Exesin 25

Exemestane.

Each film coated tablet contains Exemestane 25 mg.
Excipients/Inactive Ingredients: Tablet core: Mannitol / Microcrystalline Cellulose / Crospovidone / Sodium Starch Glycolate / Hypromellose E5 / Polysorbate 80 / Colloidal Anhydrous Silica / Magnesium Stearate.
Tablet coating: Hypromellose 6cp (E464) / Macrogol (400) / Titanium Dioxide (E171).

Pharmacology: Pharmacodynamics: Mechanism of action: Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione. In postmenopausal women, oestrogens are produced primarily form 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, Exemestane p.o. significantly lowered serum oestrogen concentrations starting for 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%.
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 dose 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. Glucocorticoid or mineralocorticoid replacements are therefore not needed. A non dose dependent slight increase in serum LH and FSH levels has been observed even at low doses: this effect is, however, expected for the pharmacological class and is probably the result of feedback at the pituitary level due to the reduction in oestrogen levels that stimulate the pituitary secretion of gonadotropins also in postmenopausal women.
Adjuvant Treatment of Early Breast Cancer: In a multicentre, randomized, double-blind study, conducted in 4724 postmenopausal patients with oestrogen receptor positive or unknown primary breast cancer, patients who had remained disease free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive 3 to 2 years of Exemestane (25 mg/day) or tamoxifen (20 or 30 mg/day) to complete a total of 5 years of hormonal therapy.
After a median duration of therapy of about 30 months and a median follow-up of about 52 months, results showed that sequential treatment with Exemestane after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in disease free survival (DFS) compared with continuation of tamoxifen therapy. Analysis showed that in the observed study period Exemestane reduced the risk of breast cancer recurrence by 24% compared with tamoxifen (hazard ratio 0.76; p=0.00015).
The beneficial effect of Exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy.
Exemestane also significantly reduced the risk of contralateral breast cancer (hazard ratio 0.57, p=0.04158).
In the whole study population, a trend for improved overall survival was observed for Exemestane (222 deaths) compared to tamoxifen (262 deaths) with a hazard ratio 0.85 (logrank test: p=0.07362), representing a 15% reduction in the risk of death in favor of Exemestane. A statistically significant 23% reduction in the risk of dying (hazard ratio for overall survival 0.77; Wald chi square test: p=0.0069) was observed for Exemestane compared to tamoxifen when adjusting for the prespecified prognostic factors (i.e., ER status, nodal status, prior chemotherapy, use of HRT and use of biphosphonates).
Main efficacy results in all patients (intention to treat population) and oestrogen receptor positive patients are summarised in the table as follows: See Table 1.

Click on icon to see table/diagram/image

In the additional analysis for the subset of patients with oestrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.83 (log rank test: p=0.04250), representing a clinically and statistically significant 17% reduction in the risk of dying.
Results from a bone sub study demonstrated that women treated with Exemestane following 2 to 3 years of tamoxifen treatment experienced moderate reduction in bone mineral density. In the overall study, the treatment emergent fracture incidence evaluated during the 30 months treatment period was higher in patients treated with Exemestane compared with tamoxifen (4.5% and 3.3% correspondingly, p=0.038.
Results from a endometrial sub study indicate that after 2 years of treatment there was a median 33% reduction of endometrial thickness in the Exemestane treated patients compared with no notable variation in the tamoxifen treated patients. Endometrial thickening, reported at the start of study treatment, was reversed to normal (< 5 mm) for 54% of patients treated with Exemestane.
Treatment of Advanced Breast Cancer: Exemestane is used in the treatment of advanced breast cancer in postmenopausal women disease has progressed following tamoxifen therapy. Efficacy was evaluated in one comparative study (versus megestrol acetate) and 2 single-arm studies in postmenopausal women with advanced breast cancer that progressed after tamoxifen therapy for metastatic disease or as adjuvant therapy; some patients also received prior chemotherapy either for metastasis or as adjuvant therapy. The studies evaluated objective response rates (complete and partial response); time to tumor progression (TTP) and overall survival also were assessed in the comparative study. In the comparative study, objective response rates for exemestane and megestrol were comparable at 15 and 12.4%, respectively. Response rates of exemestane in the 2 single-arm studies were 23.4 and 28.1%. In the comparative study, the median duration of response was 76.1 and 71 weeks for exemestane and megestrol, respectively, and the median TTP was 20.3 and 16.6 weeks, respectively. No conclusions could be drawn related to overall survival differences with the limited study data available.
Pharmacokinetics: Absorption: After oral administration of Exemestane tablets. Exemestane is absorbed rapidly. The fraction of the dose absorbed from the gastrointestinal tract is high. The absolute bioavailability in humans is unknown, although it is anticipated to be limited by an extensive first pass effect. A similar effect resulted in an absolute bioavailability in rats and dogs of 5%. After a single dose of 25 mg, maximum plasma levels of 18 ng/ml are reached after 2 hours. Concomitant intake with food increases the bioavailability by 40%.
Distribution: The volume of distribution of Exemestane, not corrected for the oral bioavailability, is ca 20000 l. The kinetics is linear and the terminal elimination half life is 24 h. Binding to plasma proteins is 90% and is concentration independent. Exemestane and its metabolites do not bind to red blood cells.
Exemestane does not accumulate in an unexpected way after repeated dosing.
Metabolism and excretion: Exemestane is metabolised by oxidation of the methylene moiety on the 6 position by CYP 3A4 isoenzyme and/or reduction of the 17-keto group by aldoketoreductase followed by conjugation. The clearance of Exemestane is ca 500 l/h, not corrected for the oral bioavailability. The metabolites are inactive or the inhibition of aromatase is less than the parent compound.
The amount excreted unchanged in urine is 1% of the dose. In urine and faces equal amounts (40%) of 14C labeled Exemestane were eliminated within a week.
Special populations: Age: No significant correlation between the systemic exposure of Exemestane and the age of subjects has been observed.
Renal insufficiency: In patients with severe renal impairment (CLcr < 30 ml/min) the systemic exposure to Exemestane was 2 times higher compared with healthy volunteers. Given the safety profile of Exemestane, no dose adjustment is considered to be necessary.
Hepatic insufficiency: In patients with moderate or severe hepatic impairment the exposure of Exemestane is 2-3 fold higher compare with healthy volunteers. Given the safety profile of Exemestane, no dose adjustment is considered to be necessary.

Exemestane 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.
Exemestane is indicated for the treatment of advanced breast cancer in women with natural or induced postmenopausal status whose disease has progressed following antioestrogen therapy. Efficacy has not been demonstrated in patients with oestrogen receptor negative status.

Adult and elderly patients: The recommended dose of Exemestane is one 25 mg tablet to be taken once a day after a meal.
In patients with early breast cancer, treatment with Exemestane should continue until completion of five years of combined sequential adjuvant hormonal therapy (tamoxifen followed by Exemestane), or earlier if tumour relapse occurs.
In patients with advanced breast cancer, treatment with Exemestane should continue until tumour progression is evident.
No dose adjustments are required for patients with hepatic or renal insufficiency.
Children: Not recommended for use in children.

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 postmenopausal 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.

Exemestane tablets are contraindicated in patients with a known hypersensitivity to the active substance or to any of the excipients, in premenopausal women and in pregnant or lactating women.

Exemestane should not be administered to women with premenopausal endocrine status. Therefore, whenever clinically appropriate, the postmenopausal 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.
Exemestane tablets contain a forbidden substance which is being able to provide a positive result in a doping control tests.
Exemestane 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 Exemestane, women with osteoporosis or at risk of osteoporosis should treatment baseline bone mineral health assessment, based on current clinical guidelines and practice. Patients with advanced disease should have their bone mineral density (BMD) 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 Exemestane are not available, patients treated with Exemestane tablets 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 or aromatase inhibitor treatment should be considered, due to the high prevalence of severe deficiency 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: No clinical data on exposed pregnancies are available with Exemestane. Studies on animals have shown reproductive toxicity. Exemestane is therefore contraindicated in pregnant women.
Lactation: It is not known whether Exemestane is excreted into human milk. Exemestane should not be administered to lactating woman.
Women of perimenopausal status or childbearing 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.

Exemestane was generally well tolerated across all clinical studies conducted with Exemestane 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 Exemestane 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 as follows 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) and not known (cannot be estimated from available data). (See Table 2.)

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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 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 coadministration 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.
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.

Do not store above 30°C.

Cancer Hormone Therapy

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

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