Anastrozole 1 mg, film-coated tablets.

Each tablet contains 1 mg anastrozole.

Excipient: each tablet contains 93 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

Film-coated tablet.

White film-coated round biconvex tablets, debossed with “ANA” and “1” on one side.

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.

Adults including the elderly

One tablet (1 mg) 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 sections 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.

Anastrozole is contraindicated in:

– Premenopausal women.

– Pregnant or lactating women.

– Patients with severe renal impairment (creatinine clearance less than 20 ml/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).

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 the pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole reduces estradiol levels, it 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 20 ml/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 clinical trials.

As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequential increased risk of fracture. The use of bisphosphonates may stop further bone mineral loss caused by anastrozole in postmenopausal women and should 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.

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 the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed drugs. There were no clinically significant interactions with bisphosphonates (see section 5.1)

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).

Anastrozole is contraindicated in pregnant and lactating women.

Anastrozole is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

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)

*Vaginal bleeding has been reported commonly, 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.

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.

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 60 mg in a single dose given to healthy male volunteers, and up to 10 mg 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.

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 1 mg 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 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, 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.

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.

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.

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 anastrozole 1mg/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 anastrozole alone (N=42), those in the moderate group were randomised to anastrozole plus risedronate 35mg once a week (N=77) or anastrozole plus placebo (N=77) and those in the high risk group received anastrozole plus risedronate 35mg once a week (N=38). The primary endpoint was changed 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 anastrozole 1mg/day in combination with risedronate 35mg once a week. In addition, a decrease in BMD which was not statistically significant was seen in the low risk group treated with anastrozole 1mg/day alone. These findings were mirrored in the secondary efficacy variable of change from baseline 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 anastrozole.

Lipids

In the SABRE study there was a neutral effect on plasma lipids in those patients treated with anastrozole plus risedronate.

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)

The European Medicines Agency has waived the obligation to submit the results of studies with anastrozole in one or several subsets of the paediatric population in short stature due to growth hormone deficiency (GHD), testotoxicosis, gynaecomastia, and McCune-Albright syndrome.

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 1mg/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 a 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.

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 anastrozole 1mg/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 anastrozole 1mg treated group and the placebo group.

Trial 0001 was an open-label, multiple-dose pharmacokinetic study of anastrozole 1mg/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 calliper) 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 anastrozole in 28 girls (aged 2 to 10 years) with McCune-Albright Syndrome (MAS). The primary objective was to evaluate the safety and efficacy of anastrozole 1mg/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 of 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.

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 1 mg 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. Triazole, a major metabolite in plasma and urine, does not inhibit aromatase.

Elimination

Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours.

The apparent clearance of anastrozole after oral intake in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers.

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 50mg/kg/day by the intraperitoneal route. In an oral acute toxicity study in the dog, the median lethal dose was greater than 45mg/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 (1mg/kg/day) and mid doses (dog 3mg/kg/day; rat 5mg/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

In a fertility study weanling male rats were dosed orally with 50 or 400mg/1 anastrozole via their drinking water for 10 weeks. Measured mean plasma concentrations were 44.4 (± 14.7) ng/ml and 165 (± 90) ng/ml respectively. Mating indices were adversely affected in both dose groups, whilst a reduction in fertility was evident only at the 400mg/1 dose level. The reduction was transient as all mating and fertility parameters were similar to control group values following a 9-week treatment-free recovery period.

Oral administration of anastrozole to female rats produced a high incidence of infertility at 1mg/kg/day and increased pre-implantation loss at 0.02mg/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 0.2mg/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 0.02mg/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 increasein incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25mg/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.

Tablet core

Lactose monohydrate

Sodium starch glycolate (type A)

Povidone (K31) (E1201)

Magnesium stearate (E572)

Film-coating

Macrogol 400

Hypromellose (E464)

Titanium dioxide (E171)

Not applicable.

36 months.

This medicinal product does not require any special storage conditions.

Cardboard boxes containing PVC/PE/PVDC/Aluminium blisters of 10, 14, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100 or 300 tablets and hospital blisters (PVC/PE/PVDC/ Aluminium) with 28, 50, 84, 98, 300 or 500 tablets.

Not all pack sizes may be marketed.

No special requirements.

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

PL 17780/0280

19/07/2007

21/12/2010

POM