Adverse reaction data for adjuvant therapy are based on the adjuvant trial (see CLINICAL PHARMACOLOGY - Clinical Studies - Adjuvant Treatment of Breast Cancer in Postmenopausal Women). At a median follow-up of 33 months, the combination of ARIMIDEX 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. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving ARIMIDEX 1 mg and tamoxifen 20 mg, respectively.

Adverse events occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 8.

COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms.

N = Number of patients receiving the treatment.
*A patient may have had more than 1 adverse event, including more han 1 adverse event in the same body system.
^†Vaginal Hemorrhage without further diagnosis.
**The combination arm was discontinued due to lack of efficacy at 33 months of follow up.

Certain adverse events and combinations of adverse events were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (See table 9).

¹Patients with multiple events in the same category are counted only once in that category.
²Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia.
³Percentages calculated based upon the numbers of patients with an intact uterus at baseline.

Patients receiving ARIMIDEX had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving ARIMIDEX had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving tamoxifen [209 (7%)]. Patients receiving ARIMIDEX had a decrease in hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen.

Patients receiving ARIMIDEX had an increase in hypercholesterolemia (278 [9%]) compared to patients receiving tamoxifen (108 [3.5%]). Angina pectoris was reported in 71 [2.3%] patients in the ARIMIDEX arm and 51 [1.6%] patients in the tamoxifen arm; myocardial infarction was reported in 37 [1.2%] patients in the ARIMIDEX arm and in 34 [1.1%] patients in the tamoxifen arm.

Results from the ATAC trial bone substudy, at 12 and 24 months demonstrated that patients receiving ARIMIDEX 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.

ARIMIDEX was generally well tolerated in two well-controlled clinical trials (ie, Trials 0030 and 0027). Adverse events occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 10.

Table 10

^aA patient may have had more than 1 adverse event.

Less frequent adverse experiences reported in patients receiving ARIMIDEX l mg in either Trial 0030 or Trial 0027 were similar to those reported for second-line therapy.

Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 prespecified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups.

Table 11

^aA patient may have had more than 1 adverse event
^bIncludes pulmonary embolus, thrombophlebitis, retinal vein thrombosis
^cIncludes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct

Despite the lack of estrogenic activity for ARIMIDEX, there was no increase in myocardial infarction or fracture when compared with tamoxifen.

ARIMIDEX was generally well tolerated in two well-controlled clinical trials (ie, Trials 0004 and 0005), with less than 3.3% of the ARIMIDEX-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse event.

The principal adverse event more common with ARIMIDEX than megestrol acetate was diarrhea. Adverse events reported in greater than 5% of the patients in any of the treatment groups in these two well-controlled clinical trials, regardless of causality, are presented below:

Table 12- Number (n) and Percentage of Patients with Adverse Event^†

^†A patient may have more than one adverse event.

Other less frequent (2% to 5%) adverse experiences reported in patients receiving ARIMIDEX l mg in either Trial 0004 or Trial 0005 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; SGOT increased; SGPT 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 ARIMIDEX. 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 incidences 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 six groups, and the adverse events captured in the groups, were prospectively defined. The results are shown in the table below.

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.

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.

During clinical trials and postmarketing experience joint pain/stiffness has been reported in association with the use of ARIMIDEX.

ARIMIDEX may also be associated with rash including very rare cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome. Very rare cases of allergic reactions including angioedema, urticaria and anaphylaxis have been reported in patients receiving ARIMIDEX.

(See CLINICAL PHARMACOLOGY) Anastrozole inhibited in vitro metabolic reactions catalyzed by cytochromes P450 1A2, 2C8/9, and 3A4 but only at relatively high concentrations. Anastrozole did not inhibit P450 2A6 or the polymorphic P450 2D6 in human liver microsomes. Anastrozole did not alter the pharmacokinetics of antipyrine. Although there have been no formal interaction studies other than with antipyrine, based on these in vivo and in vitro studies, it is unlikely that co-administration of a 1 mg dose of ARIMIDEX with other drugs will result in clinically significant drug inhibition of cytochrome P450-mediated metabolism of the other drugs.

An interaction study with warfarin showed no clinically significant effect of anastrozole on warfarin pharmacokinetics or anticoagulant activity.

At a median follow-up of 33 months, the combination of ARIMIDEX 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 (see CLINICAL PHARMACOLOGY - Drug Interactions and CLINICAL PHARMACOLOGY - Clinical Studies - Adjuvant Treatment of Breast Cancer in Postmenopausal Women subsections). Co-administration of anastrozole and tamoxifen resulted in a reduction of anastrozole plasma levels by 27% compared with those achieved with anastrozole alone.

Estrogen-containing therapies should not be used with ARIMIDEX as they may diminish its pharmacologic action.

Drug/Laboratory Test Interactions

No clinically significant changes in the results of clinical laboratory tests have been observed.

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