BIO-LETROZOLE

5 mg tablet once daily. In the adjuvant setting, the intended duration of treatment is 5 years. In the extended adjuvant setting, treatment with Bio-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, Bio-LETROZOLE treatment should continue until further tumour progression is evident.

Special populations Hepatic impairment:

No dose adjustment of Bio-LETROZOLE is required for patients with mild to moderate hepatic impairment (Child-Pugh score A or B). Insufficient data are available to recommend Serious Warnings and Precautions Bio-LETROZOLE should be prescribed and managed by a qualified physician who is experienced in the use of anti-cancer agents.

Bio-LETROZOLE increases the risk of osteoporosis and bone fractures (see 7 WARNINGS AND PRECAUTIONS, Musculoskeletal). PrBio-LETROZOLE (letrozole) Tablets Page 6 of 67 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.

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. PrBio-LETROZOLE (letrozole) Tablets Page 9 of 67 Endocrine and Metabolism Hyperlipidemia: The use of aromatase inhibitors, including Bio-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 Bio-LETROZOLE.

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

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.

Bio-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): Bio-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 PrBio-LETROZOLE (letrozole) Tablets Page 5 of 67 of letrozole.

4 Geriatrics). 2 CONTRAINDICATIONS Bio-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.

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

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

Special populations Hepatic impairment:

Bio-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.

• Premenopausal women (see 7 WARNINGS AND PRECAUTIONS). 1 Pregnant Women). 2 Breast-feeding). • Children or adolescents under 18 years of age.