Anastrozole

1 INDICATIONS AND USAGE Anastrozole is an aromatase inhibitor indicated for: Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer ( 1.1 ) First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer ( 1.2 ) 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 ( 1.3 ) 1.1 Adjuvant Treatment Anastrozole is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. 1.2 First-Line Treatment Anastrozole is indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer. 1.3 Second-Line Treatment Anastrozole is indicated for the 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.

2 DOSAGE AND ADMINISTRATION One 1 mg tablet taken once daily ( 2.1 ) 2.1 Recommended Dose The dose of anastrozole is one 1 mg tablet taken once a 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 was 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) ]. 2.2 Patients with Hepatic Impairment No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anastrozole tablets have not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ].

5 WARNINGS AND PRECAUTIONS 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 ) Decreases in bone mineral density may occur. Consider bone mineral density monitoring. ( 5.2 , 6.1 ) Increases in total cholesterol may occur. Consider cholesterol monitoring. ( 5.3 , 6.1 ) Embryo-Fetal Toxicity: anastrozole tablets may cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.4 , 8.1 ) 5.1 Ischemic Cardiovascular Events In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with anastrozole in the ATAC trial (17% of patients on anastrozole and 10% of patients on tamoxifen). Consider risk and benefits of anastrozole therapy in patients with pre-existing ischemic heart disease [see Adverse Reactions (6.1) ]. 5.2 Bone Effects Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Consider bone mineral density monitoring in patients treated with anastrozole tablets[see Adverse Reactions (6.1) ]. 5.3 Cholesterol During the ATAC trial, more patients receiving anastrozole were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively) [see Adverse Reactions (6.1) ]. 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, anastrozole can cause fetal harm when administered to a pregnant woman. Anastrozole caused embryo-fetal toxicities in rats at maternal exposure that were 9 times the human clinical exposure, based on area under the curve (AUC). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m 2 basis. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with anastrozole and for at least 3 weeks after the last dose [ see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology (12.1) ].

4 CONTRAINDICATIONS Patients with demonstrated hypersensitivity to anastrozole tablets or any excipient ( 4 ) Hypersensitivity Anastrozole is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria [see Adverse Reactions (6.2) ].

7 DRUG INTERACTIONS Tamoxifen: Do not use in combination with anastrozole tablets. No additional benefit seen over tamoxifen monotherapy. ( 7.1 , 14.1 ) Estrogen-containing products: Combination use may diminish activity of Anastrozole Tablets. ( 7.2 ) 7.1 Tamoxifen Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the co-administration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of anastrozole 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. 7.2 Estrogen Estrogen-containing therapies should not be used with anastrozole as they may diminish its pharmacological action. 7.3 Warfarin In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by Cmax and AUC) and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R- and S-warfarin. 7.4 Cytochrome P450 Based on in vitro and in vivo results, it is unlikely that co-administration of anastrozole 1 mg will affect other drugs as a result of inhibition of cytochrome P450 [see Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, anastrozole may cause fetal harm when administered to a pregnant woman [ see Clinical Pharmacology (12.1) ]. There are no studies of anastrozole use in pregnant women. Anastrozole caused embryo-fetal toxicities in rats at maternal exposure that were 9 times the human clinical exposure, based on area under the curve (AUC). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m2 basis. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In animal reproduction studies, pregnant rats and rabbits received anastrozole during organogenesis at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively, (about 1 and 1/3 the recommended human dose on a mg/m 2 basis, respectively). 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 at doses equal to or greater than 0.1 mg/kg/day. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at anastrozole doses of 1 mg/kg/day that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUC 0-24 hr 9 times higher). 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 a mg/m 2 basis).

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiation of anastrozole. Contraception Females Based on animal studies, anastrozole can cause fetal harm when administered to a pregnant woman [ see Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with anastrozole tablets and for at least 3 weeks after the last dose. Infertility Females Based on studies in female animals, anastrozole may impair fertility in females of reproductive potential [ see Nonclinical Toxicology (13.1) ].

6 ADVERSE REACTIONS Serious adverse reactions with anastrozole occurring in less than 1 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 a 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 included: hot flashes, asthenia, arthritis, pain, arthralgia, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, 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 a result of hot flashes in the anastrozole group. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Adjuvant Therapy Adverse reaction data for adjuvant therapy are based on the ATAC trial [ see Clinical Studies (14.1) ]. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and tamoxifen 20 mg, respectively. Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1. Table 1 — Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment, or within 14 days of the end of treatment in the ATAC trial * Body system and adverse reactions by COSTART † preferred term † Anastrozole 1 mg (N § = 3,092) Tamoxifen 20 mg (N § = 3,094) Body as a whole Asthenia 575 (19) 544 (18) Pain 533 (17) 485 (16) Back pain 321 (10) 309 (10) Headache 314 (10) 249 (8) Abdominal pain 271 (9) 276 (9) Infection 285 (9) 276 (9) Accidental injury 311 (10) 303 (10) Flu syndrome 175 (6) 195 (6) Chest pain 200 (7) 150 (5) Neoplasm 162 (5) 144 (5) Cyst 138 (5) 162 (5) Cardiovascular Vasodilatation 1,104 (36) 1,264 (41) Hypertension 402 (13) 349 (11) Digestive Nausea 343 (11) 335 (11) Constipation 249 (8) 252 (8) Diarrhea 265 (9) 216 (7) Dyspepsia 206 (7) 169 (6) Gastrointestinal disorder 210 (7) 158 (5) Hemic and lymphatic Lymphedema 304 (10) 341 (11) Anemia 113 (4) 159 (5) Metabolic and nutritional Peripheral edema 311 (10) 343 (11) Weight gain 285 (9) 274 (9) Hypercholesterolemia 278 (9) 108 (3.5) Musculoskeletal Arthritis 512 (17) 445 (14) Arthralgia 467 (15) 344 (11) Osteoporosis 325 (11) 226 (7) Fracture 315 (10) 209 (7) Bone pain 201 (7) 185 (6) Arthrosis 207 (7) 156…