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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 post-menopausal 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 even 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. The incidence of contralateral breast cancer was statistically reduced for Arimidex compared to tamoxifen. (See Table 1.)
Click on icon to see table/diagram/imageThe 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.
With an updated follow-up at a median of 10 years, long term comparison of the treatment effects of Arimidex relative to tamoxifen were shown to be consistent with previous analyses.
As with all treatment decisions, women with breast cancer and their physician should assess the relative benefits and risks of the treatment.
Adjuvant treatment of early breast cancer for patients being treated with adjuvant tamoxifen: In a phase III trial (ABCSG 8) conducted in 2579 post-menopausal women with hormone receptor positive early breast cancer who had received surgery with or without radiotherapy and no chemotherapy, switching to Arimidex after 2 years adjuvant treatment with tamoxifen was statistically superior in disease-free survival when compared to remaining on tamoxifen, after a median follow-up of 24 months.
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. (See Table 2.)
Click on icon to see table/diagram/imageTwo further similar trials (GABG/ARNO 95 and ITA), in one of which patients had received surgery and chemotherapy, 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.
Study of anastrozole with the bisphosphonate risedronate (SABRE): Bone Mineral Density (BMD): In the phase III/IV SABRE study, 234 postmenopausal women with hormone receptor positive early breast cancer scheduled for treatment with Arimidex 1 mg/day were stratified to low, moderate and high risk groups according to their existing risk of fragility fracture. The primary efficacy parameter was the analysis of lumbar spine bone mass density using DEXA scanning. All patients received treatment with vitamin D and calcium. Patients in the low risk group received Arimidex alone (N=42), those in the moderate group were randomised to Arimidex plus risedronate 35 mg once a week (N=77) or Arimidex plus placebo (N=77) and those in the high risk group received Arimidex plus risedronate 35 mg once a week (N=38). The primary endpoint was change from baseline in lumbar spine bone mass density at 12 months.
The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture showed no decrease in their bone mass density (assessed by lumbar spine bone mineral density using DEXA scanning) when managed by using Arimidex 1 mg/day in combination with risedronate 35 mg once a week. In addition, a decrease in BMD which was not statistically significant was seen in the low risk group treated with Arimidex 1 mg/day alone. These findings were mirrored in the secondary efficacy variable of change from baseline in total hip BMD at 12 months.
This study provides evidence that the use of bisphosphonates should be considered in the management of possible bone mineral loss in postmenopausal women with early breast cancer scheduled to be treated with Arimidex.
Lipids: In the SABRE study, there was a neutral effect on plasma lipids in those patients treated with Arimidex plus risedronate.
Paediatrics: Three clinical trials were conducted in paediatric patients (2 in pubertal boys with gynaecomastia and 1 in girls with McCune-Albright syndrome).
Gynaecomastia studies: Trial 0006 was a randomised, double-blind, multi-centre study of 82 pubertal boys (aged 11-18 years inclusive) with gynaecomastia of greater than 12 months duration treated with Arimidex 1 mg/day or placebo daily for up to 6 months. No significant difference in the number of patients who had a 50% or greater reduction in total breast volume after 6 months of treatment was observed between the Arimidex 1 mg treated group and the placebo group.
Trial 0001 was an open-label, multiple-dose pharmacokinetic study of Arimidex 1 mg/day in 36 pubertal boys with gynaecomastia of less than 12 months duration. The secondary objectives were to evaluate the proportion of patients with reductions from baseline in the calculated volume of gynaecomastia of both breasts combined of at least 50% between day 1 and after 6 months of study treatment, and patient tolerability and safety.
A pharmacodynamic subpopulation of 25 boys was selected in this study to explore the potential benefits of anastrozole. It was noted a decrease in total breast volume of 50% or greater at 6 months was seen in 55.6% (as measured by ultrasound) and 77.8% (as measured by caliper) of the boys (observational data only, no statistical analysis conducted on these results).
McCune-Albright Syndrome study: Trial 0046 was an international, multi-centre, open-label exploratory trial of Arimidex in 28 girls (aged 2 to ≤10 years) with McCune-Albright Syndrome (MAS). The primary objective was to evaluate the safety and efficacy of Arimidex1 mg/day in patients with MAS. The efficacy of study treatment was based on the proportion of patients fulfilling defined criteria relating to vaginal bleeding, bone age, and growth velocity.
No statistically significant change in the frequency of vaginal bleeding days on treatment was observed. There were no clinically significant changes in Tanner staging, mean ovarian volume or mean uterine volume. No statistically significant change in the rate of increase in bone age on treatment compared to the rate during baseline was observed. Growth rate (in cm/year) was significantly reduced (p<0.05) from pre-treatment through month 0 to month 12, and from pre-treatment to the second 6 months (month 7 to month 12). Of the patients with baseline vaginal bleeding, 28% experienced a ≥50% reduction in the frequency of bleeding days on treatment; 40% experienced a cessation over a 6-month period, and 12% experienced a cessation over a 12-month period.
The overall assessment of the adverse events in children less than 18 years of age raised no safety or tolerability concerns.
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 are independent of age in post-menopausal women.
Anastrozole is only 40% bound to plasma proteins.
In boys with pubertal gynaecomastia, anastrozole was rapidly absorbed, was widely distributed, and was eliminated slowly with a half-life of approximately 2 days. Clearance of anastrozole was lower in girls than in boys and exposure higher. Anastrozole in girls was widely distributed and slowly eliminated with an estimated half-life of approximately 0.8 days.
Anastrozole is extensively metabolised by post-menopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing. 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 relevant to the prescriber: 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 doses (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 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 occurred at clinically relevant doses. An effect in man cannot be excluded. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period.
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.
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.
