Letrozole

Registered South African indications:

• Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer
• Extended adjuvant treatment of early invasive breast cancer in post-menopausal women who have received prior standard adjuvant tamoxifen therapy for five 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 is not indicated

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 Letrozole is not indicated in hormone receptor negative disease

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Premenopausal endocrine status
• Pregnancy
• Breastfeeding
• Severe hepatic impairment (Child-Pugh grade C)
• Severe renal impairment (CrCl < 10ml/min)

South African recommendations

Bone effects

• Osteoporosis and/or bone fractures have been reported with the use of letrozole
• Monitoring of overall bone health is recommended during treatment

Tendon disorders

• The use of third generation aromatase inhibitors, including letrozole, were found to be associated with tendonitis and tenosynovitis in randomised controlled trials
• Tendon rupture was found to be a potential risk
• Tendonitis and tenosynovitis were estimated to be of uncommon occurrence, and tendon rupture of rare occurrence
• Monitor patients for signs and symptoms of tendon disorders during treatment with letrozole

Menopausal status

• In patients whose menopausal status is unclear, luteinising hormone (LH), follicle–stimulating hormone (FSH) and/or oestradiol levels should be measured before initiating treatment with letrozole
• Only women of confirmed postmenopausal endocrine status should receive letrozole

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

Interactions

• 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

Excipient information (Lactose)

• Patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose-galactose malabsorption or fructose intolerance should not take letrozole

Effects on ability to drive and use machines

• Fatigue, dizziness and somnolence have been observed with the use of letrozole. Patients should be advised that their physical and/or mental abilities required for operating machinery or driving a car may be impaired

Forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Adjuvant treatment of postmenopausal women with hormone receptor positive invasive early breast cancer
Extended adjuvant treatment of early invasive breast cancer in post-menopausal women who have received prior standard adjuvant tamoxifen therapy for five years

• Oral (fct, tab): 2.5mg, once dly; Treatment duration: Continue for 5 years or until disease relapse/recurrence occurs, whichever comes first

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In the adjuvant and extended adjuvant setting, treatment with letrozole should continue for 5 years or until disease relapse/recurrence occurs, whichever comes first

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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

• Oral (fct, tab): 2.5mg, once dly; Treatment duration: Continue until tumour progression is evident

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In patients with metastatic disease, treatment with letrozole should continue until tumour progression is evident

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Neo-adjuvant treatment of postmenopausal women with hormone receptor positive, HER-2 negative breast cancer where chemotherapy is not suitable and immediate surgery is not indicated

• Oral (fct, tab): 2.5mg, once dly; Treatment duration: Continued for 4 to 8 months in order to establish optimal tumour reduction

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In the neoadjuvant (preoperative) setting, treatment with letrozole should 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, surgery scheduled and/or further treatment options discussed with the patient 

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Method of administration

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

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Missed dose

A 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 their regular dosage schedule. Doses should not be doubled, because with daily doses over 2.5mg recommended dose, over-proportionality in systemic exposure was observed

Not established for use in children

 

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The safety and efficacy in children and adolescents aged up to 17 years have not been established. Limited data are available

Pregnancy

South African recommendations

• Contraindicated
• Letrozole may cause foetal harm when administered to a pregnant woman. The patient should be apprised of the potential risk to the foetus, if letrozole is used during pregnancy or if the patient becomes pregnant while taking this medicine. There are no clinical trials conducted in pregnant women with letrozole. There have been post marketing reports of spontaneous abortions and congenital anomalies in infants of mothers who have taken letrozole
• Cases of birth defects (labial fusion, ambiguous genitalia) have been reported in infants born to woman exposed to off label use (infertility treatment, ovulation induction) of letrozole during pregnancy

Breastfeeding

South African recommendations

• Contraindicated
• It is not known if letrozole is excreted in human milk. There are no data on the effects of letrozole on the breastfed child or the effects of letrozole on milk production

Fertility

South African recommendations

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

South African recommendations

• Mild to moderate (CrCl ≥ 10ml/min): No dose adjustment recommended
• Severe (CrCl < 10ml/min): Contraindicated
  Insufficient data are available to establish dosage recommendations

South African recommendations

• Mild to moderate (Child Pugh score A and B): No dose adjustment recommended
• Severe (Child Pugh score C): Contraindicated
  Insufficient data are available for patients with severe hepatic impairment (Child Pugh score C) and should be kept under close supervision

South African recommendations

• No dose adjustment recommended

Central Nervous System Disorders

• Depression
• Anxiety
• Nervousness
• Irritability
• Headache
• Dizziness
• Somnolence
• Insomnia
• Memory impairment
• Dysaesthesia
• Cerebrovascular accident
• Fatigue
• Asthenia

Cardiovascular Disorders

• Palpitations
• Tachycardia
• Ischaemic cardiac events
• Angina
• Myocardial infarction
• Myocardial ischaemia
• Hypertension
• Thrombophlebitis
• Arterial thrombosis
• Cerebrovascular infarction

Respiratory Disorders

• Dyspnoea
• Cough
• Pulmonary embolism

Gastrointestinal Disorders

• Nausea and vomiting
• Dyspepsia
• Constipation
• Abdominal pain
• Diarrhoea
• Dry mouth
• Stomatitis
• Mucosal dryness

Hepatobiliary Disorders

• Increased hepatic enzymes
• Hepatitis
• Hyperbilirubinemia
• Jaundice

Genitourinary Disorders

• Urinary tract infection
• Increased urinary frequency
• Vaginal bleeding
• Vaginal discharge
• Vaginal dryness
• Breast pain

Endocrine and Metabolic Disorders

• Hypercholesterolaemia
• Anorexia
• Increased appetite
• Thirst
• Increased weight
• Weight loss

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Bone pain
• Osteoporosis
• Bone fractures
• Arthritis
• Tendonitis
• Tendon rupture
• Trigger finger

Skin and Subcutaneous Tissue Disorders

• Increased sweating
• Alopecia
• Rash
• Dry skin
• Pruritus
• Urticaria
• Angioedema
• Toxic epidermal necrolysis
• Erythema multiforme

Immune, Blood and Lymphatic System Disorders

• Leukopenia
• Anaphylactic reaction
• Pyrexia

Sensory Disorders

• Cataract
• Eye irritation
• Blurred vision
• Taste disturbance
• Tumour pain
• Carpal tunnel syndrome
• Hot flushes
• Chest pain
• Oedema
• Mucosal dryness
• Peripheral oedema

• CYP450 inhibitors
• Oestrogens
• Other anticancer agents
• Tamoxifen
• Other anti-oestrogen agents
• Oestrogen-containing therapies
• Phenytoin
• Clopidrogel

• Lipid profile
• Hepatic function
• Bone mineral density

Specific cases may require

• Luteinising hormone (LH), follicle-stimulating hormone (FSH) and/or oestradiol levels

Letrozole, a non-steroidal aromatase inhibitor, inhibits the aromatase enzyme by competing for binding to the haem of the cytochrome P450 subunit of the enzyme. This reduces oestrogen biosynthesis in all tissues. The suppression of oestrogen biosynthesis in the cancer tissue itself as well as peripheral tissues can therefore be accomplished by specific inhibition of the aromatase enzyme. This eradication of the oestrogen-mediated stimulatory effects is a prerequisite for tumour response in instances where the growth of tumour tissue depends on the presence of oestrogens.

Tablet 2.5mg

• Accord Letrozole (Accord)
• Cipla Letrozole (Cipla)
• Femzole (Adcock)
• Laradex (Eurolab)
• Letrozole 2.5mg Hetero (Hetero Drugs South Africa)
• Trozolt (Brimpharm)
• Femara (Novartis)