Arimidex - Arimidex Side Effects

Pharmacology: Many breast cancers have estrogen receptors and growth of these tumors can be stimulated by estrogens. In postmenopausal 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 tumor-generated estrogens is uncertain.

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

Anastrozole is a potent and selective nonsteroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.

The relationship between dose and response, measured as suppression of serum estradiol, was studied in postmenopausal women. Daily doses of anastrozole 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 anastrozole.

In a study of 14 postmenopausal women diagnosed with locally advanced (Stage T3-T4) breast cancer with noninflammatory, estrogen-receptor positive tumors, anastrozole was shown to be a potent suppressor of intratumoral estrogen levels. Following use as a 15-week primary systemic treatment (prior to any local surgery and/or radiotherapy), anastrozole-suppressed intratumoral concentrations of estradiol(E 2), estrone (E 1) and estrone sulfate (E 1S) to mean values of 11.1%, 16.7% and 26.6%, respectively, of baseline levels. Three patients had intratumoral levels of E 2, E 1 and E 1S suppressed below assay detection limits.

Because of its pharmacological action, patients with estrogen and/or progesterone receptor-positive disease are more likely to respond to anastrozole.

The selectivity of anastrozole 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 anastrozole up to 10 mg, produced a normal response in terms of cortisol and aldosterone secretion. Therefore, patients treated with anastrozole do not require glucocorticoid or mineralocorticoid replacement therapy.

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

Pharmacokinetics: 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.

Anastrozole is eliminated slowly with a plasma elimination half-life of approximately 50 hours in postmenopausal women. 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 3- to 4-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.

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%). 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.

Special Populations: Geriatrics: 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.

Japanese Patients: 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.

Renal Insufficiency: Anastrozole pharmacokinetics have been investigated in subjects with renal insufficiency. Anastrozole renal clearance decreased proportionately with creatinine clearance andapproximately 50% lower in volunteers with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m 2 or 0.5 mL/sec/1.73 m 2) 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 (see Dosage).

Hepatic Insufficiency: 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 hepatic dysfunction is not necessary (see Dosage).

Drug Interactions : 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 anastrozole 1 mg will result in clinically significant inhibition of cytochrome P450-mediated metabolism of coadministered drugs.

The effect of anastrozole on tamoxifen (20 mg daily) pharmacokinetics has been studied in postmenopausal women with early breast cancer who were already receiving tamoxifen as adjuvant therapy. There was no evidence of anastrozole having any significant effect on blood levels of tamoxifen compared to placebo (p=0.919).

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 anticoagulant activity of warfarin.

Clinical Experience: Treatment of Postmenopausal Women with Advanced Breast Cancer: Anastrozole was studied in 2, double-blind, controlled trials of similar design (0030, a North American study; 0027, a predominantly European study) in 1021 postmenopausal women with advanced breast cancer. Eligible patients were randomized to receive a single daily dose of either anastrozole 1 mg or tamoxifen 20 mg. The trials were designed to allow data to be pooled.

Demographics and other baseline characteristics were similar for the 2 treatment groups, however, there were differences in hormone receptor status between the 2 trials. In Trial 0030, 88.3% of anastrozole-treated patients and 89.0% of tamoxifen-treated patients were known to be estrogen- and/or progesterone-receptor positive, compared to 45.3% and 43.9% (respectively) of patients in Trial 0027.

Anastrozole was shown to be at least as effective as tamoxifen for the primary endpoints of time to progression and objective response rate. In Trial 0030, a non-protocolled analysis indicated that anastrozole had a statistically significant advantage over tamoxifen (p=0.005) for time to progression (11.1 months versus 5.6 months, respectively) (see Figure I). Trial 0027 showed anastrozole to be at least as effective as tamoxifen for time to progression (8.2 months versus 8.3 months, respectively) (see Figure II) and objective response rate. The combined data from the 2 trials showed anastrozole to be numerically superior to tamoxifen for time to progression (8.5 months versus 7.0 months, respectively) (see Figure III). In a retrospective data analysis, patients from Trial 0027 who were known to be estrogen- and/or progesterone-receptor positive were shown to have longer median times to progression (271 days) when treated with anastrozole than those treated with tamoxifen (237 days) (see Figure IV). In addition, combined data from both trials, for patients who were estrogen- and/or progesterone-receptor positive, showed median times to progression of 10.7 months versus 6.4 months for anastrozole- versus tamoxifen-treated patients. These subgroup analyses support the results of Trial 0030 in suggesting numerical superiority for anastrozole over tamoxifen in patients known to be estrogen- and/or progesterone-receptor positive.

Patients with estrogen receptor-negative disease rarely responded to anastrozole, but there were too few patients in this group for a meaningful analysis.


Indications: For hormonal treatment of advanced breast cancer in postmenopausal women.

Contraindications: Patients with hypersensitivity to the drug or any of its components.

Pregnancy and Lactation: Anastrozole is contraindicated in pregnant or lactating women.


Warnings: Premenopausal Women: Anastrozole is not recommended for use in premenopausal women as safety and efficacy have not been established in this group of patients.

Pregnancy: There are no adequate and well-controlled studies in pregnant women using anastrozole. If the 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 (see Contraindications).

Reproductive Toxicology: 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 3/4 and 1/3, respectively, the recommended human dose on a mg/m 2 basis), administered during the period of organogenesis showed that anastrozole increased pregnancy loss (increased pre- and/or postimplantation 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),observed in rats administered doses of 1 mg/kg/day (about 7 times the recommended human dose on a mg/m 2 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/m 2 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/m 2 basis).

Children: The safety and efficacy of anastrozole in pediatric patients have not been established.

Severe Hepatic/Renal Impairment: Anastrozole has not been investigated in patients with severe hepatic or severe renal impairment. The potential risk/benefit to such patients should be carefully considered before administration of anastrozole (see Pharmacology, Special Populations, Renal Insufficiency, Hepatic Insufficiency and Dosage).

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

Precautions: General: Anastrozole should be administered under the supervision of a qualified physician experienced in the use of anti-cancer agents.

Drug Interactions : Antipyrine, cimetidine, tamoxifen and warfarin clinical interaction studies indicate that the coadministration of anastrozole with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P 450 (see Pharmacology, Drug Interactions). A study of combination treatment of anastrozole with tamoxifen has shown that anastrozole does not have a significant effect on blood levels of tamoxifen and estradiol suppression is consistent with that seen in patients treated with anastrozole alone.

Drug/Laboratory Test Interactions : Anastrozole has not been observed to interfere with routine clinical laboratory tests results.

Occupational Hazards: Effect on Ability to Drive and Use Machinery: Anastrozole is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

Adverse Effects: 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 anastrozole may give rise to certain expected effects. These include hot flushes, vaginal dryness and hair thinning. Anastrozole may also be associated with gastrointestinal disturbances (anorexia, nausea, vomiting and diarrhea), asthenia, joint pain/stiffness, somnolence, headache or rash.

Hepatic changes (elevated gamma-GT or less commonly alkaline phosphatase) have been reported in patients with advanced breast cancer, many of whom had liver and/or bone metastases. A causal relationship for these changes has not been established. Slight increases in total cholesterol have also been observed in clinical trials with anastrozole.

Patients With Advanced Breast Cancer: Two controlled clinical trials involving postmenopausal women with advanced breast cancer compared treatment with tamoxifen (20 mg daily) versus treatment with anastrozole (1 mg daily). Table III presents adverse events reported in these trials with an incidence of greater than 5% in either treatment group, regardless of causality.

Other less frequent (2 to 5%) adverse experiences reported in patients receiving anastrozole 1 mg in the 2 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.

Body as a Whole: flu syndrome, fever, neck pain, malaise, accidental injury, infection.

Cardiovascular: hypertension, thrombophlebitis.

Hepatic: gamma GT increased, ALT increased, AST increased.

Hematologic: anemia, leukopenia.

Metabolic and Nutritional: alkaline phosphatase increased, weight loss.

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

Musculoskeletal: myalgia, arthralgia, pathological fracture.

Nervous: somnolence, confusion, insomnia, anxiety, nervousness.

Respiratory: sinusitis, bronchitis, rhinitis.

Skin and Appendages: hair thinning, pruritus.

Urogenital: urinary tract infection, breast pain.

The incidence of the following adverse event groups, potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes and vaginal dryness. These 6 groups, and the adverse events captured in the groups, were prospectively defined. The results are shown in Table VI.

More patients treated with megestrol acetate reported weight gain as an adverse event compared to patients treated with anastrozole 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 anastrozole 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 3 and 6 kg.

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

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

Overdose: Symptoms and Treatment: There is no clinical experience of accidental overdosage. In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of anastrozole, 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 well tolerated. A single dose of anastrozole 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, consideration should be given to the possibility that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.


Dosage: Anastrozole should be administered 1 mg orally, once a day. Concomitant administration of steroid therapy is not necessary.

Patients With Hepatic Impairment: 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. Anastrozole has not been studied in patients with severe hepatic impairment (see Pharmacology, Special Populations-Hepatic Insufficiency).

Patients with Renal Impairment: No changes in dose are necessary for patients with renal impairment (see Pharmacology, Special Populations-Renal Insufficiency).


Supplied: Each white, biconvex, film-coated tablet, intagliated with Adx 1 on one side and a logo on the other side (A for Arimidex), contains: anastrozole 1 mg. Nonmedicinal ingredients: hypromellose, lactose monohydrate, macrogol 300, magnesium stearate, povidone, sodium starch glycolate and titanium dioxide. Calendar packs of 30. Store at room temperature (15 to 30°C).