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Letrozole Denk 2.5 (2.5 mg letrozole)

Pharmacotherapeutic group: Endocrine therapy. Hormone antagonist and related agents: aromatase inhibitor, ATC code: L02BG04.

The elimination of oestrogen-mediated growth stimulation is a prerequisite for tumour response in cases where the growth of tumour tissue depends on the presence of oestrogens and endocrine therapy is used.

In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens – primarily androstenedione and testosterone – to oestrone and oestradiol. The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the haem of the aromatase cytochrome P450, resulting in a reduction of oestrogen biosynthesis in all tissues where present.

Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxyprogesterone, and ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1 to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid and mineralocorticoid supplementation is not necessary.

Therapeutic indications

Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer.
Extended adjuvant treatment of hormone-dependent 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 anti-oestrogens.
Neo-adjuvant 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.

Posology and method of administration

Adult and elderly patients: The recommended dose of letrozole is 2.5 mg once daily. No dose adjustment is required forelderly patients.

In patients with advanced or metastatic breast cancer, treatment with letrozole should continue until tumour progression is evident.

In the adjuvant and extended adjuvant setting, treatment with letrozole should continue for 5 years or until tumour relapse occurs, whichever is first.

In the adjuvant setting a sequential treatment schedule (letrozole 2 years followed by tamoxifen 3 years) could also be considered

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

Paediatric population: letrozole is not recommended for use in children and adolescents. The safety and efficacy ofletrozole in children and adolescents aged up to 17 years have not been established. Limited dataare available and no recommendation on a posology can be made.

Renal impairment: No dosage adjustment of letrozole is required for patients with renal insufficiency withcreatinine clearance ≥10 ml/min. insufficient data are available in cases of renal insufficiencywith creatinine clearance lower than 10 ml/min (see sections 4.4 and 5.2).

Hepatic impairment: No dose adjustment of letrozole is required for patients with mild to moderate hepaticinsufficiency (Child-Pugh A or B). Insufficient data are available for patients with severe hepaticimpairment. Patients with severe hepatic impairment (Child-Pugh C) require close supervision.

Method of administration

Letrozole should be taken orally and can be taken with or without food.

Contraindications

Hypersensitivity to the active substance or to any of the excipients
Premenopausal endocrine status
Pregnancy
Breast-feeding

Special warnings and precautions for use

Menopausal status: In patients whose menopausal status is unclear, luteinising hormone (LH), follicle-stimulatinghormone (FSH) and/or oestradiol levels should be measured before initiating treatment withletrozole. Only women of postmenopausal endocrine status should receive letrozole.

Renal impairment: Letrozole has not been investigated in a sufficient number of patients with a creatinine clearance lower than 10 ml/min. The potential risk/benefit to such patients should be carefully considered before administration of letrozole.

Hepatic impairment: In patients with severe hepatic impairment (Child-Pugh C), systemic exposure and terminal halflife were approximately doubled compared to healthy volunteers. Such patients should therefore be kept under close supervision.

Bone effects: Letrozole is a potent oestrogen-lowering agent. Women with a history of osteoporosis and/or fractures, or who are at increased risk of osteoporosis, should have their bone mineral density formally assessed prior to the commencement of adjuvant and extended adjuvant treatment and monitored during and following treatment with letrozole. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored. In the adjuvant setting a sequential treatment schedule (letrozole 2 years followed by tamoxifen 3 years) could also be considered depending on the patient`s safety profile.

Other warnings: Co-administration of letrozole with tamoxifen, other anti-oestrogens or oestrogen-containing therapies should be avoided as these substances may diminish the pharmacological action of letrozole.

As the tablets contain lactose, letrozole is not recommended for patients with rare hereditary problems of galactose intolerance, of severe lactase deficiency or of glucose-galactose malabsorption.

Interaction with other medicinal products and other forms of interaction

Metabolism of letrozole is partly mediated via CYP2A6 and CYP3A4. Cimetidine, a weak, unspecific inhibitor of CYP450 enzymes, did not affect the plasma concentrations of letrozole.

The effect of potent CYP450 inhibitors is unknown.

Fertility, pregnancy and lactation

Women of perimenopausal status or child-bearing potential: Letrozole should only be used in women with a clearly established postmenopausal status. As there are reports of women regaining ovarian function during treatment with letrozole despite a clear postmenopausal status at start of therapy, the physician needs to discuss adequate contraception when necessary.

Pregnancy: Based on human experience in which there have been isolated cases of birth defects (labial fusion, ambiguous genitalia), letrozole may cause congenital malformations when administered during pregnancy. Studies in animals have shown reproductive toxicity. Letrozole is contraindicated during pregnancy

Breast-feeding: It is unknown whether letrozole and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Letrozole is contraindicated during breast-feeding

Fertility: The pharmacological action of letrozole is to reduce oestrogen production by aromatase inhibition. In premenopausal women, the inhibition of oestrogen synthesis leads to feedback increases in gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth, and can induce ovulation.

Effects on ability to drive and use machines

Letrozole has minor influence on the ability to drive and use machines. Since fatigue and dizziness have been observed with the use of letrozole and somnolence has been reported uncommonly, caution is advised when driving or using machines.

Undesirable effects

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 setting 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).

Overdose

Isolated cases of overdose with letrozole have been reported.

No specific treatment for overdose is known; treatment should be symptomatic and supportive.

Letrozole Denk 2.5 (2.5 mg letrozole)

Letrozole Denk 2.5 (2.5 mg letrozole)