Anastrozole 1mg Film-coated Tablets

One film-coated tablet contains 1 mg anastrozole.

Excipients: 65.78 mg lactose/film-coated tablet

For a full list of excipients, see section 6.1

Film-coated tablet.

White, round and biconvex film-coated tablet with embossment “A1” on one side.

Treatment of advanced breast cancer in postmenopausal women. Efficacy has not been demonstrated in patients with oestrogen receptor-negative tumours 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 postmenopausal women with hormone receptor-positive early breast cancer who have already received adjuvant treatment with tamoxifen for 2 to 3 years.

Adults including elderly patients:

One film-coated Anastrozole tablet once daily.

Children and adolescents:

Children should not be treated with Anastrozole 1mg film-coated tablets.

Impaired renal function:

No dose adjustment is required in patients with mild or moderate renal impairment.

Impaired hepatic function:

No dose adjustment is required in patients with mild hepatic impairment.

For adjuvant treatment of early breast cancer, the recommended duration of treatment is 5 years.

Anastrozole 1mg film-coated tablets are contraindicated in:

- premenopausal women

- pregnant or lactating women

- patients with known hypersensitivity to anastrozole or to any of the excipients listed in section 6.1.

Oestrogen-containing medicinal products should not be administered concomitantly with Anastrozole 1mg film-coated tablets, as these can abolish its pharmacological action.

- Concurrent tamoxifen therapy (see section 4.5).

Anastrozole 1mg film-coated tablets should not be used for the treatment of children, as safety and efficacy have not been established in this patient group.

In patients in whom there is doubt about the hormonal status, the menopause should be confirmed by hormone tests.

There are no data to support safe use of Anastrozole 1mg film-coated tablets in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance < 20 ml/min). Anastrozole may be mainly eliminated hepatically in postmenopausal women. Less than 10% of the dose are excreted in the urine in unchanged form (see section 5.2).

Women with osteoporosis or at risk of osteoporosis, should undergo bone density tests e.g. using the DEXA scanning method at the commencement of treatment and subsequently at regular intervals. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.

There are no data available on the concomitant use of anastrozole and LHRH analogues. This combination should not be used outside clinical studies.

As Anastrozole 1mg film-coated tablets lowers endogenic oestrogen levels, it may cause a reduction in bone density. Adequate data on the effect of bisphosphonates on reduction of bone density caused by anastrozole, or a potential benefit in prophylactic use, are not available to date.

Patients with the rare hereditary galactose intolerance, the lactase deficiency or glucose-galactose malabsorption should not take Anastrozole 1mg film-coated tablets.

Anastrozole inhibited cytochrome P 450 1A2, 2C8/9 and 3A4 in vitro. The clinical relevance of these findings is unknown. Until further data are available, caution should be exercised in combinations with drugs which are metabolised by these enzymes. This applies particularly to drugs with a narrow therapeutic index.

No clinically relevant interactions with bisphosphonates have been identified.

Oestrogen-containing medicinal products should not be co-administered with Anastrozole 1mg film-coated tablets, as these abolish its pharmacological action.

Tamoxifen should not be co-administered with Anastrozole 1mg film-coated tablets, as this may reduce its pharmacological action (see section 4.3).

Anastrozole is contraindicated in pregnant or lactating women (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 1mg film-coated tablets are unlikely to impair the ability to drive and operate machinery. However, asthenia and somnolence have been observed during treatment with Anastrozole 1mg film-coated tablets and caution should be observed when driving or operating machinery as long as such symptoms persist.

(See table)

*Vaginal bleeding has been reported uncommonly, above all in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If such bleeding persists, further evaluation is required.

As anastrozole lowers endogenic oestrogen levels, it may cause a reduction in bone density placing some patients at a higher risk of bone fracture (see section 4.4).

The table above shows the frequency of pre-specified adverse events that occurred in the context of the ATAC study, irrespective of a potential causal relationship. These adverse events were reported for patients during the study and up to 14 days after completion of the study.

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 fracture rate observed for anastrozole is similar to the reference range reported in age-matched postmenopausal women. It has not been determined whether the rates of fracture and osteoporosis observed in the context of the ATAC study 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 to date of accidental overdose. In animal studies, anastrozole demonstrated low acute toxicity.

In clinical studies with various dosages of anastrozole healthy male volunteers were given single doses of up to 60 mg and postmenopausal women with advanced breast cancer up to 10 mg daily; 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 and treatment must therefore be symptomatic.

In the management of overdose, consideration should be given to the possibility that several medicinal products may have been taken. Activated charcoal should be administered if the patient is conscious. Dialysis may be useful because anastrozole is not highly protein bound. In addition, 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 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 in plasma has been shown to produce a beneficial effect in women with breast cancer. Using a highly sensitive assay method, it was demonstrated in postmenopausal women that anastrozole at a daily dose of 1 mg reduces the oestradiol level by more than 80%.

Anastrozole has no progestogenic, androgenic or oestrogenic effect.

Daily doses of anastrozole of up to 10 mg have no effect on cortisol or aldosterone production, measured before and after an ACTH challenge test. Corticoid supplements are therefore not required.

Primary adjuvant treatment of early breast cancer

In a large phase III clinical 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 benefit was observed for disease-free survival in favour of anastrozole in comparison with tamoxifen for the prospectively defined hormone receptor positive population. Anastrozole was statistically superior to tamoxifen in time to recurrence of the disease. The difference was of even greater benefit than in the endpoint disease-free survival for both the Intention To Treat (ITT) population and the hormone receptor positive population. Anastrozole was statistically superior to tamoxifen in terms of time to development of distant metastasis. The incidence of contralateral tumour was statistically reduced for anastrozole compared to tamoxifen. After 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 in comparison with tamoxifen. With a median follow-up of 68 months, patients 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 in comparison with tamoxifen.

(see next table)

ATAC Endpoint summary: Final analysis after 5-years of treatment

a. Disease-free survival includes all recurrent events and is defined as the time to first local recurrence, first occurrence of contralateral breast cancer, occurrence of distant metastasis or until death (for any reason).

b. Metastasis-free survival is defined as the time to first occurrence of distant metastasis or until death (for any reason).

c. Time to recurrence is defined as the time to first local recurrence, first occurrence of contralateral breast cancer, occurrence of distant metastasis or death due to breast cancer.

d. Time to occurrence of distant metastasis is defined as the time to first occurrence of distant metastasis or death due to breast cancer.

e. Number (%) of patients who had died.

As with all treatment decisions, physicians should assess the relative benefits and risks of the treatment together with the women suffering from breast cancer.

When anastrozole and tamoxifen were co-administered, the efficacy and safety were similar to administration of tamoxifen alone, irrespective of hormone receptor status. The exact mechanism of this is not yet clear. It is not assumed that a reduction in the oestradiol suppression effect of anastrozole is responsible.

Adjuvant treatment of early breast cancer in patients being treated with adjuvant tamoxifen

In a phase III clinical study (ABCSG 8) conducted in 2579 postmenopausal women with hormone receptor-positive early breast cancer who had received surgery with or without subsequent radiotherapy (but no chemotherapy), switching to anastrozole from tamoxifen was investigated. In this study with a median follow-up of 24 months, it was demonstrated that switching to anastrozole after 2-year adjuvant treatment with tamoxifen was statistically superior when compared to remaining on tamoxifen.

The time to disease recurrence, local recurrence or occurrence of distant metastasis, and occurrence of only distant metastasis confirmed a statistical advantage for anastrozole, consistent with the results for disease-free survival.

The incidence of primary tumour in the contralateral breast was very low in both study treatment groups with a numerical advantage, however, for anastrozole. Overall survival was equal in both study treatment groups.

(see table below)

Two further similar studies (GABG/ARNO 95 and ITA) have been conducted, in one of which patients had received surgery and chemotherapy. A combined analysis of ABCSG 8 and GABG/ARNO 95 also supports these results.

The safety profile in these three studies was consistent with the safety profile established in postmenopausal patients with hormone receptor-positive early breast cancer.

ABCSG 8 Summary of the endpoints and the study results

After oral administration, absorption of anastrozole is rapid and peak plasma concentrations typically occur within 2 hours of dosing (under fasting conditions). Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. Food intake slightly decreases the rate of absorption but has no effect on the extent of absorption. The small delay in absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of anastrozole. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are attained after 7 days. There is no evidence of time- or dose-dependency of the anastrozole pharmacokinetic parameters.

The pharmacokinetics of anastrozole is independent of age in postmenopausal women.

Pharmacokinetics has not been studied in children.

Only 40% of anastrozole is bound to plasma proteins.

Anastrozole is extensively metabolised in postmenopausal women with less than 10% of the dose being excreted in the urine in unchanged form within 72 hours. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted mainly with the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase.

The oral clearance of anastrozole 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.

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 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 was compromised. These effects were related to the pharmacological effects of the compound on parturition.

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

Carcinogenicity studies have been performed in rats and mice.

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.

In mice 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) were observed. These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant.

Tablet core:

lactose monohydrate

cellulose microcrystalline

sodium starch glycollate type A

magnesium stearate

silica colloidal anhydrous

hydroxypropylcellulose

Tablet coating:

Opadry II white:

lactose monohydrate

hypromellose

macrogol 4000

titanium dioxide E 171

Not applicable.

3 years

PVC/aluminium blister

This medicinal product does not require any special storage conditions.

HDPE container

Do not store above 30°C.

PVC/aluminium blister or HDPE container

pack sizes 10, 20, 28, 30, 50, 56, 84, 98, 100 film-coated tablets

Not all pack sizes may be marketed.

No special requirements

Sandoz Limited

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

PL 04416/1157

06^th November 2009

15/04/2011