3 DOSAGE FORMS AND STRENGTHS

The tablets are white, biconvex, film-coated containing 1 mg of anastrozole. The tablets are impressed on one side with a logo consisting of a letter “A” (upper case) with an arrowhead attached to the foot of the extended right leg of the “A” and on the reverse with the tablet strength marking “Adx 1”.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

PREGNANCY CATEGORY X [see Contraindications (4.1)]

ARIMIDEX may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. ARIMIDEX is contraindicated in women who are or may become pregnant. In animal studies, anastrozole caused pregnancy failure, increased pregnancy loss, and signs of delayed fetal development. There are no studies of ARIMIDEX use in pregnant women. If ARIMIDEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and potential risk for pregnancy loss.

In animal reproduction studies, pregnant rats and rabbits received anastrozole during organogenesis at doses equal to or greater than 1 (rats) and 1/3 (rabbits) the recommended human dose on a mg/m2 basis. In both species, anastrozole crossed the placenta, and there was increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses). In rats, these effects were dose related, and placental weights were significantly increased. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at anastrozole doses that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUC0-24hr 9 times higher). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m2 basis [see Animal Toxicology and/or Pharmacology (13.2)].

8.3 Nursing Mothers

It is not known if anastrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Clinical studies in pediatric patients included a placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and a single-arm trial in girls with McCune-Albright Syndrome and progressive precocious puberty. The efficacy of ARIMIDEX in the treatment of pubertal gynecomastia in adolescent boys and in the treatment of precocious puberty in girls with McCune-Albright Syndrome has not been demonstrated.

Gynecomastia Study

A randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged 11 to 18 years. Patients were randomized to a daily regimen of either ARIMIDEX 1 mg or placebo. After 6 months of treatment there was no statistically significant difference in the percentage of patients who experienced a ≥50% reduction in gynecomastia (primary efficacy analysis). Secondary efficacy analyses (absolute change in breast volume, the percentage of patients who had any reduction in the calculated volume of gynecomastia, breast pain resolution) were consistent with the primary efficacy analysis. Serum estradiol concentrations at Month 6 of treatment were reduced by 15.4% in the ARIMIDEX group and 4.5% in the placebo group.

Adverse reactions that were assessed as treatment-related by the investigators occurred in 16.3% of the ARIMIDEX-treated patients and 8.1% of the placebo- treated patients with the most frequent being acne (7% ARIMIDEX and 2.7% placebo) and headache (7% ARIMIDEX and 0% placebo); all other adverse reactions showed small differences between treatment groups. One patient treated with ARIMIDEX discontinued the trial because of testicular enlargement. The mean baseline-subtracted change in testicular volume after 6 months of treatment was + 6.6 ± 7.9 cm3 in the ARIMIDEX-treated patients and + 5.2 ± 8.0 cm3 in the placebo group.

McCune-Albright Syndrome Study

A multi-center, single-arm, open-label study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged 2 to <10 years. All patients received a 1 mg daily dose of ARIMIDEX. The trial duration was 12 months. Patients were enrolled on the basis of a diagnosis of typical (27/28) or atypical (1/27) McCune-Albright Syndrome, precocious puberty, history of vaginal bleeding, and/or advanced bone age. Patients’ baseline characteristics included the following: a mean chronological age of 5.9 ± 2.0 years, a mean bone age of 8.6 ± 2.6 years, a mean growth rate of 7.9 ± 2.9 cm/year and a mean Tanner stage for breast of 2.7 ± 0.81. Compared to pre- treatment data there were no on-treatment statistically significant reductions in the frequency of vaginal bleeding days, or in the rate of increase of bone age (defined as a ratio between the change in bone age over the change of chronological age). There were no clinically significant changes in Tanner staging, mean ovarian volume, mean uterine volume and mean predicted adult height. A small but statistically significant reduction of growth rate from 7.9 ± 2.9 cm/year to 6.5 ± 2.8 cm/year was observed but the absence of a control group precludes attribution of this effect to treatment or to other confounding factors such as variations in endogenous estrogen levels commonly seen in McCune-Albright Syndrome patients.

Five patients (18%) experienced adverse reactions that were considered possibly related to ARIMIDEX. These were nausea, acne, pain in an extremity, increased alanine transaminase and aspartate transaminase, and allergic dermatitis.

Pharmacokinetics in Pediatric Patients

Following 1 mg once daily multiple administration in pediatric patients, the mean time to reach the maximum anastrozole concentration was 1 hr. The mean (range) disposition parameters of anastrozole in pediatric patients were described by a CL/F of 1.54 L/h (0.77-4.53 L/h) and V/F of 98.4 L (50.7-330.0 L). The terminal elimination half-life was 46.8 h, which was similar to that observed in postmenopausal women treated with anastrozole for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetics of anastrozole was similar in boys with pubertal gynecomastia and girls with McCune-Albright Syndrome.

8.5 Geriatric Use

In studies 0030 and 0027, about 50% of patients were 65 or older. Patients ≥ 65 years of age had moderately better tumor response and time to tumor progression than patients < 65 years of age regardless of randomized treatment. In studies 0004 and 0005, 50% of patients were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients.

In the ATAC study, 45% of patients were 65 years of age or older. The efficacy of ARIMIDEX compared to tamoxifen in patients who were 65 years or older (N=1413 for ARIMIDEX and N=1410 for tamoxifen, the hazard ratio for disease- free survival was 0.93 [95% CI: 0.80, 1.08]) was less than efficacy observed in patients who were less than 65 years of age (N=1712 for ARIMIDEX and N=1706 for tamoxifen, the hazard ratio for disease-free survival was 0.79 [95% CI: 0.67, 0.94]).

The pharmacokinetics of anastrozole are not affected by age.

8.6 Renal Impairment

Since only about 10% of anastrozole is excreted unchanged in the urine, the renal impairment does not influence the total body clearance. Dosage adjustment in patients with renal impairment is not necessary [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

The plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Therefore, dosage adjustment is also not necessary in patients with stable hepatic cirrhosis. ARIMIDEX has not been studied in patients with severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Clinical trials have been conducted with ARIMIDEX, 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 tolerated. A single dose of ARIMIDEX 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, consider that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because ARIMIDEX is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

11 DESCRIPTION

ARIMIDEX (anastrozole) tablets for oral administration contain 1 mg of anastrozole, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C17H19N5 and its structural formula is:


Anastrozole is an off-white powder with a molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.

Each tablet contains as inactive ingredients: lactose, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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 Cmax of anastrozole decreased by 16% and the median Tmax 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 Cmax 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/1.73m2) 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)].

16 HOW SUPPLIED/STORAGE AND HANDLING

These tablets are supplied in bottles of 30 tablets (NDC 54868-5000-0).

Storage

Store at controlled room temperature, 20-25°C (68-77°F) [see USP].

FDA-Approved Patient Labeling

PATIENT INFORMATION

ARIMIDEX®

(anastrozole) (an as' troe zole)

Tablets

Read the information that comes with ARIMIDEX before you start taking it and each time you get a refill. The information may have changed. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. Talk with your doctor about ARIMIDEX when you start taking it and at regular checkups.

What is ARIMIDEX?

ARIMIDEX is a prescription medicine used in women who have finished menopause (“the change of life”) for:

• treatment of early breast cancer

  • after surgery, with or without radiation

  • in women whose breast cancer is hormone receptor-positive

• first treatment of locally advanced or metastatic breast cancer, in women whose breast cancer is hormone receptor-positive or the hormone receptors are not known.

• treatment of advanced breast cancer, if the cancer has grown, or the disease has spread after tamoxifen therapy.

ARIMIDEX does not work in women with breast cancer who have not finished menopause (premenopausal women).

Who should not take ARIMIDEX?

Do not take ARIMIDEX if you:

• are pregnant, think you may be pregnant, or plan to get pregnant. ARIMIDEX may harm your unborn child. If you become pregnant while taking ARIMIDEX, tell your doctor right away.

• have not finished menopause (are premenopausal).

• are allergic to any of the ingredients in ARIMIDEX. See the end of this leaflet for a list of the ingredients in ARIMIDEX.

• are a man or child.

What is the most important information I should know about ARIMIDEX?

ARIMIDEX may cause serious side effects including:

***Heart disease.**Women with early breast cancer, who have a history of blockages in heart arteries (ischemic heart disease) and who take ARIMIDEX may have a slight increase in this type of heart disease compared to similar patients who take tamoxifen.

* Stop taking ARIMIDEX and call your doctor right away if you have chest pain or shortness of breath. These can be symptoms of heart disease.

*Osteoporosis (bone softening and weakening). ARIMIDEX lowers estrogen in your body, which may cause your bones to become softer and weaker. This can increase your chance of fractures, specifically of the spine, hip and wrist. Your doctor may order a test for you called a bone mineral density study before you start taking ARIMIDEX and during treatment with ARIMIDEX as needed.

What should I tell my doctor before taking ARIMIDEX?

ARIMIDEX may not be right for you. Before taking ARIMIDEX, tell your doctor about all your medical conditions, including if you:

• have not finished menopause. Talk to your doctor if you are not sure. See “Who should not take ARIMIDEX?”

• have had a previous heart problem

• have a condition called osteoporosis

• have high cholesterol

• are pregnant, planning to become pregnant, or breast feeding. See “Who should not take ARIMIDEX?”

• are nursing a baby. It is not known if ARIMIDEX passes into breast milk. You and your doctor should decide if you will take ARIMIDEX or breast feed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

*Tamoxifen. You should not takeARIMIDEX with tamoxifen. Taking tamoxifen with ARIMIDEX may lower the amount of ARIMIDEX in your blood and may cause ARIMIDEX not to work as well.

***Medicines containing estrogen.**ARIMIDEX may not work if taken with one of these medicines:

* hormone replacement therapy

* birth control pills

* estrogen creams

* vaginal rings

* vaginal suppositories

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.

How should I take ARIMIDEX?

• Take ARIMIDEX exactly as prescribed by your doctor. Keep taking ARIMIDEX for as along as your doctor prescribes it for you.

• Take one ARIMIDEX tablet each day.

• ARIMIDEX can be taken with or without food.

• If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.

• If you have taken more ARIMIDEX than your doctor has prescribed, contact your doctor right away. Do not take any additional ARIMIDEX until instructed to do so by your doctor.

Talk with your doctor about any health changes you have while taking ARIMIDEX.

What are possible side effects of ARIMIDEX?

ARIMIDEX can cause serious side effects including:

• See “What is the most important information I should know about ARIMIDEX?”

*increased blood cholesterol (fat in the blood). Your doctor may check your cholesterol while you take ARIMIDEX therapy.

*skin reactions. Stop taking ARIMIDEX and call your doctor right away if you get any skin lesions, ulcers, or blisters.

*severe allergic reactions. Get medical help right away if you have:

* swelling of the face, lips, tongue, or throat.

* trouble swallowing

* trouble breathing

*liver problems. ARIMIDEX can cause inflammation of the liver and changes in blood tests of the liver function. Your doctor may monitor you for this. Stop taking ARIMIDEX and call your doctor right away if you have any of these signs or symptoms of a liver problem:

* a general feeling of not being well

* yellowing of the skin or whites of the eyes

* pain on the right side of your abdomen

Common side effects in women taking ARIMIDEX include:

• hot flashes

• weakness

• joint pain

• carpal tunnel syndrome (tingling, pain, coldness, weakness in parts of the hand)

• pain

• sore throat

• mood changes

• high blood pressure

• depression

• nausea and vomiting

• thinning of the hair (hair loss)

• rash

• back pain

• sleep problems

• bone pain

• headache

• swelling

• increased cough

• shortness of breath

• lymphedema (build up of lymph fluid in the tissues of your affected arm)

• trigger finger (a condition in which one of your fingers or your thumb catches in a bent position)

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

HOW SHOULD I STORE ARIMIDEX?

• Store ARIMIDEX at 68°F to 77°F (20°C to 25°C).

• Keep ARIMIDEX and all medicines out of the reach of children.

General information about ARIMIDEX.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take ARIMIDEX for a condition for which it was not prescribed. Do not give ARIMIDEX to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about ARIMIDEX. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about ARIMIDEX that is written for health professionals. For more information call 1-866-992-9276 or go to www.ARIMIDEX.com.

What are the ingredients in ARIMIDEX?

Active ingredient: anastrozole

Inactive ingredients: lactose, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide.

ARIMIDEX is a registered trademark of the AstraZeneca group of companies. ©2009 AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. All rights reserved.

35303–XX

Rev 04/2011

Additional barcode labeling by:
Physicians Total Care, inc.
Tulsa, Oklahoma 74146