Anastrozole-Vista film-coated tablets 1 mg blister No. 28

Instructions Anastrozole-Vista film-coated tablets 1 mg blister No. 28

Composition

active ingredient: anastrozole;

1 film-coated tablet contains 1 mg of anastrozole;

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

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

* - excipients related to the film coating

Dosage form

Film-coated tablets.

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

Pharmacotherapeutic group

Hormone antagonists and related agents. Aromatase inhibitors. ATX code L02B G03.

Pharmacological properties

Pharmacodynamics.

Mechanism of action and pharmacodynamic effects.

Anastrozole is a potent and highly selective nonsteroidal aromatase inhibitor. In postmenopausal women, estradiol is primarily produced by the conversion of androstenedione to estrone in peripheral tissues by the aromatase enzyme complex. Estrone is further converted to estradiol. Lowering circulating estradiol levels has been shown to have a therapeutic effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg resulted in an 80% reduction in estradiol levels, as confirmed by a highly sensitive analytical test.

Anastrozole has no progestogenic, androgenic, or estrogenic 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, there is no need for replacement corticosteroids.

Clinical efficacy and safety.

Breast cancer is common.

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

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

The primary endpoint of study 1033IL/0030 demonstrated that anastrozole had a statistically significant advantage over tamoxifen in terms of time to 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 tumour response rate was similar for anastrozole and tamoxifen. Study 1033IL/0027 demonstrated that the objective tumour response rate and time to progression were similar for anastrozole and tamoxifen. The secondary endpoints confirmed the primary efficacy endpoints. The relatively low mortality rates in the treatment groups of both studies did not allow conclusions to be drawn about differences in overall survival.

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

Anastrozole was studied in two controlled clinical trials (Studies 0004 and 0005) in postmenopausal women with advanced breast cancer who had progressed after tamoxifen treatment for advanced breast cancer or early breast cancer. A total of 764 patients were randomised to receive anastrozole 1 mg or 10 mg once daily or megestrol acetate 40 mg four times daily. Time to progression and objective response rate were the primary efficacy endpoints. The incidence of prolonged (>24 weeks) stable disease, progression rate and overall survival were also assessed. In both trials, there were no significant differences between treatment groups in any of the efficacy parameters. Adjuvant treatment of hormone receptor-positive early invasive breast cancer.

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

Summary table of endpoints obtained during the ATAS study:

analysis after completion of treatment, which lasted 5 years

Table 1

aDisease-free survival includes all recurrences and is defined as the first episode of locoregional recurrence, contralateral breast cancer, distant recurrence, or death (from any cause).

bMetastatic disease-free survival is defined as the first episode of metastatic recurrence or death (from any cause).

Time to recurrence is defined as the first episode of locoregional recurrence, contralateral breast cancer, distant recurrence, or death from breast cancer.

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

eNumber (%) of patients who died.

The combination of anastrozole and tamoxifen did not demonstrate superior efficacy compared with tamoxifen in all patients or in the hormone receptor-positive group. This treatment group was withdrawn from the study. Based on updated follow-up data with a median follow-up of 10 years, the long-term effects of anastrozole treatment compared with tamoxifen are consistent with the previous analysis.

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

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

Summary table of endpoints and results of the ABCSG 8 study

Table 2

Two subsequent similar studies (GABG/ARNO 95 and ITA), one of which included surgery and chemotherapy, and a combined analysis of ABCSG 8 and GABG/ARNO 95, support these findings.

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

Bone mineral density (BMD).

In the Phase III/IV Study of Anastrozole with the Bisphosphonate Risedronate [SABRE], 234 postmenopausal women with hormone receptor-positive early breast cancer who were scheduled to receive anastrozole 1 mg/day were stratified into low, intermediate, and high risk groups based on their risk of osteoporotic fracture. The primary efficacy parameter was lumbar spine bone 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 intermediate-risk group were randomized to receive anastrozole plus risedronate 35 mg once weekly (N = 77) or anastrozole plus placebo (N = 77), and patients in the high-risk group received anastrozole plus risedronate 35 mg once weekly (N = 38). The primary endpoint was change from baseline in lumbar spine bone density at 12 months.

The primary analysis at 12 months showed that patients at intermediate and high risk of osteoporotic fracture did not experience a reduction in bone mineral density (as assessed by lumbar spine bone mineral density using DEXA scanning) when anastrozole 1 mg/day was used in combination with risedronate 35 mg once weekly. In addition, a reduction in BMD, which was not statistically significant, was observed in the low-risk group when anastrozole 1 mg/day was used alone. These results were reflected in the secondary efficacy variable, change from baseline in total hip BMD at 12 months.

This study suggests that bisphosphonates should be considered for potential bone loss in postmenopausal women with early breast cancer who are scheduled to receive anastrozole. Pharmacokinetics.

Absorption.

Absorption of anastrozole is rapid, with peak plasma concentrations usually occurring within 2 hours (fasting). Food slightly slows the rate, but not the extent, of absorption. Minor changes in the rate of absorption do not have a clinically significant effect on steady-state plasma concentrations with once-daily dosing of anastrozole tablets. Approximately 90–95% of steady-state plasma concentrations of anastrozole are achieved after 7 days of dosing, with accumulation being 3–4-fold. There is no evidence of a time or dose-dependent relationship between the pharmacokinetics of anastrozole.

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

Only 40% of anastrozole binds to blood plasma proteins.

Breeding.

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

Impaired kidney or liver function.

Anastrozole plasma concentrations in volunteers with liver cirrhosis were within the range of concentrations observed in healthy volunteers.

Anastrozole plasma concentrations observed in long-term efficacy studies in patients with renal impairment were within the range of anastrozole plasma concentrations observed in patients without renal impairment. Anastrozole should be used with caution in patients with severe renal impairment.

Indication

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

Adjuvant treatment of early hormone receptor-positive 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.

Contraindication

Pregnancy or breastfeeding.

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

Special safety precautions

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

Interaction with other medicinal products and other types of interactions

Anastrozole inhibits CYP 1A2, 2C8/9 and 3A4 enzymes 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 and R- and S-warfarin. These data suggest that concomitant use of anastrozole with other medicinal products is unlikely to result in clinically significant drug interactions mediated by CYP enzymes. Enzymes mediating the metabolism of anastrozole have not been identified. Cimetidine, a weak non-specific inhibitor of CYP enzymes, does not affect plasma concentrations of anastrozole. There are no data on the effects of potent CYP inhibitors. A review of the safety database accumulated during clinical trials did not reveal any clinically significant drug interactions in patients taking anastrozole concomitantly with other commonly prescribed medicinal products. No clinically significant interactions with bisphosphonates have been reported. Concomitant use of tamoxifen or estrogen-containing agents with anastrozole should be avoided as this may reduce the pharmacological action of the latter.

Application features

General.

Anastrozole-Vista should not be used in premenopausal women. Menopause should be confirmed by biochemical tests (luteinizing hormone [LH], follicle-stimulating hormone [FSH] and/or estradiol levels) if the patient's menopausal status is in doubt. There are no data to support the use of anastrozole with luteinizing hormone-releasing factor (LHR) analogues.

The concomitant use of tamoxifen or estrogen-containing agents with anastrozole should be avoided as this may reduce the pharmacological effect of the latter.

In women with pre-existing coronary heart disease, an increased incidence of ischemic cardiovascular events was observed with anastrozole in the ATAC study (17% of patients taking anastrozole and 10% of patients taking tamoxifen). The risks and benefits of treating patients with pre-existing coronary heart disease with anastrozole should be weighed (see section 4.8).

Effect on bone mineral density.

As anastrozole reduces circulating oestrogen levels, this may lead to a decrease in bone mineral density with a possible increase in the risk of fracture. In women with osteoporosis or at risk of osteoporosis, bone mineral density should be assessed by bone densitometry, e.g. using dual-energy X-ray absorptiometry (DEHA), at the start of treatment and at regular intervals thereafter. If necessary, a medicinal product for the treatment or prevention of osteoporosis should be prescribed and the patient should be closely monitored. The use of specific agents, e.g. bisphosphonates, may halt further loss of bone mineral density caused by anastrozole in postmenopausal women and should therefore be considered.

Liver dysfunction.

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; caution should be exercised when using anastrozole in patients with moderate or severe hepatic impairment. Treatment should be based on an assessment of the benefit-risk ratio for the individual patient.

Kidney dysfunction.

Anastrozole has not been studied in breast cancer patients with severe renal impairment. Anastrozole exposure was not increased in patients with severe renal impairment (glomerular filtration rate [GFR] < 30 mL/min); caution should be exercised when using anastrozole in patients with severe renal impairment.

Children.

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

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

Important information about excipients.

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

Use during pregnancy or breastfeeding

Pregnancy: There are no data on the use of anastrozole in pregnant women. Anastrozole-Vista is contraindicated during pregnancy.

Breastfeeding. There are no data on the use of anastrozole during breastfeeding, therefore the drug is contraindicated during this period.

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

Animal studies have shown reproductive toxicity.

Ability to influence reaction speed when driving vehicles or other mechanisms

Anastrozole has no or negligible influence on the ability to drive and use machines. However, cases of asthenia and drowsiness have been reported in association with anastrozole. Therefore, caution should be exercised when driving or operating machinery if these symptoms occur.

Method of administration and doses

Anastrozole-Vista is taken orally.

The recommended dose for adults, including elderly women, is 1 tablet (1 mg) once a day.

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

Kidney dysfunction.

No dose adjustment is required in patients with mild or moderate renal impairment. Caution is required when using Anastrozole-Vista in patients with severe renal impairment.

Liver dysfunction.

No dose adjustment is required in patients with mild liver disease. The drug should be used with caution in patients with moderate to severe liver dysfunction.

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 has shown low acute toxicity. In clinical studies, various doses of anastrozole have been used: up to 60 mg once in healthy male volunteers and up to 10 mg daily in postmenopausal women with advanced breast cancer; these doses were well tolerated. A single dose of anastrozole resulting in life-threatening symptoms has not been established. Treatment. There is no specific antidote for overdose; treatment should be symptomatic. In the treatment of overdose, the possibility that multiple substances have been ingested should be considered. If the patient is not unconscious, vomiting may be induced. Dialysis may be useful, as anastrozole is not significantly protein bound. General supportive treatment, including frequent monitoring of vital signs, and close observation of the patient is recommended.

Side effects

The following adverse reactions are listed by frequency and system organ class (SOC). The frequency of occurrence is defined using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000) and very rare (<1/10,000). The most frequently reported adverse reactions are: headache, flushing, nausea, rash, arthralgia, joint mobility disorders, arthritis and asthenia.

Adverse reactions by SOC class and frequency

Table 3

**Since no cases of cutaneous vasculitis and Henoch-Schonlein purpura were observed in the ATAC study, the frequency of these events can be considered rare (≥ 0.01%, < 0.1%) based on the worst-case point estimate.

***Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer, during the first few weeks after switching from hormone therapy to anastrozole. If bleeding persists, further evaluation should be performed.

Reporting of suspected adverse reactions.

Reporting adverse reactions after registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of a medicinal product to the State Expert Center of the Ministry of Health of Ukraine at the link: https://aisf.dec.gov.ua/

Expiration date

3 years.

Storage conditions

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

Packaging

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

Vacation category

According to the recipe.

Producer

Manufacturer responsible for packaging and batch release:

Sinton Hispania, S.L.

Location of the manufacturer and address of its place of business.

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