Anastrozole — vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANASTROZOLE-VISTA (ANASTROZOLE-VISTA)

Composition:

Active substance: anastrozole;

1 film-coated tablet contains 1 mg of anastrozole;

Excipients: lactose monohydrate; sodium starch glycolate, povidone, magnesium stearate;

polyethylene glycol (PEG 400)*, hypromellose*, titanium dioxide (E 171)*.

* - excipients belonging to the film coating

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Hormone antagonists and related agents. Aromatase inhibitors. ATC code: L02B G03.

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 the conversion of androstenedione to estrone in peripheral tissues via the enzyme complex aromatase. Estrone is then further converted to estradiol. Reduction in 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 resulted in an 80% reduction in estradiol levels, as confirmed by a highly sensitive analytical assay.

Anastrozole has no progestagenic, androgenic, or estrogenic activity.

Anastrozole at daily doses up to 10 mg does not affect the secretion of cortisol and aldosterone, as measured before and after a standard adrenocorticotropic hormone (ACTH) stimulation test. Therefore, there is no need for corticosteroid replacement therapy. Clinical Efficacy and Safety.

Advanced Breast Cancer.

First-line therapy in postmenopausal women with advanced breast cancer.

Two double-blind, controlled clinical trials with similar designs (study 1033IL/0030 and study 1033IL/0027) were conducted to evaluate the efficacy of anastrozole compared to tamoxifen as first-line therapy for the treatment of locally advanced or metastatic breast cancer with positive or unknown hormone receptor status in postmenopausal women. Overall, 1021 patients were randomized to receive either anastrozole 1 mg once daily or tamoxifen 20 mg once daily. The primary endpoints in both studies were time to tumor progression, objective tumor response rate, and safety.

Evaluation of the primary endpoints in study 1033IL/0030 demonstrated that anastrozole had a statistically significant advantage over tamoxifen in terms of time to tumor progression (hazard ratio (HR) 1.42; 95% confidence interval (CI) [1.11; 1.82], median time to progression 11.1 and 5.6 months for anastrozole and tamoxifen, respectively, p = 0.006); the objective tumor response rate was similar for anastrozole and tamoxifen. Study 1033IL/0027 showed that the objective tumor response rate and time to tumor progression were similar between anastrozole and tamoxifen. Assessment of secondary endpoints confirmed the evaluation of primary efficacy endpoints. The relatively low number of deaths in the treatment groups of both studies did not allow conclusions to be drawn regarding differences in overall survival rates.

Second-line therapy in postmenopausal women with advanced breast cancer.

Anastrozole was evaluated in two controlled clinical trials (study 0004 and study 0005) involving postmenopausal women with advanced breast cancer whose disease had progressed after prior tamoxifen treatment for either advanced or early-stage breast cancer. A total of 764 patients were randomized to receive either anastrozole 1 mg or 10 mg once daily or megestrol acetate 40 mg four times daily. Time to tumor progression and objective response rate were the primary efficacy endpoints. Additional endpoints included the rate of prolonged (more than 24 weeks) stable disease, progression rate, and overall survival. In both studies, no significant differences between treatment groups were observed for any of the efficacy parameters. Adjuvant Treatment of Early-Stage Hormone Receptor-Positive Invasive Breast Cancer.

In a large phase III trial involving 9366 postmenopausal women with operable breast cancer treated over 5 years (see below), anastrozole demonstrated statistically superior disease-free survival compared to tamoxifen. Significantly greater benefits in disease-free survival in favor of anastrozole compared to tamoxifen were observed in the prospectively defined population with hormone receptor-positive tumors.

Summary table of endpoints from the ATAC trial:

analysis after completion of 5 years of treatment

Table 1

aDisease-free survival includes all recurrence events and is defined as the first occurrence of local or regional recurrence, contralateral breast cancer, distant recurrence, or death from any cause.

bMetastasis-free survival is defined as the first occurrence of metastatic recurrence or death from any cause.

cTime to recurrence is defined as the first occurrence of local or regional recurrence, contralateral breast cancer, distant recurrence, or death from breast cancer.

dTime to metastatic recurrence is defined as the first occurrence of metastatic recurrence or death from breast cancer.

eNumber (%) of patients who died.

The combination of anastrozole and tamoxifen did not demonstrate greater efficacy compared to tamoxifen alone in all patients, or in the subgroup of patients with hormone receptor-positive disease. This treatment arm was discontinued from the study. According to updated follow-up data with a median of 10 years, the long-term effects of anastrozole treatment compared to tamoxifen are consistent with the previous analysis.

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

In a Phase III clinical trial (Austrian Breast and Colorectal Cancer Study Group [ABCSG] 8), which included 2,579 postmenopausal women with early-stage hormone receptor-positive breast cancer who had undergone surgery with or without radiotherapy but had not received chemotherapy (see below), disease-free survival was statistically superior in the group of patients who were switched to anastrozole after 2 years of adjuvant tamoxifen therapy compared to the group who continued tamoxifen, after a median follow-up period of 24 months.

Summary table of study endpoints and results from ABCSG 8

Table 2

Two further similar studies (GABG/ARNO 95 and ITA), one of which included patients who received surgical treatment and chemotherapy, as well as a combined analysis of the ABCSG 8 and GABG/ARNO 95 studies, confirm these results.

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

Bone mineral density (BMD).

In a Phase III/IV study (Study of Anastrozole with the Bisphosphonate Risedronate [SABRE]), 234 postmenopausal women with hormone receptor-positive early breast cancer scheduled to receive anastrozole 1 mg daily were stratified into low, medium, and high-risk groups based on their existing risk of osteoporotic fracture. The primary efficacy parameter was analysis of lumbar spine bone mineral density using DEXA scanning. All patients received vitamin D and calcium. Patients in the low-risk group received anastrozole alone (N = 42); patients in the medium-risk group were randomized to receive either anastrozole plus risedronate 35 mg once weekly (N = 77) or anastrozole plus placebo (N = 77); patients in the high-risk group received anastrozole plus risedronate 35 mg once weekly (N = 38). The primary endpoint was the change in lumbar spine bone mineral density at 12 months compared to baseline.

The primary analysis at 12 months showed that in patients at medium and high risk of osteoporotic fracture, there was no reduction in bone mineral density (assessed by DEXA scanning of lumbar spine BMD) when anastrozole 1 mg daily was administered in combination with risedronate 35 mg once weekly. Additionally, a non-statistically significant decrease in BMD was observed in the low-risk group receiving anastrozole alone at 1 mg daily. These findings were mirrored in the secondary efficacy variable, change in total hip BMD at 12 months compared to baseline.

This study supports the consideration of bisphosphonate use to prevent potential bone loss in postmenopausal women with early-stage breast cancer who are planned to receive anastrozole.

Pharmacokinetics.

Absorption.

Anastrozole is rapidly absorbed, with peak plasma concentrations usually reached within 2 hours (fasting). Food slightly slows the rate, but not the extent, of absorption. The minor changes in absorption rate do not result in 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 dosing, 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 elimination half-life of 40–50 hours. Food slightly slows the rate of absorption but does not affect its extent. 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 primarily excreted in urine. Triazole, the major metabolite in plasma, does not inhibit aromatase.

Renal or hepatic impairment.

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

Plasma concentrations of anastrozole observed during long-term efficacy studies in patients with renal impairment were within the range seen in patients with normal renal function. Caution is advised when administering anastrozole to patients with severe renal impairment.

Clinical characteristics.

Indications.

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

Contraindications.

• Pregnancy or breastfeeding.
• Known hypersensitivity to anastrozole or to any of the excipients of the medicinal product.

Safety precautions.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Anastrozole inhibits the CYP 1A2, 2C8/9, and 3A4 enzymes in vitro. Clinical studies using antipyrine and warfarin have demonstrated that anastrozole at a dose of 1 mg does not significantly inhibit the metabolism of antipyrine or R- and S-warfarin. These data suggest that co-administration of anastrozole with other medicinal products is unlikely to result in clinically significant drug interactions mediated by CYP enzymes. The enzymes responsible for the metabolism of anastrozole have not been identified. Cimetidine, a weak non-specific inhibitor of CYP enzymes, does not affect plasma concentrations of anastrozole. Data on the effect of strong CYP inhibitors are lacking. Review of the safety database accumulated during clinical trials has not revealed evidence of clinically significant drug interactions in patients who received anastrozole concomitantly with other commonly prescribed medicinal products. No clinically significant interactions with bisphosphonates have been reported. Concomitant use of tamoxifen or estrogen-containing products with anastrozole should be avoided, as this may diminish the pharmacological effect of anastrozole.

Special precautions for use.

General.

Anastrozole-Vista should not be used in premenopausal women. Menopause should be confirmed by biochemical testing (levels of luteinizing hormone [LH], follicle-stimulating hormone [FSH], and/or estradiol) in cases of uncertainty regarding the menopausal status of the patient. There are no data supporting the use of anastrozole in combination with luteinizing hormone-releasing hormone (LHRH) analogues.

Concomitant use of tamoxifen or estrogen-containing products with anastrozole should be avoided, as this may reduce the pharmacological effect of the latter.

In women with existing ischemic heart disease, during the ATAC trial an increased frequency of ischemic cardiovascular events was observed with anastrozole treatment (in 17% of patients receiving anastrozole and in 10% of patients receiving tamoxifen). The risks and benefits of anastrozole treatment should be carefully considered in patients with pre-existing ischemic heart disease (see section "Adverse reactions").

Effect on bone mineral density.

Since anastrozole reduces circulating estrogen levels, it may lead to decreased bone mineral density and a potential increased risk of fracture. In women with osteoporosis or at risk of osteoporosis, bone mineral density should be assessed by bone densitometry, for example, using dual-energy X-ray absorptiometry (DEXA), at the beginning of treatment and at regular intervals during therapy. If necessary, a medicinal product for the treatment or prevention of osteoporosis should be prescribed, and the patient should be closely monitored. Specific treatments, such as bisphosphonates, may prevent further bone mineral density loss caused by anastrozole in postmenopausal women; therefore, the appropriateness of such treatment should be evaluated.

Hepatic impairment.

Anastrozole has not been studied in patients with breast cancer and moderate or severe hepatic impairment. Exposure to anastrozole may be increased in patients with hepatic impairment; therefore, caution is required when administering anastrozole 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.

Anastrozole has not been studied in patients with breast cancer and severe renal impairment. Exposure to anastrozole was not increased in patients with severe renal impairment (glomerular filtration rate [GFR] < 30 mL/min); however, caution is required when administering anastrozole to patients with severe renal impairment.

Children.

Anastrozole-Vista is not indicated for use in children, as safety and efficacy have not been established in this patient group.

Anastrozole should not be used in boys with growth hormone deficiency as an adjunct to growth hormone therapy. Efficacy was not demonstrated and safety has not been established in the pivotal clinical trial. Since anastrozole reduces estradiol levels, it should not be used in girls with growth hormone deficiency as an adjunct to growth hormone therapy. Long-term safety data for use in children are lacking.

Important information about excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of anastrozole in pregnant women are lacking. Anastrozole-Vista is contraindicated during pregnancy.

Breastfeeding. Data on the use of anastrozole during breastfeeding are lacking; therefore, the medicinal product is contraindicated during this period.

Fertility. The effect of anastrozole on human fertility has not been studied.

Animal studies have demonstrated reproductive toxicity.

Ability to influence reaction speed when driving or operating machinery.

Anastrozole has no effect or has a negligible effect on the ability to drive or operate machinery. However, cases of asthenia and somnolence associated with anastrozole have been reported. Therefore, caution should be exercised when driving or operating machinery if such symptoms occur.

Method of administration and dosage.

Anastrozole-Vista is administered orally.

The recommended dose for adults, including elderly women, is 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. Anastrozole-Vista should be used with caution in patients with severe renal impairment.

Hepatic impairment.

Dose adjustment is not required in patients with mild hepatic disease. Anastrozole-Vista should be used with caution in patients with moderate or severe hepatic impairment.

Children.

Anastrozole-Vista is not recommended for use in children due to insufficient data on safety and efficacy.

Overdose.

Symptoms. 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. Treatment. There is no specific antidote for overdose; treatment should be symptomatic. When managing overdose, consider the possibility that multiple substances may have been ingested. If the patient is conscious, induced emesis may be considered. Dialysis may be beneficial since anastrozole is not highly protein-bound. General supportive care, including frequent monitoring of vital functions and close observation of the patient, is recommended.

Adverse reactions

The adverse reactions listed below are classified by frequency and by system organ classes (SOC). The 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 mobility limitation, arthritis, and asthenia.

Adverse reactions by SOC classes and frequency

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 identifiable risk factors for developing this condition.

**As cases of cutaneous vasculitis and Henoch-Schönlein purpura were not observed in the ATAC trial, the frequency of these events can be considered rare (≥ 0.01%, < 0.1%) based on the worst-case 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 evaluation should be conducted.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua/

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging. 14 tablets in a blister, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Manufacturer responsible for packaging and batch release:

Cinfa España, S.L.

Manufacturer's address and location of operations.

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.