ARIMIDEX Film-coated tablets Ref.[6190] Active ingredients: Anastrozole

General

Arimidex should not be used in premenopausal women. The menopause should be defined biochemically (luteinizing-hormone [LH], follicle stimulating hormone [FSH], and/or estradiol levels) in any patient where there is doubt about menopausal status. There are no data to support the use of Arimidex with LHRH analogues.

Co-administration of tamoxifen or estrogen-containing therapies with Arimidex should be avoided as this may diminish its pharmacological action (see section 4.5 and 5.1).

Effect on bone mineral density

As Arimidex lowers circulating estrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture (see section 4.8).

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 Arimidex in postmenopausal women and could be considered (see section 4.8).

Hepatic impairment

Arimidex has not been investigated in breast cancer patients with moderate or severe hepatic impairment. Exposure to anastrozole can be increased in subjects with hepatic impairment (see section 5.2); administration of Arimidex in patients with moderate and severe hepatic impairment should be performed with caution (see section 4.2). Treatment should be based on a benefit-risk evaluation for the individual patient.

Renal impairment

Arimidex has not been investigated in breast cancer patients with severe renal impairment. Exposure to anastrozole is not increased in subjects with severe renal impairment (GRF<30ml/min, see section 5.2); in patients with severe renal impairment, administration of Arimidex should be performed with caution (see section 4.2).

Paediatric population

Arimidex is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see section 5.1).

Arimidex should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. In the pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole reduces estradiol levels, Arimidex must not be used in girls with growth hormone deficiency in addition to growth hormone treatment. Long-term safety data in children and adolescents are not available.

Hypersensitivity to lactose

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Anastrozole inhibits CYPs 1A2, 2C8/9 and 3A4 in vitro. Clinical studies with antipyrine and warfarin showed that anastrozole at a 1 mg dose did not significantly inhibit the metabolism of antipyrine and R– and S-warfarin indicating the co-administration of Arimidex with other medicinal products is unlikely to result in clinically significant medicinal product interactions mediated by CYP enzymes.

The enzymes mediating metabolism of anastrozole have not been identified. Cimetidine, a weak, unspecific inhibitor of CYP enzymes, did not affect the plasma concentrations of anastrozole. The effect of potent CYP inhibitors is unknown.

A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with Arimidex who also received other commonly prescribed medicinal products. There were no clinically significant interactions with bisphosphonates (see section 5.1).

Co-administration of tamoxifen or estrogen-containing therapies with Arimidex should be avoided as this may diminish its pharmacological action (see section 4.4 and 5.1).

Pregnancy

There are no data from the use of Arimidex in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Arimidex is contraindicated during pregnancy (see section 4.3).

Breastfeeding

There are no data on the use of Arimidex during lactation. Arimidex is contraindicated during breastfeeding (see section 4.3).

Fertility

The effects of Arimidex on fertility in humans have not been studied. Studies in animals have shown reproductive toxicity (see section 5.3).

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

The following table 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 Arimidex, 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.

Table 1. Adverse reactions by System Organ Class and frequency:

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 Arimidex 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 Arimidex. 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.

Table 2. 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 Arimidex and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for Arimidex is similar to the range reported in age-matched postmenopausal populations. The incidence of osteoporosis was 10.5% in patients treated with Arimidex 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 Arimidex treatment reflect a protective effect of tamoxifen, a specific effect of Arimidex, or both.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.

Not applicable.