Nateran

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.
Nateran tablets for oral administration contain 25 mg of exemestane, an irreversible, steroidal aromatase inactivator.
Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula C₂₀H₂₄0₂.

Pharmacology: Mechanism of action: 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, Exemestane p.o. 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%.
Pharmacokinetics: The pharmacokinetics parameters of 56 subjects (54 subjects completed all 4 study periods and 2 subjects completed 2 study periods) were calculated and results were statistically analyzed for average bioequivalence in 2-treatment 4-period 2-sequence replicate crossover design.
After oral administration of Exemestane 25 mg film-coated tablets (test product) the mean of the maximum plasma concentration (C_max) (rate of absorption) was 24.70 ng/ml and this C_max was reached at the mean T_max of 1.55 h. The extent of absorption is expressed in Area Under the curve (AUC)_0-t and AUC_0-inf. The mean values were 54.88 ng.h/ml and 59.08 ng.h/ml respectively. The mean elimination half-life (t_½) of exemestane 25 mg film-coated tablets was 8.01 h.
The ratios and confidence intervals between test and reference product were as follows: For C_max the ratio was 100.42% (94.12%-107.17%). For AUC_0-t the ratio was 103.72% (100.81-106.72%). For AUC_0-inf, the ratio was 103.49% (100.62%-106.44%). The results of the study showed that the ratios are within the acceptance range for bioequivalence, therefore it can be concluded that the test product, Exemestane 25 mg film-coated tablets, is bioequivalent with the reference product.

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 of 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.

Exemestane given up to 800 mg in single dose to healthy female and up to 600 mg daily to post-menopausal women with advanced breast cancer 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 mg/m² basis.
There is no specific antidote to overdose and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patients, is indicated.

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, PSH and oestradiol levels.
Exemestane should be used with caution in patients with hepatic or renal impairment.
As Exemestane is a potent estrogen lowering agent, reduction in bone mineral density can be anticipated. During adjuvant treatment with exemestane, a woman 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 adviced that, if these events occur, their physical and/or mental abilities required for operating machinery or driving a car may be impaired.

No clinical data on exposed pregnancies are available with exemestane. Studies on animals have shown reproductive toxicity. Exemestane therefore contraindicated in pregnant women. It is not known whether Exemestane is excreted into human milk. Exemestane should not be administered to lactating women.

The most commonly reported adverse reactions were hot flushes, arthralgia, fatigue and nausea. Most adverse reactions can be attributed to the normal pharmacological consequences of estrogen deprivation (e.g., hot flushes).
The reported adverse reactions are listed as follows by MedDRA 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).
Metabolism and nutrition disorders: Common: Anorexia.
Psychiatric disorders: Very common: Depression, Insomnia.
Nervous system disorders: Very common: Headache, dizziness.
Common: Carpal tunnel syndrome.
Vascular disorders: Very common: Hot flushes.
Gastrointestinal disorders: Very common: Abdominal pain, nausea.
Common: Vomiting, diarrhoea, 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*.
Common: Fracture, osteoporosis.
General disorders and administration site conditions: Very common: Pain, fatigue.
Common: Oedema peripheral, asthenia.
*Include arthralgia, and less frequent pain in limb, osteoarthritis, back pain, arthritis, myalgia and joint stiffness.
In patients with advanced breast cancer, an occasional decrease in lymphocyte has been observed 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.
The frequency of ischemic cardiac events in the exemestane and tamoxifen treatment arms respectively. No significant difference was noted for any individual cardiovascular event including hypertension, myocardial infarction and cardiac failure.
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 exanthematous pustulosis.

The drug is metabolised through cytochrome P450 (CYP) 3A4 and aldo-keto reductases and does not inhibit any of the no major CYP ISOENZYMES. The specific inhibition of CYP 3A4 by ketoconazole showed to 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 not be used cautiously with drugs that are metabolized 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.
An interaction with rifampicin, a potent CYP450 inducer, the AUC was reduced C_max the co-administration of drugs, such as rifampicin, anticonvulsants (e.g. phenytoin and carbamazepine) and herbal preparation containing Hypericum perforatum/(St Johns Wort) known to induce CYP3A4, may reduce the efficacy of Nateran.

Incompatibilities: Not applicable.

Store below 30°C.
Shelf life: 24 Months.

Cancer Hormone Therapy

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

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