Each film coated tablet contains: 1 mg Anastrozole.
Anastrozole tablets for oral administration contain 1 mg of anastrozole, a non-steroidal. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C17H19N5.
Anastrozole is an off-white powder with a molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.
Excipients/Inactive Ingredients: Lactose monohydrate, Magnesium stearate, Isopropyl alcohol, povidone, sodium starch glycolate, and Opadry white Y-1-7000 (Hypromellose, Titanium dioxide, Macrogol/PEG).
Pharmacology: Pharmacodynamics: Mechanism of Action: The growth of many cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.
In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme. Anastrozole is a potent and selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.
Pharmacodynamic Properties: Effect on Estradiol: Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of anastrozole tablets in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, anastrozole tablets 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with anastrozole tablets 1 mg.
The effect of anastrozole tablets in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women, anastrozole tablets would not be expected to lower estradiol levels in premenopausal women.
Effect on Corticosteroids: In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of anastrozole was assessed by examining effects on corticosteroid synthesis. For all doses, anastrozole did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with anastrozole.
Other Endocrine Effects: In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of anastrozole tablets. Anastrozole tablet does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.
Pharmacokinetics: Absorption: Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within 2 hours of dosing under fasted conditions. Studies with radiolabeled drug have demonstrated that orally administered anastrozole is well absorbed into the systemic circulation. Food reduces the rate but not the overall extent of anastrozole absorption. The mean Cmax of anastrozole decreased by 16% and the median Tmax was delayed from 2 to 5 hours when anastrozole was administered 30 minutes after food. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg, and do not change with repeated dosing. The pharmacokinetics of anastrozole were similar in patients and healthy volunteers.
Distribution: Steady-state plasma levels are approximately 3- to 4-fold higher than levels observed after a single dose of anastrozole tablets. Plasma concentrations approach steady-state levels at about 7 days of once daily dosing. Anastrozole is 40% bound to plasma proteins in the therapeutic range.
Metabolism: Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of anastrozole (triazole, a glucuronide conjugate of hydroxy anastrozole, and a glucuronide conjugate of anastrozole itself) have been identified in human plasma and urine. The major circulating metabolite of anastrozole, triazole, lacks pharmacologic activity.
Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.
Excretion: Eighty-five percent of radiolabeled anastrozole was recovered in feces and urine. Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination accounts for approximately 10% of total clearance. The mean elimination half-life of anastrozole is 50 hours.
Effect of Gender and Age: Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age related effects were seen over the range <50 to >80 years.
Effect of Race: Estradiol and estrone sulfate serum levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of anastrozole daily for 16 days. Anastrozole mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.
Effect of Renal Impairment: Anastrozole pharmacokinetics have been investigated in subjects with renal impairment. Anastrozole renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance < 30 mL/min/1.73m2) compared to controls. Total clearance was only reduced 10%. No dosage adjustment is needed for renal impairment [see Dosage & Administration].
Effect of Hepatic Impairment: Anastrozole pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of anastrozole was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, these plasma concentrations were still with the range of values observed in normal subjects. The effect of severe hepatic impairment was not studied. No dose adjustment is necessary for stable hepatic cirrhosis [see Dosage & Administration and Use in Pregnancy & Lactation].
Treatment of advanced breast cancer in postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen.
The dose of anastrozole tablet for adults including elderly is one 1 mg tablet taken once a day. Anastrozole tablets can be taken with or without food.
Children: Anastrozole is not recommended for use in children.
Renal impairment: No dose change is recommended in patients with mild or moderate renal impairment.
Hepatic impairment: No dose change is recommended in patients with mild hepatic disease.
Clinical trials have been conducted with anastrozole tablets, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were tolerated. A single dose of anastrozole tablets that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consider that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole tablet is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
Anastrozole is contraindicated in: premenopausal women; pregnant or lactating women; patients with severe renal impairment (creatinine clearance less than 20 ml/min); patients with moderate or severe hepatic disease; patients with known hypersensitivity to anastrozole or to any of the excipients listed under Description.
Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.
Concurrent tamoxifen therapy (see Interactions).
Anastrozole is not recommended for use in children as safety and efficacy have not been established in this group of patients.
The menopause should be defined biochemically in any patient where there is doubt about menopausal status.
There are no data to support the safe use of Anastrozole in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20 ml/min).
Women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.
There are no data available for the use of anastrozole with LHRH analogues. This combination should not be used outside clinical trials.
As Anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fractures. The use of bisphosphonates may stop further bone mineral loss caused by Anastrozole in postmenopausal women and could be considered.
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Anastrazole is contraindicated in pregnant or lactating women.
Pregnancy Category X.
[See Contraindications].
Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years (ATAC Study). (See Table 1.)
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The table as follows presents the frequency of pre-specified adverse events in the ATAC study, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy. (See Table 2.)
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The ATAC trial data showed that patients receiving Anastrozole had an increase in joint disorders (including arthritis, arthrosis, and arthralgia) compared with patients receiving tamoxifen. Patients receiving Anastrozole had an increase in the incidence of fractures (including fractures of spine, hip and wrist) compared with patients receiving tamoxifen. These differences were statistically significant. Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the Anastrozole and tamoxifen groups, respectively, after a median follow up of 68 months. The observed fracture rate for Anastrozole is similar to the range reported in age-matched postmenopausal populations.
It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.
The incidence of osteoporosis was 10.5% in patients treated with Anastrozole and 7.3% in patients treated with tamoxifen.
Patients receiving Anastrozole had a decrease in hot flushes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events (including deep venous thrombosis) and ischaemic cerebrovascular events compared with patients receiving tamoxifen. These differences were statistically significant.
Results from the ATAC trial bone substudy, at 12 and 24 months demonstrated that patients receiving Anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline.
Slight increases in total cholesterol have also been observed in clinical trials with Anastrozole, although the clinical significance has not been determined.
Tamoxifen: Co-administration of anastrozole and tamoxifen in breast cancer patients reduced Anastrozole plasma concentration by 27%. However, the co-administration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of anastrozole tablets and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.
Estrogen: Estrogen-containing therapies should not be used with anastrozole tablets as they may diminish its pharmacological action.
Warfarin: In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by Cmax and AUC) and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R- and S-warfarin.
Cytochrome P450: Based on in vitro and in vivo results, it is unlikely that co-administration of anastrozole tablets 1 mg will affect other drugs as a result inhibition of cytochrome P450 [see Pharmacology under Actions].
Store below 30°C and protect from moisture.
L02BG03 - anastrozole ; Belongs to the class of enzyme inhibitors. Used in treatment of neoplastic diseases.
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