ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS Serious adverse reactions with anastrozole tablets occurring in less than in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include general feeling of not being well, with or without jaundice, liver pain or liver swelling [see Adverse Reactions, (6.2)]. Common adverse reactions (occurring with an incidence of >10%) in women taking anastrozole tablets included: hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, pain, headache, bone pain, peripheral edema, increased cough, dyspnea, pharyngitis and lymphedema. In the ATAC trial, the most common reported adverse reaction (>0.1%) leading to discontinuation of therapy for both treatment groups was hot flashes, although there were fewer patients who discontinued therapy as result of hot flashes in the anastrozole tablets group. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. To report suspected adverse reactions and 1-800-FDA-1088. In the early breast cancer (ATAC) study, the most common (occurring with an incidence of >10%) side effects occurring in women taking anastrozole tablets included: hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema and lymphedema, regardless of causality. 6.1) In the advanced breast cancer studies, the most common (occurring with an incidence of >10%) side effects occurring in women taking anastrozole tablets included: hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis and peripheral edema. 6.1).

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or PharmacologyReproductive Toxicology Anastrozole has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits (about and 1.9 times the recommended human dose, respectively, on 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 and 1/3, respectively, the recommended human dose on mg/m2 basis), administered during the period of organogenesis showed that anastrozole increased pregnancy loss (increased pre- and/or postimplantation 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 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 times and 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 1.0 mg/kg/day. In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on mg/m2 basis); there was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about times the recommended human dose on mg/m2 basis).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 mg/m2 basis) administered by oral gavage for up to 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. dose related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUC0-24 hr levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. separate carcinogenicity study in mice at oral doses of to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on mg/m2 basis) for up to years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. 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 50mg/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 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at mg/kg/day (about 10 times the recommended human dose on mg/m2 basis and times higher than the AUC0-24 hr found in postmenopausal volunteers at the recommended dose). Preimplantation 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 mg/m2 basis). Recovery of fertility was observed following 5-week non-dosing period which followed 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 months at doses equal to or greater than mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 and 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 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY12.1 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 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with anastrozole tablets mg daily, tamoxifen 20 mg daily, or 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 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 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). Table - Demographic and Baseline Characteristics for ATAC TrialDemographicCharacteristicAnastrozole tablets1 mg(N=3125)Tamoxifen20 mg(N=3116)Anastrozole tablets mgplus Tamoxifen 20 mg(N=3125)Mean age (yrs.)Age Range (yrs.)Age Distribution (%)<45 yrs.45-60 yrs.>60 <70 yrs.>70 yrs.Mean Weight (kg)Receptor Status(%)Positive Negative Other Other Treatment (%) prior to RandomizationMastectomyBreast conservation Axillary surgeryRadiotherapyChemotherapyNeoadjuvant TamoxifenPrimary Tumor Size (%)T1 (<=2 cm)T2 (>2 cm and <=5 cm)T3 (>5 cm)Nodal Status (%)Node positive1-3 (of nodes)4-9>9Tumor Grade (%)Well-differentiatedModerately differentiatedPoorly/undifferentiatedNot assessed/recorded 64.138.1 92.8 0.734.638.026.770.8 83.57.48.8 47.852.395.563.322.31.6 63.932.62.7 34.924.47.52.9 20.846.823.78.7 64.132.8 94.9 0.435.037.127.471.1 83.18.08.6 47.352.895.762.520.81.6 62.934.22.2 33.624.46.42.7 20.547.823.38.4 64.337.0 92.2 0.534.537.727.371.3 84.07.09.0 48.151.995.261.920.81.7 64.132.92.3 33.524.36.82.3 21.246.523.78.5 N=Number of patients randomized to the treatment+ The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up Includes patients who were estrogen receptor (ER) positive or progesterone receptor (PgR) positive, or both positive Includes patients with both ER negative and PgR negative receptor status Includes all other combinations of ER and PgR receptor status unknown Among the patients who had breast conservation, radiotherapy was administered to 95.0% of patients in the anastrozole tablets arm, 94.1% in the tamoxifen arm and 94.5% in the anastrozole tablets plus tamoxifen arm. Patients in the two monotherapy arms of the ATAC trial were treated for median of 60 months (5 years) and followed for 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 tablets arm compared to the tamoxifen arm. In the hormone receptorpositive 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 tablets 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 tablets 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 tablets 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 - All Recurrence and Death Events Intent-To-Treat Population Hormone Receptor-PositiveSubpopulation Anastrozoletablets mg(N+=3125)Tamoxifen20 mg(N+=3116)Anastrozoletablets mg(N+=2618)Tamoxifen20 mg(N+=2598)Median Duration of Therapy (mo)Median Efficacy Follow-up (mo)Loco-regional recurrenceContralateral breast cancerInvasiveDuctal carcinoma in situUnknownDistant recurrenceDeath from Any CauseDeath breast cancerDeath other reason (including unknown) 6068119 (3.8)35 (1.1)27 (0.9)8 (0.3)0324 (10.4)411 (13.2)218 (7.0)193 (6.2)6068149 (4.8)59 (1.9)52 (1.7)6 (0.2)1 (<0.1)375 (12.0)420 (13.5)248 (8.0)172 (5.5)606876 (2.9)26 (1.0)21 (0.8)5 (0.2)0226 (8.6)296 (11.3)138 (5.3)158 (6.0)6068101 (3.9)54 (2.1)48 (1.8)5 (0.2)1 (<0.1)265 (10.2)301 (11.6)160 (6.2)141 (5.4) The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up+ N=Number of patients randomized Patients may fall into more than one category. summary of the study efficacy results is provided in Table 9. Table - ATAC Efficacy Summary Intent-To-Treat PopulationHormone Receptor-PositiveSubpopulation Anastrozoletablets mg(N=3125)Tamoxifen20 mg(N=3116)Anastrozoletablets mg(N=2618)Tamoxifen20 mg(N=2598) Number of Events Number of Events Disease free SurvivalHazard ratio2-sided 95% CIp-valueDistant Disease-free SurvivalHazard ratio2-sided 95% CIOverall SurvivalHazard ratio2-sided 95% CI575 500 411 0.870.78 to 0.970.01270.940.83 to 1.060.970.85 to 1.12651 530 420 424 370 296 0.830.73 to 0.940.00490.930.80 to 1.070.970.83 to 1.14497 394 301 The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. Figure 1. Figure 2.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS4.1. Pregnancy and Premenopausal Women Anastrozole tablets may cause fetal harm when administered to pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole tablets are contraindicated in women who are or may become pregnant. There are no adequate and well controlled studies in pregnant women using anastrozole tablets. If anastrozole tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to fetus or potential risk for loss of the pregnancy. [see Use in Specific Populations (8.1)].

DESCRIPTION SECTION.

Anastrozole tablets for oral administration contain mg of anastrozole, 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 molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25C); 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 monohydrate, magnesium stearate, hypromellose, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide.. Anastrozole Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2. DOSAGE AND ADMINISTRATION2.1. Recommended Dose The dose of anastrozole tablets are one mg tablet taken once day. For patients with advanced breast cancer, anastrozole tablets should be continued until tumor progression. Anastrozole tablets can be taken with or without food. For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial anastrozole tablets were administered for five years. [see Clinical Studies (14.1)] No dosage adjustment is necessary for patients with renal impairment or for elderly patients. [see Use in Specific Populations (8.6)] One mg tablet taken once daily 2.1).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS The tablets are white, biconvex, film-coated containing mg of anastrozole. The tablets are debossed with AN and 1 on one side and plain surface on the other side.. mg tablets 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS7.1 Tamoxifen Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the coadministration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or Ndesmethyltamoxifen. At 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. [see Clinical Studies (14.1)]. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.. Tamoxifen: Do not use in combination with anastrozole tablets. No additional benefit seen over tamoxifen monotherapy 7.1, 14.1).o Estrogen-containing products: Combination use may diminish activity of anastrozole tablets 7.2).

GERIATRIC USE SECTION.

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 anastrozole tablets compared to tamoxifen in patients who were 65 years or older (N=1413 for anastrozole tablets 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 anastrozole tablets 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING These tablets are supplied in bottles of 30 tablets (NDC 67877-171-30) Storage Store at controlled room temperature, 20-25C (68-77F) [see USP].

INDICATIONS & USAGE SECTION.

1. INDICATIONS AND USAGE1.1. Adjuvant Treatment Anastrozole tablets are indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.. Anastrozole tablets are an aromatase inhibitor indicated for:o Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer 1.1)o First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer 1.2)o Treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to anastrozole tablets 1.3).

INFORMATION FOR PATIENTS SECTION.

17.7 FDA-Approved Patient LabelingPATIENT INFORMATIONANASTROZOLE TABLETSRead the information that comes with anastrozole tablets before you start taking it and each time you get 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 tabletsAnastrozole tablet is prescription medicine used in women who have finished menopause (the change of life) for:o treatment of early breast cancer after surgery, with or without radiation in women whose breast cancer is hormone receptor-positiveo 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.o treatment of advanced breast cancer, if the cancer has grown, or the disease has spread after tamoxifen therapy.Anastrozole tablets does 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:o are pregnant, think you may be pregnant, or plan to get pregnant. Anastrozole tablets may harm your unborn child. If you become pregnant while taking anastrozole tablets, tell your doctor right away.o have not finished menopause (are premenopausal)o are allergic to any of the ingredients in anastrozole tablets. See the end of this leaflet for list of the ingredients in anastrozole tablets.o are man or child What is the most important information should know about anastrozole tablets Anastrozole tablets may cause serious side effects including:o Heart disease. Women with early breast cancer, who have history of blockages in heart arteries (ischemic heart disease) and who take anastrozole tablets may have 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.o Osteoporosis (bone softening and weakening). Anastrozole tablets 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 test for you called bone mineral density study before you start taking anastrozole tablets and during treatment with anastrozole tablets as needed. What should tell my doctor before taking anastrozole tabletsAnastrozole 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 tabletso have had previous heart problemo have condition called osteoporosiso have high cholesterolo are pregnant, planning to become pregnant, or breast feeding. See Who should not take anastrozole tabletso are nursing baby. It is not known if anastrozole tablets 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:o Tamoxifen. You should not take anastrozole tablets with tamoxifen. Taking tamoxifen with anastrozole tablets may lower the amount of anastrozole tablets in your blood and may cause anastrozole tablets not to work as well.o 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 suppositoriesKnow the medicines you take. Keep list of them and show it to your doctor and pharmacist each time you get new medicine. How should 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.o Take one anastrozole tablets tablet each day.o Anastrozole tablets can be taken with or without food.o If you miss 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.o 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:o See What is the most important information should know about anastrozole tablets increased blood cholesterol (fat in the blood). Your doctor may check your cholesterol while you take anastrozole tablets therapy.o skin reactions. Stop taking anastrozole tablets and call your doctor right away if you get any skin lesions, ulcers, or blisters.o severe allergic reactions. Get medical help right away if you have:o swelling of the face, lips, tongue, or throat.o trouble swallowingo trouble breathingo liver problems. Anastrozole tablets 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 liver problem:o general feeling of not being wello yellowing of the skin or whites of the eyeso pain on the right side of your abdomen Common side effects in women taking anastrozole tablets include:o hot flasheso weaknesso joint paino carpal tunnel syndrome (tingling, pain, coldness, weakness in parts of the hand)o paino sore throato mood changeso high blood pressureo depressiono nausea and vomitingo thinning of the hair (hair loss)o rasho back paino sleep problemso bone paino headacheo swellingo increased cougho shortness of breatho lymphedema (build up of lymph fluid in the tissues of your affected arm)o trigger finger (a condition in which one of your fingers or your thumb catches in bent position) HOW SHOULD STORE ANASTROZOLE TABLETS Store anastrozole tablets at 68F to 77F (20C to 25C).o 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 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. What are the ingredients in anastrozole tablets Active ingredient: anastrozoleInactive ingredients: lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide. Manufactured by:Natco Pharma LimitedKothur 509 228. A.P. India. Mfd for:Ascend Laboratories, LLCMontvale, NJ 07645 346033 Rev 01/Jan/2010.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY.

NURSING MOTHERS SECTION.

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, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.

10 OVERDOSAGE Clinical trials have been conducted with anastrozole tablets, up to 60 mg in 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. single dose of anastrozole tablets 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 anastrozole tablets are not highly protein bound. General supportive care, including frequent monitoring of vital. signs and close observation of the patient, is indicated.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

ASCENDLaboratories, LLCNDC 67877-171-30ANASTROZOLE TABLETS1 mg30 tabletsRx onlyDispense in original containerMfd by: Natco Pharma LimitedKothur 509 228. A.P. India.. Ascend Anastrozole Tablets 1 mg product label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Clinical studies in pediatric patients included placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and single-arm trial in girls with McCune-Albright Syndrome and progressive precocious puberty. The efficacy of anastrozole tablets 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 randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged 11 to 18 years. Patients were randomized to daily regimen of either anastrozole tablets mg or placebo. After months of treatment there was no statistically significant difference in the percentage of patients who experienced >=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 of treatment were reduced by 15.4 in the anastrozole tablets 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 anastrozole tabletstreated patients and 8.1% of the placebo-treated patients with the most frequent being acne (7% anastrozole tablets and 2.7% placebo) and headache (7% anastrozole tablets and 0% placebo); all other adverse reactions showed small differences between treatment groups. One patient treated with anastrozole tablets discontinued the trial because of testicular enlargement. The mean baseline-subtracted change in testicular volume after months of treatment was 6.6 +- 7.9 cm3 in the anastrozole tablets-treated patients and 5.2 +- 8.0 cm3 in the placebo group). McCune- Albright Syndrome Study multi-center, single-arm, open-label, study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged to <10 years. All patients received 1 mg daily dose of anastrozole tablets. The trial duration was 12 months. Patients were enrolled on the basis of 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: mean chronological age of 5.9 +- 2.0 years, mean bone age of 8.6 +- 2.6 years, mean growth rate of 7.9 +- 2.9 cm/year and 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 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. 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 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 anastrozole tablets. These were nausea, acne, pain in an extremity, increased alanine transaminase and aspartate transa minase, and allergic dermatitis. Pharmacokinetics in Pediatric Patients Following mg once daily multiple administration in pediatric patients, the mean time to reach the maximum anastrozole concentration was hr. The mean (range) disposition Parameters of anastrozole in pediatric patients were described by CL/F of 1.54 L/h (0.77 4.53 L/h) and V/F of 98.4 (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 population pharmacokinetic analysis, the pharmacokinetics of anastrozole was similar in boys with pubertal gynecomastia and girls with McCune- Albright Syndrome.

PHARMACODYNAMICS SECTION.

12.2 PharmacodynamicsEffect on Estradiol Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, 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 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 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 days after cessation of daily dosing with anastrozole tablets mg. The effect of anastrozole tablets in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not 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, 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 and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of anastrozole tablets. Anastrozole tablets does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.

PHARMACOKINETICS SECTION.

12.3 PharmacokineticsAbsorption Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within 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 to hours when anastrozole was administered 30 minutes after food. The pharmacokinetics of anastrozole are linear over the dose range of 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 single dose of anastrozole tablets. Plasma concentrations approach steady-state levels at about 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, glucuronide conjugate of hydroxy-anastrozole, and 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 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of 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 halflife 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 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)].

PREGNANCY SECTION.

8.1 Pregnancy PREGNANCY CATEGORY [see Contraindications (4.1)] Anastrozole tablets may cause fetal harm when administered to pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole tablets are 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 anastrozole tablets use in pregnant women. If anastrozole tablets are 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 (rats) and 1/3 (rabbits) the recommended human dose on 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 times higher). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on mg/m2 basis. [see Animal Toxicology and/or Pharmacology (13.2)].

RECENT MAJOR CHANGES SECTION.

Contraindications Premenopausal Women and Pregnancy 4.1, 8.1) 01/2010Warnings and Precautions- Ischemic Cardiovascular Events 5.1, 6.1) 01/2010.

SPL UNCLASSIFIED SECTION.

FULL PRESCRIBING INFORMATION: CONTENTS INDICATIONS AND USAGE 1.1 Adjuvant Treatment 1.2 First-Line Treatment 1.3 Second-Line Treatment DOSAGE AND ADMINISTRATION 2.1 Recommended Dose 2.2 Patients with Hepatic Impairment DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS 4.1 Pregnancy and Premenopausal Women 4.2 Hypersensitivity WARNINGS AND PRECAUTIONS 5.1 Ischemic Cardiovascular Events 5.2 Bone Effects 5.3 Cholesterol ADVERSE REACTIONS 6.1 Clinical Trials Experience Adjuvant Therapy First-Line Therapy Second-Line Therapy 6.2 Post-Marketing Experience DRUG INTERACTIONS 7.1 Tamoxifen 7.2 Estrogen 7.3 Warfarin 7.4 Cytochrome P450 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Pharmacology and/or Toxicology 14 CLINICAL STUDIES 14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women 14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer 14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy 16 HOW SUPPLIED/STORAGE AND HANDLING Storage: 17 PATIENT COUNSELING INFORMATION 17.1 Pregnancy 17.2 Allergic (Hypersensitivity) Reactions 17.3 Ischemic Cardiovascular Events 17.4 Bone Effects 17.5 Cholesterol 17.6 Tamoxifen 17.7 FDA-Approved Patient Labeling Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pediatric patients: Efficacy has not been demonstrated for pubertal boys of adolescent age with gynecomastia or girls with McCune-Albright Syndrome and progressive precocious puberty. 8.4)See 17 for PATIENT COUNSELING INFORMATION and FDA approved Patient Labeling.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS5.1. Ischemic Cardiovascular Events In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with anastrozole tablets in the ATAC trial (17% of patients on anastrozole tablets and 10% of patients on tamoxifen). Consider risk and benefits of anastrozole tablets therapy in patients with pre-existing ischemic heart disease. [see Adverse Reactions (6.1)] o In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events occurred with anastrozole tablets use compared to tamoxifen use. Consider risks and benefits. 5.1, 6.1)o Decreases in bone mineral density may occur. Consider bone mineral density monitoring. 5.2, 6.1)o Increases in total cholesterol may occur. Consider cholesterol monitoring. 5.3, 6.1).