ARIMIDEX Anastrozole 1 mg Tablet, 30-count — NDC 62559-670-30 (Billing 62559-0670-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The growth of many cancers of the breast is stimulated or maintained by estrogens. 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 selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.

12.2Pharmacodynamics 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 ARIMIDEX 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, ARIMIDEX 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 ARIMIDEX 1 mg. The effect of ARIMIDEX 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, ARIMIDEX 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 ARIMIDEX. ARIMIDEX does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.

12.3Pharmacokinetics 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 C max of anastrozole decreased by 16% and the median T max 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 ARIMIDEX. 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 P45… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The growth of many cancers of the breast is stimulated or maintained by estrogens. 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 selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.

12.3Pharmacokinetics 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 C max of anastrozole decreased by 16% and the median T max 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 ARIMIDEX. 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 C max 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/1.73m 2 ) compared to controls. Total clearance was only reduced 10%.

No dosage adjustment is needed for renal impairment [see Dosage and Administration ( 2.1 ) and Use in Specific Populations ( 8.6 )] . 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 and Administration ( 2.2 ) and Use in Specific Populations ( 8.7 )] .

12.2Pharmacodynamics 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 ARIMIDEX 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, ARIMIDEX 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 ARIMIDEX 1 mg. The effect of ARIMIDEX 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, ARIMIDEX 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 ARIMIDEX. ARIMIDEX does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.

14 CLINICAL STUDIES

14.1Adjuvant Treatment of Breast Cancer in Postmenopausal Women A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with ARIMIDEX 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease. The primary endpoint of the trial was disease-free survival (i.e., time to occurrence of a distant or local recurrence, or contralateral breast cancer or death from any cause). Secondary endpoints of the trial included distant disease-free survival, the incidence of contralateral breast cancer and overall survival.

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 Drug Interactions ( 7.1 )] .

Demographic and other baseline characteristics were similar among the three treatment groups (see Table 7). Table 7 - Demographic and Baseline Characteristics for ATAC Trial Demographic Characteristic ARIMIDEX 1 mg (N N=Number of patients randomized to the treatment =3125) Tamoxifen 20 mg (N =3116) ARIMIDEX 1 mg plus Tamoxifen The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up 20 mg (N =3125) Mean age (yrs.) 64.1 64.1

64.3Age Range (yrs.) 38.1 - 92.8 32.8 - 94.9 37.0 -

92.2Age Distribution (%) <45 yrs. 0.7 0.4 0.5 45-60 yrs. 34.6 35.0 34.5 >60 <70 yrs. 38.0 37.1 37.7 >70 yrs. 26.7 27.4

27.3Mean Weight (kg) 70.8 71.1

71.3Receptor Status (%) Positive Includes patients who were estrogen receptor (ER) positive or progesterone receptor (PgR) positive, or both positive 83.5 83.1

84.0Negative Includes patients with both ER negative and PgR negative receptor status 7.4 8.0

7.0Other Includes all other combinations of ER and PgR receptor status unknown 8.8 8.6

9.0Other Treatment (%) prior to Randomization Mastectomy 47.8 47.3

48.1Breast conservation Among the patients who had breast conservation, radiotherapy was administered to 95.0% of patients in the ARIMIDEX arm, 94.1% in the tamoxifen arm and 94.5% in the ARIMIDEX plus tamoxifen arm. 52.3 52.8

51.9Axillary surgery 95.5 95.7

95.2Radiotherapy 63.3 62.5

61.9Chemotherapy 22.3 20.8

20.8Neoadjuvant Tamoxifen 1.6 1.6

1.7Primary Tumor Size (%) T1 (≤2 cm) 63.9 62.9

64.1T2 (>2 cm and ≤5 cm) 32.6 34.2

32.9T3 (>5 cm) 2.7 2.2

2.3Nodal Status (%) Node positive 34.9 33.6 33.5 1-3 (# of nodes) 24.4 24.4 24.3 4-9 7.5 6.4 6.8 >9 2.9 2.7

2.3Tumor Grade (%) Well-differentiated 20.8 20.5

21.2Moderately differentiated 46.8 47.8

46.5Poorly/undifferentiated 23.7 23.3

23.7Not assessed/recorded 8.7 8.4

8.5Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the ARIMIDEX arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.83, 95% CI: 0.73, 0.94, p=0.0049) in the ARIMIDEX arm compared to the tamoxifen arm.

Figure 1 - Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to ARIMIDEX or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat) Figure 2 - Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to ARIMIDEX or Tamoxifen Monotherapy in the ATAC Trial The survival data with 68 months follow-up is presented in Table 9. In the group of patients who had previous adjuvant chemotherapy (N=698 for ARIMIDEX and N=64… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/m 2 basis) administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose-related increase was observed in the incidence of ovarian and uterine hyperplasia in females.

At 25 mg/kg/day, plasma AUC 0-24 hr levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/m 2 basis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose-related increase in the incidence of ovarian hyperplasia was also observed in female mice.

These ovarian changes are considered to be rodent-specific effects of aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50 mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose.

ARIMIDEX has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats). Oral administration of anastrozole to female rats (from 2 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended human dose on a mg/m 2 basis and 9 times higher than the AUC 0-24 hr found in postmenopausal volunteers at the recommended dose).

Pre-implantation loss of ova or fetus was increased at doses equal to or greater than 0.02 mg/kg/day (about one-fifth the recommended human dose on a mg/m 2 basis). Recovery of fertility was observed following a 5-week non-dosing period which followed 3 weeks of dosing. It is not known whether these effects observed in female rats are indicative of impaired fertility in humans.

Multiple-dose studies in rats administered anastrozole for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole C ssmax and AUC 0-24 hr that were 19 and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose) resulted in hypertrophy of the ovaries and the presence of follicular cysts. In addition, hyperplastic uteri were observed in 6-month studies in female dogs administered doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole C ssmax and AUC 0-24 hr that were 22 times and 16 times higher than the respective values found in postmenopausal women at the recommended dose).

It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in premenopausal women.