Axastrol

Excipient(s): Each tablet contains 65 mg of Lactose monohydrate

For a full list of excipients, see section 6.1.

White, round film-coated tablet with a diameter of 6.6 mm approximately.

Treatment of advanced breast cancer in postmenopausal women. The efficacy of AXASTROL has not been demonstrated in oestrogen-receptor negative patients, unless they have had a previous positive clinical response to tamoxifen.

4.2 Posology and method of administration

For adults and elderly patients 1 film-coated tablet to be taken orally once a day.

There is no relevant indication for use of AXASTROL in children.

In mild to moderate impairment of renal function no adjustment of the dose is required.

In mild impairment of hepatic function no adjustment of the dose is required.

In early-stage breast cancer the recommended duration of treatment is 5 years.

4.3 Contraindications

The use of [Product name] is contraindicated:

- in hypersensitivity to anastrozole or to any of the excipients of the product;

- during the pre-menopausal period;

- during pregnancy and lactation;

- in severe renal impairment (if creatinine clearance is below 20 ml/min);

- in moderate or severe hepatic diseases;

- in patients being treated concomitantly with oestrogen-containing medicinal products (see section 4.5);

- in patients being treated concomitantly with tamoxifen (see section 4.5).

4.4 Special warnings and precautions for use

The onset of the menopause must be confirmed biochemically if the hormonal status of the patient cannot be established with clinical methods.

There are no data to support the safe use of AXASTROL in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance below 20 ml/min).

The use of oestrogen-lowering medicinal products, including AXASTROL, may reduce bone mineral density and, as a possible consequence, may be accompanied by an increased risk of fractures.

In patients with osteoporosis or at risk of that disease, bone density checks are required at the initiation of therapy and at regular intervals thereafter. If considered necessary, preventive and adjuvant treatment is recommended with careful monitoring.

No data are available on its concomitant administration with LHRH analogues; therefore, this combination is restricted for use only in clinical studies.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

No clinically significant interactions between Anastrozole and other drugs were observed.

Tamoxifen and/or other oestrogen-containing medicines should not be administered concomitantly with AXASTROL, as they may diminish the pharmacological and therapeutic action of anastrozole.

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 is contraindicated in pregnancy.

Lactation

It is unknown whether Anastrozole is excreted in human milk. contraindicated during breast-feeding

4.7 Effects on ability to drive and use machines

AXASTROL is unlikely to impair the ability of the patient to react quickly. However, if asthenia or somnolence occurs with its use, patients must not drive vehicles or perform dangerous work while such symptoms persist.

4.8 Undesirable effects

Due to the pharmacological actions of anastrozole, hot flushes, vaginal dryness and hair thinning may develop. During the use of AXASTROL gastrointestinal complaints (anorexia, nausea, vomiting and diarrhoea), asthenia, joint pain/stiffness, somnolence, headache and mild rashes may occur, including rare forms of mucodermal disorders, such as erythema multiforme and Stevens-Johnson syndrome.

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 of the patient is necessary.

4.9 Overdose

There is limited clinical experience of overdose of anastrozole.

In animal studies, anastrozole demonstrated low acute toxicity.

Clinical trials have been conducted with various dosages of anastrozole, up to 60 mg in a single dose geven 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 simultaneously. If the patient is alert, it is recommended to induce vomiting.

Dialysis may be helpful for the elimination of the medicine that has been absorbed already because anastrozole is not highly protein bound.

General supportive care, including frequent monitoring of vital signs and close observation of the patient, is recommended.

Pharmacotherapeutic group: Enzyme Inhibitors, ATC code: L02BG03

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex present in peripheral tissues. Estrone is subsequently converted to estradiol.

Reducing the levels of circulating estradiol has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg suppressed estradiol levels by more than 80 %.

Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity.

Regular daily doses of anastrozole up to 10 mg did not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed during its administration.

In a large phase III clinical study conducted in 9,366 postmenopausal women with early-stage invasive breast cancer, adjuvant treatment with anastrozole continued for 5 years after surgery was shown to be statistically superior to tamoxifen in disease-free survival. This benefit in favour of anastrozole versus tamoxifen was more pronounced in patients with hormone-receptor positive tumours.

Anastrozole proved to be statistically superior to tamoxifen in time to recurrence. The difference was of even greater magnitude than the one observed in disease-free survival for both the Intention To Treat (ITT) population and hormone-receptor positive population.

Anastrozole proved to be statistically superior to tamoxifen in terms of time to distant recurrence. A numerical trend could be detected in favour of anastrozole also for distant disease-free survival.

The incidence of contralateral breast cancers was statistically reduced for anastrozole compared to the tamoxifen arm.

The overall survival benefit of tamoxifen was maintained with anastrozole treatment. The additional analysis of the time to death following recurrence showed a numerical trend in favour of anastrozole compared to tamoxifen.

Overall, anastrozole was well tolerated. The following adverse events were reported regardless of causality: Patients receiving anastrozole had a decrease in hot flushes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and cerebrovascular events compared with patients in the tamoxifen arm. However, patients treated with anastrozole had a higher incidence of joint disorders (including arthritis, arthrosis and arthralgia) and of fractures. During a follow up of 68 months, a fracture rate of 22 per 1,000 patient years was observed in the anastrozole arm and 15 per 1,000 patient years with the tamoxifen group. The fracture rate for anastrozole remained within the broad range of the fracture rates reported in an age matched postmenopausal population.

The combination of anastrozole and tamoxifen did not demonstrate any therapeutic benefit in comparison to tamoxifen alone either in the whole population or in hormone-receptor positive patients. The combination treatment arm of the study was discontinued.

The safety profile of anastrozole obtained in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor positive, early-stage breast cancer.

5.2 Pharmacokinetic properties

The pharmacokinetics of anastrozole are independent of age in postmenopausal women. Pharmacokinetics have not been studied in children.

Absorption

Absorption of anastrozole, the active substance of AXASTROL, is rapid. Maximum plasma concentrations typically occur within two hours of dosing if the medicine is given under fasting conditions. Food causes a slight decrease in the rate but not in the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on the steady-state plasma concentrations during once daily dosing of AXASTROL tablets. After 7 daily doses, the plasma anastrozole concentrations attained are 90-95% of the steady-state concentration. There is no evidence of a time or dose-dependency of the pharmacokinetic parameters of anastrozole.

Distribution

Anastrozole is 40% bound to plasma proteins.

Metabolism

Anastrozole is extensively metabolised by postmenopausal women, with less than 10 % of the dose excreted unchanged in the urine 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 of anastrozole in plasma, does not inhibit the aromatase enzyme.

Excretion

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

In volunteers with stable hepatic cirrhosis or renal impairment, the oral clearance of anastrozole remained in the range observed in healthy volunteers.

5.3 Preclinical safety data

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 performed 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
• Maize starch
• Povidone K-30
• Cellulose microcrystalline pH 102
• Sodium starch glycolate Type A
• Silica colloidal anhydrous
• Magnesium stearate (E 572)
• Talc

Film-coating:

• Hypromellose 5cp (E 464)
• Macrogol 400
• Titanium dioxide (E 171)
• Talc

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/Aluminium blisters.

Pack sizes: 20, 28, 30, 50, 84, 98, 100 and 300 tablets contained in a carton.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling