Egistrozole

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EGISTROZOL (EGISTROZOL)

Composition:

Active substance: anastrozole;

1 tablet contains 1 mg of anastrozole;

Excipients: lactose monohydrate, sodium starch glycolate (type A), povidone, magnesium stearate, polyethylene glycol 400, hypromellose, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets with the imprint "ANA" and "1" on one side.

Pharmacotherapeutic group. Hormone antagonists and related agents.
Enzyme inhibitors. ATC code: L02BG03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action and pharmacodynamic effects

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is primarily produced by conversion of androstenedione to estrone in peripheral tissues via the aromatase enzyme complex. Estrone is then converted to estradi0l. Reduction of circulating estradiol levels has been shown to exert a therapeutic effect in women with breast cancer. In postmenopausal women, administration of anastrozole at a daily dose of 1 mg resulted in a reduction of estradiol levels by more than 80%, as confirmed by a highly sensitive assay.

Anastrozole has no progestogenic or androgenic activity.

Anastrozole at daily doses up to 10 mg does not affect cortisol or aldosterone secretion, measured before and after a standard adrenocorticotropic hormone (ACTH) stimulation test. Therefore, corticosteroid replacement therapy is not required.

Pharmacokinetics.

Absorption

Anastrozole is rapidly absorbed, with peak plasma concentrations typically reached within 2 hours (on an empty stomach). Food slightly slows the rate but not the extent of absorption. Minor changes in absorption rate do not lead to clinically significant effects on steady-state plasma concentrations when anastrozole tablets are administered once daily. Approximately 90–95% of steady-state plasma concentrations of anastrozole are achieved after 7 days of treatment, with accumulation being 3- to 4-fold. There is no evidence of time- or dose-dependent changes in the pharmacokinetic parameters of anastrozole.

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

Distribution

Only 40% of anastrozole is protein-bound in plasma.

Elimination

Anastrozole is eliminated slowly, with a plasma half-life of 40–50 hours. Food slightly slows the rate of absorption but not its extent. Anastrozole is extensively metabolized in postmenopausal women, with less than 10% of the dose excreted unchanged in urine within 72 hours after dose administration. Metabolism of anastrozole occurs via N-dealkylation, hydroxylation, and glucuronidation. Metabolites are primarily excreted in urine. Triazole, the major metabolite in plasma, does not inhibit aromatase.

Renal or hepatic impairment

Compared to matched controls, the apparent clearance (CL/F) of anastrozole after oral administration was approximately 30% lower in volunteers with compensated liver cirrhosis (study 1033IL/0014).

Plasma concentrations of anastrozole in volunteers with liver cirrhosis were within the range observed in healthy subjects.

In study 1033IL/0018, in volunteers with severe renal impairment (glomerular filtration rate [GFR] <30 mL/min), the apparent clearance (CL/F) of anastrozole after oral administration was unchanged, consistent with the fact that anastrozole is primarily eliminated by metabolism.

Plasma concentrations of anastrozole observed during long-term efficacy studies in patients with renal impairment were within the range of concentrations observed in patients with normal renal function. Use of anastrozole in patients with severe renal impairment should be undertaken with caution.

Clinical characteristics.

Indications.

Treatment of hormone receptor-positive advanced breast cancer in postmenopausal women.

Adjuvant treatment of early-stage hormone receptor-positive invasive breast cancer in postmenopausal women.

Adjuvant treatment of early-stage hormone receptor-positive invasive breast cancer in postmenopausal women who have received 2 to 3 years of prior adjuvant tamoxifen therapy.

Contraindications.

Egistrozole is contraindicated in patients:

• during pregnancy or breastfeeding;
• with known hypersensitivity to anastrozole or to any of the excipients.

Safety precautions.

Any unused medicinal products or waste materials should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Anastrozole inhibits CYP 1A2, 2C8/9, and 3A4 in vitro. Clinical studies using antipyrine and warfarin have shown that anastrozole at a dose of 1 mg does not significantly inhibit the metabolism of antipyrine or R- and S-warfarin, indicating that coadministration of Egistrozole with other medicinal products is unlikely to result in clinically significant drug interactions mediated by CYP enzymes. In a study conducted in 16 healthy volunteers, anastrozole did not affect exposure (defined by Cmax and AUC) or anticoagulant activity (defined by prothrombin time, activated partial thromboplastin time, and thrombin time) of R- and S-warfarin.

The enzymes mediating anastrozole metabolism have not been identified. Cimetidine, a weak non-specific CYP enzyme inhibitor, does not affect plasma concentrations of anastrozole. Data on the effect of strong CYP inhibitors are lacking.

Review of the drug safety database accumulated during clinical trials revealed no evidence of clinically significant drug interactions in patients who received Egistrozole concomitantly with other commonly prescribed medications.

Tamoxifen should not be administered together with Egistrozole, as it may reduce the pharmacological effect of the latter (see sections "Special precautions for use" and "Pharmacological properties").

Estrogens should not be administered concurrently with Egistrozole, as these agents have opposing pharmacological effects.

No significant clinical interactions have been reported with bisphosphonates (see section "Pharmacological properties").

Special precautions for use.

General

Egistrozole should not be used in premenopausal women.

Menopause should be confirmed by biochemical test results (levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or estradiol). There are no data on the use of anastrozole with luteinizing hormone-releasing hormone (LHRH) analogues. Concomitant use of anastrozole and tamoxifen or estrogen-containing products should be avoided, as this may reduce their pharmacological effect. The risks and benefits of anastrozole treatment should be carefully considered in patients with existing ischemic heart disease (see section "Adverse reactions").

Liver function impairment

There are no data on the safety of Egistrozole use in patients with moderate to severe liver function impairment. In patients with impaired liver function, exposure to anastrozole may be increased; therefore, caution is required when administering Egistrozole to patients with moderate to severe hepatic impairment. Treatment should be based on an individual assessment of benefit-risk ratio for each patient.

Kidney function impairment

There are no data on the safety of Egistrozole use in patients with severe renal impairment (glomerular filtration rate below 30 mL/min). Use of the drug in patients with severe renal impairment requires caution.

Effect on bone mineral density

Since Egistrozole reduces circulating estrogen levels, it may lead to decreased bone mineral density and a potential increase in fracture risk. In women with osteoporosis or at risk of osteoporosis, bone mineral density should be assessed at the beginning of treatment and monitored regularly thereafter using bone densitometry, for example, DEXA scanning. If necessary, treatment or prophylaxis of osteoporosis should be initiated, and the patient should be monitored. The use of specific agents, such as bisphosphonates, may prevent further bone mineral density loss caused by anastrozole in postmenopausal women, and the appropriateness of such use should be evaluated.

The product contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Data on the use of Egistrozole in pregnant women are lacking. Egistrozole is contraindicated during pregnancy (see section "Contraindications").

The effect of the drug on reproductive function in humans has not been studied. Animal studies have shown reproductive toxicity.

Data on the use of Egistrozole during lactation are lacking. Egistrozole is contraindicated during breastfeeding (see section "Contraindications").

Fertility

The effect of Egistrozole on human fertility has not been studied. Animal studies have demonstrated reproductive toxicity.

Ability to affect reaction speed when driving or operating machinery.

Egistrozole has no effect or has a negligible effect on the ability to drive or operate machinery. However, there have been reports of asthenia and somnolence associated with the use of Egistrozole, and caution should be exercised when driving or operating machinery if these symptoms occur.

Method of administration and dosage.

Egistrozole is administered orally.

The recommended dose for adults, including elderly women, is 1 tablet of Egistrozole (1 mg) once daily.

For early-stage invasive hormone receptor-positive breast cancer in postmenopausal women, the recommended duration of adjuvant endocrine therapy is 5 years.

Renal impairment: Dose adjustment is not required in patients with mild or moderate renal impairment. Egistrozole should be used with caution in patients with severe renal impairment (see sections "Special precautions" and "Pharmacological properties").

Hepatic impairment: Dose adjustment is not required in patients with mild hepatic impairment. Egistrozole should be used with caution in patients with moderate or severe hepatic impairment (see section "Special precautions").

For early-stage invasive hormone receptor-positive breast cancer in postmenopausal women, the recommended duration of adjuvant endocrine therapy is 5 years.

Children.

Egistrozole is not recommended for use in children due to insufficient data on safety and efficacy (see section "Special precautions").

Overdose.

Clinical experience with accidental overdose is limited. In animal studies, anastrozole demonstrated low acute toxicity. During clinical trials, various doses of anastrozole were administered: up to 60 mg as a single dose to healthy male volunteers and up to 10 mg daily to postmenopausal women with advanced breast cancer; these doses were well tolerated. A single dose of anastrozole causing life-threatening symptoms has not been established. There is no specific antidote; treatment is symptomatic.

When managing overdose, the possibility of ingestion of multiple substances should be considered. If the patient is not unconscious, vomiting may be induced. Dialysis may be beneficial, as anastrozole is not highly protein-bound. General supportive therapy is recommended, including frequent monitoring of vital functions and careful observation of the patient.

Side effects

During the use of Exemestane, as with any medication, adverse reactions may occur.

The adverse reactions listed below are classified by frequency and by system organ classes (SOC). The frequency classification is based on the following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000). The most frequently reported adverse reactions were: headache, hot flushes, nausea, rash, arthralgia, joint stiffness, arthritis, and asthenia.

Table 3

*The incidence of carpal tunnel syndrome was higher in patients receiving anastrozole in clinical trials compared to those receiving tamoxifen. However, most of these cases occurred in patients with defined risk factors for developing this condition.

**Since cases of cutaneous vasculitis and Henoch–Schönlein purpura were not observed in the ATAC trial, the frequency of these events can be considered rare (from ≥0.01% to <0.1%) based on the worst-case value of the point estimate.

***Vaginal bleeding occurred commonly, primarily in patients with advanced breast cancer during the first few weeks after switching from hormonal therapy to anastrozole treatment. If bleeding persists, further investigation should be performed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the drug. Healthcare professionals are asked to report any suspected adverse reactions.

Shelf life. 4 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of the reach of children.

Packaging.

14 tablets in a blister; 2 blisters in a cardboard box;

or 10 tablets in a blister; 3 or 9 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

EGIS Pharmaceuticals PLC, Hungary / EGIS Pharmaceuticals PLC, Hungary.

Synthon Hispania, S.L., Spain / Synthon Hispania, S.L., Spain.

Manufacturer's address and location of operations.

1165 Budapest, Bokenyfoldi ut. 118-120, Hungary /
1165 Budapest, Bokenyfoldi ut. 118-120, Hungary.

C/ Castello, no 1, Sant Boi de Llobregat, Barcelona, 08830, Spain /
C/ Castello, no 1, Sant Boi de Llobregat, Barcelona, 08830, Spain.