Anastrozole

In patients with severe renal impairment, administration of anastrozole should be performed with caution.

Caution is advised in patients with moderate to severe hepatic impairment.

The effects of anastrozole on fertility in humans have not been studied. Studies in animals have shown reproductive toxicity.

Co-administration of tamoxifen or estrogen-containing therapies with anastrazole should be avoided as this may diminish its pharmacological action.

As anastrozole lowers circulating estrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture.

Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored. The use of specific treatments, e.g. bisphosphonates, may stop further bone mineral loss caused by anastrozole in postmenopausal women and could be considered.

There are no data from the use of anastrozole in pregnant women. Studies in animals have shown reproductive toxicity. Anastrozole is contraindicated during pregnancy.

There are no data on the use of anastrozole during lactation. Anastrozole is contraindicated during breastfeeding.

Fertility

The effects of anastrozole on fertility in humans have not been studied. Studies in animals have shown reproductive toxicity.

Anastrozole has no or negligible influence on the ability to drive and use machines. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

The following list presents adverse reactions from clinical trials, post-marketing studies or spontaneous reports. Unless specified, the frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9,366 postmenopausal women with operable breast cancer given adjuvant treatment for five years (the Anastrozole, Tamoxifen, Alone or in Combination [ATAC] study).

Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency groupings are defined according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000). The most frequently reported adverse reactions were headache, hot flushes, nausea, rash, arthralgia, joint stiffness, arthritis, and asthenia.

Metabolism and nutrition disorders

Common: Anorexia, Hypercholesterolaemia

Uncommon: Hypercalcaemia (with or without an increase in parathyroid hormone)

Nervous system disorders

Very common: Headache

Common: Somnolence, Carpal Tunnel Syndrome*, Sensory disturbances (including paraesthesia, taste loss and taste perversion)

Vascular disorders

Very common: Hot flushes

Gastrointestinal disorders

Very common: Nausea

__Common:__Diarrhoea, Vomiting

Hepatobiliary disorders

__Common:__Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase

Uncommon: Increases in gamma-GT and bilirubin, Hepatitis

Skin and subcutaneous tissue disorders

Very common: Rash

__Common:__Hair thinning (alopecia)

Allergic reactions

Uncommon: Urticaria

Rare: Erythema multiforme, Anaphylactoid reaction, Cutaneous vasculitis (including some reports of Henoch-Schönlein purpura)**

Very rare: Stevens-Johnson syndrome Angioedema

Musculoskeletal and connective tissue disorders

Very common: Arthralgia/joint stiffness, Arthritis, Osteoporosis

__Common:__Bone pain, Myalgia

Uncommon: Trigger finger

Reproductive system and breast disorders

__Common:__Vaginal dryness, Vaginal bleeding***

General disorders and administration site conditions

Very common: Asthenia

* Events of Carpal Tunnel Syndrome have been reported in patients receiving anastrozole treatment in clinical trials in greater numbers than those receiving treatment with tamoxifen. However, the majority of these events occurred in patients with identifiable risk factors for the development of the condition.
** Since cutaneous vasculitis and Henoch-Schönlein purpura was not observed in ATAC, the frequency category for these events can be considered as ‘Rare’ (≥0.01% and <0.1%) based on the worst value of the point estimate.
*** Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.

The table below presents the frequency of pre-specified adverse events in the ATAC study after a median follow-up of 68 months, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.

ATAC study pre-specified adverse events:

Fracture rates of 22 per 1,000 patient-years and 15 per 1,000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen.

It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.