ANASTROZOLE: 11,394 Adverse Event Reports & Safety Profile

Anastrozole Tablets，USP for oral administration contain 1 mg of anastrozole, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C 17 H 19 N 5 and its structural formula is: Anastrozole, USP is an off-white powder with a molecular weight of 293.4. Anastrozole, USP has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Anastrozole, USP is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile. Each tablet contains as inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol/macrogol sodium starch glycolate, and titanium dioxide .

Chemical

Structure for anastrozole

AND USAGE Anastrozole is an aromatase inhibitor indicated for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer ( Error! Hyperlink reference not valid. )
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer ( Error! Hyperlink reference not valid. )
• 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 ( Error! Hyperlink reference not valid. )

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.

AND ADMINISTRATION One 1 mg tablet taken once daily ( 2.1 )

2.1 Recommended Dose The dose of anastrozole tablets 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 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 ) ].

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 ) ].

4 CONTRAINDICATIONS

• Women of premenopausal endocrine status, including pregnant women ( 4.1 , 8.1 )
• Patients with demonstrated hypersensitivity to anastrozole or any excipient ( 4.2 )

4.1 Pregnancy and Premenopausal Women Anastrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies in pregnant women using anastrozole. If anastrozole is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus or potential risk for loss of the pregnancy <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span>.

4.2 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>.

REACTIONS Serious adverse reactions with anastrozole tablets 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 tablets 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 tablets 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 AvKARE, Inc. at 1-855-361-3993 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole tablets 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 tablets 1 mg (N N=Number of patients receiving the treatment. = 3092)

Tamoxifen

20 mg (N = 3094) 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

1104 (36) 1264 (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 (5)

Joint Disorder

184 (6) 160 (5)

Myalgia

179 (6) 160 (5) Nervous system Depression 413 (13) 382 (12)

Insomnia

309 (10) 281 (9)

Dizziness

236 (8) 234 (8)

Anxiety

195 (6) 180 (6)

Paresthesia

215 (7) 145 (5)

Respiratory Pharyngitis

443 (14) 422 (14) Cough increased 261 (8) 287 (9)

Dyspnea

234 (8) 237 (8)

Sinusitis

184 (6) 159 (5)

Bronchitis

167 (5) 153 (5) Skin and appendages Rash 333 (11) 387 (13)

Sweating

145 (5) 177 (6)

Special Senses Cataract Specified

182 (6) 213 (7)

Urogenital Leukorrhea

86 (3) 286 (9) Urinary tract infection 244 (8) 313 (10) Breast pain 251 (8) 169 (6)

Breast Neoplasm

164 (5) 139 (5)

Vulvovaginitis

194 (6) 150 (5)

Vaginal Hemorrhage Vaginal

Hemorrhage without further diagnosis. 122 (4) 180 (6)

Vaginitis

125 (4) 158 (5) 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 tablets N=3092 (%) Tamoxifen N=3094 (%) Odds-ratio 95% CI Hot Flashes 1104 (36) 1264(41) 0.80 0.73 -

0.89 Musculoskeletal Events Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. 1100 (36) 911 (29) 1.32 1.19 -

1.47 Fatigue/Asthenia 575 (19) 544 (18) 1.07 0.94 -

1.22 Mood Disturbances 597 (19) 554 (18) 1.10 0.97 -

1.25 Nausea and Vomiting 393 (13) 384 (12) 1.03 0.88 -

1.19 All Fractures 315 (10) 209 (7) 1.57 1.30 -

1.88 Fractures of Spine, Hip, or Wrist 133 (4) 91 (3) 1.48 1.13 -

1.95 Wrist/Colles&apos; fractures 67 (2) 50 (2) Spine fractures 43 (1) 22 (1) Hip fractures 28 (1) 26 (1)

Cataracts

182 (6) 213 (7) 0.85 0.69 -

1.04 Vaginal Bleeding 167 (5) 317 (10) 0.50 0.41 -

0.61 Ischemic Cardiovascular Disease 127 (4) 104 (3) 1.23 0.95 -

1.60 Vaginal Discharge 109 (4) 408 (13) 0.24 0.19 -

0.30 Venous Thromboembolic Events 87 (3) 140 (5) 0.61 0.47 -

0.80 Deep Venous Thromboembolic Events 48 (2) 74 (2) 0.64 0.45 -

0.93 Ischemic Cerebrovascular Event 62 (2) 88 (3) 0.70 0.50 -

0.97 Endometrial Cancer Percentages calculated based upon the numbers of patients with an intact uterus at baseline. 4 (0.2) 13 (0.6) 0.31 0.10 -

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 tablets vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the anastrozole tablets arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the anastrozole tablets 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 tablets and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving anastrozole tablets and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving anastrozole tablets 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 tablets 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 tablets lowers circulating estrogen levels it may cause a reduction in bone mineral density. A post-marketing trial assessed the combined effects of anastrozole tablets 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 tablets 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 tablets 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 tablets on lipid profile. In the primary analysis population for lipids (anastrozole tablets 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 tablets+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 tablets alone had a neutral effect on lipid profile. Combination treatment with anastrozole tablets 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 tablets 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 tablets had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole tablets 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 tablets 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 tablets-treated patients 317 (10%) versus 167 (5%), respectively. Patients receiving anastrozole tablets 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 tablets (50%) and tamoxifen (51%). Cardiovascular events were consistent with the known safety profiles of anastrozole tablets 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets (N=506) Tamoxifen (N=511) Whole body Asthenia 83 (16) 81 (16)

Pain

70 (14) 73 (14) Back pain 60 (12) 68 (13)

Headache

47 (9) 40 (8) Abdominal pain 40 (8) 38 (7) Chest pain 37 (7) 37 (7) Flu syndrome 35 (7) 30 (6) Pelvic pain 23 (5) 30 (6)

Cardiovascular Vasodilation

128 (25) 106 (21)

Hypertension

25 (5) 36 (7)

Digestive Nausea

94 (19) 106 (21)

Constipation

47 (9) 66 (13)

Diarrhea

40 (8) 33 (6)

Vomiting

38 (8) 36 (7)

Anorexia

26 (5) 46 (9) Metabolic and Nutritional Peripheral edema 51 (10) 41 (8)

Musculoskeletal

Bone pain 54 (11) 52 (10)

Nervous Dizziness

30 (6) 22 (4)

Insomnia

30 (6) 38 (7)

Depression

23 (5) 32 (6)

Hypertonia

16 (3) 26 (5)

Respiratory

Cough increased 55 (11) 52 (10)

Dyspnea

51 (10) 47 (9)

Pharyngitis

49 (10) 68 (13) Skin and appendages Rash 38 (8) 34 (8)

Urogenital Leukorrhea

9 (2) 31 (6) Less frequent adverse experiences reported in patients receiving anastrozole tablets 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 tablets 1 mg (N=506) n (%) NOLVADEX 20 mg (N=511) n (%)

Depression

23 (5) 32 (6)

Tumor Flare

15 (3) 18 (4)

Thromboembolic Disease

Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis. 18 (4) 33 (6)

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 (34) 196 (38)

Hot Flushes

134 (26) 118 (23)

Vaginal Dryness

9 (2) 3 (1)

Lethargy

6 (1) 15 (3)

Vaginal Bleeding

5 (1) 11 (2)

Weight Gain

11 (2) 8 (2) Second-Line Therapy Anastrozole tablets were tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the anastrozole tablets-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 tablets 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 Adverse Reaction A patient may have had more than one adverse reaction. Anastrozole tablets 1 mg (N=262) n (%) Anastrozole tablets 10 mg (N=246) n (%)

Megestrol Acetate

160 mg (N=253) n (%)

Asthenia

42 (16) 33 (13) 47 (19)

Nausea

41 (16) 48 (20) 28 (11)

Headache

34 (13) 44 (18) 24 (9)

Hot Flashes

32 (12) 29 (11) 21 (8)

Pain

28 (11) 38 (15) 29 (11)

Back Pain

28 (11) 26 (11) 19 (8)

Dyspnea

24 (9) 27 (11) 53 (21)

Vomiting

24 (9) 26 (11) 16 (6)

Cough Increased

22 (8) 18 (7) 19 (8)

Diarrhea

22 (8) 18 (7) 7 (3)

Constipation

18 (7) 18 (7) 21 (8)

Abdominal Pain

18 (7) 14 (6) 18 (7)

Anorexia

18 (7) 19 (8) 11 (4)

Bone Pain

17 (6) 26 (12) 19 (8)

Pharyngitis

16 (6) 23 (9) 15 (6)

Dizziness

16 (6) 12 (5) 15 (6)

Rash

15 (6) 15 (6) 19 (8)

Dry Mouth

15 (6) 11 (4) 13 (5)

Peripheral Edema

14 (5) 21 (9) 28 (11)

Pelvic Pain

14 (5) 17 (7) 13 (5)

Depression

14 (5) 6 (2) 5 (2)

Chest Pain

13 (5) 18 (7) 13 (5)

Paresthesia

12 (5) 15 (6) 9 (4)

Vaginal Hemorrhage

6 (2) 4 (2) 13 (5)

Weight Gain

4 (2) 9 (4) 30 (12)

Sweating

4 (2) 3 (1) 16 (6)

Increased Appetite

0 (0) 1 (0) 13 (5) Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole tablets 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 tablets. 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 Adverse Reaction Group Anastrozole tablets 1 mg (N=262) n (%) Anastrozole tablets 10 mg (N=246) n (%)

Megestrol Acetate

160 mg (N=253) n (%)

Gastrointestinal Disturbance

77 (29) 81 (33) 54 (21)

Hot Flushes

33 (13) 29 (12) 35 (14)

Edema

19 (7) 28 (11) 35 (14)

Thromboembolic Disease

9 (3) 4 (2) 12 (5)

Vaginal Dryness

5 (2) 3 (1) 2 (1)

Weight Gain

4 (2) 10 (4) 30 (12)

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 tablets: 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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> Myalgia, trigger finger and hypercalcemia (with or without an increase in parathyroid hormone) To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )
• Decreases in bone mineral density may occur. Consider bone mineral density monitoring. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )
• Increases in total cholesterol may occur. Consider cholesterol monitoring. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )
• Embryo-Fetal Toxicity: anastrozole tablets may cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )

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 <span class="opacity-50 text-xs">[see Error! Hyperlink reference not valid. ]</span>.

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<span class="opacity-50 text-xs">[see Error! Hyperlink reference not valid. ]</span>.

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) <span class="opacity-50 text-xs">[see Error! Hyperlink reference not valid. ]</span>.

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 ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) and Error! Hyperlink reference not valid. ].

INTERACTIONS

• Tamoxifen: Do not use in combination with anastrozole tablets. No additional benefit seen over tamoxifen monotherapy. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )
• Estrogen-containing products: Combination use may diminish activity of Anastrozole Tablets. ( Error! Hyperlink reference not valid. )

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 Error! Hyperlink reference not valid. ]. 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 <span class="opacity-50 text-xs">[see Error! Hyperlink reference not valid. ]</span>.