1. Name Of The Medicinal Product
Anastrozole 1mg Tablets
2. Qualitative And Quantitative Composition
Each tablet contains 1mg anastrozole.
Excipient: each tablet contains 93mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
White film-coated round biconvex tablets, debossed with “ANA” and “1” on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of advanced breast cancer in postmenopausal women. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen.
Adjuvant treatment of postmenopausal women with hormone receptor positive early invasive breast cancer.
Adjuvant treatment of early breast cancer in hormone receptor positive postmenopausal women who have received 2 to 3 years of adjuvant tamoxifen.
4.2 Posology And Method Of Administration
Adults including the elderly
One tablet (1mg) to be taken orally once a day.
Children
Anastrozole is not recommended for use in children due to insufficient data on safety and efficacy (see section 4.4 and 5.1).
Renal impairment
No dose change is recommended in patients with mild or moderate renal impairment.
Hepatic impairment
No dose change is recommended in patients with mild hepatic disease.
For early disease, the recommended duration of treatment should be 5 years.
4.3 Contraindications
Anastrozole is contraindicated in:
• Premenopausal women.
• Pregnant or lactating women.
• Patients with severe renal impairment (creatinine clearance less than 20ml/min).
• Patients with moderate or severe hepatic disease.
• Patients with known hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1.
Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.
Concurrent tamoxifen therapy (see section 4.5).
4.4 Special Warnings And Precautions For Use
Anastrozole is not recommended for use in children as safety and efficacy have not been established in this group of patients(see section 5.1).
Anastrozole should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. In a pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole reduces estradiol levels, anastrozole must not be used in girls with growth hormone deficiency in addition to growth hormone treatment. Long-term safety data in children and adolescents are not available.
The menopause should be defined biochemically in any patient where there is doubt about hormonal status.
There are no data to support the safe use of anastrozole in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20ml/min).
Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.
There are no data available for the use of anastrozole with LHRH analogues. This combination should not be used outside the clinical trials.
As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture. The use of bisphosphonates may stop further bone mineral loss caused by anastrozole in postmenopausal women and could be considered.
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Anastrozole inhibited cytochrome P450 1A2, 2C8/9 and 3A4 in vitro, but a clinical interaction study with warfarin indicated that anastrozole at a 1 mg dose does not significantly inhibit the metabolism of substances that are metabolised via cytochrome P450. Additionally, antipyrine and cimetidine clinical interaction studies indicate that the co-administration of anastrozole with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450.
A review of a clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed drugs. No clinically significant interactions between anastrozole and bisphosphonates have been identified.
Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.
Tamoxifen should not be co-administered with anastrozole, as this may diminish its pharmacological action (see section 4.3).
4.6 Pregnancy And Lactation
Pregnancy
There are no data on the use of anastrozole in pregnant patients. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Anastrozole is contraindicated in pregnant women.
Lactation
It is unknown whether anastrozole is excreted in human milk. Anastrozole is contraindicated in lactating women.
4.7 Effects On Ability To Drive And Use Machines
Anastrozole is unlikely to impair the ability of patients to drive or operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed while driving or operating machinery while such symptoms persist.
4.8 Undesirable Effects
Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for five years (ATAC study).
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*Vaginal bleeding has been reported uncommonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.
** Cannot be estimated from the available data.
As anastrozole lowers circulating oestrogen levels, it may cause a reduction in bone mineral density placing some patients at a higher risk of fracture (see section 4.4). The table below presents the frequency of pre-specified adverse events in the ATAC study, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.
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Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.
The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen.
4.9 Overdose
There is limited clinical experience of accidental overdosage.
In animal studies, anastrozole demonstrated low acute toxicity.
Clinical trials have been conducted with various doses of anastrozole, up to 60mg in a single dose given to healthy male volunteers, and up to 10mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established.
There is no specific antidote to overdosage and treatment must be symptomatic.
In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken.
Vomiting may be induced if the patient is alert.
Dialysis may be helpful because anastrozole is not highly protein-bound.
General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Enzyme inhibitors
ATC Code: L02B G03
Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, oestradiol is produced primarily by the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently converted to oestradiol. Lowering circulating oestradiol levels has been shown to produce a beneficial effect in women with breast cancer.
In postmenopausal women, a daily dose of 1mg of anastrozole produced oestradiol suppression of greater than 80% using a highly sensitive assay.
Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity.
Daily doses of anastrozole up to 10mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.
An extensive phase III clinical study programme showed that anastrozole is an effective treatment of hormone-receptor positive breast cancer in postmenopausal women.
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, anastrozole 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 anastrozole versus tamoxifen for the prospectively defined hormone receptor positive population. Anastrozole 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. Anastrozole was statistically superior to tamoxifen in terms of time to distant recurrence. The incidence of contralateral breast cancer was statistically reduced for anastrozole compared to tamoxifen. Following 5 years of therapy, anastrozole is at least as effective as tamoxifen in terms of overall survival. However, due to low death rates, additional follow-up is required to determine more precisely the long-term survival for anastrozole relative to tamoxifen. With 68 months median follow-up, patients in the ATAC study have not been followed up for sufficient time after 5 years of treatment, to enable a comparison of long-term post treatment effects of anastrozole relative to tamoxifen.
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a Disease-free survival includes all recurrence events and is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death (for any reason).
b Distant disease-free survival is defined as the first occurrence of distant recurrence or death (for any reason).
c Time to recurrence is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death due to breast cancer.
d Time to distant recurrence is defined as the first occurrence of distant recurrence or death due to breast cancer.
e Number (%) of patients who had died.
As with all treatment decisions, women with breast cancer and their physician should assess the relative benefits and risks of the treatment.
When anastrozole and tamoxifen were co-administered, the efficacy and safety were similar to tamoxifen when given alone, irrespective of hormone receptor status. The exact mechanism of this is not yet clear. It is not believed to be due to a reduction in the degree of estradiol suppression produced by anastrozole.
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 who had received surgery with or without radiotherapy and no chemotherapy, switching to anastrozole 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 anastrozole, 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 anastrozole. Overall survival was similar for the two treatment groups.
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Two 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 anastrozole safety profile in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor positive early breast cancer.
Paediatrics
Anastrozole is not indicated for use in children. Efficacy has not been established in the paediatric populations studied (see below). The number of children treated was too limited to draw any reliable conclusions on safety. No data on the potential long-term effects of anastrozole treatment in children are available (see also section 5.3).
Short stature due to growth hormone deficiency
A randomised, double-blind, multi-centre study evaluated 52 pubertal boys (aged 11-16 years inclusive) with GHD treated for 12 to 36 months with anastrozole 1 mg/day or placebo in combination with growth hormone. Only 14 subjects on anastrozole completed 36 months.
After 3 years anastrozole was found to statistically significantly slow bone maturation in pubertal boys on growth hormone therapy. No statistically significant difference with placebo was observed for the growth related parameters of predicted adult height, height, height SDS, and height velocity. Final height data were not available. While the number of children treated was too limited to draw any reliable conclusions on safety, there was an increased fracture rate and a trend towards reduced bone mineral density in the anastrozole arm compared to placebo.
Testotoxicosis
An open-label, non-comparative, multi-centre study evaluated 14 male patients (aged 2-9) with familial male-limited precocious puberty, also known as testotoxicosis, treated with combination of anastrozole and bicalutamide. The primary objective was to assess the efficacy and safety of this combination regimen over 12 months. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). There was no significant difference in growth rate after 12 months of treatment, relative to the growth rate during the 6 months prior to entering the study.
5.2 Pharmacokinetic Properties
Anastrozole pharmacokinetics are independent of age in postmenopausal women.
Pharmacokinetics have not been studied in children.
Absorption
Absorption of anastrozole is rapid and maximum plasma concentrations are typically reached within two hours of dosing (under fasted conditions).
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 Anastrozole 1mg 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.
Distribution
Anastrozole is only 40% bound to plasma proteins.
Biotransformation
Anastrozole is extensively metabolised by postmenopausal 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. Triazo
