Anastrozole, Zentiva is indicated in the

Treatment of advanced breast cancer, hormone receptor positive in women, menopausal

Dosage

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


Population, pediatric

Anastrozole Zentiva is not recommended for use in children and adolescents due to insufficient tolerance and efficacy data (see sections 4.4 and 4.4) and its precautions and pharmacodynamic properties. >

Renal insufficiency

No dosage adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, administration of Anastrozole Zentiva should be carried out 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 section 4.4).


Anastrozole Zentiva should be taken orally.
White, round, biconvex film-coated tablet marked "ANA" and "1" on one side.
Class: Pharmacotherapeutic: Enzyme inhibitors, ATC code, L02B G03

Mechanism of action and pharmacodynamic effects

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In menopausal women, estradiol mainly results from the conversion of androstenedione into estrone via the enzymatic complex of aromatase in peripheral tissues. The estrone is then converted to estradiol. Reduction in the level of circulating estradiol has been shown to have a beneficial effect in women with breast cancer.In postmenopausal women, Anastrozole, at a daily dose of 1 mg , Eliminated by more than 80% the production of estradiol measured by a highly sensitive assay method.

Anastrozole is devoid of any progestational, androgenic or estrogenic activity.


Clinical efficacy and safety

Breast cancer at a stage, advanced

First-line treatment of advanced breast cancer in postmenopausal women

Two studies were conducted in order to compare the efficacy of Anastrozole with that of tamoxifen in the first line of treatment in patients treated with a double-blind, controlled and similar study (study 1033IL / 0030 and study 1033IL / 0027). Menopausal women with locally advanced or metastatic breast cancer with 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), the rates of objective response Tumor 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 confirmed the results on the main efficacy criteria. The number of deaths in all treatment groups in the two trials was too low to allow conclusions about a difference in overall 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 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 a day. The main criteria of effectiveness were the time until progression and the rate of objective response. Prolonged stable disease rate (> 24 weeks), progression rate and survival were also calculated.
In both studies there were no significant differences between treatment arms no matter Are the efficiency parameters.

Pediatric population

Anastrozole is not indicated for use in children and adolescents.Efficacy has not been established in the pediatric populations studied (see below). The number of children being treated was too limited to allow reliable conclusions about the security of employment. No data on the potential effects of long-term treatment with Anastrozole in children and adolescents are available (see also Preclinical Safety Data).
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The European Medicines Agency has granted a waiver of the obligation to submit results of studies with Anastrozole in one or more subgroups of children, small in size due to deficit, hormone Growth, testotoxicosis, gynecomastia or McCune-Albright syndrome (see section Posology and method of administration).
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Small size due to growth hormone deficiency

A multicenter, randomized, double-blind 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 36 months of treatment.
No statistically significant differences were observed from placebo on growth-related parameters (predicted adult size, size, size, SDS [standard deviation score] and velocity; growth). 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, Observed in children treated with Anastrozole compared to those under placebo.

Testotoxicosis

An open-label, multicenter, non-comparative study evaluated 14 male children (ages 2 to 9 years) with familial precocious puberty limited to boys, also called testotoxicosis, treated with Anastrozole and bicalutamide. The primary objective of this study was to evaluate the efficacy and safety of this association for 12 months. Of the 14 patients included in the study, 13 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 in comparison with the 6 months preceding the 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), having gynecomastia for at least 12 months receiving either Anastrozole 1 mg daily or placebo For at least 6 months. No significant difference was observed between the group treated with Arimidex 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, treatment .

Test 001 was an open-label, 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 a multicenter, open-label, international, exploratory trial in 28 girls (2 to 10 years of age included) with 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 osteoporotic women or at risk for osteoporosis, the bone mineral density must be rigorously evaluated at the beginning of treatment and then at regular intervals. Appropriate treatment or prevention of osteoporosis should be instituted and monitored carefully The use of specific therapies such as bisphosphonates can stop bone mineral loss due to Anastrozole Zentiva in menopausal women and can be (See section on Undesirable effects).
Hepatic Insufficiency

Anastrozole Zentiva 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 (see Zentiva in patients with moderate and severe hepatic impairment should be performed with caution (see section 4.2). Treatment should be based on an evaluation of the report, benefit benefit risk for each patient individually

Renal insufficiency

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

In vitro, anastrozole inhibits cytochromes CYP1A2, 2C8 / 9 and 3A4. Clinical studies with antipyrin and warfarin showed that anastrozole at a dose of 1 mg did not significantly inhibit the metabolism of antipyrin and warfarin (R and S), indicating That it is unlikely that administration of Anastrozole Zentiva with other medicinal products will result in clinically significant drug interactions originating in cytochromes CYP.


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 tolerance database from the clinical studies did not reveal clinically significant interaction in patients receiving Anastrozole Zentiva also receiving other frequently prescribed drugs. There is no clinically significant interaction with bisphosphonates (see Pharmacodynamic properties).

Concomitant administration of Anastrozole Zentiva with tamoxifen or estrogen-containing therapies should be avoided as it may diminish its pharmacological action (see sections 4.4 and 4.4) .

Without object.

The clinical experience associated with an accidental overdose is limited. In animal studies, anastrozole has demonstrated low acute toxicity. Clinical trials were conducted with various dosages, from Anastrozole up to a maximum dose of 60 mg in single administration to healthy volunteers of the male sex and up to a maximum daily dose of 10 mg administered to Women with postmenopausal breast cancer 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 related 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 Zentiva in pregnant women. Studies in animals have shown reproductive toxicity (see section 4.4 Preclinical safety data). Anastrozole Zentiva is contraindicated during pregnancy (see section Contraindications).


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

The effects of Anastrozole Zentiva on fertility in the human species have not been studied. Studies in animals have shown reproductive toxicity (see section Safety data, preclinical).

The following table presents adverse reactions from clinical trials, post-marketing studies, or spontaneous declarations. Unless specified, frequency groups were calculated from the number of adverse events reported, in a large Phase III study 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,