Anastrozoleside effects

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. 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 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. In the advanced breast cancer studies, the most common (occurring with an incidence of >10%) side effects occurring in women taking anastrozole included: hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis and peripheral edema. To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 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. 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 The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. Body system and adverse reactions by COSTART COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms. preferred term A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system. Anastrozole 1 mg (N N=Number of patients receiving the treatment. = 3092) Tamoxifen 20 mg (N = 3094) Body as a whole Asthenia 575 544 Pain 533 485 Back pain 321 309 Headache 314 249 Abdominal pain 271 276 Infection 285 276 Accidental injury 311 303 Flu syndrome 175 195 Chest pain 200 150 Neoplasm 162 144 Cyst 138 162 Cardiovascular Vasodilatation 1104 1264 Hypertension 402 349 Digestive Nausea 343 335 Constipation 249 252 Diarrhea 265 216 Dyspepsia 206 169 Gastrointestinal disorder 210 158 Hemic and lymphatic Lymphedema 304 341 Anemia 113 159 Metabolic and nutritional Peripheral edema 311 343 Weight gain 285 274 Hypercholesterolemia 278 108 Musculoskeletal Arthritis 512 445 Arthralgia 467 344 Osteoporosis 325 226 Fracture 315 209 Bone pain 201 185 Arthrosis 207 156 Joint Disorder 184 160 Myalgia 179 160 Nervous system Depression 413 382 Insomnia 309 281 Dizziness 236 234 Anxiety 195 180 Paresthesia 215 145 Respiratory Pharyngitis 443 422 Cough increased 261 287 Dyspnea 234 237 Sinusitis 184 159 Bronchitis 167 153 Skin and appendages Rash 333 387 Sweating 145 177 Special Senses Cataract Specified 182 213 Urogenital Leukorrhea 86 286 Urinary tract infection 244 313 Breast pain 251 169 Breast Neoplasm 164 139 Vulvovaginitis 194 150 Vaginal Hemorrhage Vaginal Hemorrhage without further diagnosis. 122 180 Vaginitis 125 158 Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see Table 2 ). Table 2 — Number of Patients with Pre-specified Adverse Reactions in ATAC Trial Patients with multiple events in the same category are counted only once in that category. Anastrozole N=3092 (%) Tamoxifen N=3094 (%) Odds-ratio 95% CI Hot Flashes 1104 1264 0.80 0.73 to

0.89 Musculoskeletal

Events Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. 1100 911 1.32 1.19 to 1.47 Fatigue/Asthenia 575 544 1.07 0.94 to 1.22 Mood Disturbances 597 554 1.10 0.97 to

1.25 Nausea and

Vomiting 393 384 1.03 0.88 to 1.19 All Fractures 315 209 1.57 1.30 to

1.88 Fractures of

Spine, Hip, or Wrist 133 91 1.48 1.13 to

1.95 Wrist/Colles’ fractures 67 50

Spine fractures 43 22 Hip fractures 28 26 Cataracts 182 213 0.85 0.69 to

1.04 Vaginal

Bleeding 167 317 0.50 0.41 to

0.61 Ischemic

Cardiovascular Disease 127 104 1.23 0.95 to

1.60 Vaginal

Discharge 109 408 0.24 0.19 to

0.30 Venous Thromboembolic

Events 87 140 0.61 0.47 to

0.80 Deep Venous

Thromboembolic Events 48 74 0.64 0.45 to

0.93 Ischemic

Cerebrovascular Event 62 88 0.70 0.50 to

0.97 Endometrial

Cancer Percentages calculated based upon the numbers of patients with an intact uterus at baseline 4 13 0.31 0.10 to

0.94 Ischemic

Cardiovascular Events Between treatment arms in the overall population of 6186 patients, there was no statistical difference in ischemic cardiovascular events (4% anastrozole vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the anastrozole arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the anastrozole arm and 34/3094 (1.1%) patients in the tamoxifen arm. In women with pre-existing ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on anastrozole and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving anastrozole and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving anastrozole and 8/249 (3.2%) patients receiving tamoxifen. Bone Mineral Density Findings 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. Because anastrozole lowers circulating estrogen levels it may cause a reduction in bone mineral density. A post-marketing trial assessed the combined effects of anastrozole and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor-positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates. Bisphosphonate treatment preserved bone density in most patients at risk of fracture. Postmenopausal women with early breast cancer scheduled to be treated with anastrozole should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture. Cholesterol During the ATAC trial, more patients receiving anastrozole were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively). A post-marketing trial also evaluated any potential effects of anastrozole on lipid profile. In the primary analysis population for lipids (anastrozole alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months. In secondary population for lipids (anastrozole+risedronate), there also was no clinically significant change in LDL-C and HDL-C from baseline to 12 months. In both populations for lipids, there was no clinically significant difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months compared with baseline. In this trial, treatment for 12 months with anastrozole alone had a neutral effect on lipid profile. Combination treatment with anastrozole and risedronate also had a neutral effect on lipid profile. The trial provides evidence that postmenopausal women with early breast cancer scheduled to be treated with anastrozole should be managed using the current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations. Other Adverse Reactions Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving tamoxifen [209 (7%)]. Patients receiving anastrozole had a higher incidence of carpal tunnel syndrome [78 (2.5%)] compared with patients receiving tamoxifen [22 (0.7%)]. Vaginal bleeding occurred more frequently in the tamoxifen-treated patients versus the anastrozole -treated patients 317 (10%) versus 167 (5%), respectively. Patients receiving anastrozole had a lower incidence of hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen. 10-year median follow-up Safety Results from the ATAC Trial Results are consistent with the previous analyses. Serious adverse reactions were similar between anastrozole (50%) and tamoxifen (51%). Cardiovascular events were consistent with the known safety profiles of anastrozole and tamoxifen. The cumulative incidences of all first fractures (both serious and non-serious, occurring either during or after treatment) was higher in the anastrozole group (15%) compared to the tamoxifen group (11%). This increased first fracture rate during treatment did not continue in the post-treatment follow-up period. The cumulative incidence of new primary cancers was similar in the anastrozole group (13.7%) compared to the tamoxifen group (13.9%). Consistent with the previous analyses, endometrial cancer was higher in the tamoxifen group (0.8%) compared to the anastrozole group (0.2%). The overall number of deaths (during or off-trial treatment) was similar between the treatment groups. There were more deaths related to breast cancer in the tamoxifen than in the anastrozole treatment group. First-Line Therapy Adverse reactions occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 3. Table 3 — Adverse Reactions Occurring with an Incidence of at Least 5% in Trials 0030 and 0027 Body system Adverse Reaction A patient may have had more than 1 adverse event. Number (%) of subjects Anastrozole (N=506) Tamoxifen (N=511) Whole body Asthenia 83 81 Pain 70 73 Back pain 60 68 Headache 47 40 Abdominal pain 40 38 Chest pain 37 37 Flu syndrome 35 30 Pelvic pain 23 30 Cardiovascular Vasodilation 128 106 Hypertension 25 36 Digestive Nausea 94 106 Constipation 47 66 Diarrhea 40 33 Vomiting 38 36 Anorexia 26 46 Metabolic and Nutritional Peripheral edema 51 41 Musculoskeletal Bone pain 54 52 Nervous Dizziness 30 22 Insomnia 30 38 Depression 23 32 Hypertonia 16 26 Respiratory Cough increased 55 52 Dyspnea 51 47 Pharyngitis 49 68 Skin and appendages Rash 38 34 Urogenital Leukorrhea 9 31 Less frequent adverse experiences reported in patients receiving anastrozole 1 mg in either Trial 0030 or Trial 0027 were similar to those reported for second-line therapy. Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 pre-specified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups. Table 4 — Number of Patients with Pre-specified Adverse Reactions in Trials 0030 and 0027 Number (n) and Percentage of Patients Adverse Reaction A patient may have had more than 1 adverse reaction. Anastrozole 1 mg (N=506) n (%) NOLVADEX 20 mg (N=511) n (%) Depression 23 32 Tumor Flare 15 18 Thromboembolic Disease Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis. 18 33 Venous 5 15 Coronary and Cerebral Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct. 13 19 Gastrointestinal Disturbance 170 196 Hot Flushes 134 118 Vaginal Dryness 9 3 Lethargy 6 15 Vaginal Bleeding 5 11 Weight Gain 11 8 Second-Line Therapy Anastrozole was tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the anastrozole-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse reaction. The principal adverse reaction more common with anastrozole than megestrol acetate was diarrhea. Adverse reactions reported in greater than 5% of the patients in any of the treatment groups in these two controlled clinical trials, regardless of causality, are presented below: Table 5 — Number (n) and Percentage of Patients with Adverse Reactions in Trials 0004 and 0005 A patient may have had more than one adverse reaction Adverse Reaction Anastrozole Anastrozole Megesterol Acetate 1 mg 10 mg 160 mg (N=262) (N=246) (N=253) n % n % n % Asthenia 42 33 47 Nausea 41 48 28 Headache 34 44 24 Hot Flashes 32 29 21 Pain 28 38 29 Back Pain 28 26 19 Dyspnea 24 27 53 Vomiting 24 26 16 Cough Increased 22 18 19 Diarrhea 22 18 7 Constipation 18 18 21 Abdominal Pain 18 14 18 Anorexia 18 19 11 Bone Pain 17 26 19 Pharyngitis 16 23 15 Dizziness 16 12 15 Rash 15 15 19 Dry Mouth 15 11 13 Peripheral Edema 14 21 28 Pelvic Pain 14 17 13 Depression 14 6 5 Chest Pain 13 18 13 Paresthesia 12 15 9 Vaginal Hemorrhage 6 4 13 Weight Gain 4 9 30 Sweating 4 3 16 Increased Appetite 0 1 13 Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole 1 mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.

Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection Cardiovascular: Hypertension; thrombophlebitis Hepatic: Gamma GT increased; SGOT increased;

SGPT increased Hematologic: Anemia; leukopenia Metabolic and Nutritional: Alkaline phosphatase increased; weight loss Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving anastrozole. Increases in LDL cholesterol have been shown to contribute to these changes.

Musculoskeletal: Myalgia; arthralgia; pathological fracture Nervous: Somnolence; confusion; insomnia; anxiety; nervousness Respiratory: Sinusitis; bronchitis; rhinitis Skin and Appendages: Hair thinning (alopecia); pruritus Urogenital: Urinary tract infection; breast pain The incidences of the following adverse reaction groups potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes, and vaginal dryness. These six groups, and the adverse reactions captured in the groups, were prospectively defined. The results are shown in the table below. Table 6 — Number (n) and Percentage of Patients with Pre-specified Adverse Reactions in Trials 0004 and 0005 Anastrozole Anastrozole Megestrol Acetate 1 mg 10 mg 160 mg (n=262) (n=246) (n=253) Adverse Reaction Group n (%) n (%) n (%) Gastrointestinal Disturbance 77 81 54 Hot Flushes 33 29 35 Edema 19 28 35 Thromboembolic Disease 9 4 12 Vaginal Dryness 5 3 2 Weight Gain 4 10 30

6.2 Post-Marketing

Experience These adverse reactions are reported voluntarily from a population of uncertain size. Therefore, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The following have been reported in post-approval use of anastrozole: Hepatobiliary events including increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-GT, and bilirubin; hepatitis Rash including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome. Cases of allergic reactions including angioedema, urticaria and anaphylaxis. Myalgia,and hypercalcemia (with or without an increase in parathyroid hormone) Tendon disorders including tendon rupture, tendonitis, tenosynovitis, and tenosynovitis stenosans (trigger finger)