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AROMASIN™ 25 mg (Tablets)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

AROMASIN™ 25 mg (Tablets)

COMPOSITION:
Each sugar-coated tablet contains 25 mg exemestane
Preservative: methyl p-hydroxybenzoate 0,003% m/m

PHARMACOLOGICAL CLASSIFICATION:
A 21.12 Hormone inhibitors

PHARMACOLOGICAL ACTION:
Pharmacodynamics:
AROMASIN is an irreversible, steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione. In postmenopausal women, oestrogens are produced primarily from the conversion of androgens into oestrogens through the aromatase enzyme in peripheral tissues. AROMASIN 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%.
AROMASIN 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, AROMASIN 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.
A non dose-dependent slight increase in serum LH and FSH levels has been observed even at low doses.
Pharmacokinetics:
Absorption: Following oral administration, AROMASIN is rapidly absorbed. Animal data suggest that the oral bioavailability could be incomplete due to first-pass metabolism. At a single dose of 25 mg given after a meal, average peak plasma levels of 18 ng/mL are achieved within 2 hours post-dosing. Food was shown to enhance absorption, resulting in plasma levels 40% higher than those observed in subjects under fasting conditions.
Distribution: After the peak, plasma levels of AROMASIN decline in a polyexponential manner with a terminal half-life of approximately 24 hours. AROMASIN is extensively distributed into tissues as reflected by a high volume of distribution. The plasma protein binding of AROMASIN is approximately 90% and the fraction bound is independent from the total concentration. The distribution of the drug and/or its metabolites into blood cells is negligible.
Metabolism and excretion: No significant deviations from dose-proportional pharmacokinetics were observed in healthy volunteers up to a 50 mg oral dose. Following repeated daily administration of 25 mg, plasma concentrations of the unchanged drug were of a similar order to those measured after single dosing. Following oral administration of a single dose radiolabelled AROMASIN, the elimination of drug-related products was shown to be essentially complete within 1 week, with approximately equal proportions of the dose eliminated in urine and faeces. The amount of drug excreted unchanged in urine is less than 1% of the dose. The clearance of AROMASIN is high, mainly due to metabolism. The biotransformation proceeds through oxidation of the methylene group at position 6 via the CYP 3A4 isoenzyme and/or reduction of 17-keto group by aldoketoreductases. Subsequently, many secondary metabolites are formed, each accounting for a limited amount of the drug. The metabolites are either inactive or less active than the parent drug in inhibiting aromatase.
Special populations:
Age: No significant correlation between the systemic exposure of AROMASIN and the age of subjects has been observed.
Renal insufficiency: AROMASIN pharmacokinetics have been investigated in subjects with severe renal insufficiency (CLCR <30 mL/min). In these subjects the systemic exposure of AROMASIN after a single dose was found to be approximately double that of healthy volunteers.
Hepatic insufficiency: AROMASIN pharmacokinetics have been investigated in subjects with moderate and severe hepatic insufficiency. The systemic exposure to AROMASIN was 2-3 times higher than in healthy volunteers.

INDICATIONS:
Aromasin is indicated for the treatment of advanced oestrogen receptor positive breast cancer in women with natural or induced postmenopausal status whose disease has progressed following anti-oestrogen (eg. Tamoxifen) therapy.

CONTRA-INDICATIONS:
AROMASIN tablets are contra-indicated in patients with a known hypersensitivity to exemestane or to any of the excipients, in pre-menopausal women and in pregnant or lactating women.

DOSAGE AND DIRECTIONS FOR USE:
Adults and elderly patients:
The recommended dose of AROMASIN is one 25 mg tablet to be taken once daily, preferably after a meal. Treatment with AROMASIN 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.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
In the clinical studies conducted with Aromasin, the withdrawal discontinuation rate due to adverse events was 2,8% in the overall patient population receiving the standard dose of 25 mg. The most frequent common adverse events were hot flushes, nausea, fatigue, increased sweating and dizziness. Other less common adverse events reported with an incidence higher than or equal to 2% were include headache, insomnia, pain, skin rash, abdominal pain, anorexia, vomiting, depression, alopecia, peripheral or leg oedema, constipation and dyspepsia.
A decrease in lymphocytes has been observed in approximately 20% of patients receiving Aromasin particularly in patients with pre-existing lymphopenia; however, mean lymphocyte values in these patients did not change significantly over time.
Thrombocytopenia and leucopenia have been reported.
Elevation of liver enzymes and alkaline phosphatase have been observed. In a controlled study. These elevations occurred mainly in patients with liver or bone metastasis or other impaired liver conditions.
Special Precautions:
Due to its mode of action,Aromasin should not be administered to pre-menopausal women. Therefore, the postmenopausal status should be ascertained by assessment of LH, FSH and oestradiol levels.
Aromasin should not be co-administered with oestrogen-containing medicines as these would negate its pharmacological action.
Interactions:
No formal drug interaction studies have been carried out. In vitro evidence showed that the exemestane 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. A possible decrease of exemestane plasma levels by known inducers of CYP 34A cannot be excluded.
Pregnancy and lactation:
AROMASIN is contra-indicated in pregnant or lactating women. If AROMASIN is taken accidentally, administration should be immediately discontinued.
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.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Clinical trials have been conducted with Aromasin 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 Aromasin 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, respectively, 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.

IDENTIFICATION:
Round, biconvex, off-white to slightly greyish sugar-coated tablets, printed with number 7663 on
one side in black ink.

PRESENTATION:
Blister packs of 30.

STORAGE INSTRUCTIONS:
Store below 30°C. Keep out of reach of children.

REGISTRATION NUMBER:
35/21.12/0011

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George Street
MIDRAND
1684

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
26 February 2001

New addition to this site: February 2005
Source: Pharmaceutical Industry
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