Anastrozole genepharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANASTROZOLE GENEPHARM (ANASTROZOLE GENEPHARM)

Composition:

active substance: anastrozole;

1 film-coated tablet contains 1 mg of anastrozole;

excipients: lactose monohydrate, povidone K-30, sodium starch glycolate (type A), magnesium stearate;

tablet coating: hypromellose (5 cP), macrogol 300, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, white or almost white, biconvex film-coated tablets.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of Action and Pharmacodynamic Effects

Anastrozole is a potent, highly selective, non-steroidal aromatase inhibitor. In postmenopausal women, estrogens are primarily produced through the conversion of androstenedione to estrone by the aromatase enzyme complex in peripheral tissues. Estrone is then further converted to estradiol. 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 more than 80% reduction in estradiol levels, as confirmed by a highly sensitive assay.

Anastrozole has no progestagenic, androgenic, or estrogenic activity.

Anastrozole at daily doses up to 10 mg does not affect the secretion of cortisol or 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 locally advanced or metastatic hormone receptor-positive or receptor status unknown breast cancer in postmenopausal women. A total of 1021 patients were randomized to receive either anastrozole 1 mg once daily or tamoxifen 20 mg once daily. 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 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. Secondary endpoint results supported the findings of the primary efficacy endpoints. The relatively low mortality rate in the treatment groups of both studies did not allow conclusions to be drawn regarding differences in overall survival.

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 following tamoxifen treatment for either advanced or early-stage breast cancer. A total of 764 patients were randomized 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. Additional parameters included the rate of prolonged disease stabilization (>24 weeks), 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 were observed in favor of anastrozole compared to tamoxifen in the prospectively defined population with hormone receptor-positive tumors.

Table 1

Summary of endpoints from the ATAC trial: analysis after completion of 5 years of treatment

aDisease-free survival includes all recurrence events and is defined as the first occurrence of local or regional recurrence, contralateral new primary 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 new primary breast cancer, distant recurrence, or death due to breast cancer.

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

eNumber (%) of patients who died.

The combination of anastrozole and tamoxifen did not demonstrate greater efficacy compared to tamoxifen in all patients, or in the hormone receptor-positive population. 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 previously treated with adjuvant tamoxifen therapy

In a Phase III clinical trial (Austrian Breast and Colorectal Cancer Study Group [ABCSG] 8), which included 2579 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 outcomes were statistically superior in the group switched to anastrozole after 2 years of adjuvant tamoxifen therapy compared to the group that continued tamoxifen, following a median follow-up period of 24 months.

Table 2

Summary table of endpoints and results from the ABCSG 8 study

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 profile 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 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 for osteoporotic fracture. The primary efficacy endpoint was the 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 only (N = 42), those 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), and 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 12-month analysis 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) with treatment using anastrozole 1 mg daily in combination with risedronate 35 mg once weekly. Additionally, a non-statistically significant decrease in BMD was observed in the low-risk group treated with anastrozole 1 mg daily alone. These findings were mirrored by a secondary efficacy endpoint—the change in total hip BMD at 12 months compared to baseline.

This study supports considering the use of bisphosphonates in postmenopausal women with early-stage breast cancer treated with anastrozole who are at risk of decreased bone mineral density.

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 have a clinically significant impact 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 daily 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 not influenced by the age of postmenopausal women.

Distribution

Only 40% of anastrozole is bound to plasma proteins.

Elimination

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 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

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). However, plasma concentrations of anastrozole in volunteers with cirrhosis were within the range observed in healthy subjects from other studies. Plasma concentrations of anastrozole observed in long-term efficacy studies in patients with hepatic impairment were within the range seen in patients without hepatic dysfunction.

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 via metabolism. Plasma concentrations of anastrozole observed during long-term efficacy studies in patients with renal impairment were within the range observed in patients without renal dysfunction. Anastrozole should be used with caution in patients with severe renal impairment (see sections "Dosage and Administration" and "Special Warnings and Precautions").

Clinical characteristics.

Indications.

Anastrozole GenePharm is indicated for:

• 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 2–3 years of prior adjuvant tamoxifen therapy;
• treatment of advanced hormone receptor-positive breast cancer in postmenopausal women.

Contraindications.

Anastrozole GenePharm is contraindicated in patients:

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

Safety precautions.

Unused medicinal product or waste material must 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 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, suggesting that concomitant administration of anastrozole with other medicinal products is unlikely to result in clinically significant interactions mediated by CYP enzymes.

The enzymes responsible for the metabolism of anastrozole 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 safety database accumulated during clinical trials did not reveal any information on clinically significant drug interactions in patients who received anastrozole concomitantly with other commonly prescribed medications. No clinically significant interactions with bisphosphonates have been reported (see section "Pharmacological properties").

Concomitant use of tamoxifen or estrogen-containing products with anastrozole should be avoided, as this may reduce its pharmacological effect (see sections "Special precautions for use" and "Pharmacological properties").

Special precautions for use

Anastrozole 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) if there is any doubt regarding a patient's menopausal status. 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 its pharmacological effect (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacological properties").

Effect on bone mineral density

Since anastrozole reduces circulating estrogen levels, it may lead to decreased bone mineral density and an increased risk of fracture (see section "Undesirable effects").

In women with osteoporosis or at risk of osteoporosis, bone mineral density should be assessed at the beginning of treatment and monitored regularly during treatment. If necessary, treatment or prophylaxis for osteoporosis should be initiated, and patients should be closely monitored. The use of specific agents, such as bisphosphonates, may prevent further bone mineral loss caused by anastrozole in postmenopausal women; therefore, the appropriateness of such treatment should be evaluated (see section "Undesirable effects").

Hepatic impairment

The use of anastrozole has not been studied in patients with breast cancer and moderate or severe hepatic impairment. Anastrozole exposure may be increased in patients with hepatic impairment (see section "Pharmacological properties"); therefore, anastrozole should be used with caution in patients with moderate or severe hepatic impairment (see section "Method of administration and dosage"). Treatment should be based on an individual assessment of benefit versus risk for each patient.

Renal impairment

The use of anastrozole 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 "Pharmacological properties"); however, anastrozole should be used with caution in patients with severe renal impairment (see section "Method of administration and dosage").

Children

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

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 a 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.

Lactose intolerance

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

Use during pregnancy or breastfeeding

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

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

Fertility

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

Ability to affect 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, there have been reports of asthenia and somnolence associated with anastrozole use; therefore, caution should be exercised when driving or operating machinery if these symptoms occur.

Method of Administration and Dosage

Anastrozole Jenepharm is administered orally.

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

For postmenopausal women with early-stage hormone receptor-positive invasive breast cancer, 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 Jenepharm should be used with caution in patients with severe renal impairment (see sections "Special Warnings and Precautions for Use" and "Pharmacological Properties").

Hepatic Impairment

Dose adjustment is not required in patients with mild liver disease. Anastrozole Jenepharm should be used with caution in patients with moderate or severe hepatic impairment (see section "Special Warnings and Precautions for Use").

Children

Anastrozole Jenepharm 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 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 for overdose; treatment should be symptomatic.

When managing overdose, consider the possibility that multiple substances may have been ingested. If the patient is not unconscious, vomiting may be induced. Dialysis may be beneficial since anastrozole is not highly protein-bound. General supportive care is recommended, including frequent monitoring of vital functions and careful observation of the patient.

Adverse reactions.

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

The adverse reactions listed below are classified by frequency and organ systems. Frequency classification was performed according to 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 commonly 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 during clinical trials compared to those receiving tamoxifen. However, most of these cases occurred in patients with identifiable risk factors for developing this condition.

**Since cases of cutaneous vasculitis and Henoch-Schönlein purpura were not observed in the ATAC study, the frequency of these events can be considered rare (from ≥0.01% to <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 prior hormonal therapy to anastrozole treatment. If bleeding persists, further evaluation should be conducted.

Table 4 presents the frequency of pre-specified adverse reactions observed during the ATAC study (with a median observation period of 68 months), regardless of causality, in patients who received the investigational treatment and within the period up to 14 days after discontinuation of therapy.

Table 4

Frequency of pre-specified adverse reactions in the ATAC study

In the anastrozole and tamoxifen groups, the number of fractures observed was 22 per 1000 patient-years and 15 per 1000 patient-years, respectively (observation period with a median of 68 months). The fracture rate in the anastrozole group was similar to that observed in women of corresponding age in the postmenopausal period. The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in those treated with tamoxifen.

It has not been established whether the fracture rate and osteoporosis incidence observed in the ATAC trial in patients receiving anastrozole reflect the protective effect of tamoxifen, a specific effect of anastrozole, or both effects.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer.

Jenepharm S.A., Greece

Manufacturer's address and location of its business operations.

18th km Marathona Avenue, Pallini Attiki, 15351, Greece