4.1. Therapeutic indications

Exemestane is indicated for the adjuvant treatment of postmenopausal women with oestrogen receptor positive invasive early breast cancer (EBC), following 2 – 3 years of initial adjuvant tamoxifen therapy.

Exemestane is indicated for the treatment of advanced breast cancer in women with natural or induced postmenopausal status whose disease has progressed following anti-oestrogen therapy. Efficacy has not been demonstrated in patients with oestrogen receptor negative status.

4.2. Posology and method of administration

Adult and elderly patients

The recommended dose of Exemestane is one film-coated tablet (25mg) to be taken orally once a day, after a meal.

In patients with early breast cancer, treatment with Exemestane should continue until completion of five years of combined sequential adjuvant hormonal therapy (tamoxifen followed by Exemestane), or earlier if tumour relapse occurs.

In patients with advanced breast cancer, treatment with Exemestane should continue until tumour progression is evident.

No dose adjustments are required for patients with hepatic or renal insufficiency (see section 5.2).

Children and adolescents

Not recommended for use in children and adolescents

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In pre-menopausal women and in pregnant or lactating women.

4.4. Special warnings and precautions for use

Exemestane should not be administered to women with pre-menopausal endocrine status. Therefore, whenever clinically appropriate, the post-menopausal status should be ascertained by assessment of LH, FSH and oestradiol levels.

Exemestane should be used with caution in patients with hepatic or renal impairment.

Exemestane is a potent oestrogen lowering agent, and a reduction in bone mineral density (BMD) and an increased fracture rate have been observed following administration (see section 5.1). At the commencement of adjuvant treatment with Exemestane, women with osteoporosis or at risk of osteoporosis should have treatment baseline bone mineral health assessment based on current clinical guidelines and practice. Patients with advanced disease should have their bone mineral density assessed on a case-by-case basis. Although adequate data to show the effects of therapy in the treatment of the bone mineral density loss caused by Exemestane are not available, patients treated with Exemestane should be carefully monitored and treatment for, or prophylaxis of, osteoporosis should be initiated in at risk patients.

Routine assessment of 25 hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be considered, due to the high prevalence of severe deficiency in women with early breast cancer. Women with Vitamin D deficiency should receive supplementation with Vitamin D.

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

In vitro evidence showed that the drug is metabolised through cytochrome P450 (CYP) 3A4 and aldoketoreductases (see 5.2) and does not inhibit any of the major CYP isoenzymes. In a clinical pharmacokinetic study, the specific inhibition of CYP 3A4 by ketoconazole showed no significant effects on the pharmacokinetics of exemestane.

In an interaction study with rifampicin, a potent CYP450 inducer, at a dose of 600mg daily and a single dose of exemestane 25mg, the AUC of exemestane was reduced by 54% and Cmax by 41%. Since the clinical relevance of this interaction has not been evaluated, the co-administration of drugs, such as rifampicin, anticonvulsants (e.g. phenytoin and carbamazepine) and herbal preparations containing hypericum perforatum (St John's Wort) known to induce CYP3A4 may reduce the efficacy of Exemestane.

Exemestane should be used cautiously with drugs that are metabolised via CYP3A4 and have a narrow therapeutic window. There is no clinical experience of the concomitant use of Exemestane with other anticancer drugs.

Exemestane should not be co administered with oestrogen-containing medicines as these would negate its pharmacological action.

4.6. Fertility, pregnancy and lactation

Pregnancy

No clinical data on exposed pregnancies are available with Exemestane. Studies on animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Exemestane is therefore contraindicated in pregnant women.

Breast-feeding

It unknown whether exemestane is excreted in human milk. Exemestane should not be administered to lactating woman.

Women of perimenopausal status or child-bearing potential

The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who have recently become postmenopausal, until their postmenopausal status is fully established (see sections 4.3 and 4.4).

4.7. Effects on ability to drive and use machines

Exemestane has moderate influence on the ability to drive and use machines.

Drowsiness, somnolence, asthenia and dizziness have been reported with the use of the drug. Patients should be advised that, if these events occur, their physical and/or mental abilities required for operating machinery or driving a car may be impaired.

4.8. Undesirable effects

Exemestane was generally well tolerated across all clinical studies conducted with Exemestane at a standard dose of 25 mg/day, and undesirable effects were usually mild to moderate.

The withdrawal rate due to adverse events was 7.4% in patients with early breast cancer receiving adjuvant treatment with Exemestane following initial adjuvant tamoxifen therapy. The most commonly reported adverse reactions were hot flushes (22%), arthralgia (18%) and fatigue (16%).

The withdrawal rate due to adverse events was 2.8% in the overall patient population with advanced breast cancer. The most commonly reported adverse reactions were hot flushes (14%) and nausea (12%).

Most adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes).

The reported adverse reactions from clinical studies and post-marketing experience are listed below by system organ class and by frequency.

Frequencies are defined as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1000 to ≤ 1/100); Rare (≥1/10,000 to <1/1000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Very common

Common

Not known

Leucopenia(**)

Thrombocytopenia(**)

Lymphocyte count decreased(**)

Immune system disorders:

Uncommon

Hypersensitivity

Metabolism and nutrition disorders:

Common

Anorexia

Psychiatric disorders:

Very common

Depression, insomnia

Nervous system disorders:

Very common

Common

Rare

Headache, dizziness

Carpal tunnel syndrome, paraesthesia

Somnolence

Vascular disorders:

Very common

Hot flushes

Gastrointestinal disorders:

Very common

Common

Abdominal pain, nausea

Vomiting, diarrhoea, constipation, dyspepsia

Hepatobiliary disorders:

Very common

Rare

Hepatic enzyme increased, blood bilirubin increased, blood alkaline phosphatase increased

Hepatitis (†), cholestatic hepatitis (†)

Skin and subcutaneous tissue disorders:

Very common

Common

Rare

Increased sweating

Alopecia, rash, urticaria, pruritus

Acute generalised exanthematous pustulosis (†)

Musculoskeletal and bone disorders:

Very common

Common

Joint and musculoskeletal pain (*)

Fracture, osteoporosis

General disorders and administration site conditions:

Very common

Common

Pain, fatigue

Oedema peripheral, asthenia

(*) Includes: arthralgia, and less frequently pain in extremity, osteoarthritis, back pain, arthritis, myalgia and joint stiffness.

(**) In patients with advanced breast cancer thrombocytopenia and leucopenia have been rarely reported. An occasional decrease in lymphocytes has been observed in approximately 20% of patients receiving Exemestane, particularly in patients with pre-existing lymphopenia; however, mean lymphocyte values in these patients did not change significantly over time and no corresponding increase in viral infections was observed. These effects have not been observed in patients treated in early breast cancer studies.

(†) Frequency calculated by rule of 3/X.

The table below presents the frequency of pre-specified adverse events and illnesses in the early breast cancer study (IES), irrespective of causality, reported in patients receiving trial therapy and up to 30 days after cessation of trial therapy.

Adverse events and illnesses

Exemestane

(N = 2249)

Tamoxifen

(N = 2279)

Hot flushes

491 (21.8%)

457 (20.1%)

Fatigue

367 (16.3%)

344 (15.1%)

Headache

305 (13.6%)

255 (11.2%)

Insomnia

290 (12.9%)

204 (9.0%)

Sweating increased

270 (12.0%)

242 (10.6%)

Gynaecological

235 (10.5%)

340 (14.9%)

Dizziness

224 (10.0%)

200 (8.8%)

Nausea

200 (8.9%)

208 (9.1%)

Osteoporosis

116 (5.2%)

66 (2.9%)

Vaginal haemorrhage

90 (4.0%)

121 (5.3%)

Other primary cancer

84 (3.6%)

125 (5.3%)

Vomiting

50 (2.2%)

54 (2.4%)

Visual disturbance

45 (2.0%)

53 (2.3%)

Thromboembolism

16 (0.7%)

42 (1.8%)

Osteoporotic fracture

14 (0.6%)

12 (0.5%)

Myocardial infarction

13 (0.6%)

4 (0.2%)

In the IES study, the frequency of ischemic cardiac events in the exemestane and tamoxifen treatment arms was 4.5% versus 4.2%, respectively. No significant difference was noted for any individual cardiovascular event including hypertension (9.9% versus 8.4%), myocardial infarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%).

In the IES study, exemestane was associated with a greater incidence of hypercholesterolemia compared with tamoxifen (3.7% vs. 2.1%).

In a separate double blinded, randomized study of postmenopausal women with early breast cancer at low risk treated with exemestane (N=73) or placebo (N=73) for 24 months , exemestane was associated with an average 7-9% mean reduction in plasma HDL-cholesterol, versus a 1% increase on placebo. There was also a 5-6% reduction in apolipoprotein A1 in the exemestane group versus 0-2% for placebo. The effect on the other lipid parameters analysed (total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-B and lipoprotein-a) was very similar in the two treatment groups . The clinical significance of these results is unclear.

In the IES study, gastric ulcer was observed at a higher frequency in the exemestane arm compared to tamoxifen (0.7% versus <0.1%). The majority of patients on exemestane with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.

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

Clinical trials have been conducted with Exemestane given up to 800 mg in a single dose to healthy female volunteers and up to 600 mg daily to postmenopausal women with advanced breast cancer; these dosages were well tolerated. The single dose of Exemestane that could result in life-threatening symptoms is not known. In rats and dogs, lethality was observed after single oral doses equivalent respectively to 2000 and 4000 times the recommended human dose on a mg/m2 basis. There is no specific antidote to overdosing and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.