Arimidex 1 mg

Interactions with particular food has not been established.

A review of AstraZeneca’s global clinical trial safety database showed that there are no clinically significant interactions with bisphosphonates. Results from the SABRE trial demonstrate that anastrozole in combination with the bisphosphonate, risedronate, was well tolerated.

ARIMIDEX has not been observed to interfere with routine clinical laboratory tests results.

Interactions with herbal products have not been established. Estrogen-containing herb therapies should not be used with ARIMIDEX as they may counteract the goal of achieving estrogen suppression.

The pharmacokinetics and anticoagulant activity of warfarin (25 mg) coadministered with anastrozole (1 mg daily) have been studied in healthy male volunteers. The mean plasma concentrations of anastrozole achieved throughout the warfarin dosing and sampling period were within the range seen in postmenopausal women with advanced breast cancer taking the clinically recommended dose of the drug. Overall, there was no evidence to suggest that anastrozole has any clinically relevant effects on the pharmacokinetics or anti-coagulant activity of warfarin.

Anastrozole inhibits reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which are approximately 30 times higher than the mean plasma steady-state C_max values observed following a 1 mg daily dose. Anastrozole has no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg or multiple 10 mg doses of anastrozole to subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. Based on these in vitro and in vivo results, it is unlikely that the administration of ARIMIDEX 1 mg will result in clinically significant inhibition of cytochrome P450-mediated metabolism of coadministered drugs.

Antipyrine, cimetidine, tamoxifen and warfarin clinical interaction studies indicate that the coadministration of ARIMIDEX (anastrozole) with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450.

A review of AstraZeneca’s global clinical trial safety database did not reveal evidence of clinically significant interactions in patients treated with ARIMIDEX who also received other commonly prescribed drugs.

Estrogen-containing therapies should not be used with ARIMIDEX as they may counteract the goal of achieving estrogen suppression.

Patients should be postmenopausal.

ARIMIDEX (anastrozole) should be administered 1 mg orally, once a day.

In the adjuvant setting, it is currently recommended that treatment be given for 5 years.

Patients should swallow ARIMIDEX with fluids.

Patients should try to take ARIMIDEX at the same time each day.

A missed dose should be taken as soon as possible, as long as it is taken at least 12 hours before the next dose is due. A missed dose should not be taken within 12 hours of the next dose.

Although the apparent oral clearance of anastrozole was decreased in subjects with cirrhosis due to alcohol abuse, plasma anastrozole concentrations remained within the range seen across all clinical trials in subjects without liver disease. Therefore, no changes in dose are recommended for patients with mild-to-moderate hepatic impairment, although patients should be monitored for side effects. ARIMIDEX has not been studied in patients with severe hepatic impairment. The potential risk/benefit to such patients should be carefully considered before administration of ARIMIDEX.

No changes in dose are necessary for elderly patients.

No changes in dose are necessary for patients with renal impairment. The potential risk/benefit to patients with severe renal impairment should still be considered prior to the administration of ARIMIDEX in these patients.

Other less frequent (2% to 5%) adverse experiences reported in patients receiving ARIMIDEX 1 mg in the two pivotal clinical trials are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.

A case of severe acute hepatitis has been reported. Although late onset hepatotoxicity due to previous chemotherapy could not be ruled out, the temporal evidence suggested ARIMIDEX as a possible cause. Rare cases of toxic hepatitis have been reported in association with ARIMIDEX administration.

Systematic collection of laboratory results (including total cholesterol) was not performed as specific endpoints in the ATAC trial. Abnormal laboratory results in ATAC are reported as an adverse event. During the ATAC trial, more patients receiving ARIMIDEX were reported to have elevated serum cholesterol levels compared to patients receiving tamoxifen (9% versus 3.5%, respectively). In the SABRE trial, which was designed to specifically evaluate lipid levels in patients on ARIMIDEX, no difference was observed in levels of low density lipoprotein-cholesterol (LDL-C), total cholesterol or triglycerides in patients taking ARIMIDEX for 12 months compared to levels prior to commencing ARIMIDEX treatment. There was a statistically significant increase in high density lipoprotein-cholesterol (HDL-C) in patients taking ARIMIDEX for 12 months compared to levels prior to commencing ARIMIDEX treatment. On the basis of the SABRE data, no specific requirements for lipid monitoring due to ARIMIDEX therapy are recommended.

More patients treated with megestrol acetate reported weight gain as an adverse event compared to patients treated with ARIMIDEX 1 mg (p<0.0001). Other differences were not statistically significant.

An examination of the magnitude of change in weight in all patients was also conducted. Thirty-four percent (87/253) of the patients treated with megestrol acetate experienced weight gain of 5% or more and 11% (27/253) of the patients treated with megestrol acetate experienced weight gain of 10% or more. Among patients treated with ARIMIDEX 1 mg, 13% (33/262) experienced weight gain of 5% or more and 3% (6/262) experienced weight gain of 10% or more. On average, this 5 to 10% weight gain represented between 6 and 12 pounds.

No patients receiving ARIMIDEX or megestrol acetate discontinued treatment due to drug-related weight gain.

hair thinning; pruritus.

flu syndrome; fever; neck pain; malaise; accidental injury; infection.

sinusitis; bronchitis; rhinitis.

anemia; leukopenia.

myalgia; arthralgia; pathological fracture.

ARIMIDEX (anastrozole) has generally been well tolerated. Adverse events have usually been mild to moderate with few withdrawals from treatment due to undesirable events.

The pharmacological action of ARIMIDEX may give rise to certain expected effects. Hot flushes were reported very commonly (≥10%). Common adverse reactions (≥1%-10%) are: asthenia, joint pain/stiffness, carpal tunnel syndrome, vaginal dryness, hair thinning (alopecia), rash, nausea, diarrhea, headache and increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase. Uncommonly reported adverse reactions (≥0.1%-1%) are: vaginal bleeding, trigger finger, anorexia, hypercholesterolaemia, vomiting, and somnolence, hepatitis and increases in gamma-GT and bilirubin. Very rare cases (<0.01%) of erythema multiforme, Stevens-Johnson syndrome and allergic reactions including angioedema, urticaria and anaphylaxis have also been reported. These reported frequencies are generated from a number of ARIMIDEX studies as well as post-marketing reports.

In the ATAC trial, ischemic cardiovascular events were reported more frequently in patients treated with ARIMIDEX compared to those treated with tamoxifen, although the difference was not statistically significant. A retrospective evaluation has shown that this numerical difference was associated with a sub-group of patients with pre-existing ischemic heart disease. A statistical analysis could not be performed on this subgroup evaluation. Serious adverse events continued to be collected during the off-treatment follow-up and the incidence of cardiovascular events reported was similar in the ARIMIDEX and tamoxifen arms (3.9% vs. 3.7%, respectively).

Events of carpal tunnel syndrome have been reported in patients receiving ARIMIDEX treatment in clinical trials in greater numbers than those receiving treatment with tamoxifen. The majority of these events occurred in patients with identifiable risk factors for the development of the condition. In the ATAC adjuvant trial, 83 events of carpal tunnel syndrome occurred in 78 patients in the ARIMIDEX monotherapy arm, and 22 events occurred in 22 patients in the tamoxifen arm.

Vaginal bleeding has been reported infrequently, mainly in patients during the first few weeks after changing from existing hormonal therapy to treatment with ARIMIDEX. If bleeding persists, further evaluation should be considered.

alkaline phosphatase increased; weight loss.

Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving ARIMIDEX. Increases in LDL cholesterol have been shown to contribute to these changes.

somnolence; confusion; insomnia; anxiety; nervousness.

hypertension; thrombophlebitis.

gamma GT increased; AST increased; ALT increased.

No changes in dose are necessary for elderly patients.

ARIMIDEX is not recommended for use in pediatric patients as safety and efficacy have not been established in this group of patients.

Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. The pharmacokinetics were similar in volunteers and in patients, and no age related effects were seen.

Anastrozole pharmacokinetics have been investigated in subjects with renal insufficiency. Anastrozole renal clearance decreased proportionately with creatinine clearance and was approximately 50% lower in subjects with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m² or 0.5 mL/sec/1.73 m²) compared to controls. Because renal clearance is not a significant pathway of elimination, the apparent oral clearance of anastrozole is unchanged even in severe renal impairment. Dosage adjustment in patients with renal dysfunction is not necessary.

ARIMIDEX has not been investigated in patients with breast cancer and severe renal impairment. The potential risk/benefit to patients with severe renal impairment should be carefully considered prior to the administration of ARIMIDEX.

The use of estrogen lowering agents, including ARIMIDEX, may cause a reduction in bone mineral density with a possible consequent increased risk of fracture. Data available from a phase III/IV study [SABRE (Study of Anastrozole with the Bisphosphonate RisedronatE)] showed that in postmenopausal women with hormone receptor positive early breast cancer with existing moderate (T-score <−1.0 in either lumbar spine or total hip, provided neither of these was less than −2.0, and with no personal history of a fragility fracture) or high risk (T-score <−2.0 in either the lumbar spine, or hip, or a personal history of fragility fracture) of fragility fracture, bone mineral density (BMD) loss could be inhibited by using ARIMIDEX together with a bisphosphonate (risedronate). All patients in the study received vitamin D and calcium supplementation. Patients at existing low risk (T-score in both the lumbar spine, and total hip, of −1.0 or higher, and no personal history of fragility fracture) of fragility fracture in the study were treated with ARIMIDEX only and did not have a loss of lumbar spine BMD following 12 months of treatment although statistically significant changes were seen following 24 months of treatment (estimated percentage change −2.07%; 95% CI: −3.60, −0.53; p=0.0109). No change in total hip BMD was seen at 12 and 24 months in the low-risk group. Women should have their osteoporosis risk assessed and managed according to local clinical practice and guidelines.

Anastrozole pharmacokinetics have been investigated in subjects with stable hepatic cirrhosis related to alcohol abuse. The apparent oral clearance of anastrozole was approximately 30% lower in subjects with hepatic cirrhosis than in control subjects with normal liver function. However, plasma anastrozole concentrations in the subjects with hepatic cirrhosis are within the range of concentrations seen in normal subjects across all clinical trials. Dosage adjustment in patients with mild-to-moderate hepatic dysfunction is not necessary.

ARIMIDEX has not been investigated in patients with severe hepatic impairment. The potential risk/benefit to such patients should be carefully considered before administration of ARIMIDEX.

ARIMIDEX has not been observed to interfere with routine clinical laboratory test results.

During the ATAC trial, more patients receiving ARIMIDEX were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9.0% versus 3.5%, respectively). Lipid profile was assessed as part of the SABRE trial. In this study, treatment for 12 months with ARIMIDEX alone had a neutral effect on lipid profile.

ARIMIDEX has not been investigated in patients with any degree of brain or leptomeningeal involvement or with pulmonary lymphangitic disseminated disease.

ARIMIDEX is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of ARIMIDEX and caution should be observed when driving or operating machinery while such symptoms persist.

ARIMIDEX is not recommended for use in pediatric patients as safety and efficacy have not been established.

ARIMIDEX is contraindicated in pregnant women.

The extent of exposure in pregnancy to ARIMIDEX during clinical trials and postmarketing is very limited to individual cases only. If a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

Anastrozole has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits. Studies in both rats and rabbits at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively (about 1 and 1/3, respectively, the recommended human dose on a mg/m² basis), administered during the period of organogenesis showed that anastrozole increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption and decreased numbers of live fetuses). Effects were dose related in rats. Placental weights were significantly increased in rats at doses of 0.1 mg/kg/day or more.

Evidence of fetotoxicity, including delayed fetal development (i.e. incomplete ossification and depressed fetal body weights), was observed in rats administered doses of 1 mg/kg/day (about 8 times the recommended human dose on a mg/m² basis). There was no evidence of teratogenicity in rats administered doses up to 1 mg/kg/day. In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1 mg/kg/day (about 16 times the recommended human dose on a mg/m² basis). There was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/m² basis).

ARIMIDEX is contraindicated in lactating women.

In the ATAC trial, ischemic cardiovascular events were reported more frequently in patients treated with ARIMIDEX compared to those treated with tamoxifen, although the difference was not statistically significant. A retrospective evaluation has shown that this numerical difference was associated with a sub-group of patients with pre-existing ischemic heart disease. A statistical analysis could not be performed on this subgroup evaluation. Serious adverse events continued to be collected during the off-treatment follow-up and the incidence of cardiovascular events reported was similar in the ARIMIDEX and tamoxifen arms (3.9% vs. 3.7%, respectively).

Anastrozole pharmacokinetics have been investigated in subjects with stable hepatic cirrhosis related to alcohol abuse. The apparent oral clearance of anastrozole was approximately 30% lower in subjects with hepatic cirrhosis than in control subjects with normal liver function. However, plasma anastrozole concentrations in the subjects with hepatic cirrhosis are within the range of concentrations seen in normal subjects across all clinical trials. Dosage adjustment in patients with mild to moderate hepatic impairment is not necessary. ARIMIDEX has not been studied in patients with severe hepatic impairment. The potential risk/benefit to such patients should be carefully considered before administration of ARIMIDEX.

Anastrozole pharmacokinetics have been investigated in post-menopausal female volunteers and patients with breast cancer. The pharmacokinetics were similar in volunteers and in patients and no age related effects were seen.

The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg and do not change with repeated dosing. Consistent with the 50-hour plasma elimination half-life, plasma concentrations of anastrozole approach steady-state concentrations after 7 days of once daily dosing and are approximately three- to four-fold higher than the concentrations observed after a single dose of anastrozole. The protein binding of anastrozole to plasma proteins is about 40% and independent of concentration over a range, which includes therapeutic concentrations.

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.

Many breast cancers have estrogen receptors and growth of these tumours can be stimulated by estrogens. In post-menopausal women, the principal source of circulating estrogen (primarily estrone) is conversion of adrenally-generated androstenedione to estrone by aromatase in peripheral tissues, such as adipose tissue, with further conversion of estrone to estradiol. Many breast cancers also contain aromatase; the importance of tumour-generated estrogens is uncertain.

Treatment of breast cancer has included efforts to decrease estrogen levels by ovariectomy pre-menopausally and by use of anti-estrogens and progestational agents both pre- and post-menopausally, and these interventions lead to decreased tumour mass or delayed progression of tumour growth in some women.

ARIMIDEX (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.

Anastrozole pharmacodynamics and pharmacokinetics have been studied in healthy, postmenopausal women in Japan, dosed for 16 days. The pharmacodynamic effect and pharmacokinetics of anastrozole 1 mg daily were similar in Japanese and Caucasian volunteers, and there was no indication that there would be any clinically significant differences in therapeutic responses to anastrozole between Japanese and Caucasian patients with breast cancer.

Studies in postmenopausal women with radiolabeled anastrozole demonstrated that elimination occurs primarily via metabolism (approximately 85%) and to a lesser extent renal excretion of unchanged anastrozole (approximately 11%). Anastrozole is eliminated slowly with a plasma elimination half-life of approximately 50 hours in postmenopausal women.

Anastrozole pharmacokinetics have been investigated in subjects with renal insufficiency. Anastrozole renal clearance decreased proportionately with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m² or 0.5 mL/sec/1.73 m²) compared to controls. Because renal clearance is not a significant pathway of elimination, the apparent oral clearance of anastrozole is unchanged even in severe renal impairment. Dosage adjustment in patients with renal dysfunction is not necessary. The potential risk/benefit to patients with severe renal impairment should still be considered prior to the administration of ARIMIDEX in these patients.

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 or urine. Several minor (less than 5% of the radioactive dose) metabolites excreted in the urine have not been identified. The major metabolite of anastrozole in the circulation, triazole, lacks pharmacologic activity.

Inhibition of aromatase activity is primarily due to anastrozole, the parent drug.

The relationship between dose and response, measured as suppression of serum estradiol, was studied in postmenopausal women. Daily doses of ARIMIDEX at 1 mg for 14 days produced estradiol suppression of greater than 80%. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with 1 mg ARIMIDEX.

In a study of 14 postmenopausal women diagnosed with locally advanced (Stage T3-T4) breast cancer with non-inflammatory, estrogen-receptor positive tumours, anastrozole was shown to be a potent suppressor of intra-tumoural estrogen levels. Following use as a 15-week primary systemic treatment (prior to any local surgery and/or radiotherapy), anastrozole suppressed intra-tumoural concentrations of estradiol (E₂), estrone (E₁) and estrone sulfate (E₁S) to mean values of 11.1%, 16.7% and 26.6%, respectively, of baseline levels. Three patients had intra-tumoural levels of E₂, E₁ and E₁S suppressed below assay detection limits.

The selectivity of ARIMIDEX to the aromatase enzyme, rather than other cytochrome P450 enzymes controlling glucocorticoid and mineralocorticoid synthesis in the adrenal gland, has been established. Furthermore, provocative stimulation of the adrenal glands by ACTH in subjects under treatment with ARIMIDEX up to 10 mg, produced a normal response in terms of cortisol and aldosterone secretion. Therefore, patients treated with ARIMIDEX do not require glucocorticoid or mineralocorticoid replacement therapy.

ARIMIDEX does not possess direct progestogenic, androgenic or estrogenic activity and does not interfere with secretion of thyroid stimulating hormone (TSH).

Because of its pharmacological action, patients with estrogen and/or progesterone receptor-positive disease are the most appropriate population for ARIMIDEX therapy.