ANASTROZOLE RANBAXY is indicated in the

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

Dosage

The recommended dosage of ANASTROZOLE RANBAXY in adults, including the elderly, is 1 mg once daily.


Pediatric population

ANASTROZOLE RANBAXY is not recommended for use in children and adolescents due to 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 RANBAXY should be carried out with caution (see Warnings and Precautions, and Pharmacokinetics).
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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 RANBAXY should be taken orally.
Class: Pharmacotherapeutic: Enzyme inhibitors, ATC code, L02BG03.

Mechanism of action and effects, pharmacodynamics

ANASTROZOLE RANBAXY is a potent and highly selective non-steroidal inhibitor of aromatase. In postmenopausal women, estradiol results mainly from the conversion, in peripheral tissues, of androstenedione to estrone via the enzymatic 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 RANBAXY is devoid of any progestational, androgenic or estrogenic activity.
Daily doses of ANASTROZOLE RANBAXY 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 studies were carried out to compare the efficacy of Anastrozole with that of tamoxifen in the first line of treatment in patients with dual, blind, and controlled clinical trials (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 the time to tumor progression, tumor-specific response rate, and tolerance

For the main criteria, study 1033IL / 0030 showed an advantage, statistically significant for Anastrozole compared with tamoxifen in terms of time to progression tumor (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 study, 234 postmenopausal patients with early hormone receptor breast cancer positive and eligible for Anastrozole 1 mg per day were randomly assigned to the study of anastrozole with the Bisphosphonate Risedronate. Stratified in groups, low, moderate and high risk, depending on their existing risk of fragility, fracture. The primary efficacy endpoint was the bone mineral density of the lumbar spine determined by DEXA scan and 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 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 Anastrozole1 mg / day in combination with risedronate 35 mg once weekly, and a non-statistically significant decrease in BMD was observed in the low-risk group treated with Anastrozole1 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

Anastrozol 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 in children and adolescents are available (see also section 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 randomized, double-blind multicenter study evaluated 52 pubescent boys (ages 11 to 16 years) with growth hormone deficiency treated with 1 mg / day of Anastrozole or placebo for 12 to 36 months In combination with growth hormone. Only 14 subjects under Anastrozole have completed the 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

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 (aged 11 to 18 inclusive) with gynecomastia, present 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 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 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 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 bone mineral loss due to ANASTROZOLE RANBAXY in menopausal women and can be prevented (See section on Undesirable effects).
Hepatic impairment

ANASTROZOLE RANBAXY has not been evaluated in patients with breast cancer and with moderate to severe hepatic impairment, and exposure to anastrozole may be increased in subjects with hepatic impairment (see Administration of ANASTROZOLE RANBAXY in patients with moderate and severe hepatic impairment should be performed with caution (see section 4.2). Treatment should be based on an assessment of benefit / risk ratio for each patient individually

Renal insufficiency

ANASTROZOLE RANBAXY 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 RANBAXY should not be administered in combination with growth hormone therapy in boys with growth hormone deficiency. In the pivotal clinical trial, efficacy and safety of use have not been demonstrated (see section on Pharmacodynamic properties) .; Anastrozole reduces estradiol levels, ANASTROZOLE, RANBAXY 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 medicine contains lactose. Its use is not recommended, in patients with galactose intolerance, Lapp lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases). >

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 RANBAXY with other medicinal products is unlikely to lead to 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 ANASTROZOLE RANBAXY patients receiving other frequently prescribed drugs. There is no clinically significant interaction with bisphosphonates (see Pharmacodynamic properties)

The concomitant administration of ANASTROZOLE RANBAXY with tamoxifen or estrogen-containing therapies should be avoided as it may diminish 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 strengths: Anastrozole, up to a maximum dose of 60 mg administered, single to healthy male volunteers, and up to a maximum daily dose of 10 mg administered to Of menopausal women with advanced breast cancer these doses were well tolerated. No single dose of Anastrozole resulting in life - threatening symptoms has been identified. There is no specific antidote in case of overdose and the treatment should be symptomatic.


Pregnancy

There is no data on the use of ANASTROZOLE RANBAXY in pregnant women. Studies in animals have shown reproductive toxicity (see section Safety data, preclinical). ANASTROZOLE RANBAXY is contraindicated during pregnancy (see section Contraindications).
Breastfeeding

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

The effects of ANASTROZOLE and RANBAXY 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 classified by frequency and organ system class (SOC). Frequency groups are defined according to the following convention: very common (≥ 1/10), frequent (≥ 1/100,