Letrozole

Letrozole is a non-steroidal inhibitor of aromatase, the enzyme that makes oestrogens from androgens. In hormone-dependent breast cancer, removing oestrogen-driven growth stimulation is a prerequisite for tumour response. After the menopause most oestrogen comes from aromatase converting androgens, so specific inhibition of the enzyme suppresses oestrogen synthesis in peripheral tissues and in the tumour tissue itself.

Mechanism of Action

• Aromatase inhibition: letrozole binds competitively to the haem group of the cytochrome P450 subunit of aromatase, which reduces oestrogen synthesis in all tissues where the enzyme is present.
• Source of oestrogen after the menopause: in postmenopausal women, aromatase converts androgens, mainly androstenedione and testosterone, into oestrone and oestradiol.
• Suppression in healthy postmenopausal women: single doses of 0.1 mg, 0.5 mg and 2.5 mg reduced serum oestrone and oestradiol by 75%, 78% and 78% from baseline. Maximum suppression was reached within 48–78 hours.
• Suppression in advanced breast cancer: daily doses of 0.1 mg to 5 mg lowered plasma oestradiol, oestrone and oestrone sulphate by 75–95% from baseline in all treated patients. With doses of 0.5 mg and above, many oestrone and oestrone sulphate values fell below the detection limit of the assays, indicating a greater degree of suppression. Suppression was maintained throughout treatment.
• Selectivity: third-generation aromatase inhibitors such as letrozole do not significantly alter cortisol, aldosterone or thyroxine levels.

Pharmacokinetics

• Absorption: rapid and complete from the gut, with a mean absolute bioavailability of 99.9%. Food slightly slows absorption (median tmax 1 hour fasting versus 2 hours with food; mean Cmax 129 versus 98.7 nmol/L) but does not change its extent (AUC), so letrozole can be taken regardless of meals.
• Distribution: about 60% is bound to plasma proteins, mainly albumin (55%); red-cell concentrations are about 80% of plasma concentrations. After a radiolabelled 2.5 mg dose, about 82% of plasma radioactivity was unchanged letrozole, so exposure to metabolites is low. Distribution to the tissues is rapid and extensive, with an apparent volume of distribution at steady state of 1.87 ± 0.47 L/kg.
• Metabolism: the main route of elimination is metabolic conversion to a pharmacologically inactive carbinol metabolite (metabolic clearance 2.1 L/h, slow compared with hepatic blood flow of about 90 L/h). CYP3A4 and CYP2A6 can both form this metabolite. Minor unidentified metabolites and direct renal or faecal excretion play only a small part.
• Elimination: within 2 weeks of a radiolabelled 2.5 mg dose in healthy postmenopausal volunteers, 88.2% of the radioactivity was recovered in urine and 3.8% in faeces. At least 75% of the radioactivity in urine over 216 hours was the glucuronide of the carbinol metabolite, about 9% two unidentified metabolites and 6% unchanged letrozole. The apparent terminal half-life in plasma is about 2 to 4 days.
• Steady state and linearity: with 2.5 mg daily, steady state is reached in 2–6 weeks. Steady-state concentrations are about 7 times those after a single dose and stay stable over time, so there is no continuing accumulation. Exposure was dose-proportional up to single doses of 10 mg and daily doses of 1.0 mg; above that it rises more than proportionally, probably because metabolic elimination saturates.
• Special populations: age has no effect on the pharmacokinetics. Renal function (creatinine clearance 9–116 mL/min) did not affect exposure after a single 2.5 mg dose. In moderate hepatic impairment (Child-Pugh B) the mean AUC was 37% higher than in normal subjects, still within the normal range; in eight men with cirrhosis and severe hepatic impairment (Child-Pugh C), AUC rose by 95% and half-life by 187%.

Letrozole is authorised for postmenopausal women. Its efficacy has not been demonstrated in patients with hormone receptor-negative breast cancer.

• Early breast cancer (adjuvant): adjuvant treatment of hormone receptor-positive invasive early breast cancer.
• Extended adjuvant treatment: extended adjuvant treatment of hormone-dependent invasive breast cancer in women who have previously received standard adjuvant tamoxifen for 5 years.
• Advanced breast cancer, first line: first-line treatment of hormone-dependent advanced breast cancer.
• Advanced breast cancer after antioestrogens: advanced breast cancer in women with a natural or artificially induced postmenopausal endocrine status, after relapse or progression of the disease, who have previously been treated with antioestrogens.
• Neoadjuvant (pre-operative) treatment: HER-2-negative, hormone receptor-positive breast cancer in women for whom chemotherapy is not appropriate and immediate surgery is not indicated.

• Hypersensitivity to letrozole or to any of the excipients.
• Premenopausal endocrine status.
• Pregnancy.
• Breastfeeding.

The frequencies below come mainly from clinical studies, supplemented by post-marketing experience. Up to about one third of patients treated in the metastatic indication and about 80% of those in the adjuvant and extended adjuvant indications had side effects, and most appeared in the first weeks of treatment. The most frequent were hot flushes, hypercholesterolaemia, joint pain, fatigue, increased sweating and nausea. Other important reactions are bone events (osteoporosis, fractures) and cardiovascular events, including cerebrovascular and thromboembolic events.

Very common (≥1/10): hypercholesterolaemia, hot flushes, hyperhidrosis (increased sweating), arthralgia, fatigue (including asthenia and malaise).

Common (≥1/100 to <1/10): decreased appetite, increased appetite, depression, headache, dizziness, palpitations, hypertension, nausea, dyspepsia, constipation, abdominal pain, diarrhoea, vomiting, alopecia, rash (including erythematous, maculopapular, psoriasiform and vesicular), dry skin, myalgia, bone pain, osteoporosis, bone fractures, arthritis, vaginal bleeding, peripheral oedema, chest pain, weight increase. Palpitations, dyspepsia and bone pain were reported only in the metastatic indication.

Uncommon (≥1/1,000 to <1/100): urinary tract infection, tumour pain, leucopenia, anxiety (including nervousness), irritability, somnolence, insomnia, memory impairment, dysaesthesia (including paraesthesia and hypoaesthesia), dysgeusia, cerebrovascular accident, carpal tunnel syndrome, cataract, eye irritation, blurred vision, tachycardia, ischaemic cardiac events (including new or worsening angina, angina requiring surgery, myocardial infarction and myocardial ischaemia), thrombophlebitis (including superficial and deep vein thrombophlebitis), dyspnoea, cough, dry mouth, stomatitis, increased liver enzymes, hyperbilirubinaemia, jaundice, pruritus, urticaria, tendinitis, pollakiuria, generalised oedema, dryness of mucous membranes, thirst, pyrexia, weight loss. Tumour pain and stomatitis were reported only in the metastatic indication.

Rare (≥1/10,000 to <1/1,000): pulmonary embolism, arterial thrombosis, cerebral infarction, tendon rupture.

Not known: anaphylactic reaction, hepatitis, angioedema, toxic epidermal necrolysis, erythema multiforme, trigger finger, vaginal discharge, vulvovaginal dryness, breast pain.

Adjuvant letrozole compared with adjuvant tamoxifen (2,448 versus 2,447 women; incidence during treatment, median 5 years, and at any time after randomisation, median 8 years):

• More often with letrozole: bone fracture 10.2% and 14.7% versus 7.2% and 11.4%; osteoporosis 5.1% and 5.1% versus 2.7% and 2.7%; myocardial infarction 1.0% and 1.7% versus 0.5% and 1.1%.
• Less often with letrozole: thromboembolic events 2.1% and 3.2% versus 3.6% and 4.6%; endometrial hyperplasia or endometrial cancer 0.2% and 0.4% versus 2.3% and 2.9%.

Reactions that need prompt attention include thromboembolic and cerebrovascular events, ischaemic cardiac events, fractures from bone loss, tendinitis and tendon rupture, hepatitis, anaphylaxis and severe skin reactions (toxic epidermal necrolysis, erythema multiforme, angioedema).

• Tamoxifen, other antioestrogens and oestrogen-containing therapy: they can weaken the pharmacological action of letrozole. Tamoxifen given with letrozole markedly lowers letrozole plasma concentrations. Avoid the combinations. There is no clinical experience of letrozole with oestrogens or with anticancer agents other than tamoxifen.
• CYP-mediated metabolism: letrozole is partly metabolised by CYP2A6 and CYP3A4. Cimetidine, a weak non-specific CYP450 inhibitor, did not change letrozole plasma concentrations; the effect of potent CYP450 inhibitors is unknown.
• Medicines cleared by CYP2A6 or CYP2C19: in vitro, letrozole inhibits CYP2A6 and, moderately, CYP2C19; the clinical relevance is unknown. Take care with medicines that depend mainly on these enzymes and have a narrow therapeutic index, such as phenytoin and clopidogrel.
• Food: letrozole can be taken with or without food.

Letrozole is taken by mouth, once a day, with or without food. Treatment is prescribed by a doctor experienced in treating breast cancer.

Recommended Dose

• 2.5 mg once daily for adults, including elderly patients.
• Advanced or metastatic breast cancer: continue until tumour progression is evident.
• Adjuvant and extended adjuvant treatment: continue for 5 years or until tumour relapse, whichever comes first. In the adjuvant setting, a sequential schedule (letrozole for 2 years followed by tamoxifen for 3 years) may also be considered.
• Neoadjuvant treatment: may continue for 4 to 8 months to establish the optimal tumour reduction. If the response is not adequate, treatment should be stopped, surgery scheduled and/or other treatment options discussed with the patient.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment when creatinine clearance is 10 mL/min or higher. Data are insufficient below 10 mL/min, so benefit and risk must be weighed carefully.
• Hepatic impairment: no adjustment in mild to moderate impairment (Child-Pugh A or B). Data in severe impairment are insufficient; patients with Child-Pugh C impairment need close supervision.
• Children and adolescents: not recommended. Safety and efficacy have not been established up to the age of 17, and the limited data do not allow a dose recommendation.

Missed Dose

Take the missed dose as soon as it is remembered. If it is almost time for the next dose (within the next 2 or 3 hours), skip the missed dose and go back to the regular schedule. Do not take a double dose: above the recommended 2.5 mg a day, systemic exposure rises more than proportionally.

Menopausal Status

Only women with a postmenopausal endocrine status should receive letrozole. Where menopausal status is unclear, luteinising hormone, follicle-stimulating hormone and/or oestradiol levels should be measured before treatment starts.

Bone Effects

Letrozole is a potent oestrogen-lowering agent. Women with a history of osteoporosis and/or fractures, or at increased risk of osteoporosis, should have a formal bone mineral density assessment before adjuvant or extended adjuvant treatment, and be monitored during and after treatment. Treatment or prophylaxis of osteoporosis should be started when appropriate and monitored carefully. In the adjuvant setting, a sequential schedule (letrozole for 2 years followed by tamoxifen for 3 years) may be considered, depending on the patient’s safety profile.

Tendinitis and Tendon Rupture

Tendinitis and tendon rupture (rare) can occur. Patients should be monitored closely and appropriate measures, such as immobilisation, taken for the affected tendon.

Renal and Hepatic Impairment

Letrozole has not been studied in enough patients with creatinine clearance below 10 mL/min, so benefit and risk must be weighed carefully before it is given. In severe hepatic impairment (Child-Pugh C), exposure and terminal half-life were roughly doubled or more compared with healthy volunteers; these patients must be kept under close supervision.

Combination With Tamoxifen, Other Antioestrogens or Oestrogens

These should not be given with letrozole because they can weaken its pharmacological action.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: contraindicated. Isolated cases of birth defects (labial fusion, ambiguous genitalia) suggest that letrozole may cause congenital malformations when given during pregnancy, and animal studies showed reproductive toxicity.
• Breastfeeding: contraindicated. It is not known whether letrozole or its metabolites pass into breast milk, and a risk to the newborn or infant cannot be excluded.
• Women of childbearing potential or perimenopausal status: only women with a clearly established postmenopausal status should use letrozole. Because some women have recovered ovarian function during treatment despite a clear postmenopausal status at the start, the doctor should discuss the need for adequate contraception where necessary.
• Fertility: letrozole acts by reducing oestrogen production through aromatase inhibition. In premenopausal women, the fall in oestrogen synthesis raises gonadotropin (LH and FSH) levels; the higher FSH stimulates follicle growth and can induce ovulation.

Lactose and Sodium

The tablets contain lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) sodium, so it is essentially ‘sodium-free’.

Doping Tests

Letrozole may produce a positive result in anti-doping tests, and athletes should be told so.

Effect on Driving

Letrozole has a small influence on the ability to drive and use machines. Fatigue and dizziness have been observed and somnolence has been reported uncommonly, so patients should take care while driving or using machines.

Femara 2.5 mg tablets (as in the Spanish SmPC) do not need refrigeration. Do not store above 30 °C, and keep the tablets in the original package to protect them from moisture. They are supplied in PVC/PE/PVDC/aluminium blister packs of 10, 14, 28, 30 or 100 tablets; not all pack sizes may be marketed.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), started by a doctor experienced in treating breast cancer. Letrozole tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.