Anastrozole

Anastrozole, USP is a white to off-white powder with a molecular weight of 293.37. 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: anhydrous lactose, hypromellose, magnesium stearate, polydextrose, polyethylene glycol, sodium starch glycolate, titanium dioxide and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The growth of many cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.

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 potent and 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 mg, 1 mg, 3 mg, 5 mg and 10 mg of anastrozole tablets 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, anastrozole tablets 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 anastrozole tablets 1 mg.

The effect of anastrozole 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, anastrozole tablets would not be expected to lower estradiol levels in premenopausal women.

Effect on Corticosteroids

In multiple daily dosing trials with 3 mg, 5 mg, 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 mg and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of anastrozole tablets. Anastrozole tablets do 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 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 mg 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 anastrozole tablets. 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/1.73 m²) 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)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A conventional carcinogenesis study in rats at doses of 1 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/m² 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/m² 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.

Anastrozole tablets have 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/m² 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/m² 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.

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology

Anastrozole has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits (about 1 and 1.9 times the recommended human dose, respectively, on a mg/m² basis). Studies in both rats and rabbits at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively (about 1 and 1/3, respectively, the recommended human dose on a mg/m² basis), administered during the period of organogenesis showed that anastrozole increased pregnancy loss (increased pre- and/or post-implantation 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), was observed in rats administered doses of 1 mg/kg/day (which produced plasma anastrozole C_ssmax and AUC_{0-24 hr} that were 19 times and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose). 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/m² 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/m² basis).

14 CLINICAL STUDIES

14.1 Adjuvant 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 anastrozole tablets 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for 5 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 anastrozole tablets 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).

Patients 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 anastrozole 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 anastrozole arm compared to the tamoxifen arm.

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 anastrozole and N = 647 for tamoxifen), the hazard ratio for disease-free survival was 0.91 (95% CI: 0.73 to 1.13) in the anastrozole arm compared to the tamoxifen arm.

The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 8.

Table 8: All Recurrence and Death EventsThe combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.

	Intent-To-Treat Population Patients may fall into more than one category.		Hormone Receptor-Positive Subpopulation Patients may fall into more than one category.
	Anastrozole 1 mg    (N N = Number of patients randomized = 3,125)	Tamoxifen 20 mg   (N N = Number of patients randomized = 3,116)	Anastrozole 1 mg   (N N = Number of patients randomized = 2,618)	Tamoxifen 20 mg   (N N = Number of patients randomized = 2.598)
Median Duration of Therapy (mo)	60	60	60	60
Median Efficacy Follow-up (mo)	68	68	68	68
Loco-regional recurrence	119 (3.8)	149 (4.8)	76 (2.9)	101 (3.9)
Contralateral breast cancer	35 (1.1)	59 (1.9)	26 (1)	54 (2.1)
Invasive	27 (0.9)	52 (1.7)	21 (0.8)	48 (1.8)
Ductal carcinoma in situ	8 (0.3)	6 (0.2)	5 (0.2)	5 (0.2)
Unknown	0	1 (< 0.1)	0	1 (< 0.1)
Distant recurrence	324 (10.4)	375 (12)	226 (8.6)	265 (10.2)
Death from Any Cause	411 (13.2)	420 (13.5)	296 (11.3)	301 (11.6)
Death breast cancer	218 (7)	248 (8)	138 (5.3)	160 (6.2)
Death other reason (including unknown)	193 (6.2)	172 (5.5)	158 (6)	141 (5.4)

A summary of the study efficacy results is provided in Table 9.

Table 9: ATAC Efficacy SummaryThe combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.

	Intent-To-Treat Population		Hormone Receptor-Positive Subpopulation
	Anastrozole 1 mg (N = 3,125)	Tamoxifen 20 mg (N = 3,116)	Anastrozole 1 mg (N = 2,618)	Tamoxifen 20 mg (N = 2,598)
	Number of Events
Disease-free Survival	575	651	424	497
Hazard ratio	0.87		0.83
2-sided 95% CI	0.78 to 0.97		0.73 to 0.94
p-value	0.0127		0.0049
Distant Disease-free Survival	500	530	370	394
Hazard ratio	0.94		0.93
2-sided 95% CI	0.83 to 1.06		0.80 to 1.07
Overall Survival	411	420	296	301
Hazard ratio	0.97		0.97
2-sided 95% CI	0.85 to 1.12		0.83 to 1.14

14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer

Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of anastrozole compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients between the ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of anastrozole once daily or 20 mg of tamoxifen once daily. The primary end points for both trials were time to tumor progression, objective tumor response rate, and safety.

Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027.

For the primary endpoints, trial 0030 showed that anastrozole had a statistically significant advantage over tamoxifen (p = 0.006) for time to tumor progression; objective tumor response rates were similar for anastrozole and tamoxifen. Trial 0027 showed that anastrozole and tamoxifen had similar objective tumor response rates and time to tumor progression (see Table 11 and Figure 3 and 4).

Table 11 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.

Results from the secondary endpoints were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences.

14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer Who had Disease Progression Following Tamoxifen Therapy

Anastrozole was studied in two controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER-negative; the ER-negative patients were eligible only if they had had a positive response to tamoxifen. Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of anastrozole or megestrol acetate 40 mg 4 times a day. The studies were double-blinded with respect to anastrozole. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were calculated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated.

Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients entered who had prior tamoxifen therapy for advanced disease (58% in Trial 0004; 57% in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative. In Trial 0005, 58% of patients were ER-positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0004, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases.

Efficacy results from the two studies were similar as presented in Table 12. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters listed in the table below.

When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to anastrozole 1 mg and megestrol acetate. There is, in this data, no indication that anastrozole tablets 10 mg are superior to anastrozole tablets 1 mg.

16 HOW SUPPLIED/STORAGE AND HANDLING

Anastrozole Tablets are available containing 1 mg of anastrozole, USP. The 1 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the tablet and 34 on the other side. They are available as follows:

NDC 0378-6034-93
bottles of 30 tablets

NDC 0378-6034-77
bottles of 90 tablets

NDC 0378-6034-05
bottles of 500 tablets

Storage: Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Patient Information Leaflet with each prescription.

17 PATIENT COUNSELING INFORMATION

17.1 Pregnancy

Patients should be advised that anastrozole may cause fetal harm. They should also be advised that anastrozole tablets are not for use in premenopausal women; therefore, if they become pregnant they should stop taking anastrozole tablets and immediately contact their doctor.

17.2 Allergic (Hypersensitivity) Reactions

Patients should be informed of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to immediately report this to their doctor.

17.3 Ischemic Cardiovascular Events

Patients with preexisting ischemic heart disease should be informed that an increased incidence of cardiovascular events has been observed with anastrozole use compared to tamoxifen use.

17.4 Bone Effects

Patients should be informed that anastrozole lowers the level of estrogen. This may lead to a loss of the mineral content of bones, which might decrease bone strength. A possible consequence of decreased mineral content of bones is an increase in the risk of fractures.

17.5 Cholesterol

Patients should be informed that an increased level of cholesterol might be seen while receiving anastrozole.

17.6 Tamoxifen

Patients should be advised not to take anastrozole with tamoxifen.

17.7 FDA-Approved Patient Labeling

PATIENT INFORMATION LEAFLET
ANASTROZOLE TABLETS
1 mg

Read the information that comes with anastrozole tablets 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 anastrozole tablets when you start taking it and at regular checkups.

What are anastrozole tablets?

Anastrozole tablets are 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.

Anastrozole tablets do not work in women with breast cancer who have not finished menopause (premenopausal women).

Who should not take anastrozole tablets?

Do not take anastrozole tablets if you:

• •are pregnant, think you may be pregnant, or plan to get pregnant. Anastrozole may harm your unborn child. If you become pregnant while taking anastrozole tablets, tell your doctor right away.
• •have not finished menopause (are premenopausal).
• •are allergic to any of the ingredients in anastrozole tablets. See the end of this leaflet for a list of the ingredients in anastrozole tablets.
• •are a man or child.

What is the most important information I should know about anastrozole tablets?

Anastrozole tablets 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 anastrozole tablets may have a slight increase in this type of heart disease compared to similar patients who take tamoxifen.
       ▪ Stop taking anastrozole tablets 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). Anastrozole tablets lower 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 anastrozole tablets and during treatment with anastrozole tablets as needed.

What should I tell my doctor before taking anastrozole tablets?

Anastrozole tablets may not be right for you. Before taking anastrozole tablets, 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 anastrozole tablets?”
• •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 anastrozole tablets?” 
• •are nursing a baby. It is not known if anastrozole passes into breast milk. You and your doctor should decide if you will take anastrozole tablets 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 take anastrozole tablets with tamoxifen. Taking tamoxifen with anastrozole tablets may lower the amount of anastrozole in your blood and may cause anastrozole not to work as well.
• • Medicines containing estrogen. Anastrozole tablets 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 anastrozole tablets?

• •Take anastrozole tablets exactly as prescribed by your doctor. Keep taking anastrozole tablets for as along as your doctor prescribes it for you.
• •Take one anastrozole tablet each day.
• •Anastrozole tablets 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 anastrozole tablets than your doctor has prescribed, contact your doctor right away. Do not take any additional anastrozole tablets until instructed to do so by your doctor.

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

What are possible side effects of anastrozole tablets?

Anastrozole tablets can cause serious side effects including:

• •See “What is the most important information I should know about anastrozole tablets?”
• • increased blood cholesterol (fat in the blood). Your doctor may check your cholesterol while you take anastrozole therapy.
• • skin reactions. Stop taking anastrozole tablets 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. Anastrozole can cause inflammation of the liver and changes in blood tests of the liver function. Your doctor may monitor you for this. Stop taking anastrozole tablets 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 anastrozole tablets 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 anastrozole tablets?

• •Store anastrozole tablets at 20° to 25°C (68° to 77°F).
• • Keep anastrozole tablets and all medicines out of the reach of children.

General information about anastrozole tablets.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take anastrozole tablets for a condition for which it was not prescribed. Do not give anastrozole tablets 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 anastrozole tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about anastrozole tablets that is written for health professionals. For more information call 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in anastrozole tablets?

Active ingredient: anastrozole

Inactive ingredients: anhydrous lactose, hypromellose, magnesium stearate, polydextrose, polyethylene glycol, sodium starch glycolate, titanium dioxide and triacetin.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

REVISED FEBRUARY 2010
ANAS:R2ppt

PRINCIPAL DISPLAY PANEL - 1 mg

NDC 0378-6034-77

Anastrozole
Tablets
1 mg

PHARMACIST: Dispense the accompanying
Patient Information Leaflet to each patient.

Rx only    90 TABLETS

Each film-coated tablet contains:
Anastrozole, USP     1 mg

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Usual Dosage: See accompanying
prescribing information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

RM6034MM2