4.1. Therapeutic indications

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.

• Primary prevention of breast cancer in postmenopausal women at moderate or high risk.

4.2. Posology and method of administration

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.

For the primary prevention of breast cancer in postmenopausal women at moderate or high risk, the treatment duration is 5 years. Anastrozole treatment for the primary prevention of breast cancer should only be initiated by a medical practitioner experienced in prescribing for this indication, and as part of a shared care pathway arrangement, with appropriate patient identification, management and follow up. Before commencing treatment, an assessment of the potential benefits and risks is essential, including calculating a patient's risk of developing breast cancer according to local guidelines and risk assessment tools. Validated algorithms are available that calculate breast cancer risk based on features such as age, family history, genetic factors, reproductive factors and history of breast disease. The use of anastrozole should be as part of a program including regular breast surveillance tailored to the individual woman, taking into account their risk of breast cancer.

Special populations

Paediatric population

Arimidex 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 Arimidex 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

Arimidex should be taken orally.

4.3. Contraindications

Arimidex is contraindicated in:

• Pregnant or breastfeeding 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

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).

In the IBIS-II primary prevention study, due to the limited number of women with a confirmed BRCA1 or 2 mutation, there is uncertainty about the absolute benefit in these patients treated with anastrozole for primary prevention of breast cancer. Higher proportions of women had hypertension (including essential hypertension, hypertension, accelerated hypertension, malignant hypertension and systolic hypertension), hypercholesterolaemia (including hypercholesterolaemia, hyperlipidaemia and blood cholesterol increased) and cardiovascular events when treated with anastrozole rather than with the placebo in the IBIS-II study. Such cardiovascular risks must be considered when starting anastrozole for primary prevention in healthy individuals as well as a potential cause of new onset/deterioration of these conditions in those already receiving treatment with anastrozole.

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 osteopenia, or at risk of osteoporosis or osteopenia, should have their bone mineral density formally assessed at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis or osteopenia should be initiated as appropriate and carefully monitored, as per local guidelines. 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).

Patients with severe osteoporosis, that is, T score <–4.0, or more than two vertebral fractures are not suitable for anastrozole use in primary prevention of breast cancer.

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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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 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).

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Table 1 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

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

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

Not known

Tendon rupture

Reproductive system and breast disorders

Common

Vaginal dryness

Vaginal bleeding ***

General disorders and administration site conditions

Very common

Asthenia

Eye disorders

Not known

Dry eye

*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.

Table 2 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

Arimidex

(N=3,092)

Tamoxifen

(N=3,094)

Hot flushes

1,104 (35.7%)

1,264 (40.9%)

Joint pain/stiffness

1,100 (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 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.

IBIS-II Study

The following table (Table 3) presents adverse event data from the large IBIS-II international randomized, controlled clinical trial investigating the efficacy and safety of chemoprevention with daily anastrozole over 5 years in postmenopausal women (see section 5.1). Over 5 years there was no significant difference in the overall rate of adverse events (AEs) for anastrozole versus placebo (89% in both groups). A summary of AEs is included in Table 3, and this includes all predefined AEs, AEs affecting at least 5% of participants, or those that differed significantly (p<0.02) between groups.

Table 3 Adverse events recorded in IBIS-II study during period of medication usage

Adverse Event

Anastrozole (n=1920)

Placebo (n=1944)

Any

1709 (89%)

1723 (89%)

Fractures

164 (9%)

149 (8%)

Arm

66 (3%)

61 (3%)

Leg

65 (3%)

57 (3%)

Rib, spine, or collarbone

23 (1%)

18 (1%)

Pelvic or hip

9 (<1%)

10 (1%)

Skull

1 (<1%)

1 (<1%)

Musculoskeletal

1226 (64%)

1124 (58%)

Arthralgia*

972 (51%)

894 (46%)

Mild

385 (20%)

386 (20%)

Moderate

422 (22%)

363 (19%)

Severe

151 (8%)

123 (6%)

Joint stiffness

143 (7%)

96 (5%)

Pain in hand or foot

178 (9%)

147 (8%)

Carpal tunnel syndrome or nerve compression

67 (3%)

43 (2%)

Vasomotor*†

1090 (57%)

961 (49%)

Mild

550 (29%)

504 (26%)

Moderate

390 (20%)

330 (17%)

Severe

150 (8%)

127 (7%)

Gynaecological

460 (24%)

423 (22%)

Vaginal dryness

357 (19%)

304 (16%)

Haemorrhage or bleeding

65 (3%)

81 (4%)

Vaginal or uterine prolapse

13 (1%)

31 (2%)

Vulvovaginal pruritus

40 (2%)

60 (3%)

Vascular

152 (8%)

127 (7%)

Hypertension

89 (5%)

55 (3%)

Myocardial infarction or cardiac failure

8 (<1%)

9 (<1%)

Thrombosis or embolism

19 (1%)

17 (1%)

Phlebitis

9 (<1%)

8 (<1%)

Cerebrovascular accident

3 (<1%)

6 (<1%)

Eye

348 (18%)

335 (17%)

Dry eyes

83 (4%)

58 (2%)

Conjunctivitis

12 (1%)

5 (<1%)

Glaucoma

12 (1%)

24 (1%)

Cataract

90 (5%)

95 (5%)

Infections

230 (12%)

217 (11%)

Influenza

25 (1%)

12 (1%)

Otitis media

18 (1%)

6 (<1%)

Data presented as n (%). *Assessments of severity broadly based on Common Terminology Criteria for Adverse Events, but some discretion by clinicians was allowed. †Vasomotor symptoms defined as hot flushes or night sweats.

During the long-term follow-up period (up to 12 years), only major AEs (defined as other cancers, cardiovascular events, fractures, and deaths) were routinely collected. Overall, there was no significant difference between anastrozole and placebo for any of the major adverse events. Less serious AEs, such as development of hypertension, were not routinely collected in the long-term follow-up.

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 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 Arimidex, 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 Arimidex 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 Arimidex is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.