ANASTROZOLE CRISTERS is indicated in the

· Treatment of advanced breast cancer at hormone receptors positive in women, menopausal

Dosage

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


Pediatric population

ANASTROZOLE CRISTERS is not recommended for use in children and adolescents because of insufficient tolerance and efficacy data (see sections 4.4 and 4.4). >

Renal insufficiency

No dosage adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, administration of ANASTROZOLE CRISTERS should be carried out with caution (see Warnings and Precautions, and Pharmacokinetic Properties).
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Hepatic impairment

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

Mode of administration

ANASTROZOLE CRISTERS should be taken orally.
Class: Pharmacotherapeutic: Enzyme inhibitors, ATC code, L02BG03.

Mechanism of action and effects, pharmacodynamics

ANASTROZOLE CRISTERS 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 women, menopausal, ANASTROZOLE, at a dose of 1 mg daily, suppressed by more than 80% the production of estradiol measured by a highly sensitive dosage method.

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

Efficacy and clinical safety

Breast cancer at a stage, advanced

First-line treatment of advanced breast cancer in postmenopausal women

Two randomized, double-blind, controlled trials of similar regimens (study 1033IL / 0030 and 1033IL / 0027) were conducted to compare the efficacy of ANASTROZOLE with that of tamoxifen in first-line treatment 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 progression, tumor, 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 tumor progression (Hazard ratio (HR) 1.42, confidence interval ) At 95% [1.11, 1.82], median time to progression of 11.1 and 5.6 months, ANASTROZOLE and tamoxifen respectively, p '= 0.006), response rates Tumor were similar for ANASTROZOLE and tamoxifen. In study 1033IL / 0027, tumor response rates and tumor progression times were similar for ANASTROZOLE and tamoxifen. The results on the secondary endpoints confirmed the results on the main criteria of effectiveness. The number of deaths in all treatment groups in the two trials was too small to allow conclusions about a difference in overall survival.
Second-line treatment of advanced 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 for effectiveness were time, progress and objective response rate, prolonged stable disease rate (over 24 weeks), progression rate and survival were also calculated. In both studies, there was no significant difference between treatment arms regardless of the parameters of efficacy.


In the Phase III / IV SABER study, 234 postmenopausal women with early hormone receptor breast cancer positive and eligible for treatment with Anastrozole 1 mg daily Were stratified in low, moderate and high risk groups according to their existing risk of fracture fracture The primary endpoint of efficacy analyzed was the bone mineral density of the lumbar spine determined by DEXA scan. All patients were treated with vitamin D and calcium.The 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 a week (n = 77) or ANASTROZOLE plus placebo (n = 77) and those in the high-risk group received ANASTROZOLE plus risedronate 35 mg once weekly, = 38). The main criterion was the change in bone mineral density of the lumbar spine at 12 months from the entry in the study

The main 12-month analysis 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, and 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 12 months compared to 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 eligible for treatment with ANASTROZOLE.

Pediatric population

ANASTROZOLE CRISTERS 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, in order to draw reliable conclusions about job security. No data on the potential effects of long-term treatment with ANASTROZOLE CRISTERS in children and adolescents are available (see also section Preclinical safety data)

The European Medicines Agency has granted a waiver of the obligation to submit the results of studies with ANASTROZOLE in one or more subgroups of children, small in size due to deficiency, 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) with growth hormone deficiency treated with 1 mg / day, ANASTROZOLE or placebo for 12 to 36 Month in combination with growth hormone. Only 14 subjects under ANASTROZOLE have 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, In children treated with ANASTROZOLE compared with placebo.

Testotoxicosis

A multicenter open-label, non-comparative study evaluated 14 male sex (ages 2 to 9 years) with early family puberty, limited to boys, also called testotoxicosis, treated with 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 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 prior to inclusion in the study.

Studies on gynecomastia

Trial 0006 was a randomized, double-blind, multicenter study of 82 pubescent boys (ages 11 to 18 inclusive) with gynecomastia, present for at least 12 months receiving either ANASTROZOLE 1 mg daily Placebo for at least 6 months. No significant difference was observed between the ANASTROZOLE 1 mg group and the placebo group in terms of the number of patients with a reduction in total breast volume, greater than or equal to 50% after 6 months of treatment .

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

Trial 0046 was an open-label international, multicenter, open-label trial in 28 girls (2 to 10 years of age, inclusive) 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 / yr) 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. The use of specific therapies such as bisphosphonates can stop the bone mineral loss due to ANASTROZOLE CRISTERS in women, menopausal and can be prevented (See section on Undesirable effects).
Hepatic impairment

ANASTROZOLE CRISTERS has not been evaluated in patients with breast cancer and with moderate or severe hepatic impairment, and exposure to anastrozole may be increased in subjects with hepatic impairment (see Pharmacokinetics), administration of ANASTROZOLE CRISTERS in patients with moderate and severe hepatic impairment should be performed with caution (see Dosage and Mode of Administration). Treatment should be based on an assessment of benefit / risk ratio for each patient individually

Renal insufficiency

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

ANASTROZOLE CRISTERS should not be administered in combination with growth hormone therapy in boys with growth hormone deficiency. In the pivotal clinical study, efficacy and safety of use have not been demonstrated (see section on Pharmacodynamic properties) .; Anastrozole reduces estradiol levels, ANASTROZOLE, CRISTERS should not be Administered in combination with growth hormone therapy in girls with growth hormone deficiency No long-term safety data in children and adolescents are available

Hypersensitivity to lactose

This product contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency or glucose / galactose malabsorption syndrome should not take this drug
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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 administration of ANASTROZOLE CRISTERS with other medicinal products is unlikely to result in 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 tolerance database from clinical studies did not reveal any clinically significant interaction in ANASTROZOLE CRISTERS patients receiving other frequently prescribed drugs. There is no clinically significant interaction with bisphosphonates (see Pharmacodynamic properties)

Concomitant administration of ANASTROZOLE CRISTERS with tamoxifen or estrogen-containing therapies should be avoided as it may decrease its pharmacological action (see sections Interactions with other medicinal products and other forms of interaction and ; Pharmacodynamic properties).

Not applicable.

The clinical experience associated with an accidental overdose is limited. In animal studies, anastrozole has demonstrated low acute toxicity. Clinical trials were conducted with different dosages from ANASTROZOLE CRISTERS up to a maximum dose of 60 mg in single administration to healthy volunteers, male to up to a daily dose, up to 10 mg administered to Of menopausal women with breast cancer at an advanced stage, these doses were well tolerated. No single dose of ANASTROZOLE CRISTERS 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, since ANASTROZOLE CRISTERS is not closely 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 is no data on the use of ANASTROZOLE CRISTERS in pregnant women. Studies in animals have shown reproductive toxicity (see section Safety data, preclinical). ANASTROZOLE CRISTERS is contraindicated during pregnancy (see section Contraindications).
Breastfeeding

There is no data on the use of ANASTROZOLE CRISTERS during breastfeeding. ANASTROZOLE CRISTERS is contraindicated during breast-feeding (see section Contraindications).
Fertility

The effects of ANASTROZOLE, CRISTERS 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 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 post-menopausal patients with operable breast cancer receiving one Adjuvant therapy for 5 years (study, ATAC: 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,