Anastrozole sandoz®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Anastrazole SANDOZ® (Anastrozole SANDOZ®)

Composition:

Active substance: anastrozole;

1 tablet contains 1.0 mg of anastrozole;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, colloidal anhydrous silicon dioxide, hydroxypropylcellulose, Opadry II White (lactose monohydrate, hypromellose, titanium dioxide (E 171), polyethylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets without a break line, embossed with A1 on one side.

Pharmacotherapeutic group. Enzyme inhibitors.

ATC code L02BG03.

Pharmacological Properties.

Pharmacodynamics.

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 enzyme aromatase. Estrone is subsequently converted to estradiol. Reduction of circulating estradiol levels exerts a therapeutic effect in women with breast cancer. In postmenopausal women, administration of anastrozole at a daily dose of 1 mg reduces estradiol levels by 80%. Anastrozole has no progestogenic or androgenic activity. Anastrozole at daily doses up to 10 mg does not affect cortisol and aldosterone secretion, measured before and after a standard adrenocorticotropic hormone (ACTH) stimulation test. Therefore, corticosteroid replacement therapy is not required.

Pharmacokinetics.

Anastrozole is rapidly absorbed, with peak plasma concentrations reached within 2 hours (on an empty stomach). Anastrozole is eliminated slowly. The elimination half-life from plasma is 40–50 hours. Food slightly slows the rate of absorption but does not affect its extent. Minor changes in absorption rate do not lead to clinically significant effects on steady-state plasma concentrations with daily administration of anastrozole once daily.

Approximately 90–95% of steady-state concentration is achieved after 7 days of treatment. There is no evidence of time- or dose-dependent changes in the pharmacokinetic parameters of anastrozole.

The pharmacokinetics of anastrozole are not influenced by the age of postmenopausal women.

The pharmacokinetics of anastrozole in children have not been studied.

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

Anastrozole is extensively metabolized in postmenopausal women, with less than 10% of the dose excreted unchanged in urine within 72 hours after administration. Metabolism of anastrozole occurs via N-dealkylation, hydroxylation, and glucuronidation. Metabolites are excreted primarily in urine. The triazole metabolite—the main circulating metabolite in plasma—does not inhibit aromatase.

The clearance of anastrozole in volunteers with stable cirrhosis of the liver or with impaired renal function does not differ from that in healthy volunteers.

Clinical Characteristics

Indications

Treatment of advanced hormone receptor-positive 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 adjuvant tamoxifen therapy.

Contraindications

Anastrozole SANDOZ® is contraindicated in patients:

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

Interaction with Other Medicinal Products and Other Forms of Interactions

Anastrozole inhibits cytochrome P450 1A2, 2C8/9, and 3A4 in vitro. Clinical studies with 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, suggesting that concomitant administration of anastrozole with other medicinal products is unlikely to result in clinically significant drug interactions mediated by CYP enzymes.

The enzymes involved in the metabolism of anastrozole have not been identified. Cimetidine, a weak non-specific inhibitor of CYP enzymes, did not affect plasma concentrations of anastrozole. The effect of strong CYP inhibitors is unknown. The clinical significance of these findings remains unclear. Until further data are available, caution should be exercised when combining anastrozole with medicinal products metabolized by these enzymes, particularly those with a narrow therapeutic index.

Review of the safety database accumulated during clinical trials has not revealed evidence of clinically significant drug interactions in patients receiving anastrozole concomitantly with other commonly prescribed medications.

Tamoxifen or estrogen-containing products should not be co-administered with Anastrozole SANDOZ® as they may counteract the pharmacological effect of the latter.

No clinically significant interactions with bisphosphonates have been reported.

Special precautions for use

General

Anastrozole SANDOZ® must 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 gonadotropin-releasing hormone (GnRH) analogues. Concomitant use of anastrozole with 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 pre-existing ischemic heart disease (see section "Side effects").

Hepatic impairment

There are no data on the safety of Anastrozole SANDOZ® in patients with moderate to severe hepatic impairment. Exposure to anastrozole may be increased in patients with hepatic impairment; therefore, caution is required when administering Anastrozole SANDOZ® to patients with moderate or severe hepatic impairment. Treatment decisions should be based on an individual assessment of benefit versus risk for each patient.

Renal impairment

There are no data on the safety of Anastrozole SANDOZ® 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 Anastrozole SANDOZ® 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 by bone densitometry (e.g., DEXA scanning) at the start of treatment and monitored regularly during therapy. If necessary, treatment or prophylaxis of osteoporosis should be initiated and the patient monitored. The use of specific agents, such as bisphosphonates, may prevent further bone mineral density loss induced by anastrozole in postmenopausal women, and the appropriateness of such treatment should be evaluated.

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

Use during pregnancy or breastfeeding

Animal studies have shown reproductive toxicity.

There are no data on the use of anastrozole in pregnant or breastfeeding women.

Anastrozole SANDOZ® is contraindicated during pregnancy and breastfeeding. The effect on human fertility has not been studied.

Ability to affect reaction speed when driving or operating machinery

Anastrozole SANDOZ® has no effect or has a negligible effect on the ability to drive or operate machinery. However, due to reports of asthenia and somnolence associated with the use of the drug, caution is advised when driving or operating machinery.

Method of administration and dosage.

Astrazole Sandoz® is administered orally.

Adult women, including elderly women – 1 tablet (1 mg) once daily.

For early-stage hormone receptor-positive invasive 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. Use of Astrazole Sandoz® in patients with severe renal impairment should be undertaken with caution.

Hepatic impairment: Dose adjustment is not required in patients with mild hepatic impairment. Astrazole Sandoz® should be used with caution in patients with moderate to severe hepatic impairment.

Pediatric population: Astrazole Sandoz® is not recommended for use in children.

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.

In 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.

Adverse Reactions

During treatment with the medicinal product Anastrozole SANDOZ®, as with any medicinal products, adverse events may occur.

The table below presents adverse reactions observed during clinical and post-marketing studies or reported spontaneously.

The adverse reactions listed below are classified by frequency and by system organ classes. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <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.

*Vaginal bleeding has been frequently reported, occurring mainly in patients with advanced breast cancer during the first few weeks after switching from hormonal therapy to anastrozole treatment. If bleeding persists, the patient should be further investigated.

** Cases of carpal tunnel syndrome were observed significantly more often in patients receiving anastrozole treatment during clinical trials compared to those receiving tamoxifen.

In a study conducted in postmenopausal women with operable breast cancer who were treated for 5 years, ischemic events related to the cardiovascular system were more frequent in patients taking anastrozole compared to those receiving tamoxifen, although the difference was not statistically significant. The observed difference was mainly driven by reports of angina pectoris and was associated with the subgroup of patients who had previously suffered from ischemic heart disease.

Anastrozole SANDOZ® reduces circulating estrogen levels, which may lead to decreased bone mineral density and consequently increases the risk of fractures in some patients.

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 30°C. Store in the original packaging to protect from light. Keep out of reach of children.

Packaging. 14 tablets in a blister pack; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

SALUTAS Pharma GmbH.

Manufacturer's address and location of operations.

Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.

Date of last review.