Aromasin
Each tablet for oral administration contains 25 mg of exemestane, which is an irreversible, steroidal aromatase inactivator. Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structural formula is as follows: H H O CH2 CH3H O CH3
The active ingredient is a white to slightly yellow crystalline powder with a molecular weight of 296.41. Exemestane is freely soluble in N,N-dimethylformamide, soluble in methanol and practically insoluble in water.
For the full list of excipients, see Section 6.1.
Sugar-coated tablet.
Round, biconvex, off-white to slightly greyish sugar-coated tablets, about 6 mm diameter printed with numbers 7663 on one side in black ink.
Exemestane is indicated for the treatment of advanced breast cancer in women with natural or induced post-menopausal status whose disease has progressed following anti-oestrogen therapy. Patient selection should be based on positive oestrogen and/or progesterone receptor status, because efficacy has not been demonstrated when it is absent.
Exemestane is indicated for the adjuvant treatment of post-menopausal women with estrogen-receptor positive early breast cancer, following 2-3 years of initial adjuvant tamoxifen therapy.
The recommended dose of exemestane is one 25 mg tablet to be taken once daily, preferably after a meal.
In patients with advanced breast cancer, treatment with exemestane should continue until tumor progression is evident.
In patients with early breast cancer, treatment with exemestane should continue until completion of five years of adjuvant endocrine therapy, or until local or distant recurrence or new contralateral breast cancer.
No dose adjustments are required for patients with hepatic or renal insufficiency.
Not recommended for use in children.
Exemestane is contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients, in pre-menopausal women and in pregnant or lactating women.
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.
As exemestane is a potent estrogen lowering agent, reductions in bone mineral density can be anticipated. During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment. Patients treated with exemestane should be carefully monitored and treatment for osteoporosis should be initiated as appropriate.
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 associated in women with early breast cancer (EBC). Women with Vitamin D deficiency should receive supplementation with Vitamin D.
In vitro evidence showed that the drug is metabolised through cytochrome P450 (CYP)3A4 and aldo-keto reductases 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.
Although administration of rifampicin, a potent CYP3A4 inducer, significantly decreased exemestane systemic exposure (C max and AUC), the suppression of plasma estrogen levels (estrone sulfate) produced by exemestane was not influenced. Therefore, exemestane can be given concomitantly with inducers of CYP3A4 without dosage adjustment.
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.
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 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.
No clinical data on exposed pregnancies are available with exemestane. Studies on animals have shown reproductive toxicity. Exemestane is therefore contraindicated in pregnant women.
It is not known whether exemestane is excreted into human milk. Exemestane should not be administered to women who are lactating.
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.
Clinical Trials:
Exemestane was generally well tolerated across all studies and in the clinical studies, conducted with exemestane 25 mg/day, adverse events were usually mild to moderate.
The discontinuation rate due to adverse events in studies was 7.4% in patients with early breast cancer receiving adjuvant treatment with exemestane following initial adjuvant tamoxifen therapy. The most commonly reported adverse reaction were hot flush (22%), arthralgia (18%), and fatigue (16%).
The discontinuation 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 flush (14%) and nausea (12%).
Most adverse reactions can be attributed to the normal pharmacological consequences of estrogen deprivation (e.g., hot flush).
Drug-related adverse events that occurred during clinical trials are listed below. Data from post-marketing surveillance are also included. The reported adverse reactions are listed below within each MedDRA System Organ Class (SOC) by decreasing order of medical seriousness.
* Adverse Drug Reaction (ADR) identified post-marketing.
§ ADR frequency represented by the estimated upper limit of the 95% confidence interval calculated using the “Rule of 3”.
a Includes: arthralgia, and less frequently pain in limb, osteoarthritis, back pain, arthritis, myalgia and joint stiffness.
In patients with advanced breast cancer, 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. Thrombocytopenia and leucopenia have been occasionally reported.
In the early breast cancer trial, the frequency of ischemic cardiac events in the exemestane and tamoxifen treatment arms was 4.5% vs. 4.2%, respectively. No significant difference was noted for any individual cardiovascular event including hypertension (9.9% vs. 8.4%), myocardial infarction (0.6% vs. 0.2%) and cardiac failure (1.1% vs. 0.7%).
In the early breast cancer trial, gastric ulcer was observed at a slightly higher frequency in the exemestane arm compared to tamoxifen (0.7% vs. <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:
Pusat Farmakovigilans/MESO Nasional Direktorat Pengawasan Keamanan, Mutu, dan Ekspor Impor Obat, Narkotika, Psikotropika, Prekursor dan Zat Adiktif Badan Pengawas Obat dan Makanan Jl. Percetakan Negara No. 23, Jakarta Pusat, 10560 Email: admin@frankenthalerfoundation.org Phone: +62-21-4244691 Ext.1079 Website: https://e-meso .pom.go.id/ADR
PT Pfizer Indonesia Email: admin@frankenthalerfoundation.org Website: www.pfizersafetyreporting.com
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 post-menopausal 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 overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
Pharmacotherapeutic group: steroidal aromatase inhibitor; anti-neoplastic agent.
Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione. In post-menopausal women, oestrogens are produced primarily from the conversion of androgens into oestrogens through the aromatase enzyme in peripheral tissues. Oestrogen deprivation through aromatase inhibition is an effective and selective treatment for hormone dependent breast cancer in post-menopausal women. In post-menopausal women, orally administered exemestane significantly lowered serum oestrogen concentrations starting from a 5 mg dose, reaching maximal suppression (>90%) with a dose of 10-25 mg. In post-menopausal breast cancer patients treated with the 25 mg daily dose, whole body aromatization was reduced by 98%.
In the randomised peer reviewed controlled clinical trial, Aromasin at the daily dose of 25 mg has demonstrated statistically significant prolongation of survival, Time to Progression (TTP), Time to Treatment Failure (TTF) as compared to a standard hormonal treatment with megestrol acetate in post-menopausal patients with advanced breast cancer that had progressed following or during treatment with tamoxifen either as adjuvant therapy or as first-line treatment for advanced disease.
Exemestane does not possess any progestogenic or oestrogenic activity. A slight androgenic activity, probably due to the 17-hydro derivative, has been observed mainly at high doses. In multiple daily doses trials, Exemestane had no detectable effects on adrenal biosynthesis of cortisol or aldosterone, measured before or after ACTH challenge, thus demonstrating its selectivity with regard to the other enzymes involved in the steroidogenic pathway. These findings indicate that glucocorticoid or mineralocorticoid replacements are not warranted.
A slight non-dose-dependent increase in serum LH and FSH levels has been ob
