Enzyme inhibitors - ATC code: L02B G03

Anastrozole

Each film-coated tablet contains 1 mg anastrozole. Excipients Each film-coated tablet contains 93 mg of lactose monohydrate.

Film-coated tablet. White, round, biconvex tablet with logo on one side and strength on the other.

Arimidex is indicated for the:

• Treatment of hormone receptor-positive advanced breast cancer in postmenopausal women.

• Adjuvant treatment of hormone receptor-positive early invasive breast cancer in postmenopausal women.

• Adjuvant treatment of hormone receptor-positive early invasive breast cancer in postmenopausal women who have received 2 to 3 years of adjuvant tamoxifen.

Posology

The recommended dose of Arimidex for adults including the elderly is one 1 mg tablet once a day.

For postmenopausal women with hormone receptor-positive early invasive breast cancer, the recommended duration of adjuvant endocrine treatment is 5 years.

Special populations

Renal impairment

No dose change is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, administration of Arimidex should be performed with caution.

Hepatic impairment

No dose change is recommended in patients with mild hepatic disease. Caution is advised in patients with moderate to severe hepatic impairment.

Method of administration

Arimidex should be taken orally.

Arimidex is not recommended for use in children and adolescents due to insufficient data on safety and efficacy.

Arimidex is contraindicated in:

• Pregnant or breast-feeding women.

• Patients with known hypersensitivity to anastrozole or to any of the excipients

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.

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.

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.

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; administration of Arimidex in patients with moderate and severe hepatic impairment should be performed with caution. 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; in patients with severe renal impairment, administration of Arimidex should be performed with caution.

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.

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. 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.

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

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

*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.

AstraZeneca UK Limited

(POM)

12 April 2012