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.

ARIMIDEX (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 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 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 (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 intratumoral levels of E₂, E₁ and E₁S suppressed below assay detection limits.

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

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 anastrozole 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).

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 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 (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).

Treatment of Postmenopausal Women with Advanced Breast Cancer: ARIMIDEX 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 ARIMIDEX 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 ARIMIDEX-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.

ARIMIDEX 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 ARIMIDEX had a statistically significant advantage over tamoxifen (p=0.005) for time to progression (11.1 months versus 5.6 months, respectively) (see Figure 1). Trial 0027 showed ARIMIDEX to be at least as effective as tamoxifen for time to progression (8.2 months versus 8.3 months, respectively) (see Figure 2) and objective response rate. The combined data from the 2 trials showed ARIMIDEX to be numerically superior to tamoxifen for time to progression (8.5 months versus 7.0 months, respectively) (see Figure 3). 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 ARIMIDEX, than those treated with tamoxifen (237 days) (see Figure 4). 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 ARIMIDEX versus tamoxifen treated patients: (two sided, p=0.022, retrospective analysis). These subgroup analyses support the results of Trial 0030 in suggesting numerical superiority for ARIMIDEX over tamoxifen in patients known to be estrogen- and/or progesterone-receptor positive. Furthermore, these analyses demonstrate that patients with estrogen and/or progesterone receptor positive tumours are clearly the most appropriate population for ARIMIDEX therapy.

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Figure 1-ARIMIDEX (Advanced Breast Cancer)

Kaplan-Meier Plot of Time to Progression—Intent to Treat Population—Trial 0030 all patients

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Figure 2-ARIMIDEX (Advanced Breast Cancer)

Kaplan-Meier Plot of Time to Progression—Intent to Treat Population—Trial 0027 all patients

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Figure 3-ARIMIDEX (Advanced Breast Cancer)

Kaplan-Meier Plot of Time to Progression—Intent to Treat Population—Trials 0030 and 0027 combined

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Figure 4-ARIMIDEX (Advanced Breast Cancer)

Kaplan-Meier Plot of Time to Progression—Intent to Treat Population—Trial 0027 estrogen/progesterone-receptor positive patients only

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Results from the secondary endpoints of time to treatment failure, duration of response, and duration of clinical benefit were supportive of the results of the primary efficacy endpoints. The number of patients who experienced clinical benefit (best objective response of complete response [CR], partial response [PR] or stable disease [SD] ≥24 weeks) is shown in Table 1.

Table 1: ARIMIDEX (Advanced Breast Cancer)

Patients Who Experienced Clinical Benefit

Clinical Benefit	Number (%) of Patients
	Trial 0030		Trial 0027		Combined Trials
	ARIMIDEX 1 mg (n=171)	Tamoxifen 20 mg (n=182)	ARIMIDEX 1 mg (n=340)	Tamoxifen 20 mg (n=328)	ARIMIDEX 1 mg (n=511)	Tamoxifen 20 mg (n=510)
CR	5 (2.9)	5 (2.7)	19 (5.6)	16 (4.9)	24 (4.7)	21 (4.1)
PR	31 (18.1)	26 (14.3)	93 (27.4)	91 (27.7)	124 (24.3)	117 (22.9)
SD ≥24 weeks	65 (38.0)	52 (28.6)	79 (23.2)	75 (22.9)	144 (28.2)	127 (24.9)
Total	101 (59.1)a	83 (45.6)a	191 (56.2)	182 (55.5)	292 (57.1)	265 (52.0)

^a. Two-sided p=0.0098, Retrospective analysis.

Legend:

There were too few deaths occurring across treatment groups of both trials to assess overall survival differences at the time of data analysis.

Treatment of Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy: ARIMIDEX was studied in 2 well-controlled clinical trials (0004, a North American study; 0005, a predominantly European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy. Most patients were estrogen receptor-positive; a smaller fraction was estrogen receptor-unknown or estrogen receptor-negative. Eligible patients were randomized to receive either a single daily dose of 1 or 10 mg of ARIMIDEX, or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to ARIMIDEX. Approximately 1/3 of the patients in each treatment group in both studies had either an objective response or stabilization of their disease for greater than 24 weeks. Hazard ratios for time to progression and odds ratios for response rates were calculated for the pooled studies and were shown to be similar. After analysis of mature data involving 473 patients among 764 randomized participants, the hazard ratios for survival demonstrated a significant prolongation of survival in the 1 mg ARIMIDEX group compared to hormonal treatment with megestrol acetate. See Table 2.

Table 2: ARIMIDEX (Advanced Breast Cancer)

Analysis of Time to Death for Patients in Trials 0004 and 0005 Combined

	Trial Treatment			Hazard Ratioa, (97.5% CI), and p-valuesb
Time to Death	ARIMIDEX 1 mg	ARIMIDEX 10 mg	MA	ARIMIDEX 1 mg vs MA	ARIMIDEX 10 mg vs MA
Number of Patients who Died (%)	151 of 263 (57.4)	151 of 248 (60.9)	171 of 253 (67.6)
2-year Survival Rate	56.1%	54.6%	46.3%
Median Time to Death (months)	26.7	25.5	22.5	0.78 (0.6040 to 0.9996) p=0.0248c	0.83 (0.6452 to 1.0662) p=0.0951c

^a. Hazard ratio greater than 1.00 indicated that the first treatment is associated with shorter time to death than is the second treatment.
^b. The critical p-value for statistical significance is 0.025.
^c. Calculated using Cox's regression model.

Legend:

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

ARIMIDEX (anastrozole) is indicated for hormonal treatment of advanced breast cancer in postmenopausal women.

ARIMIDEX (anastrozole) is contraindicated in patients with hypersensitivity to the drug or any of its components.

ARIMIDEX is contraindicated in pregnant women.

ARIMIDEX is contraindicated in lactating women.

Premenopausal Women: ARIMIDEX (anastrozole) is not recommended for use in premenopausal women as safety and efficacy have not been established in this group of patients.

ARIMIDEX (anastrozole) should be administered under the supervision of a qualified physician experienced in the use of anti-cancer agents.

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

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.

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

Effect on Ability to Drive and Use Machinery: 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 (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. These include hot flushes, vaginal dryness and hair thinning. ARIMIDEX may also be associated with gastrointestinal disturbances (anorexia, nausea, vomiting and diarrhea), asthenia, joint pain/stiffness, somnolence, headache or rash including very rare (<0.1%) cases of mucocutaneous disorders such as erythema multiforme, Stevens-Johnson syndrome and allergic reactions including angioedema, urticaria and anaphylaxis.

Elevated gamma-GT and alkaline phosphatase have been reported in patients uncommonly (≥0.1% and <1%). A causal relationship for these changes has not been established. Slight increases in total cholesterol have also been observed in clinical trials with ARIMIDEX.

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 3 presents adverse events reported in these trials with an incidence of greater than 5% in either treatment group, regardless of causality.

Table 3: ARIMIDEX (Advanced Breast Cancer)

Number (%) of Patients with Adverse Event<sup>a

a.</sup> A patient may have more than 1 adverse event.

Based on results from the established safety profiles of ARIMIDEX and tamoxifen, the incidences of 9 prespecified adverse event categories, potentially causally related to one or both therapies because of their pharmacology, were statistically analyzed. No statistically significant differences were seen between treatment groups. The results are shown in Table 4.

Table 4: ARIMIDEX (Advanced Breast Cancer)

Number (%) of Patients^a

Adverse Event Categories	ARIMIDEX 1 mg (n=506)	Tamoxifen 20 mg (n=511)
Tumor Flare	15 (3.0)	18 (3.5)
Vaginal Dryness	15 (3.0)	13 (2.5)
Weight Gain	11 (2.2)	8 (1.6)
Depression	23 (4.5)	32 (6.3)
Hot Flushes	134 (26.5)	118 (23.1)
Vaginal Bleeding	5 (1.0)	11 (2.2)
Gastrointestinal Disturbances	170 (33.6)	196 (38.4)
Lethargy	6 (1.2)	15 (2.9)
Thromboembolic Disease	23 (4.5)	39 (7.6)

^a. Patients may appear in more than 1 row.

The low incidence of vaginal bleeding and vaginal discharge was consistent with the known pharmacology of ARIMIDEX, which would be predicted to have no estrogenic effect and no effect on the endometrium. Despite the lack of estrogenic activity, there was no increase in myocardial infarction or pathological fracture when compared with tamoxifen. There was a low incidence of thromboembolic disease.

Patients with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy: For 2 controlled clinical trials comparing ARIMIDEX (1 mg and 10 mg) versus megestrol acetate (160 mg), adverse events reported in greater than 5% of the patients in any of the treatment groups, regardless of causality, are presented in Table 5.

Table 5: ARIMIDEX (Advanced Breast Cancer)

Number (n) and Percentage of Patients with Adverse Event<sup>a

a.</sup> A patient may have more than 1 adverse event.

Other less frequent (2 to 5%) adverse experiences reported in patients receiving ARIMIDEX 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.

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

hypertension, thrombophlebitis.

gamma GT increased, ALT increased, AST increased.

anemia, leukopenia.

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.

myalgia, arthralgia, pathological fracture.

somnolence, confusion, insomnia, anxiety, nervousness.

sinusitis, bronchitis, rhinitis.

hair thinning, pruritus.

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 6.