Arimidex film-coated tablets 1 mg No. 28

Instructions for Arimidex film-coated tablets 1 mg No. 28

Composition

active ingredient: anastrozole;

1 film-coated tablet contains 1 mg of anastrozole;

excipients: lactose monohydrate; povidone, sodium starch glycolate (type A), magnesium stearate; film coating: hypromellose, macrogol 300, titanium dioxide (E 171).

Dosage form

Film-coated tablets.

Main physicochemical properties: round, white, biconvex tablets, film-coated. The tablets are engraved.

Pharmacotherapeutic group

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

Pharmacological properties

Pharmacodynamics

Mechanism of action and pharmacodynamic effects

Arimidex is a potent, 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. It has been demonstrated that lowering circulating estradiol levels has a therapeutic effect in women with breast cancer. In postmenopausal women, Arimidex at a daily dose of 1 mg resulted in a reduction in estradiol levels of more than 80%, as confirmed by a highly sensitive assay.

Arimidex has no progestogenic, androgenic, or estrogenic activity.

Arimidex 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

Advanced breast cancer

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 Arimidex compared with tamoxifen as first-line therapy for hormone receptor-positive or unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1,021 patients were randomized to receive Arimidex 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.

The evaluation of the primary endpoints of study 1033IL/0030 demonstrated that Arimidex 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 Arimidex and tamoxifen, respectively, p = 0.006); the objective tumor response rate was similar for Arimidex and tamoxifen. Study 1033IL/0027 demonstrated that the objective tumor response rate and time to tumor progression were similar for Arimidex and tamoxifen. The results of the secondary endpoints confirmed the results of the primary efficacy endpoints. The sufficiently low mortality rates in the treatment groups of both studies did not allow conclusions to be drawn about differences in overall survival rates.

Second-line therapy for postmenopausal women with advanced breast cancer

Arimidex was studied in two controlled clinical trials (Study 0004 and Study 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 randomized to receive Arimidex 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) disease stabilization, progression rate, and overall survival were also determined. In both studies, there were no significant differences between treatment groups in any of the efficacy parameters.

Adjuvant treatment of early hormone receptor-positive invasive breast cancer

In a large phase III study of 9,366 postmenopausal women with operable breast cancer treated for 5 years (see below), Arimidex was shown to be statistically superior to tamoxifen in terms of disease-free survival. Significantly greater disease-free survival benefits were observed in favor of Arimidex compared to tamoxifen in the prospectively defined hormone receptor-positive population.

Table 1

Summary table of endpoints obtained during the ATAS study: analysis after completion of treatment lasting 5 years

aDisease-free survival includes all recurrences and is defined as the first episode of locoregional recurrence, new 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).

cTime to recurrence is defined as the first episode of local or regional recurrence, new 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 Arimidex and tamoxifen did not demonstrate superior efficacy compared to tamoxifen alone in all patients, nor in the hormone receptor-positive population. This treatment group was withdrawn from the study.

According to updated follow-up data with a median of 10 years, the long-term effects of Arimidex 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 rate in the group that switched to Arimidex after 2 years of adjuvant tamoxifen therapy was statistically superior to that in the group that remained on tamoxifen after a median follow-up of 24 months.

Table 2

Summary table of endpoints and results of the ABCSG 8 study

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 profile of Arimidex 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 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 Arimidex 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 Arimidex alone (N = 42), patients in the intermediate-risk group were randomized to receive Arimidex plus risedronate 35 mg once weekly (N = 77) or Arimidex plus placebo (N = 77), and patients in the high-risk group received Arimidex 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 decrease in bone mineral density (as assessed by lumbar spine bone mineral density using DEXA scanning) when treated with Arimidex 1 mg/day in combination with risedronate 35 mg once weekly. In addition, a decrease in BMD, which was not statistically significant, was observed in the low-risk group when treated with Arimidex 1 mg/day alone. These results were reflected in the secondary efficacy endpoint of change from baseline in total hip BMD at 12 months.

This study demonstrates that it is appropriate to consider the use of bisphosphonates in the event of possible bone mineral density loss in postmenopausal women with early-stage breast cancer who are being treated with Arimidex.

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 have no clinically significant effect on steady-state plasma concentrations with once-daily dosing of Arimidex tablets. Approximately 90–95% of steady-state plasma concentrations of anastrozole are achieved after 7 days of daily dosing, with accumulation being 3–4-fold. There is no evidence of a time- or dose-dependent pharmacokinetic relationship for anastrozole.

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

Distribution

Only 40% of anastrozole binds to plasma proteins.

Breeding

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

Impaired kidney or liver function

Compared to matched controls, the apparent oral clearance (CL/F) of anastrozole in volunteers with compensated cirrhosis was approximately 30% lower (study 1033IL/0014). However, plasma concentrations of anastrozole in volunteers with cirrhosis were within the range of concentrations observed in healthy subjects in other studies. Plasma concentrations of anastrozole observed in long-term efficacy studies in patients with hepatic impairment were within the range of plasma concentrations of anastrozole observed in patients without hepatic impairment.

In study 1033IL/0018, in volunteers with severe renal impairment (glomerular filtration rate [GFR] < 30 mL/min), the apparent oral clearance (CL/F) of anastrozole was not altered, consistent with the fact that anastrozole is eliminated primarily by metabolism. Plasma concentrations of anastrozole observed in long-term efficacy studies in patients with renal impairment were within the range of plasma concentrations of anastrozole observed in patients without renal impairment. Caution should be exercised when using Arimidex in patients with severe renal impairment (see sections 4.2 and 4.4).

Indication

Arimidex is indicated for:

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

Arimidex is contraindicated in patients:

during pregnancy and breastfeeding;

with known hypersensitivity to anastrozole or to any of the excipients.

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, and these data indicate that concomitant use of Arimidex with other drugs 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 from clinical trials has not revealed any clinically significant drug interactions in patients receiving Arimidex concomitantly with other commonly prescribed drugs. No clinically significant interactions have been reported with bisphosphonates (see section 5.1).

The concomitant use of tamoxifen or estrogen-containing agents with Arimidex should be avoided as this may weaken its pharmacological action (see sections “Special warnings and precautions for use” and “Pharmacological properties”).

Application features

General

Arimidex 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 there is any doubt about the patient's menopausal status. There are no data to support the use of Arimidex with luteinizing hormone-releasing factor (LHR) analogues.

The concomitant use of tamoxifen or estrogen-containing products with Arimidex should be avoided as this may reduce its pharmacological effect (see sections “Interaction with other medicinal products and other types of interactions” and “Pharmacological properties”).

Effect on bone mineral density

Because Arimidex reduces circulating estrogen levels, this may lead to a decrease in bone mineral density with a possible increase in the risk of fracture (see section "Adverse reactions").

In women with osteoporosis or at risk of osteoporosis, bone mineral density should be assessed at the start of treatment and at regular intervals thereafter. If necessary, osteoporosis treatment or prophylaxis should be initiated and the patient should be closely monitored. The use of specific agents, such as bisphosphonates, may prevent further loss of bone mineral density caused by Arimidex in postmenopausal women and should be considered (see section 4.8).

Liver dysfunction

Arimidex 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 (see section 5.2); caution should be exercised when using Arimidex in patients with moderate or severe hepatic impairment (see section 4.2). Treatment should be based on an assessment of the benefit-risk ratio for each individual patient.

Kidney dysfunction

Arimidex has not been studied in patients with breast cancer and severe renal impairment. Anastrozole exposure is not increased in patients with severe renal impairment (glomerular filtration rate [GFR] < 30 mL/min, see section 5.1); Arimidex should be used with caution in patients with severe renal impairment (see section 4.2).

Children

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

Arimidex 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, Arimidex 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.

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

Use during pregnancy or breastfeeding

There are no data on the use of Arimidex in pregnant women. Animal studies have shown reproductive toxicity. Arimidex is contraindicated during pregnancy (see section "Contraindications").

There are no data on the use of Arimidex during lactation. Arimidex is contraindicated during breastfeeding (see section "Contraindications").

Fertility

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

Ability to influence reaction speed when driving vehicles or other mechanisms

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

Method of administration and doses

Arimidex 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. Arimidex should be used with caution in patients with severe renal impairment (see sections 4.4 and 5.1).

Liver dysfunction

No dose adjustment is required in patients with mild liver disease. Patients with moderate to severe hepatic impairment should use the drug with caution (see section "Special warnings and precautions for use").

Children.

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

Overdose

Clinical experience with accidental overdose is limited. In animal studies, anastrozole has shown low acute toxicity. In clinical studies, various doses of Arimidex were 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 Arimidex that results in life-threatening symptoms has not been established. There is no specific antidote for overdose; treatment should be symptomatic.

In the treatment of overdose, the possibility that multiple substances may have been ingested should be considered. If the patient is not unconscious, vomiting may be induced. Dialysis may be useful, as Arimidex is not significantly protein bound. General supportive care, including frequent monitoring of vital signs, and close observation of the patient are recommended.

Adverse reactions.

Table 3 presents adverse reactions observed in clinical and post-marketing studies or from spontaneous reports. Unless otherwise stated, frequency categories were calculated based on the number of adverse reactions observed in a large phase III study of 9,366 postmenopausal women with operable breast cancer who received adjuvant therapy for five years (the Arimidex, Tamoxifen, Alone or in Combination [ATAC] study).

The following adverse reactions are classified by frequency and system organ class (SOC). The frequency classification was made using the following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). The most frequently reported adverse reactions were: headache, flushing, nausea, rash, arthralgia, joint mobility disorders, arthritis and asthenia.

Table 3

*The incidence of carpal tunnel syndrome was higher in patients treated with Arimidex in clinical trials compared to patients treated with tamoxifen. However, the majority of these cases occurred in patients with established risk factors for the condition.

**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% to <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 Arimidex. If bleeding persists, further evaluation should be performed.

Table 4 presents the frequency of pre-specified adverse reactions in the ATAS study (median follow-up period of 68 months) regardless of cause, observed in patients receiving study therapy and up to 14 days after discontinuation of treatment.

Table 4

Frequency of pre-specified adverse reactions in the ATAS study

The rates of fractures observed in the Arimidex and tamoxifen groups were 22 per 1000 patient-years and 15 per 1000 patient-years, respectively (median follow-up period of 68 months). The incidence of fractures in the Arimidex group was similar to that observed in age-matched postmenopausal patients. The incidence of osteoporosis was 10.5% in patients treated with Arimidex and 7.3% in patients treated with tamoxifen.

It has not been established whether the incidence of fractures and osteoporosis observed in the ATAC study in patients taking Arimidex reflects the protective effect of tamoxifen, a specific effect of Arimidex, or both.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorised is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Side effects

General

The concomitant use of tamoxifen or estrogen-containing products with Arimidex should be avoided as this may reduce its pharmacological effect (see sections “Interaction with other medicinal products and other types of interactions” and “Pharmacological properties”).

Effect on bone mineral density

Because Arimidex reduces circulating estrogen levels, this may lead to a decrease in bone mineral density with a possible increase in the risk of fracture (see section "Adverse reactions").

In women with osteoporosis or at risk of osteoporosis, bone mineral density should be assessed at the start of treatment and at regular intervals thereafter. If necessary, osteoporosis treatment or prophylaxis should be initiated and the patient should be closely monitored. The use of specific agents, such as bisphosphonates, may prevent further loss of bone mineral density caused by Arimidex in postmenopausal women and should be considered (see section 4.8).

Liver dysfunction

Arimidex 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 (see section 5.2); caution should be exercised when using Arimidex in patients with moderate or severe hepatic impairment (see section 4.2). Treatment should be based on an assessment of the benefit-risk ratio for each individual patient.

Kidney dysfunction

Arimidex has not been studied in patients with breast cancer and severe renal impairment. Anastrozole exposure is not increased in patients with severe renal impairment (glomerular filtration rate [GFR] < 30 mL/min, see section 5.1); Arimidex should be used with caution in patients with severe renal impairment (see section 4.2).

Children

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

Arimidex 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, Arimidex 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.

Lactose hypersensitivity

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

Use during pregnancy or breastfeeding.

There are no data on the use of Arimidex in pregnant women. Animal studies have shown reproductive toxicity. Arimidex is contraindicated during pregnancy (see section 4.4).