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Pharmacotherapeutic group: Enzyme inhibitors. ATC code: L02BG03.
Pharmacology: Pharmacodynamics: ARIMIDEX is a potent and highly selective non-steroidal aromatase inhibitor. In post-menopausal women, oestradiol is produced primarily from the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently converted to oestradiol. Reducing circulating oestradiol levels has been shown to produce a beneficial effect in women with breast cancer.
In post-menopausal women, ARIMIDEX at a daily dose of 1 mg produced oestradiol suppression of greater than 80% using a highly sensitive assay.
ARIMIDEX does not possess any progestogenic, androgenic or oestrogenic activity.
Daily doses of ARIMIDEX up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.
Primary adjuvant treatment of early breast cancer: In a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years, ARIMIDEX was shown to be statistically superior to tamoxifen in disease free survival. A greater magnitude of benefit was observed for disease free survival in favour of ARIMIDEX versus tamoxifen for the prospectively defined hormone receptor positive population.
ARIMIDEX was statistically superior to tamoxifen in time to recurrence. The difference was of greater magnitude than in disease free survival for both the Intention to Treat (ITT) population and hormone receptor positive population.
ARIMIDEX was statistically superior to tamoxifen in terms of time to distant recurrence. There was also a numerical trend in favour of ARIMIDEX for distant disease free survival.
The incidence of contralateral breast cancer was statistically reduced for ARIMIDEX compared to tamoxifen.
The overall survival benefit of tamoxifen was maintained with ARIMIDEX. The additional analysis of time to death following recurrence showed a numerical trend in favour of ARIMIDEX compared to tamoxifen.
Overall, ARIMIDEX was well tolerated. The following adverse events were reported regardless of causality. Patients receiving ARIMIDEX had a decrease in hot flushes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen. Patients receiving ARIMIDEX had an increase in joint disorders (including arthritis, arthrosis and arthralgia) and fractures compared with patients receiving tamoxifen. A fracture rate of 22 per 1000 patient years was observed on ARIMIDEX and 15 per 1000 patient years with the tamoxifen group with a median follow up of 68 months. The fracture rate for ARIMIDEX falls within the broad range of the fracture rates reported in an age matched postmenopausal population.
The combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefits in comparison with tamoxifen in all patients as well as in the hormone receptor positive population. This treatment arm was discontinued from the study.
Adjuvant treatment of early breast cancer for patients being treated with adjuvant tamoxifen: In a phase III trial (ABCSG 8) conducted in 2579 postmenopausal women with hormone receptor positive early breast cancer being treated with adjuvant tamoxifen, patients had a superior disease-free survival when switched to ARIMIDEX compared with those continuing on tamoxifen.
Time to any recurrence, time to local or distant recurrence and time to distant recurrence confirmed a statistical advantage for ARIMIDEX, consistent with the results of disease free survival. The incidence of contralateral breast cancer was very low in the two treatment arms, with a numerical advantage for ARIMIDEX. Overall survival was similar for the two treatment groups.
Two further similar trials (GABG/ARNO 95 and ITA) with ARIMIDEX, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results.
The ARIMIDEX safety profile in these 3 studies was consistent with the known safety profile established in post-menopausal women with hormone-receptor positive early breast cancer.
Pharmacokinetics: Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of ARIMIDEX tablets. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are attained after 7 daily doses. There is no evidence of time or dose-dependency of anastrozole pharmacokinetic parameters. Anastrozole pharmacokinetics is independent of age in post-menopausal women. Anastrozole is only 40% bound to plasma proteins.
Anastrozole is extensively metabolized by post-menopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing, and the remainder (about 60% of the dose) is excreted in the urine as metabolites. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase.
The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers.
Toxicology: Preclinical safety data: Acute toxicity: In acute toxicity studies in rodents the median lethal dose of anastrozole was greater than 100 mg/kg/day by the oral route and greater than 50 mg/kg/day by the intraperitoneal route. In an oral acute toxicity study in the dog the median lethal dose was greater than 45 mg/kg/day.
Chronic toxicity: Multiple dose toxicity studies utilised rats and dogs. No no-effect levels were established for anastrozole in the toxicity studies, but those effects that were observed at the low dose (1 mg/kg/day) and mid doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related to either the pharmacological or enzyme inducing properties of anastrozole, and were unaccompanied by significant toxic or degenerative changes.
Mutagenicity: Genetic toxicology studies with anastrozole show that it is not a mutagen or a clastogen.
Reproductive toxicology: Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day, respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound.
Oral administration of anastrozole to female rats produced a high incidence of infertility at 1 mg/kg/day and increased pre-implantation loss at 0.02 mg/kg/day. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period.
The survival of litters born to rats given anastrozole at 0.02 mg/kg/day and above (from day 17 of pregnancy to day 22 post-partum) was compromised. These effects were related to the pharmacological effects of the compound on parturition. There were no adverse effects on behaviour or reproductive performance of the first generation offspring attributable to maternal treatment with anastrozole.
Carcinogenicity: A two-year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose, which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be clinically relevant to the treatment of patients with anastrozole.
A two-year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant to the treatment of patients with anastrozole.
