TREXOZOLA

Indications

• First-line treatment in postmenopausal women with hormone-dependent advanced breast cancer
• Adjuvant treatment of oestrogen-receptor-positive invasive early breast cancer in postmenopausal women
• Advanced breast cancer in postmenopausal women who have failed other anti-oestrogen therapy
• Extended adjuvant treatment of hormone-dependent invasive breast cancer in postmenopausal women after standard tamoxifen therapy

Dosage

Adults: 2.

Mechanism of action

Letrozole acts as a competitive inhibitor of the aromatase enzyme (CYP19A1), blocking the conversion of androgens to estrogens. This inhibition leads to decreased estrogen production, which is predominantly responsible for the growth of estrogen-dependent tumors in postmenopausal women. Unlike ovariectomy, letrozole does not increase serum FSH levels, making it an effective alternative for managing hormone-sensitive breast cancer.

Pharmacodynamics

Letrozole effectively suppresses the estrogen levels by inhibiting aromatization, thereby reducing the stimulation of breast tissue by estrogens. It is classified as a third-generation aromatase inhibitor. The drug has a long half-life of over 42 hours, allowing for once-daily dosing. Common side effects include hot flashes, joint pain, and risk of osteoporosis. Patients are advised about potential risks, including interstitial lung disease and elevated liver enzymes.

Pharmacokinetics

Letrozole is well absorbed following oral administration, with peak plasma concentrations occurring approximately 2 hours post-dose. It is extensively metabolized in the liver via the cytochrome P450 enzyme system, with an elimination half-life of around 2 days. Excretion occurs primarily through urine as metabolites. Special caution is advised in patients with hepatic impairment due to potential increased exposure.

Contra-indications

• Not indicated for premenopausal women

Adverse effects

• Alopecia
• Arthralgia
• Asthenia
• Bone fracture
• Bone pain
• Constipation
• Depression
• Diarrhoea
• Dizziness
• Gastrointestinal discomfort
• Headache
• Hot flush
• Hypercholesterolaemia
• Hyperhidrosis
• Hypertension
• Malaise
• Myalgia
• Nausea
• Oedema
• Osteoporosis
• Skin reactions
• Vaginal haemorrhage
• Vomiting
• Weight changes
• Anxiety
• Breast pain
• Cataract
• Cough
• Drowsiness
• Dry mouth
• Dysesthesia
• Dyspnoea
• Embolism and thrombosis
• Eye irritation
• Insomnia
• Irritability
• Ischaemic heart disease
• Leucopenia
• Memory loss
• Mucosal dryness
• Myocardial infarction
• Palpitations
• Stomatitis
• Tachycardia
• Taste altered
• Thirst
• Urinary frequency
• Increased urinary tract infection
• Vision blurred
• Vulvovaginal disorders

Interactions

• Caution with corticosteroids and other drugs affecting CYP enzymes

Precautions

• Susceptibility to osteoporosis
• Effective contraception required until postmenopausal status fully established
• Counsel patients regarding the risk of interstitial lung disease, pneumonitis, QT prolongation, elevated transaminase levels, neutropenia, and embryo-fetal toxicity

Pregnancy

Avoid (isolated cases of birth defects reported)

Breast-feeding

Manufacturer advises avoid

Storage

Store at room temperature, away from moisture and light

Formulations

• Tablets: 2.5 mg

Mechanism of action

Letrozole is a non-steroidal type II aromatase inhibitor. It blocks the active site, and therefore the electron transfer chain of CYP19A1. This competitive inhibition prevents the conversion of androgens to estrogen. This action leads to a reduction in uterine weight and elevated leuteinizing hormone. In postmenopausal women, the action of aromatase is responsible for the majority of estrogen production. With reduced availability of estrogen, estrogen-dependant tumors regress. Third generation aromatase inhibitors do not significantly affect cortisol, aldosterone, and thyroxine levels. 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.

Pharmacodynamics

Letrozole is an aromatase inhibitor used in the treatment of breast cancer. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue. Letrozole is a third generation type II aromatase inhibitor used to treat estrogen dependant breast cancers. It has a long duration of action as it has a half life of over 42 hours in breast cancer patients. Patients should be counselled regarding the risk of interstitial lung disease, pneumonitis, QT prolongation, elevated transaminase levels, neutropenia, and embryo-fetal toxicity.