Anastrozole

Anastrozole is a potent, highly selective, non-steroidal inhibitor of aromatase, the enzyme complex that converts androgens into oestrogens. In postmenopausal women oestradiol is produced mainly in peripheral tissues, so blocking this step lowers circulating oestrogen and removes the hormonal growth stimulus for hormone receptor-positive breast cancer.

Mechanism of Action

• Aromatase inhibition: anastrozole inhibits aromatase competitively and selectively. In postmenopausal women the enzyme converts androstenedione to oestrone in peripheral tissues, and oestrone is then converted to oestradiol; lowering the circulating oestradiol level has been shown to benefit women with breast cancer.
• Degree of suppression: at 1 mg once daily, oestradiol was suppressed by more than 80% in postmenopausal women (highly sensitive assay). The effect starts within the first day, and oestradiol stays suppressed for up to about 6 days after treatment stops.
• No other hormonal activity: anastrozole has no progestogenic, androgenic or oestrogenic activity. Daily doses of up to 10 mg do not affect cortisol or aldosterone secretion, before or after a standard ACTH stimulation test, so corticosteroid replacement is not needed.

Pharmacokinetics

• Absorption: rapid; peak plasma concentrations are usually reached within 2 hours of a dose on an empty stomach. Food slightly slows the rate but not the extent of absorption, which is not expected to matter at steady state. About 90–95% of steady-state concentrations are reached after 7 daily doses, with 3- to 4-fold accumulation. The pharmacokinetics do not depend on time or dose.
• Distribution: only about 40% is bound to plasma proteins.
• Metabolism: extensive in postmenopausal women, by N-dealkylation, hydroxylation and glucuronidation. The main plasma metabolite, triazole, does not inhibit aromatase.
• Elimination: slow, with a plasma half-life of 40 to 50 hours. Less than 10% of a dose is excreted unchanged in urine within 72 hours; the metabolites are excreted mainly by the kidneys.
• Special populations: the pharmacokinetics are independent of age in postmenopausal women. In volunteers with stable hepatic cirrhosis, apparent oral clearance was about 30% lower than in matched controls, but plasma concentrations stayed within the range seen in normal subjects. In severe renal impairment (GFR below 30 mL/min), apparent clearance was unchanged.

Anastrozole is authorised for postmenopausal women only.

• Advanced breast cancer: treatment of hormone receptor-positive advanced breast cancer.
• Early breast cancer (adjuvant treatment): adjuvant treatment of hormone receptor-positive early invasive breast cancer.
• Early breast cancer after tamoxifen: adjuvant treatment of hormone receptor-positive early invasive breast cancer in women who have already received adjuvant tamoxifen for 2 to 3 years.

• Pregnancy and breastfeeding.
• Known hypersensitivity to anastrozole or to any of the excipients.

The side effects below come from clinical trials, post-marketing studies and spontaneous reports. Unless stated otherwise, frequencies were calculated from a large phase III study (ATAC) in 9,366 postmenopausal women with operable breast cancer treated for 5 years. The most frequently reported are headache, hot flushes, nausea, rash, joint pain and stiffness, arthritis and asthenia.

Very common (≥1/10): depression, headache, hot flushes, nausea, rash, joint pain or stiffness (arthralgia), arthritis, osteoporosis, asthenia.

Common (≥1/100 to <1/10): anorexia, hypercholesterolaemia, somnolence, carpal tunnel syndrome, sensory disturbances (including paraesthesia, loss of taste and taste disturbance), diarrhoea, vomiting, increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase, hair thinning (alopecia), allergic reactions, bone pain, myalgia, vaginal dryness, vaginal bleeding.

Uncommon (≥1/1,000 to <1/100): hypercalcaemia (with or without a rise in parathyroid hormone), increases in gamma-GT and bilirubin, hepatitis, urticaria, trigger finger.

Rare (≥1/10,000 to <1/1,000): erythema multiforme, anaphylactoid reaction, cutaneous vasculitis (including some reports of Henoch-Schönlein purpura).

Very rare (<1/10,000): Stevens-Johnson syndrome, angioedema.

Not known: memory impairment, dry eye, lichenoid rash, tendinitis, tendon rupture.

Notes on individual reactions:

• Carpal tunnel syndrome was reported more often with anastrozole than with tamoxifen in clinical trials, although most cases occurred in patients with identifiable risk factors.
• Vaginal bleeding was reported mainly in women with advanced breast cancer during the first weeks after switching from earlier hormonal therapy. If it persists, further evaluation should be considered.
• Cutaneous vasculitis and Henoch-Schönlein purpura were not seen in ATAC, so their ‘rare’ category rests on the worst-case estimate.

Comparison with tamoxifen in ATAC (median follow-up 68 months, events during treatment and up to 14 days after stopping):

• More often with anastrozole: fractures 10.2% versus 6.8% (spine, hip or wrist fractures 4.3% versus 2.9%); joint pain or stiffness 35.6% versus 29.4%; ischaemic cardiovascular events 4.1% versus 3.4% (angina 2.3% versus 1.6%, myocardial infarction 1.2% versus 1.1%); osteoporosis 10.5% versus 7.3%.
• Less often with anastrozole: hot flushes 35.7% versus 40.9%; vaginal bleeding 5.4% versus 10.2%; vaginal discharge 3.5% versus 13.2%; venous thromboembolic events 2.8% versus 4.5%; ischaemic cerebrovascular events 2.0% versus 2.8%; cataracts 5.9% versus 6.9%; endometrial cancer 0.2% versus 0.6%.
• Fracture rate: 22 per 1,000 patient-years with anastrozole and 15 with tamoxifen. The rate with anastrozole is similar to that reported in age-matched postmenopausal populations. It is not known whether the difference reflects a protective effect of tamoxifen, a specific effect of anastrozole, or both.

Reactions that need prompt attention include severe skin reactions (erythema multiforme, Stevens-Johnson syndrome), angioedema and anaphylactoid reactions, hepatitis, tendon rupture, fractures from bone loss, and ischaemic cardiovascular events such as angina and myocardial infarction.

Clinically significant interactions through liver enzymes are considered unlikely, but oestrogen-modifying treatments should be avoided.

• Tamoxifen and oestrogen-containing therapy: avoid giving them with anastrozole, because they may reduce its pharmacological action.
• Medicines metabolised by CYP enzymes: anastrozole inhibits CYP1A2, CYP2C8/9 and CYP3A4 in vitro, but at 1 mg it did not significantly inhibit the metabolism of antipyrine or of R- and S-warfarin, so clinically significant interactions through these enzymes are unlikely.
• CYP inhibitors: the enzymes that metabolise anastrozole have not been identified. Cimetidine, a weak non-specific CYP inhibitor, did not change anastrozole plasma concentrations; the effect of potent CYP inhibitors is unknown.
• Bisphosphonates: no clinically significant interaction. A review of the clinical-trial safety database found no evidence of clinically significant interactions in patients who also took other commonly prescribed medicines.
• Food: anastrozole can be taken with or without food; food slows absorption slightly but not its extent.

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

Recommended Dose

• 1 mg (one tablet) once daily for adults, including elderly patients.
• Early invasive breast cancer: the recommended duration of adjuvant endocrine treatment is 5 years.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment; use with caution in severe impairment.
• Hepatic impairment: no adjustment in mild liver disease; use with caution in moderate to severe impairment.
• Children and adolescents: not recommended, because data on safety and efficacy are lacking.

Use Only After the Menopause

Anastrozole must not be used in premenopausal women. When menopausal status is in doubt, it should be confirmed biochemically (luteinising hormone, follicle-stimulating hormone and/or oestradiol levels). There are no data supporting the use of anastrozole with LHRH analogues.

Bone Health

Because anastrozole lowers circulating oestrogen, it can reduce bone mineral density and may raise the risk of fractures. Women with osteoporosis or at risk of it should have their bone mineral density assessed at the start of treatment and at regular intervals afterwards. Treatment or prophylaxis for osteoporosis should be started as appropriate and monitored carefully. Specific treatments such as bisphosphonates may halt the extra bone loss caused by anastrozole in postmenopausal women.

Hepatic and Renal Impairment

Anastrozole has not been studied in breast cancer patients with moderate or severe hepatic impairment. Exposure may be higher in hepatic impairment, so use it with caution and decide on the individual benefit and risk. It has not been studied in breast cancer patients with severe renal impairment either; exposure is not increased in severe renal impairment (GFR below 30 mL/min), but it should still be given with caution.

Combination With Tamoxifen or Oestrogens

Tamoxifen and oestrogen-containing therapy should not be given together with anastrozole, because they can weaken its pharmacological action.

Children and Growth Hormone

Anastrozole is not recommended in children and adolescents: safety and efficacy have not been established and there are no long-term safety data. It must not be given with growth hormone treatment to boys with growth hormone deficiency (efficacy was not shown and safety was not established in the pivotal trial). Because it lowers oestradiol, it should not be used with growth hormone treatment in girls with growth hormone deficiency.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: contraindicated. There are no data in pregnant women, and animal studies showed reproductive toxicity.
• Breastfeeding: contraindicated. There are no data on use during breastfeeding.
• Fertility: the effects on human fertility have not been studied; animal studies showed reproductive toxicity.

Lactose and Sodium

Each tablet contains 93 mg lactose monohydrate. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. Each tablet contains less than 1 mmol (23 mg) sodium, so it is essentially ‘sodium-free’.

Effect on Driving

Anastrozole has no or a negligible influence on the ability to drive and use machines. Asthenia and somnolence have been reported, so patients should take care while these symptoms last.

Arimidex 1 mg tablets (as in the Spanish SmPC) do not need refrigeration. Do not store above 30 °C, and keep out of the sight and reach of children. The tablets are supplied in PVC/aluminium blister packs.

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

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