Anastrozole is indicated in the treatment of advanced breast cancer, hormone receptors positive in women, menopausal

Dosage

The recommended dosage of anastrozole in adults, including the elderly, is one tablet at 1 mg once daily.


Population, pediatric

Anastrozole is not recommended for use in children and adolescents because of insufficient tolerance and efficacy data (see sections 4.4 and 4.4) Code>
Renal insufficiency

No dosage adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, anastrozole should be administered with caution (see Warnings and Precautions and Pharmacokinetics).
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Hepatic Insufficiency

No dosage adjustment is recommended in patients with mild liver disease. Precaution is recommended in patients with hepatic impairment, moderate to severe (see Warnings and Precautions for Use)

Administration mode

Anastrozole should be taken orally.

Tablet, film-coated, round, white to whitish, with the figure "93", engraved on one side of the tablet and "A10" engraved on the other side.
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Group: Pharmacotherapeutic: Enzyme inhibitors, ATC code, L02BG03.

Mechanism of action and pharmacodynamic effects

Anastrozole is a potent and highly selective non-steroidal inhibitor of aromatase. In postmenopausal women, estradiol results mainly from the conversion of androstenedione into estrone in the peripheral tissues via the enzyme complex of aromatase. The estrone is then converted to estradiol. It was demonstrated that a reduction in the level of circulating estradiol had a beneficial effect in women, breast cancer. In the postmenopausal women, anastrozole, at a dose of 1 mg daily, suppressed production by more than 80%, estradiol measured by a highly sensitive assay method Br>

Anastrozole is devoid of any progestational, androgenic or estrogenic activity.
Daily doses of anastrozole up to 10 mg per day had no effect on the secretion of cortisol or aldosterone measured before or after standard stimulation test adrenocorticotropic hormone ( ACTH). Corticosteroid supplementation is therefore not necessary

Efficacy and clinical safety

Two clinical studies were conducted to compare the efficacy of anastrozole with that of tamoxifen in the first line of treatment in patients treated with a double-blind, controlled, similar study (Study 1033IL / 0030 and Study 1033IL / 0027). Menopausal women with breast cancer, locally advanced or metastatic to hormone receptors positive or unknown. A total of 1,021 patients were randomized to receive 1 mg of anastrozole once daily or 20 mg of tamoxifen once daily. The main criteria of the two trials were time to tumor progression, tumor response rate and tolerance

For the main criteria, study 1033IL / 0030 showed an advantage, statistically significant for anastrozole compared to tamoxifen in terms of time to progression tumor (Hazard ratio (HR) 1.42, confidence interval (CI), 95% [1.11, 1.82], median time up to 11.1 and 5.6 months for anastrozole and tamoxifen respectively, p '= 0.006), Tumor response rate were similar for anastrozole and tamoxifen. In the study, 1033IL / 0027, tumor-specific response rates and tumor progression times were similar for anastrozole and tamoxifen. The results on the secondary endpoints reinforced the results on the primary efficacy endpoints The number of deaths in all treatment groups in the two trials was too low to allow conclusions Difference on; global survival.

Second-line treatment of advanced stage breast cancer in postmenopausal women

Anastrozole was studied in two controlled clinical trials (study 0004 and study 0005), postmenopausal women with advanced breast cancer having progressed, following treatment with tamoxifen for Early or early breast cancer A total of 764 patients were randomized to receive a single daily dose of 1 mg or 10 mg of anastrozole or 40 mg of megestrol acetate four times day. The main criteria of effectiveness were the time until progression and the rate of objective response. The prolonged stable disease rate (> 24 weeks), progression rate and survival were also calculated.
In both studies, there was no significant difference between treatment arms whatever Are the efficiency parameters.

Density of bone mineral (BMD)

In the phase III / IV study, 234 postmenopausal patients with early breast cancer with hormone receptor positive and eligible for treatment with anastrozole 1 mg / day (Study of Anastrozole with the Bisphosphonate Risedronate) Have been stratified in low, moderate, and high risk groups according to their existing risk of fracture fracture. The primary endpoint of efficacy was the bone mineral density of the lumbar spine determined by DEXA scan. All patients were treated with vitamin D and calcium. Patients in the low-risk group received anastrozole alone (n = 42), those in the moderate-risk group were randomized to receive anastrozole plus, risedronate 35 mg once weekly (n = 77) or; Anastrozole plus placebo (n = 77) and those in the high-risk group received anastrozole plus; risedronate 35 mg once weekly (n = 38). The main criterion was the modification of the bone mineral density of the lumbar spine at 12 months compared to the entry in the study.
The main analysis at 12 months showed that patients already exposed to a moderate to high risk of fracture fracture showed no decrease in bone mineral density (measured at the lumbar spine by DEXA; Treated with anastrozole 1 mg / day in combination with risedronate 35 mg once a week. In addition, a non-statistically significant decrease in BMD was observed in the low-risk group treated with anastrozole 1 mg / day alone. The change in total hip BMD at twelve months by comparison with inclusion in the study (secondary efficacy endpoint) was consistent with these results.

This study provided evidence that the administration of bisphosphonates could be considered in the management of possible bone mineral loss in postmenopausal women with early-stage breast cancer who are eligible for treatment with Anastrozole.

Population, pediatric

Anastrozole is not indicated for use in children and adolescents. Efficacy has not been established in pediatric populations, studied (see below). The number of children treated was too limited to permit reliable conclusions in terms of job security. No data on the potential effects of long-term anastrozole therapy in children and adolescents are available (see also Preclinical Safety Data).
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The European Agency for Drugs has granted a derogation to the obligation to submit the results of studies with anastrozole in one or more subgroups of children of small size due to a deficit Growth hormone, testotoxicosis, gynecomastia or McCune-Albright syndrome (see Dosage and Mode of Administration).

Small size due to growth hormone deficiency

A randomized, double-blind multicenter study evaluated 52 pubescent boys (ages 11 to 16 years inclusive) with growth hormone deficiency treated with 1 mg / day of anastrozole or placebo for 12 to 36 Month in combination with growth hormone. Only 14 subjects under anastrozole completed the 36 months of treatment.

No statistically significant difference was observed, compared to placebo on related parameters, growth (predicted adult size, size, SDS size and growth rate ). Final size data were not available. Although the number of children treated is too limited to allow for reliable findings on safety, employment, increased fracture rates and a tendency to decrease bone mineral density, In children, treated with anastrozole, compared to placebo.


A multicenter open-label, non-comparative study evaluated 14 male children (ages 2 to 9 years) with early familial puberty, limited to boys, also called testotoxicosis, treated with the combination of anastrozole and bicalutamide . The main objective of this study was to evaluate the efficacy and safety of this association for 12 months. Of the 14 patients enrolled in the study, 13 had completed the 12-month treatment with the combination (1 patient was lost to follow-up). After 12 months of treatment, no significant difference in growth rate was observed compared to 6 months prior to inclusion in the study. >
Studies on gynecomastia

Trial 0006 was a randomized, double-blind multicenter study of 82 boys, pubes (aged 11 to 18 years), with gynecomastia present for at least 12 months receiving either anastrozole, 1 mg per day, or Placebo for at least 6 months. No significant difference was observed between the group treated with anastrozole, 1 mg and the placebo group in terms of number of patients with a reduction in total breast volume greater than or equal to 50% after 6 months Of processing.

The 001 trial was a repeat dose open-label pharmacokinetic study of anastrozole 1 mg / day in 36 pubescent boys with gynecomastia for less than 12 months. The secondary objectives were to evaluate the proportion of patients with a reduction of at least 50% of the combined volume of the two breasts calculated between the first day of inclusion and the sixth month of treatment and to determine Tolerance and safe use of this treatment. A decrease of 50% or more of the total breast volume was observed in 56% (20/36) of boys after 6 months.
Study, in the McCune Albright syndrome

Test 0046 was an open-label, open-label, international, exploratory trial in 28 girls with a McCune Albright syndrome (SMA) treated with anastrozole. The primary objective was to evaluate the safety and efficacy of anastrozole 1 mg / day in patients with SMA. The effectiveness of the treatment of the study was determined on the basis of the proportion of patients meeting predefined criteria for vaginal bleeding, bone age, and rate of growth. No statistically significant change in the frequency of days of vaginal bleeding was observed during treatment. No clinically significant changes in the Tanner stage, mean ovarian volume, or mean uterine volume were observed. No statistically significant change in the rate of increase in age, bone under treatment compared to the initial period was observed. The growth rate (in cm / year) decreased significantly (p

In women, osteoporotic or at risk of osteoporosis, bone mineral density must be rigorously evaluated at the start of treatment, and thereafter at regular intervals. Appropriate treatment or prevention of osteoporosis should be initiated and monitored carefully The use of specific therapies such as bisphosphonates can stop bone mineral loss due to anastrozole in postmenopausal women and may Be considered (see section "Effects, undesirable").
Hepatic Insufficiency

Anastrozole has not been evaluated in patients with breast cancer with moderate or severe hepatic impairment and exposure to anastrozole may be increased in subjects with hepatic impairment ( Patients with moderate and severe hepatic impairment should be treated with caution (see section 4.2 Posology and method of administration). Treatment should be based on an evaluation of the report, benefit benefit risk for each patient individually

Renal insufficiency

Anastrozole has not been evaluated in patients with breast cancer and severe renal impairment. Exposure to anastrozole in subjects with severe renal impairment is not increased (glomerular filtration rate

In vitro, anastrozole, inhibits cytochromes CYP1A2, 2C8 / 9 and 3A4. Clinical studies with antipyrin and warfarin showed that 1 mg anastrozole did not significantly inhibit the metabolism of antipyrin and warfarin (R and S), indicating That it is unlikely that the administration of anastrozole with other medicinal products will lead to clinically significant drug interactions originating in cytochromes CYP
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The enzymes responsible for the metabolism of anastrozole have not been identified. Cimetidine, a low and non-specific inhibitor of cytochrome CYP, did not alter plasma concentrations of anastrozole. The effect of potent inhibitors of cytochrome CYP is unknown.

A review of the database of tolerance data from clinical trials did not reveal any clinically significant interaction in patients on anastrozole, and other drugs were also frequently prescribed. There is no clinically significant interaction with bisphosphonates (see section 5.1 Pharmacodynamic properties).
Concomitant administration of anastrozole with tamoxifen or estrogen-containing therapies should be avoided as it may diminish pharmacological action (see sections 4.4 and 4.4).

Not applicable.

Clinical experience related to an accidental overdose is limited .; In animal studies, anastrozole has demonstrated low acute toxicity. Clinical trials were conducted with different dosages of anastrozole up to a maximum dose of 60 mg administered to volunteers, healthy male and up to a maximum daily dose of 10 mg administered to; Of postmenopausal women with breast cancer, and at an advanced stage these doses were well tolerated. No single dose of anastrozole causing life-threatening symptoms has been identified. There is no specific antidote for overdosage and treatment should be symptomatic

The action to be taken in the face of an overdose must take into account the possibility of simultaneous ingestion of several products. If the patient is conscious, vomiting may be induced. Dialysis may be useful as anastrozole is not strongly bound to proteins. The usual measures of management, including the monitoring of the vital functions and the careful monitoring of the patient are indicated.

Pregnancy

There are no data on the use of anastrozole in pregnant women. Studies in animals have shown reproductive toxicity (see section 4.4 Preclinical safety data). Anastrozole is contraindicated during pregnancy (see section Contraindications).
Breastfeeding

There are no data on the use of anastrozole during breastfeeding. Anastrozole is contraindicated during breast-feeding (see Contraindications).
Fertility

The effects of anastrozole on fertility in the human species have not been studied. Studies in animals have shown reproductive toxicity (see section Preclinical safety data).

The following table presents the adverse effects resulting from clinical studies, studies, post-marketing or spontaneous declarations. Unless specified, frequency groups were calculated from the number of adverse events reported in a large Phase III study conducted in 9,366 postmenopausal patients with operable breast cancer treated; Adjuvant for 5 years (ATAC study: Anastrozole, Tamoxifen, Alone or in Combination study).
The adverse reactions listed below are categorized by frequency, and organ system class (SOC). Frequency groups are defined according to the following convention: very common (≥ 1/10), frequent (≥ 1/100,