AROMASIN Coated tablets Ref.[8195] Active ingredients: Exemestane

Aromasin 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.

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

Aromasin tablets contain sucrose and should not be administered to patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

Aromasin tablets contain methyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Aromasin 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 Aromasin, 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 Aromasin are not available, patients treated with Aromasin 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.

In vitro evidence showed that the drug is metabolised through cytochrome P450 CYP3A4 and aldoketoreductases (see section 5.2) and does not inhibit any of the major CYP isoenzymes. In a clinical pharmacokinetic study, the specific inhibition of CYP3A4 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 600 mg daily and a single dose of exemestane 25 mg, the AUC of exemestane was reduced by 54% and C_max by 41%. Since the clinical relevance of this interaction has not been evaluated, the co-administration of medicinal products, 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 Aromasin.

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

Aromasin should not be coadministered with oestrogen-containing medicines as these would negate its pharmacological action.

Pregnancy

No clinical data on exposed pregnancies are available with Aromasin. Studies on animals have shown reproductive toxicity (see section 5.3). Aromasin is therefore contraindicated in pregnant women.

Breast-feeding

It unknown whether exemestane is excreted in human milk. Aromasin 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).

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

Drowsiness, somnolence, asthenia and dizziness have been reported with the use of exemestane. 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.

Aromasin was generally well tolerated across all clinical studies conducted with Aromasin 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 Aromasin 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 (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Very common: Leucopenia**

Common: Thrombocytopenia**

Not known: 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: Headache, dizziness

Common: Carpal tunnel syndrome, paraesthesia

Rare: Somnolence

Vascular disorders

Very common: Hot flushes

Gastrointestinal disorders

Very common: Abdominal pain, nausea

Common: Vomiting, diarrhoea, constipation, dyspepsia

Hepatobiliary disorders

Very common: Hepatic enzyme increased, blood bilirubin increased, blood alkaline phosphatase increased

Rare: Hepatitis†, cholestatic hepatitis†

Skin and subcutaneous tissue disorders

Very common: Increased sweating

Common: Alopecia, rash, urticaria, pruritus

Rare: Acute generalised exanthematous pustulosis†

Musculoskeletal and bone disorders

Very common: Joint and musculoskeletal pain*

Common: Fracture, osteoporosis

General disorders and administration site conditions

Very common: Pain, fatigue

Common: 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 Aromasin, 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 Intergroup Exemestane Study (IES), irrespective of causality, reported in patients receiving trial therapy and up to 30 days after cessation of trial therapy.

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% versus. 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.

Not applicable.