Gerard Laboratories

Agerdex 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.

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.

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).

Anastrazole 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 anastrazole reduces estradiol levels, anastrazole 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 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 biphosponates 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.

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.Antipyrine and cimetidine clinical interaction studies indicate that the co-administration of anastrazole 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 anastrazole who also received other commonly prescribed drugs. There were no clinically significant interactions with bisphosphonates (see section 5.1).

Tamoxifen should not be co-administered with anastrozole, as this may diminish its pharmacological action (see section 4.3).

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.

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 when driving or operating machinery while such symptoms persist.

The following undesirable effects can be very common ( 1/10), common ( 1/100 to <1/10), uncommon ( 1/1,000 to 1/100), rare ( 1/10,000 to 1/1,000), very rare ( 1/10,000) and not known (cannot be estimated from the available data).

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 in 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 anastrazole lowers circulating oestrogen levels, it may cause a reduction in bone mineral density placing 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.

Absorption may be prevented by gastric lavage followed by administration of activated charcoal (adsorbant) or activated charcoal alone.

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.

A large phase III study showed that anastrozole is an effective treatment for postmenopausal women with operable breast cancer

A phase III trial showed that anastrozole is an effective treatment of hormone receptor positive early breast in postmenopausal women

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.

In animal studies toxicity related to the pharmacodynamic action was only seen at high doses.

Adverse effects have been observed in reproductive studies (reduced number of viable pregnancies and reversible infertility). These effects are related to the pharmacological effect of the substance. The safety margin is sufficient in comparison with the therapeutic dose in humans.

No teratogenic effects were observed in rats and rabbits.

Genetic toxicology studies with anastrozole showed that it is neither a mutagen nor a clastogen.

In a carcinogenicity study in rats, increases in the incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males were observed at a dose which represents 100-fold greater exposure than occurs at human therapeutic doses. These changes are considered not to be clinically relevant.

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.

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.

30 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.

McDermott Laboratories Limited, t/a Gerard Laboratories,

35/36 Baldoyle Industrial Estate,

Grange Road,

Dublin 13,

Ireland.

PA 577/88/1

Date of First Authorisation: 9th November 2007

Date of last renewal: 31st October 2009

June 2011