Anastrozole

Anastrozole is an aromatase inhibitor indicated for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer (
  
  
  1.1 Adjuvant Treatment

  Anastrozole is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.
  )
  
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic 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.
  )
  
• 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 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.
  )
  

One 1 mg tablet taken once daily (

Anastrozole Tablets, USP 1 mg are white, circular, biconvex tablets, debossed with ‘YL’ on one side, and ‘111’ on the other side.

• Lactation: Do not breastfeed. (
  
  8.2 Lactation

  Risk Summary

  
  
  
  
  There are no data on the presence of anastrozole or its metabolites in human milk, or its effects on the breast-fed child or on milk production. 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 the breast-fed child from anastrozole, advise lactating women not to breastfeed during treatment with anastrozole and for 2 weeks after the last dose.
  )
  
• Females and Males of Reproductive Potential: Verify pregnancy status prior to initiation of anastrozole tablets. (
  
  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)

  ].
  )
  
• 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 Pediatric Use

  Clinical studies in pediatric patients included a placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and a 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

  A randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged 11 to 18 years. Patients were randomized to a daily regimen of either anastrozole tablets 1 mg or placebo. After 6 months of treatment there was no statistically significant difference in the percentage of patients who experienced a ≥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 6 of treatment were reduced by 15.4% in the anastrozole 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-treated patients and 8.1% of the placebo-treated patients with the most frequent being acne (7% anastrozole and 2.7% placebo) and headache (7% Anastrozole 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 6 months of treatment was + 6.6 ± 7.9 cm³in the anastrozole-treated patients and + 5.2 ± 8.0 cm³in the placebo group.

  McCune-Albright Syndrome Study

  A multi-center, single-arm, open-label study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged 2 to <10 years. All patients received a 1 mg daily dose of anastrozole tablets. The trial duration was 12 months. Patients were enrolled on the basis of a 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: a mean chronological age of 5.9 ± 2.0 years, a mean bone age of 8.6 ± 2.6 years, a mean growth rate of 7.9 ± 2.9 cm/year and a 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 a 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. A 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 a 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 transaminase, and allergic dermatitis.

  Pharmacokinetics in Pediatric Patients

  Following 1 mg once daily multiple administration in pediatric patients, the mean time to reach the maximum anastrozole concentration was 1 hr. The mean (range) disposition parameters of anastrozole in pediatric patients were described by a CL/F of 1.54 L/h (0.77 to 4.53 L/h) and V/F of 98.4 L (50.7 to 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 a population pharmacokinetic analysis, the pharmacokinetics of anastrozole was similar in boys with pubertal gynecomastia and girls with McCune-Albright Syndrome.

• See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

• 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 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)

  ].
  ,
  
  
  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 (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¶	122 (4)	180 (6)
  Vaginitis	125 (4)	158 (5)
  *The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. †COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms. ‡A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system. §N=Number of patients receiving the treatment. ¶Vaginal Hemorrhage without further diagnosis.

  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*

  	Anastrozole N= 3,092 (%)	Tamoxifen N=3,094(%)	Odds-ratio	95% CI
  Hot Flashes	1,104 (36)	1,264 (41)	0.80	0.73 - 0.89
  Musculoskeletal Events†	1,100 (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’ 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‡	4 (0.2)	13 (0.6)	0.31	0.10 - 0.94
  *Patients with multiple events in the same category are counted only once in that category. †Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. ‡Percentages calculated based upon the numbers of patients with an intact uterus at baseline

  Ischemic Cardiovascular Events

  Between treatment arms in the overall population of 6,186 patients, there was no statistical difference in ischemic cardiovascular events (4% anastrozole vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3,092 (2.3%) patients in the anastrozole arm and 51/3,094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3,092 (1.2%) patients in the anastrozole arm and 34/3,094 (1.1%) patients in the tamoxifen arm.
  
  
  
  
  
  
  
  In women with pre-existing ischemic heart disease 465/6,186 (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%) versus167 (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*	Number (%) of subjects
  	Anastrozole (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)
  *A patient may have had more than 1 adverse event.

  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*	Anastrozole 1 mg (N=506) n (%)	NOLVADEX 20 mg (N=511) n (%)
  Depression	23 (5)	32 (6)
  Tumor Flare	15 (3)	18 (4)
  Thromboembolic Disease†	18 (4)	33 (6)
  Venous†	5	15
  Coronary and Cerebral‡	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)
  *A patient may have had more than 1 adverse reaction. †Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis. ‡Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct.

  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

  Adverse Reaction*	Anastrozole		Anastrozole		Megestrol Acetate
  	1 mg		10 mg		160 mg
  	(N=262)		(N=246)		(N=253)
  	n	%	n	%	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)
  *A patient may have had more than one adverse reaction.

  Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole1 mg in either Trial 0004 or Trial 0005are 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

  Adverse Reaction Group	Anastrozole		Anastrozole		Megestrol Acetate
  	1 mg		10 mg		160 mg
  	(N=262)		(N=246)		(N=253)
  	n	(%)	n	(%)	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)
  )
  
• Decreases in bone mineral density may occur. Consider bone mineral density monitoring. (
  
  
  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)

  ].
  ,
  
  
  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 (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¶	122 (4)	180 (6)
  Vaginitis	125 (4)	158 (5)
  *The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. †COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms. ‡A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system. §N=Number of patients receiving the treatment. ¶Vaginal Hemorrhage without further diagnosis.

  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*

  	Anastrozole N= 3,092 (%)	Tamoxifen N=3,094(%)	Odds-ratio	95% CI
  Hot Flashes	1,104 (36)	1,264 (41)	0.80	0.73 - 0.89
  Musculoskeletal Events†	1,100 (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’ 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‡	4 (0.2)	13 (0.6)	0.31	0.10 - 0.94
  *Patients with multiple events in the same category are counted only once in that category. †Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. ‡Percentages calculated based upon the numbers of patients with an intact uterus at baseline

  Ischemic Cardiovascular Events

  Between treatment arms in the overall population of 6,186 patients, there was no statistical difference in ischemic cardiovascular events (4% anastrozole vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3,092 (2.3%) patients in the anastrozole arm and 51/3,094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3,092 (1.2%) patients in the anastrozole arm and 34/3,094 (1.1%) patients in the tamoxifen arm.
  
  
  
  
  
  
  
  In women with pre-existing ischemic heart disease 465/6,186 (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%) versus167 (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*	Number (%) of subjects
  	Anastrozole (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)
  *A patient may have had more than 1 adverse event.

  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*	Anastrozole 1 mg (N=506) n (%)	NOLVADEX 20 mg (N=511) n (%)
  Depression	23 (5)	32 (6)
  Tumor Flare	15 (3)	18 (4)
  Thromboembolic Disease†	18 (4)	33 (6)
  Venous†	5	15
  Coronary and Cerebral‡	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)
  *A patient may have had more than 1 adverse reaction. †Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis. ‡Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct.

  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

  Adverse Reaction*	Anastrozole		Anastrozole		Megestrol Acetate
  	1 mg		10 mg		160 mg
  	(N=262)		(N=246)		(N=253)
  	n	%	n	%	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)
  *A patient may have had more than one adverse reaction.

  Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole1 mg in either Trial 0004 or Trial 0005are 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

  Adverse Reaction Group	Anastrozole		Anastrozole		Megestrol Acetate
  	1 mg		10 mg		160 mg
  	(N=262)		(N=246)		(N=253)
  	n	(%)	n	(%)	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)
  )
  
• Increases in total cholesterol may occur. Consider cholesterol monitoring. (
  
  
  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)].
  ,
  
  
  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 (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¶	122 (4)	180 (6)
  Vaginitis	125 (4)	158 (5)
  *The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. †COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms. ‡A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system. §N=Number of patients receiving the treatment. ¶Vaginal Hemorrhage without further diagnosis.

  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*

  	Anastrozole N= 3,092 (%)	Tamoxifen N=3,094(%)	Odds-ratio	95% CI
  Hot Flashes	1,104 (36)	1,264 (41)	0.80	0.73 - 0.89
  Musculoskeletal Events†	1,100 (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’ 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‡	4 (0.2)	13 (0.6)	0.31	0.10 - 0.94
  *Patients with multiple events in the same category are counted only once in that category. †Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. ‡Percentages calculated based upon the numbers of patients with an intact uterus at baseline

  Ischemic Cardiovascular Events

  Between treatment arms in the overall population of 6,186 patients, there was no statistical difference in ischemic cardiovascular events (4% anastrozole vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3,092 (2.3%) patients in the anastrozole arm and 51/3,094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3,092 (1.2%) patients in the anastrozole arm and 34/3,094 (1.1%) patients in the tamoxifen arm.
  
  
  
  
  
  
  
  In women with pre-existing ischemic heart disease 465/6,186 (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%) versus167 (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*	Number (%) of subjects
  	Anastrozole (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)
  *A patient may have had more than 1 adverse event.

  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*	Anastrozole 1 mg (N=506) n (%)	NOLVADEX 20 mg (N=511) n (%)
  Depression	23 (5)	32 (6)
  Tumor Flare	15 (3)	18 (4)
  Thromboembolic Disease†	18 (4)	33 (6)
  Venous†	5	15
  Coronary and Cerebral‡	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)
  *A patient may have had more than 1 adverse reaction. †Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis. ‡Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct.

  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

  Adverse Reaction*	Anastrozole		Anastrozole		Megestrol Acetate
  	1 mg		10 mg		160 mg
  	(N=262)		(N=246)		(N=253)
  	n	%	n	%	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)
  *A patient may have had more than one adverse reaction.

  Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole1 mg in either Trial 0004 or Trial 0005are 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

  Adverse Reaction Group	Anastrozole		Anastrozole		Megestrol Acetate
  	1 mg		10 mg		160 mg
  	(N=262)		(N=246)		(N=253)
  	n	(%)	n	(%)	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)
  )
  
• 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 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/m²basis. 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

  and

  Clinical Pharmacology (12.1)

  ].
  ,
  
  
  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/m²basis, 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/m²basis).
  )