Examest

Exemestane.

EXAMEST Film coated tablet, each film coated tablet contains: Exemestane 25 mg.
Excipients/Inactive Ingredients: Polysorbate 80; mannitol; hypromellose 5cP; crospovidone; microcrystalline cellulose; sodium starch glycolate; colloidal anhydrous silica; magnesium stearate, purified water.

Pharmacotherapeutic group: Steroidal aromatase inhibitor; anti-neoplastic agent.
Pharmacology: Pharmacodynamics: 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 postmenopausal women. In postmenopausal 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 postmenopausal breast cancer patients treated with the 25 mg daily dose, whole body aromatization was reduced by 98%.
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 mineralcorticoid replacements are not warranted.
A slight non-dose-dependent increase in serum LH and FSH levels has been observed even at low doses. However, this pharmacological class effect is expected and probably results from feedback at the pituitary level due to the reduction in estrogen levels that stimulate the pituitary secretion of gonadotropins (also in post-menopausal women).
Pharmacokinetics: This study was designed as a randomized open label, balanced, two treatment, two period, two sequence, single dose, crossover, bioequivalence study of Exemestane 25 mg tablets in normal, adult, healthy, post menopausal/surgically sterile female subjects under fed conditions. The study was conducted following an oral administration of one tablet 25 mg of the test drug or one tablet 25 mg of the reference drug.
Based on statistical analysis of the 90% Confidence Interval (Log-transformed data) of Test Drug and Reference Drug for AUC_0-inf, AUC_0-t, and C_max were 95.70 - 102.48, 95.77 - 102.61 and 91.76 - 107.22, respectively.
Geometric mean of Test Drug and Reference Drug were 58500.41 and 59071.31 for AUC_0-inf; 56946.55 and 57448.18 for AUC_0-t; 18612.17 and 18764.05 for C_max.
Conclusion: Based on the statistical analysis results, Exemestane 25 mg tablets is bioequivelent with the reference drug.

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.

Adult and elderly patients: 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.
Hepatic or renal insufficiency: No dose adjustments are required for patients with hepatic or renal insufficiency.
Children: Not recommended for use in children.

The single dose Exemestane that could result in life-threatening symptoms is not known. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and dose observation.

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.
Effects on 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.

Pregnancy and lactation: No data on exposed pregnancies are available with Exemestane. Exemestane is therefore contraindicated in pregnant women. It is not known whether Exemestane is excreted into human milk. Exemestane should not be administered to lactating woman.

The most commonly reported adverse reactions were hot flushes, arthralgia and fatigue. The most commonly reported adverse reactions were hot flushes and nausea. Most adverse reactions can be attributed to the normal pharmacological consequences of estrogen deprivation (e.g., hot flushes).
Metabolism and nutrition disorders: Common: Anorexia.
Psychiatric disorders: Very common: Depression, insomnia.
Nervous system disorders: Very common: Headache, dizziness.
Common: Carpal tunnel syndrome.
Uncommon: Somnolence.
Vascular disorders: Very common: Hot flushes.
Gastrointestinal disorders: Very common: Abdominal pain, nausea.
Common: Vomiting, diarrhea, constipation, dyspepsia.
Hepatobiliary disorders: Very common: Hepatic enzyme increased, blood bilirubin increased, blood alkaline phosphatase increased.
Skin and subcutaneous tissue disorders: Very common: Increased sweating.
Common: Alopecia, rash.
Musculoskeletal and bone disorders: Very common: Joint and musculoskeletal pain (includes: Arthralgia, and less frequently pain in limb, osteoarthritis, back pain, arthritis, myalgia and joint stiffness.
General disorders and administration site conditions: Very common: Pain, fatigue.
Common: Oedema peripheral, asthenia.
In patients with advanced breast cancer, an occasional decrease in lymphocytes has been observed in 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.
No significant difference was noted for any individual cardiovascular event including hypertension, myocardial infarction and cardiac failure.
In breast cancer, gastric ulcer was observed at a slightly higher frequency in the Exemestane arm compared to Tamoxifen. The majority of patients on Exemestane with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.
Post-marketing experience: Immune system disorders: Uncommon: Hypersensitivity.
Nervous system disorders: Common: Paraesthesia.
Hepatobiliary disorders: Rare: Hepatitis, hepatitis cholestatic.
Skin and subcutaneous tissue disorders: Common: Urticaria, pruritus.
Rare: Acute generalised exenthematous pustulosis.

The drug is metabolised through cytochrome P450 (CYP)3A4 and aldo-keto reductases and does not inhibit any of the major CYP isoenzymes. The specific inhibition of CYP 3A4 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 oesterogen-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. 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.

Store below 30°C.

Cancer Hormone Therapy

L02BG06 - exemestane ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.

G