Exemestane

Exemestane is an irreversible steroidal aromatase inhibitor. In postmenopausal women the main source of oestrogens is the conversion of androgens (androstenedione and testosterone) into oestrogens (oestrone and oestradiol) by aromatase in peripheral tissues. Because some breast cancers depend on oestrogen to grow, removing oestrogen by blocking aromatase is an effective and selective treatment for hormone-dependent disease in postmenopausal women.

Mechanism of Action

• Irreversible inactivation: exemestane is structurally related to the natural substrate androstenedione. It binds to the active site of aromatase and inactivates it permanently, so the enzyme has to be newly synthesised to restore function.
• Oestrogen suppression: in postmenopausal women, oral exemestane significantly lowered serum oestrogen concentrations from a 5 mg dose, with maximum suppression (more than 90%) at 10–25 mg. At 25 mg daily, whole-body aromatisation was reduced by 98% in postmenopausal patients with breast cancer.
• Selectivity: exemestane has no progestogenic or oestrogenic activity. A slight androgenic activity, probably from its 17-hydro derivative, was seen mainly at high doses. It had no detectable effect on adrenal biosynthesis of cortisol or aldosterone, before or after ACTH stimulation, so glucocorticoid or mineralocorticoid replacement is not needed.

Pharmacokinetics

• Absorption: exemestane is absorbed rapidly and a high fraction of the dose is absorbed from the gastrointestinal tract. Absolute bioavailability in humans is not known but is expected to be limited by a large first-pass effect. After a single 25 mg dose, a peak plasma level of 18 ng/mL is reached at 2 hours. Food increases bioavailability by 40%.
• Distribution: volume of distribution about 20,000 L (not corrected for bioavailability). Kinetics are linear, with a terminal half-life of 24 hours. About 90% is bound to plasma proteins, independent of concentration; exemestane and its metabolites do not bind to red blood cells. It does not accumulate unexpectedly with repeated doses.
• Metabolism: oxidation of the methylene group at position 6 by CYP3A4 and/or reduction of the 17-keto group by aldoketoreductase, followed by conjugation. The metabolites are inactive or inhibit aromatase less than the parent compound.
• Elimination: clearance is about 500 L/h (not corrected for bioavailability). Only 1% of the dose is excreted unchanged in urine, and in one week equal amounts (about 40%) of radiolabelled exemestane were eliminated in urine and faeces.
• Special populations: exposure shows no significant correlation with age. In severe renal impairment, systemic exposure was twice that of healthy volunteers, and in moderate or severe hepatic impairment it was 2–3 times higher; given the safety profile, no dose adjustment is considered necessary.

• Early breast cancer (adjuvant): adjuvant treatment of postmenopausal women with oestrogen receptor-positive invasive early breast cancer, after 2 to 3 years of initial adjuvant tamoxifen treatment.
• Advanced breast cancer: treatment of advanced breast cancer in women with natural or induced postmenopausal status whose disease has progressed after anti-oestrogen therapy. Efficacy has not been demonstrated in patients with oestrogen receptor-negative status.

• Hypersensitivity to exemestane or to any of the excipients.
• Premenopausal women.
• Pregnancy and breastfeeding.

At the usual 25 mg daily dose exemestane was generally well tolerated in clinical studies, and side effects were usually mild to moderate. Most reflect oestrogen deprivation (for example hot flushes). Treatment was stopped because of adverse reactions in 7.4% of women receiving adjuvant exemestane after initial tamoxifen for early breast cancer, and in 2.8% of all patients with advanced breast cancer. The most frequent reactions in early disease were hot flushes (22%), arthralgia (18%) and fatigue (16%); in advanced disease, hot flushes (14%) and nausea (12%).

Very common (≥1/10): leukopenia; depression, insomnia; headache, dizziness; hot flushes; abdominal pain, nausea; hyperhidrosis; joint and musculoskeletal pain (mainly arthralgia, less often pain in the limbs, osteoarthritis, back pain, arthritis, myalgia and joint stiffness); pain, fatigue; raised liver enzymes, blood bilirubin and blood alkaline phosphatase.

Common (≥1/100 to <1/10): thrombocytopenia; anorexia; carpal tunnel syndrome, paraesthesia; vomiting, diarrhoea, constipation, dyspepsia; alopecia, rash, urticaria, pruritus; fractures, osteoporosis; peripheral oedema, asthenia.

Uncommon (≥1/1,000 to <1/100): hypersensitivity.

Rare (≥1/10,000 to <1/1,000): somnolence; hepatitis, cholestatic hepatitis; acute generalised exanthematous pustulosis (the frequencies of hepatitis and pustulosis are estimated).

Not known: decreased lymphocyte count.

In advanced breast cancer, thrombocytopenia and leukopenia were reported rarely. An occasional fall in lymphocytes was seen in about 20% of patients, especially those with pre-existing lymphopenia, without a significant change in mean lymphocyte values over time or a rise in viral infections; this was not seen in the early breast cancer studies.

In the early breast cancer Intergroup Exemestane Study (exemestane 2,249 women, tamoxifen 2,279), osteoporosis was reported in 5.2% versus 2.9%, myocardial infarction in 0.6% versus 0.2% and thromboembolism in 0.7% versus 1.8%. Hypercholesterolaemia was more frequent with exemestane (3.7% versus 2.1%), as was gastric ulcer (0.7% versus less than 0.1%), mostly in patients taking NSAIDs or with a previous history. Ischaemic cardiac events (4.5% versus 4.2%) and hypertension (9.9% versus 8.4%) did not differ significantly. In a separate placebo-controlled study over 24 months, exemestane lowered HDL cholesterol by 7–9% (placebo: a 1% rise); the clinical significance is unclear.

• CYP3A4 inducers: rifampicin 600 mg daily, a potent CYP3A4 inducer, lowered the AUC of a single 25 mg exemestane dose by 54% and its Cmax by 41%. The clinical relevance has not been assessed, but rifampicin, anticonvulsants such as phenytoin and carbamazepine, and herbal products containing St John’s wort (Hypericum perforatum) may reduce the efficacy of exemestane.
• CYP3A4 inhibitors: specific CYP3A4 inhibition with ketoconazole had no significant effect on exemestane pharmacokinetics. In vitro, exemestane is metabolised by CYP3A4 and aldoketoreductases and does not inhibit any of the major CYP isoenzymes.
• CYP3A4 substrates with a narrow therapeutic margin: use exemestane with caution.
• Oestrogen-containing medicines: must not be combined with exemestane, as they may cancel its pharmacological action.
• Other anticancer medicines: there is no clinical experience of concomitant use.
• Food: food raises bioavailability by 40%; exemestane is taken preferably after a meal.

Exemestane is taken by mouth as one tablet a day. The tablets are not recommended in children.

Recommended Dose

• Adults and elderly patients: 25 mg once daily, preferably after a meal.
• Early breast cancer: continue until a total of 5 years of sequential adjuvant hormonal treatment (tamoxifen followed by exemestane) is completed, or earlier if the tumour recurs.
• Advanced breast cancer: continue until tumour progression is evident.

Special Populations

• Hepatic or renal impairment: no dose adjustment (see Pharmacokinetics); use with caution.
• Children and adolescents: use is not recommended.

Menopausal Status

Exemestane must not be given to women with a premenopausal endocrine status. Where clinically appropriate, postmenopausal status should be confirmed by measuring LH, FSH and oestradiol levels.

Bone Health and Vitamin D

Exemestane markedly lowers oestrogen, and reduced bone mineral density with a higher fracture rate has been observed. In women with osteoporosis or at risk of it, bone mineralisation should be assessed at the start of adjuvant treatment according to current clinical practice and guidelines; in advanced disease it is assessed case by case. Patients are monitored closely, and treatment or prophylaxis of osteoporosis is started in those at risk, although there are no conclusive data on treating the bone loss caused by exemestane. Because severe vitamin D deficiency is common in women with early breast cancer, periodic measurement of 25-hydroxyvitamin D should be considered before starting an aromatase inhibitor, and women with a deficiency should receive vitamin D supplements.

Hepatic or Renal Impairment

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

Doping Control

The medicine contains exemestane, which can give a positive result in doping control tests.

Excipients

• Sucrose: patients with hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take the tablets.
• Methyl parahydroxybenzoate: may cause allergic reactions, possibly delayed.
• Sodium: each tablet contains less than 1 mmol (23 mg) sodium, so it is essentially sodium-free.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no clinical data in pregnant women, and animal studies showed reproductive toxicity. Exemestane is contraindicated in pregnancy.
• Breastfeeding: it is not known whether exemestane passes into human milk. It should not be given to breastfeeding women.
• Women who are perimenopausal or could become pregnant: the doctor should discuss the need for adequate contraception, including in women in the perimenopause or who have recently become postmenopausal, until postmenopausal status is fully established.

Effect on Driving

Exemestane has a moderate influence on the ability to drive and use machines. Lethargy, somnolence, asthenia and dizziness have been reported, and patients should be warned that their physical and/or mental abilities for driving or operating machinery may be reduced if these occur.

The tablets need no special storage conditions. They are supplied in aluminium-PVDC/PVC-PVDC blisters of 15, 20, 30, 90, 100 or 120 tablets; not all pack sizes may be marketed.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Exemestane tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.