Anatero

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANATERO (ANATERO)

Composition:

Active substance: anastrozole;

1 tablet contains 1 mg of anastrozole;

Excipients: lactose monohydrate, sodium starch glycolate, povidone, magnesium stearate, Opadry white Y-1-700.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets with engraved markings «H» on one side and «1» on the other.

Pharmacotherapeutic group.
Hormone antagonists and related agents. Aromatase inhibitors. ATC code L02BG03.

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 through the conversion of androstenedione to estrone in peripheral tissues by the aromatase enzyme complex. Estrone is then converted to estradiol. Reduction in circulating estradiol levels provides therapeutic benefit 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 does not exhibit progestogenic, 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 the treatment of locally advanced or metastatic breast cancer with positive or unknown hormone receptor status in postmenopausal women. A total of 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 months for anastrozole vs. 5.6 months for tamoxifen; p=0.006). The objective tumor response rate was similar between 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 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 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 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 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.

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

Table 1

a Disease-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).

b Metastasis-free survival is defined as the first occurrence of metastatic recurrence or death (from any cause).

c Time to recurrence is defined as the first occurrence of local or regional recurrence, contralateral breast cancer, distant recurrence, or death due to breast cancer.

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

e Number (%) of patients who died.

The combination of anastrozole and tamoxifen did not demonstrate greater efficacy compared to tamoxifen alone in all patients, nor 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 women previously treated with adjuvant tamoxifen

In a Phase III clinical trial (Austrian Breast and Colorectal Cancer Study Group [ABCSG] 8), involving postmenopausal women with early-stage hormone receptor-positive breast cancer who had undergone surgery with or without radiotherapy, but who did not receive chemotherapy (see below), disease-free survival outcomes were statistically superior in the group switched to anastrozole after 2 years of adjuvant tamoxifen treatment compared to the group continuing 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 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 based on their existing risk of osteoporotic fracture. The primary efficacy parameter was the assessment 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 no decrease in bone mineral density (assessed by DEXA scanning of lumbar spine BMD) in patients at medium and high risk of osteoporotic fracture treated with anastrozole 1 mg daily in combination with risedronate 35 mg once weekly. Additionally, a non-statistically significant reduction in BMD was observed in the low-risk group treated with anastrozole 1 mg daily alone. These findings were mirrored in the secondary change in total hip BMD at 12 months compared to baseline.

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

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 dependence of anastrozole pharmacokinetic parameters on duration of administration or dose.

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. Anastrozole is extensively metabolized in postmenopausal women, with less than 10% of the dose excreted unchanged in urine within 72 hours after dose 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 with 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 liver 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 of plasma concentrations 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 clearance (CL/F) of anastrozole after oral administration was unchanged, consistent with the fact that anastrozole is primarily eliminated by metabolism. Plasma concentrations of anastrozole observed during long-term efficacy studies in patients with renal impairment were within the range of plasma concentrations observed in patients without renal impairment. Anastrozole should be used with caution in patients with severe renal impairment.

Clinical characteristics.

Indications.

• 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 adjuvant tamoxifen therapy;
• Treatment of advanced hormone receptor-positive breast cancer in postmenopausal women.

Contraindications.

ANA-THERO is contraindicated in patients:

• During pregnancy or breastfeeding;
• With known hypersensitivity to anastrozole or to any of the excipients.

Special 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 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 drug interactions mediated by CYP enzymes.

The enzymes responsible for anastrozole metabolism 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.

Analysis of safety data accumulated during clinical trials has not revealed evidence of clinically significant drug interactions in patients receiving anastrozole concomitantly with other commonly prescribed medications. 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 its pharmacological effect.

Special precautions for use

General

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

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

Effect on bone mineral density

Since anastrozole 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 at the start of treatment and at regular intervals during therapy. Treatment or prophylaxis for osteoporosis should be considered as clinically indicated, with careful monitoring of the patient. The use of specific agents, such as bisphosphonates, may prevent further bone mineral density loss caused by anastrozole in postmenopausal women, and the appropriateness of such treatment should be evaluated.

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; therefore, caution is required when administering ANATERO 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

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); however, ANATERO should be used with caution in such patients.

Children

ANATERO 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 was not 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

The 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

There are no data on the use of anastrozole in pregnant women. Animal studies have shown reproductive toxicity. ANATERO is contraindicated during pregnancy.

There are no data on the use of anastrozole during lactation. ANATERO is contraindicated during breastfeeding.

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

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

Method of Administration and Dosage

ANATERO is administered orally.

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

For early-stage postmenopausal women with 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. ANATERO should be used with caution in patients with severe renal impairment.

Hepatic Impairment

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

Children

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

Overdose

Clinical experience with accidental overdose is limited. In animal studies, anastrozole has shown 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 drugs may have been ingested. If the patient is not unconscious, vomiting may be induced. Dialysis may be beneficial, as anastrozole is not highly protein-bound. General supportive care with frequent monitoring of vital functions and careful observation of the patient is recommended.

Adverse reactions.

Table 3 presents adverse reactions observed during clinical and post-marketing studies or reported spontaneously.

The adverse reactions listed below are classified by frequency and by organ system classes (SOC). Frequency distribution was performed according to the following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000) and very rare (<1/10000). The most frequently reported adverse reactions were headache, hot flushes, nausea, rash, arthralgia, joint mobility disorders, arthritis and asthenia.

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 defined risk factors for developing this condition.

** Since 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 prior hormonal therapy to anastrozole treatment. If bleeding persists, further evaluation should be conducted.

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

Table 4

Pre-specified adverse events in the ATAC trial

In the anastrozole and tamoxifen groups, the number of fractures observed was 22 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 comparable 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 marketing authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

10 tablets in a blister, 1 or 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

HETERO LABS LIMITED.

Manufacturer's address and location of operations.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.