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 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 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. 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 her risk of breast cancer. 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. <summary id="CONTRAINDICATIONS" data-evt="smpcSectionOpen"

4.3. Contraindications

Anastrozole is contraindicated in: • Pregnant or breastfeeding women. • Patients with known hypersensitivity to anastrozole or to any of the excipients listed in section 6.1. <summary id="CLINICAL_PRECAUTIONS" data-evt="smpcSectionOpen"

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). 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 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 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 anastrozole 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. 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 lactose Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Anastrozole contains Sodium Anastrozole contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially 'sodium-free.' <summary id="INTERACTIONS" data-evt="smpcSectionOpen"

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). <summary id="PREGNANCY" data-evt="smpcSectionOpen"

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).

Breastfeeding

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

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 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) Nervous system disorders Very common Headache Common Somnolence Carpal Tunnel Syndrome* Sensory disturbances (including paraesthesia, taste loss and taste perversion) Not known Memory impairment Psychiatric disorders Very common Depression 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 Eye disorders Not known Dry eye 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' (≥1/10,000 to 1/1,000) 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. 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 Anastrozole (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 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. IBIS-II Study The following tables present 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 AEs for anastrozole versus placebo (89% in both groups). A summary of adverse events is included 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. <summary id="OVERDOSE" data-evt="smpcSectionOpen"

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.