Aromatase inhibitors.

Exemestane

Active substance: exemestane Each coated tablet contains 25 mg exemestane. Each tablet contains 30.2mg of sucrose and 0.003mg of methyl parahydroxybenzoate (E218).

Coated tablet Round, biconvex, off-white coated tablet marked 7663 on one side.

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

Adult and elderly patients

The recommended dose of Aromasin^® is one 25 mg tablet to be taken once daily, preferably after a meal.

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

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

No dose adjustments are required for patients with hepatic or renal insufficiency.

Not recommended.

Aromasin^® tablets are contraindicated in patients with a known hypersensitivity to the active substance or to any of the excipients, in pre-menopausal women and in pregnant or lactating women.

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-p-hydroxybenzoate which may cause allergic reactions (possibly delayed).

Aromasin^® is a potent oestrogen lowering agent, and a reduction in bone mineral density and an increased fracture rate-has been observed following administration. During adjuvant treatment with Aromasin®, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment. Although adequate data to show the effects of therapy in the treatment of the bone mineral density loss caused by Aromasin^® are not available, treatment for osteoporosis should be initiated in at risk patients. Patients treated with Aromasin^® should be carefully monitored.

In vitro evidence showed that the drug is metabolised through cytochrome P450 (CYP) 3A4 and aldoketoreductases 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 Aromasin^®.

Aromasin^® 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 Aromasin^® with other anticancer drugs.

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

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 are listed below by system organ class and by frequency.

Frequencies are defined as: very common (> 10%), common (> 1%, < 10%), uncommon (> 0.1%, < 1%), rare (> 0.01%, < 0.1%).

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

Blood and lymphatic system disorders

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.

Hepatobiliary disorders

Elevation of liver function test parameters including enzymes, bilirubin and alkaline phosphatase have been observed.

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.

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.

Adverse reactions from post-marketing experience

Hepatobiliary disorders: Hepatitis, cholestatic hepatitis

Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Pharmacia & Upjohn

(POM)

08 June 2009