSH are not affected by letrozole in patients, nor is thyroid function as evaluated by TSH, T4 and T3 uptake.

The effect of aromatase inhibitors, including letrozole, on estrogen suppression may consequently decrease bone mineral density (BMD) and increase the rate of bone fractures and of osteoporosis. In both the adjuvant setting and extended adjuvant setting, at a median treatment duration of 60 months, a significantly higher risk of osteoporosis as well as of clinical bone fractures was seen with letrozole compared with tamoxifen (adjuvant treatment) or placebo (extended adjuvant treatment) (see also 10 CLINICAL PHARMACOLOGY).

In a bone substudy (median follow-up of 61 months) in the extended adjuvant setting, a significantly greater decrease in median total hip BMD change from baseline was seen at 2 years for letrozole compared with placebo, but no significant changes were observed in lumbar spine BMD (see also 10 CLINICAL PHARMACOLOGY).

). 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). 37). 67). 53) (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.

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 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 NRA-LETROZOLE (see also 8 Page 9 of 62 ADVERSE REACTIONS, 10 CLINICAL PHARMACOLOGY, 14 CLINICAL TRIALS).

, MUSCULOSKELETAL 05/2024 Page 3 of 62 16. NON-CLINICAL NTOXICOLOGY ........................................................................................... 52 17. SUPPORTING PRODUCT MONOGRAPHS ............................................................................

55 PATIENT MEDICATION INFORMATION ......................................................................................... 56 Page 4 of 62 PART I: HEALTH PROFESSIONAL INFORMATION 1. INDICATIONS NRA-LETROZOLE (letrozole) film-coated tablets are 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 10 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 10 CLINICAL TRIALS).

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

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

NRA-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 the 6 DOSAGE FORMS, COMPOSITION AND PACKAGING.

• Premenopausal women (see 7 WARNINGS AND PRECAUTIONS). 1 Pregnant Women). 2 Breast-feeding). • Children or adolescents under 18 years of age. 3. SERIOUS WARNINGS AND PRECAUTIONS BOX 4. 1. 2. 5 mg tablet once daily. In the adjuvant setting, the intended duration of treatment is 5 years.

In the extended adjuvant setting, treatment with 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, NRA-LETROZOLE treatment should continue until further tumour progression is evident.

Serious Warnings and Precautions NRA-LETROZOLE (letrozole) should be prescribed and managed by a qualified physician who is experienced in the use of anti-cancer agents. NRA-LETROZOLE increases the risk of osteoporosis and bone fractures (see 7 WARNINGS AND PRECAUTIONS, Musculoskeletal).

Page 6 of 62 Special populations Hepatic impairment:

No dose adjustment of NRA-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. Insufficient data are available in cases of renal impairment with CLcr <10 mL / min. 3 Pharmacokinetics).