ANASTROZOLE ARROW 1 mg film-coated tablet is indicated for the treatment of advanced breast cancer, hormone receptor positive in women, menopausal

Dosage

The recommended dosage of ANASTROZOLE ARROW 1 mg film-coated tablet in adults, including the elderly, is one 1 mg tablet once daily.

Populations, special

Population, pediatric

ANASTROZOLE ARROW 1 mg film-coated tablet is not recommended for use in children and adolescents due to insufficient tolerance and efficacy data (see Warnings and Precautions and Properties Pharmacodynamics).

Renal insufficiency

No dose modification is recommended in patients with mild or moderate renal insufficiency. In patients with severe renal impairment, administration of ANASTROZOLE ARROW 1 mg should be done with caution (see Warnings and Precautions for Use and Properties of Pharmacokinetics). Code>
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 ARROW 1 mg tablets should be taken orally.
Film-coated tablet, round and white.

Class: Pharmacotherapeutic: enzymatic inhibitors, code; ATC: L02BG03

Mechanism of action and effects, pharmacodynamics

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 menopausal women, anastrozole, at a dose of 1 mg daily, suppressed by more than 80% the production of estradiol measured by a highly sensitive dosage 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 the standard stimulation test, adrenocorticotropic hormone (ACTH). Corticosteroid supplementation is therefore not necessary

Efficacy and clinical safety

Breast cancer in advanced stage

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

Two randomized, double-blind, controlled trials of similar regimen (study 1033IL / 0030 and study 1033IL / 0027) were conducted to compare the efficacy of anastrozole with tamoxifen in first-line treatment Menopausal women with breast cancer, locally advanced or metastatic to hormone receptors positive or unknown. A total of 1021 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

1033IL / 0030 showed statistically significant benefit for anastrozole vs. 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), rates Of tumor-like response 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, 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.

Bone mineral density (DMO)

In the Phase III / IV SABER study, 234 postmenopausal patients with early breast cancer with hormone receptor positive and eligible for treatment with anastrozole 1 mg per day were stratified in risk groups Low, moderate and elevated as a function of 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, patients in the low-risk group received anastrozole alone (n = 42), those in the risk group, moderate were randomized to receive anastrozole plus risedronate 35 mg once a week (n '= 77) or anastrozole plus a placebo (n' = 77) and those in the high-risk group received anastrozole plus risedronate 35 mg once a week ). The main criterion was the change in bone mineral density of the lumbar spine at 12 months from the time of entry into the study.
The main analysis at 12 months showed that patients who were already at risk of moderate to severe fracture fractures showed no decrease in bone mineral density (measured at the lumbar spine by DEXA scan) when Treated with anastrozole 1 mg / day in combination with risedronate 35 mg once weekly. 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 breast cancer eligible for treatment By anastrozole.

Pediatric population

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 are available on the potential effects of long-term anastrozole therapy in children (see also section Preclinical safety data).
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The European Medicines Agency has granted a derogation from 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's syndrome (see section 4.2). >
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 differences were observed relative to placebo on growth-related parameters, ie predicted adult size, size, SDS size, and growth rate. Data on final size were not available. Although the number of children treated is too limited to allow reliable conclusions on safety, employment, increased fracture rates and a tendency to decrease bone mineral density, In children, treated with anastrozole, compared to placebo.


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 pubescent boys (ages 11 to 18 years) with gynaecomastia present for at least 12 months, receiving either anastrozole 1 mg per day or one 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 the 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 pharmacokinetic study with repeated doses 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 syndrome, Albright

Trial 0046 was an international, multicenter, open-label exploratory trial in 28 girls (2 to 10 years 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 efficacy 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 growth rate. >

No statistically significant change in the frequency of the days of vaginal bleeding was observed during treatment. No clinically significant changes in Tanner's disease, mean ovarian volume or mean uterine volume were observed No statistically significant changes in the rate of increase in bone age under treatment compared to the initial period Has been 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 therapy or prevention of osteoporosis should be established 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 and with moderate or severe hepatic impairment. Exposure to anastrozole may be increased in subjects with hepatic impairment (see section Pharmacokinetic properties), anastrozole in patients with moderate to severe hepatic impairment should be performed with Precautions (see section Dosage and mode 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 with severe renal impairment. Exposure to anastrozole in patients with severe renal impairment is not increased (filtration rate, glomerularity

Anastrozole 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 and should not be administered In combination with growth hormone therapy in girls with growth hormone deficiency. No long-term job security data for the child and the adolescent is available.

Hypersensitivity to lactose

Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency or glucose / galactose malabsorption syndrome should not take this medication.




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 the administration of anastrozole with other drugs 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 clinical studies did not reveal any clinically significant interaction in patients receiving anastrozole and also other frequently prescribed drugs. There is no clinically significant interaction with bisphosphonates (see section Pharmacodynamics).

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.

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 up to a maximum dose of 60 mg in single administration to healthy male and male volunteers 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 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 Preclinical safety data). Anastrozole is contraindicated during pregnancy (see section Contraindications).
Breastfeeding

There is no data on the use of anastrozole during breastfeeding. Anastrozole is contraindicated during breast-feeding (see section 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, 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 conducted in 9366 postmenopausal patients with cancer, operable breast treated with adjuvant therapy, For 5 years (ATAC study: Arimidex, Tamoxifen, Alone or in; Combination study).
The listed adverse reactions listed below are classified by frequency and organ system class (SOC). Frequency groups are defined according to the following convention: very common (≥ 1/10), frequent (≥ 1/100,