4.1. Therapeutic indications

Anastrozole 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 adjuvant tamoxifen.

4.2. Posology and method of administration

Posology

The recommended dose of anastrozole 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

Paediatric population

Anastrozole is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see sections 4.4 and 5.1).

Renal impairment

No dose change is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, administration of Anastrozole should be performed with caution (see section 4.4 and 5.2).

Hepatic impairment

No dose change is recommended in patients with mild hepatic disease. Caution is advised in patients with moderate to severe hepatic impairment (see section 4.4).

Method of administration

Anastrozole should be taken orally.

4.3. Contraindications

Anastrozole is contraindicated in:

- pregnant or breast-feeding women

- patients with known hypersensitivity to anastrozole or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

General

Anastrozole 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 Anastrozole with LHRH analogues.

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

Effect on bone mineral density

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

Hepatic impairment

Anastrozole 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 anastrozole 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

Anastrozole 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 Anastrozole should be performed with caution (see section 4.2).

Paediatric population

Anastrozole 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).

Anastrozole 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, Anastrozole 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

Anastrozole contains 68.75mg lactose. Patients with rare hereditary problems as galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

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 Anastrozole 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 Anastrozole 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 Anastrozole should be avoided as this may diminish its pharmacological action (see section 4.4 and 5.1).

4.6. Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

There are no data on the use of Anastrozole during lactation. Anastrozole is contraindicated during breast-feeding (see section 4.3).

Fertility

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

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 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.

Table 1 Adverse reactions by System Organ Class and frequency

Adverse reactions by SOC and frequency

Metabolism and nutrition disorders

Common

Anorexia

Hypercholesterolaemia

Uncommon

Hypercalcaemia (with or without an increase in parathyroid hormone)

Psychiatric disorders

Very common

Depression

Nervous system disorders

Very common

Headache

Common

Somnolence

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

Not known

Memory impairment

Eye disorders

Not known

Dry eye

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

Not known

Lichenoid eruption

Musculoskeletal and connective tissue disorders

Very common

Arthralgia/joint stiffness

Arthritis

Osteoporosis

Common

Bone pain

Myalgia

Uncommon

Trigger finger

Not known

Tendonitis

Tendon rupture

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.

Table 2 ATAC study pre-specified adverse events

Adverse events

Anastrozole (N=3092)

Tamoxifen (N=3094)

Hot flushes

1104 (35.7%)

1264 (40.9%)

Joint pain/stiffness

1100 (35.6%)

911 (29.4%)

Mood disturbances

597 (19.3%)

554 (17.9%)

Fatigue/asthenia

575 (18.6%)

544 (17.6%)

Nausea and vomiting

393 (12.7%)

384 (12.4%)

Fractures

315 (10.2%)

209 (6.8%)

Fractures of the spine, hip, or wrist/Colles

133 (4.3%)

91 (2.9%)

Wrist/Colles fractures

67 (2.2%)

50 (1.6%)

Spine fractures

43 (1.4%)

22 (0.7%)

Hip fractures

28 (0.9%)

26 (0.8%)

Cataracts

182 (5.9%)

213 (6.9%)

Vaginal bleeding

167 (5.4%)

317 (10.2%)

Ischaemic cardiovascular disease

127 (4.1%)

104 (3.4%)

Angina pectoris

71 (2.3%)

51 (1.6%)

Myocardial infarct

37 (1.2%)

34 (1.1%)

Coronary artery disorder

25 (0.8%)

23 (0.7%)

Myocardial ischaemia

22 (0.7%)

14 (0.5%)

Vaginal discharge

109 (3.5%)

408 (13.2%)

Any venous thromboembolic event

87 (2.8%)

140 (4.5%)

Deep venous thromboembolic events including PE (pulmonary embolism)

48 (1.6%)

74 (2.4%)

Ischaemic cerebrovascular events

62 (2.0%)

88 (2.8%)

Endometrial cancer

4 (0.2%)

13 (0.6%)

Fracture rates of 22 per 1000 patient-years and 15 per 1000 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.

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is limited clinical experience of accidental overdose. In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of Anastrozole, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of Anastrozole that results in life-threatening symptoms has not been established. There is no specific antidote to overdose and treatment must be symptomatic.

In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.