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ANASTROZOLE

PD-Rx Pharmaceuticals, Inc.
PD-Rx Pharmaceuticals, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use anastrozole tablets safely and effectively. See full prescribing information for anastrozole tablets. Initial U.S. ApprovalAnastrozole tablets for oral use RECENT MAJOR CHANGESContraindications - Premenopausal Women and Pregnancy(4.1, 8.1) 01/2010 Warnings and Precautions- Ischemic Cardiovascular Events (5.1, 6.1) 01/2010INDICATIONS AND USAGE Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer (1.1) First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer (1.2) Treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to anastrozole tablets (1.3) DOSAGE AND ADMINISTRATIONOne 1 mg tablet taken once daily (2.1) DOSAGE FORMS AND STRENGTHS1 mg tablets (3) CONTRAINDICATIONS Women of premenopausal endocrine status, including pregnant women (4.1, 8.1) Patients with demonstrated hypersensitivity to anastrozole tablets or any excipient (4.2) WARNINGS AND PRECAUTIONS In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events occurred with anastrozole tablet use compared to tamoxifen use. Consider risks and benefits. (5.1, 6.1) Decreases in bone mineral density may occur. Consider bone mineral density monitoring. (5.2, 6.1) Increases in total cholesterol may occur. Consider cholesterol monitoring. (5.3, 6.1) Side EffectsTo report suspected adverse reactions and 1-800-FDA-1088 or .DRUG INTERACTIONS Tamoxifen: Do not use in combination with anastrozole tablets. No additional benefit seen over tamoxifen monotherapy (7.1, 14.1). Estrogen-containing products: Combination use may diminish activity of anastrozole tablets (7.2). USE IN SPECIFIC POPULATIONS Pediatric patients: Efficacy has not been demonstrated for pubertal boys of adolescent age with gynecomastia or girls with McCune-Albright Syndrome and progressive precocious puberty. (8.4)


FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Adjuvant Treatment


1.2 First-Line Treatment


Anastrozole tablets are 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


2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose




[see Clinical Studies (14.1)]
[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)]

3 DOSAGE FORMS AND STRENGTHS


The tablets are white, biconvex, film-coated containing 1 mg of anastrozole. The tablets are debossed with “AN” and “1” on one side and plain surface on the other side.

4 CONTRAINDICATIONS

4.1 Pregnancy and Premenopausal Women


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

4.2 Hypersensitivity


Anastrozole tablets are contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria. [see Adverse Reactions (6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Ischemic Cardiovascular Events


In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with anastrozole tablets in the ATAC trial (17% of patients on anastrozole tablets and 10% of patients on tamoxifen). Consider risk and benefits of anastrozole tablets therapy in patients with pre-existing ischemic heart disease. [see Adverse Reactions (6.1)]

5.2 Bone Effects


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 [see Adverse Reactions, (6.1)].

5.3 Cholesterol


During the ATAC trial, more patients receiving anastrozole tablets were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively) [see Adverse Reactions, (6.1)].

6 ADVERSE REACTIONS


[see Adverse Reactions, (6.2)].





6.1 Clinical Trials Experience


Adjuvant Therapy
[see Clinical Studies (14.1) ].

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.
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.
Body system and adverse reactions by COSTARTpreferred term
Anastrozole tablets 1mg
(N§ = 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
122 (4)
180 (6)
Vaginitis
125 (4)
158 (5)




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.
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

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
Fatigue/Asthenia
1100 (36)
575 (19)
911 (29)
544 (18)
1.32
1.07
1.19 - 1.47
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



Ischemic Cardiovascular Events


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.










Cholesterol















Other Adverse Reactions








First-Line Therapy


Table 3 – Adverse Reactions Occurring with an Incidence of at Least 5% in Trials 0030 and 0027

* A patient may have had more than 1 adverse event.
Body system
Adverse Reaction*
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)
Muscoloskeletal
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)







Table 4 – Number of Patients with Pre-specified Adverse Reactions in Trials 0030 and 0027



* A patient may have had more than 1 adverse event.
Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis.
Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct.
Number (n) and Percentage of Patients
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
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)




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

* A patient may have had more than one adverse reaction.
Adverse Reaction*
Anastrozole tablets 1 mg
Anastrozole tablets 10 mg
Megestrol Acetate 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)




Body as a Whole

Cardiovascular: Hypertension; thrombophlebitis


Hepatic:

Hematologic:

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:


Table 6 — Number (n) and Percentage of Patients with Pre-specified Adverse Reactions in Trials 0004 and 0005




Anastrozole tablets 1 mg
Anastrozole tablets 10 mg
Megestrol Acetate 160 mg
(N=262)
(N=246)
(N=253)
Adverse Event
Group
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)

6.2 Post-Marketing Experience



Anastrozole tablets may also be associated with rash including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome.

Cases of allergic reactions including angioedema, urticaria and anaphylaxis have been reported in patients receiving anastrozole tablets. [see Contraindications (4.2)]

Trigger finger has been reported (≥0.1% and <1%) in patients receiving anastrozole tablets.

7 DRUG INTERACTIONS

7.1 Tamoxifen


Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the coadministration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of anastrozole tablets and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial. [see Clinical Studies (14.1)]. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.

7.2 Estrogen


Estrogen-containing therapies should not be used with anastrozole tablets 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 tablets 1 mg will affect other drugs as a result inhibition of cytochrome P450 [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy


[see Contraindications (4.1)]


20-24hr 2[see Animal Toxicology and/or Pharmacology (13.2)]

8.2 Labor & Delivery

8.3 Nursing Mothers


It is not known if anastrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use



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.

Labeling describing clinical trails and pharmacokinetic studies of anastrozole in pubertal boys of adolescent age with gynecomastia and in girls with McCune- Albright Syndrome and progressive precocious puberty is approved for AstraZeneca Pharmaceuticals LP’s Arimidex ® . However, due to AstraZeneca Pharmaceuticals LP’s marketing exclusivity rights, a description of those trials and studies is not approved for this anastrozole labeling.

8.5 Geriatric Use





The pharmacokinetics of anastrozole are not affected by age.

8.6 Renal Impairment


Since only about 10% of anastrozole is excreted unchanged in the urine, the renal impairment does not influence the total body clearance. Dosage adjustment in patients with renal impairment is not necessary [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment


The plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Therefore, dosage adjustment is also not necessary in patients with stable hepatic cirrhosis. Anastrozole tablets have not been studied in patients with severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE


Clinical trials have been conducted with anastrozole tablets, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were tolerated. A single dose of anastrozole tablets that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consider that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole tablets are not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

11 DESCRIPTION


17195

ANASTROZOLE



12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action




Anastrozole is a potent and selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.

12.2 Pharmacodynamics


Effect on Estradiol





Effect on Corticosteroids


Other Endocrine Effects

12.3 Pharmacokinetics


Absorption
maxmax

Distribution


Metabolism


in vitro maxin vitro

Excretion



Effect of Gender and Age



Effect of Race


Effect of Renal Impairment
2 [see Dosage and Administration (2.1) and Use in Specific Populations (8.6)]


Effect of Hepatic Impairment
[see Dosage and Administration (2.2) and Use in Specific Populations (8.7)]

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


20-24 hr 2


in vitroin vitroin vivo

20-24 hr2

Multiple-dose studies in rats administered anastrozole for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose) resulted in hypertrophy of the ovaries and the presence of follicular cysts. In addition, hyperplastic uteri were observed in 6-month studies in female dogs administered doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 22 times and 16 times higher than the respective values found in postmenopausal women at the recommended dose). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in premenopausal women.

13.2 Animal Toxicology and/or Pharmacology


Reproductive Toxicology
22

Evidence of fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), was observed in rats administered doses of 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 times and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose). There was no evidence of teratogenicity in rats administered doses up to 1.0 mg/kg/day. In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m2 basis); there was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/m2 basis).

14 CLINICAL STUDIES

14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women

A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with anastrozole tablets 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease.

The primary endpoint of the trial was disease-free survival (i.e., time to occurrence of a distant or local recurrence, or contralateral breast cancer or death from any cause). Secondary endpoints of the trial included distant disease-free survival, the incidence of contralateral breast cancer and overall survival. At a median follow-up of 33 months, the combination of anastrozole tablets and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole. [see Drug Interactions (7.1)]

Demographic and other baseline characteristics were similar among the three treatment groups (see Table 7).


Table 7 - Demographic and Baseline Characteristics for ATAC Trial
* N=Number of patients randomized to the treatment
The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up
Includes patients who were estrogen receptor (ER) positive or progesterone receptor (PgR) positive, or both positive
§ Includes patients with both ER negative and PgR negative receptor status
Includes all other combinations of ER and PgR receptor status unknown
#Among the patients who had breast conservation, radiotherapy was administered to 95.0% of patients in the anastrozole tablets arm, 94.1% in the tamoxifen arm and 94.5% in the anastrozole tablets plus tamoxifen arm.

Demographic Characteristic

Anastrozole tablets 1 mg

Tamoxifen
20 mg

Anastrozole tablets
1 mg plus Tamoxifen
20 mg

(N*=3125)

(N*=3116)

(N*=3125)

Mean age (yrs.)

64.1

64.1

64.3

AgeRange (yrs.)

38.1 - 92.8

32.8 - 94.9

37.0 – 92.2

Age Distribution (%)

<45 yrs.

0.7

0.4

0.5

45-60 yrs.

34.6

35.0

34.5

>60 <70 yrs.

38.0

37.1

37.7

>70 yrs.

26.7

27.4

27.3

Mean Weight (kg)

70.8

71.1

71.3

Receptor Status(%)

Positive

83.5

83.1

84.0

Negative§

7.4

8.0

7.0

Other

8.8

8.6

9.0

Other Treatment (%) prior to Randomization

Mastectomy

47.8

47.3

48.1

Breast conservation#

52.3

52.8

51.9

Axillary surgery

95.5

95.7

95.2

Radiotherapy

63.3

62.5

61.9

Chemotherapy

22.3

20.8

20.8

Neoadjuvant Tamoxifen

1.6

1.6

1.7

Primary Tumor Size (%)

T1 (≤2 cm)

63.9

62.9

64.1

T2 (>2 cm and ≤5 cm)

32.6

34.2

32.9

T3 (>5 cm)

2.7

2.2

2.3

Nodal Status (%)

Node positive

34.9

33.6

33.5

1-3 (#of nodes)

24.4

24.4

24.3

4-9

7.5

6.4

6.8

>9

2.9

2.7

2.3

Tumor Grade (%)

Well-differentiated

20.8

20.5

21.2

Moderately differentiated

46.8

47.8

46.5

Poorly/undifferentiated

23.7

23.3

23.7

Not assessed/recorded

8.7

8.4

8.5






Figure 1 — Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Anastrozole Tablets or Tamoxifen Monotherapy in the ATAC trial (Intent-to-Treat)
ANASTROZOLE

Figure 2 — Disease-free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Anastrozole Tablets or Tamoxifen Monotherapy in the ATAC Trial


ANASTROZOLE

In the group of patients who had previous adjuvant chemotherapy (N=698 for anastrozole tablets and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91(95% CI: 0.73 to 1.13) in the anastrozole tablets arm compared to the tamoxifen arm.




Table 8- All Recurrence and Death Events*
* The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up
N=Number of patients randomized

Intent-To-Treat Population
Hormone Receptor-Positive
Subpopulation

Anastrozole tablets 1 mg
(N=3125)
Tamoxifen
20 mg
(N=3116)
Anastrozole tablets 1 mg
(N=2618)
Tamoxifen
20 mg
(N=2598)
Median Duration of
Therapy (mo)
60
60
60
60
Median Efficacy
Follow-up (mo)
68
68
68
68
Loco-regional recurrence
119 (3.8)
149 (4.8)
76 (2.9)
101 (3.9)
Contralateral breast cancer
35 (1.1)
59 (1.9)
26 (1.0)
54 (2.1)
Invasive
27 (0.9)
52 (1.7)
21 (0.8)
48 (1.8)
Ductal carcinoma in situ
8 (0.3)
6 (0.2)
5 (0.2)
5 (0.2)
Unknown
0
1 (<0.1)
0
1 (<0.1)
Distant recurrence
324 (10.4)
375 (12.0)
226 (8.6)
265 (10.2)
Death from Any Cause
411 (13.2)
420 (13.5)
296 (11.3)
301 (11.6)
Death breast cancer
218 (7.0)
248 (8.0)
138 (5.3)
160 (6.2)
Death other reason
(including unknown)
193 (6.2)
172 (5.5)
158 (6.0)
141 (5.4)





Table 9 - ATAC Efficacy Summary*
* The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up.

Intent-To-Treat Population
Hormone Receptor-Positive
Subpopulation

Anastrozole tablets 1 mg
(N=3125)
Tamoxifen
20 mg
(N=3116)
Anastrozole tablets 1 mg
(N=2618)
Tamoxifen
20 mg
(N=2598)

Number of Events
Number of Events
Disease free Survival
575
651
424
497
Hazard ratio
0.87
0.83
2-sided 95% CI
0.78 to 0.97
0.73 to 0.94
p-value
0.0127
0.0049
Distant Disease- free Survival
500
530
370
394
Hazard ratio
0.94
0.93
2-sided 95% CI
0.83 to 1.06
0.80 to 1.07
Overall Survival
411
420
296
301
Hazard ratio
0.97
0.97
2-sided 95% CI
0.85 to 1.12
0.83 to 1.14

14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer







Table 10 – Demographic and Other Baseline Characteristics
* ER=Estrogen receptor
PgR=Progesterone receptor

Number (%) of subjects

Trial 0030
Trial 0027
Receptor status
Anastrozole tablets 1 mg
(N=171)
Tamoxifen
20 mg
(N=182)
Anastrozole tablets 1 mg
(N=340)
Tamoxifen
20 mg
(N=328)
ER* and/or PgR
151 (88.3)
162 (89.0)
154 (45.3)
144 (43.9)
ER* unknown, PgR
Unknown
19 (11.1)
20 (11.0)
185 (54.4)
183 (55.8)






Table -11 Efficacy Results of First –line Treatment
* LCL=Lower Confidence Limit
Tamoxifen:Anastrozole tablets
CI=Confidence Interval
§ Two-sided Log Rank
CR=Complete Response
# PR=Partial Response
Anastrozole tablets:Tamoxifen

Endpoint

Trial 0030

Trial 0027


Anastrozole tablets 1 mg
(N=171)

Tamoxifen
20 mg
(N=182)

Anastrozole tablets 1 mg
(N=340)

Tamoxifen
20 mg
(N=328)

Time to progression (TTP)
Median TTP (months)

11.1

5.6

8.2

8.3

Number (%) of subjects

114 (67%)

138 (76%)

249 (73%)

247 (75%)

Who progressed
Hazard ratio (LCL* )

1.42 (1.15)

1.01 (0.87)

2-sided 95% CI

(1.11, 1.82)

(0.85, 1.20)

p-value§

0.006

0.920

Best objective response rate
Number (%) of subjects

36 (21.1%)

31 (17.0%)

112 (32.9%)

107 (32.6%)

With CR + PR#
Odds Ratio (LCL* )

1.30 (0.83)

1.01 (0.77)



Figure 3 - Kaplan-Meier probability of time to disease progression for all randomized patients (intent-to-treat) in Trial 0030
ANASTROZOLE
Figure 4 - Kaplan-Meier probability of time to progression for all randomized patients (intent-to-treat) in Trial 0027
ANASTROZOLE

Results from the secondary endpoints were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences.

14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy








Table 12– Efficacy Results of Second-line Treatment
*Surviving Patients

Anastrozole tablets 1 mg
Anastrozole tablets 10 mg
Megestrol Acetate 160 mg
Trial 0004
(N. America)
(N=128)
(N=130)
(N=128)
Median Fol1ow-up (months)*
31.3
30.9
32.9
Median Time to Death (months)
29.6
25.7
26.7
2 Year Survival Probability (%)
62.0
58.0
53.1
Median Time to Progression (months)
5.7
5.3
5.1
Objective Response
(all patients ) (%)
12.5
10.0
10.2
Stable Disease for >24 weeks (%)
35.2
29.2
32.8
Progression (%)
86.7
85.4
90.6
Trial 0005
(Europe, Australia, S. Africa)
(N=135)
(N=118)
(N=125)
Median Follow-up (months)*
31.0
30.9
31.5
Median Time to Death (months)
24.3
24.8
19.8
2 Year Survival Probability (%)
50.5
50.9
39.1
Median Time to Progression (months)
4.4
5.3
3.9
Objective Response
(all patients) (%)
12.6
15.3
14.4
Stable Disease for >24 weeks (%)
24.4
25.4
23.2
Progression (%)
91.9
89.8
92.0




Table 13 – Pooled Efficacy Results of Second-line Treatment
Trials 0004 & 0005
(Pooled Data)
Anastrozole tablets 1 mg
N=263
Anastrozole tablets 10 mg
N=248
Megestrol
Acetate 160 mg
N=253
Median Time to
Death (months)
26.7
25.5
22.5
2 Year Survival
Probability (%)
56.1
54.6
46.3
Median Time to
Progression
4.8
5.3
4.6
Objective Response
(all patients) (%)
12.5
12.5
12.3

16 HOW SUPPLIED/STORAGE AND HANDLING

These tablets are supplied in bottles of 30 tablets (NDC 51991-620-33) and bottles of 1000 tablets (NDC 51991-620-10)


Storage

17 PATIENT COUNSELING INFORMATION

17.1 Pregnancy


17.2 Allergic (Hypersensitivity) Reactions


Patients should be informed of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to immediately report this to their doctor.

17.3 Ischemic Cardiovascular Events


Patients with pre-existing ischemic heart disease should be informed that an increased incidence of cardiovascular events has been observed with anastrozole tablets use compared to tamoxifen use.

17.4 Bone Effects


17.5 Cholesterol


Patients should be informed that an increased level of cholesterol might be seen while receiving anastrozole tablets.

17.6 Tamoxifen


17.7 FDA-Approved Patient Labeling



PATIENT INFORMATION






What are anastrozole tablets?

  • treatment of early breast cancer


  • first treatment of locally advanced or metastatic breast cancer, in women whose breast cancer is hormone receptor-positive or the hormone receptors are not known.
  • treatment of advanced breast cancer, if the cancer has grown, or the disease has spread after tamoxifen therapy.



Who should not take anastrozole tablets?

  • are pregnant, think you may be pregnant, or plan to get pregnant. Anastrozole tablets may harm your unborn child. If you become pregnant while taking anastrozole tablets, tell your doctor right away.
  • have not finished menopause (are premenopausal)
  • are allergic to any of the ingredients in anastrozole tablets. See the end of this leaflet for a list of the ingredients in anastrozole tablets.
  • are a man or child

What is the most important information I should know about anastrozole tablets?

  • Heart disease. Women with early breast cancer, who have a history of blockages in heart arteries (ischemic heart disease) and who take anastrozole tablets may have a slight increase in this type of heart disease compared to similar patients who take tamoxifen.
    • Stop taking anastrozole tablets and call your doctor right away if you have chest pain or shortness of breath. These can be symptoms of heart disease.

  • Osteoporosis (bone softening and weakening). Anastrozole tablets lower estrogen in your body, which may cause your bones to become softer and weaker. This can increase your chance of fractures, specifically of the spine, hip and wrist. Your doctor may order a test for you called a bone mineral density study before you start taking anastrozole tablets and during treatment with anastrozole tablets as needed.

What should I tell my doctor before taking anastrozole tablets?
Anastrozole tablets may not be right for you. Before taking anastrozole tablets, tell your doctor about all your medical conditions, including if you:
  • have not finished menopause. Talk to your doctor if you are not sure. See “Who should not take anastrozole tablets?”
  • have had a previous heart problem
  • have a condition called osteoporosis
  • have high cholesterol
  • are pregnant, planning to become pregnant, or breast feeding. See “Who should not take anastrozole tablets?”
  • are nursing a baby. It is not known if anastrozole tablets pass into breast milk. You and your doctor should decide if you will take anastrozole tablets or breast feed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • Tamoxifen. You should not take anastrozole tablets with tamoxifen. Taking tamoxifen with anastrozole tablets may lower the amount of anastrozole tablets in your blood and may cause anastrozole tablets not to work as well.
  • Medicines containing estrogen. Anastrozole tablets may not work if taken with one of these medicines:
    • hormone replacement therapy
    • birth control pills
    • estrogen creams
    • vaginal rings
    • vaginal suppositories



How should I take anastrozole tablets?

  • Take anastrozole tablets exactly as prescribed by your doctor. Keep taking anastrozole tablets for as long as your doctor prescribes it for you.
  • Take one anastrozole tablet each day.
  • Anastrozole tablets can be taken with or without food.
  • If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.
  • If you have taken more anastrozole tablets than your doctor has prescribed, contact your doctor right away. Do not take any additional anastrozole tablets until instructed to do so by your doctor.

Talk with your doctor about any health changes you have while taking anastrozole tablets.

What are possible side effects of anastrozole tablets?

Anastrozole tablets can cause serious side effects including:

  • See “What is the most important information I should know about anastrozole tablets?”
  • increased blood cholesterol (fat in the blood). Your doctor may check your cholesterol while you take anastrozole tablets therapy.
  • skin reactions. Stop taking anastrozole tablets and call your doctor right away if you get any skin lesions, ulcers, or blisters.
  • severe allergic reactions. Get medical help right away if you have:

· swelling of the face, lips, tongue, or throat.

· trouble swallowing

· trouble breathing

  • liver problems. Anastrozole tablets can cause inflammation of the liver and changes in blood tests of the liver function. Your doctor may monitor you for this. Stop taking anastrozole tablets and call your doctor right away if you have any of these signs or symptoms of a liver problem:

· a general feeling of not being well

· yellowing of the skin or whites of the eyes

· pain on the right side of your abdomen


· hot flashes

· weakness

· joint pain

· carpal tunnel syndrome (tingling, pain, coldness, weakness in parts of the hand)

· pain

· sore throat

· mood changes

· high blood pressure

· depression

· nausea and vomiting

· thinning of the hair (hair loss)

· rash

· back pain

· sleep problems

· bone pain

· headache

· swelling

· increased cough

· shortness of breath

· lymphedema (build up of lymph fluid in the tissues of your affected arm)




Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.



HOW SHOULD I STORE ANASTROZOLE TABLETS?
  • Store anastrozole tablets at 68ºF to 77ºF (20ºC to 25ºC).
  • Keep anastrozole tablets and all medicines out of the reach of children.

General information about anastrozole tablets.





What are the ingredients in anastrozole tablets?








Anastrozole tablets 1mg - 30 tablets

Anastrozole Tablets 1 mg

RX Only

Each tablet contains 1 mg of anastrozole USP

USUAL DOSAGE: See accompanying Prescribing Information.

WARNING: As with all medications, keep out of the reach of children.




ANASTROZOLE

ANASTROZOLE

ANASTROZOLE TABLET

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:43063-383(NDC:51991-620)
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
Anastrozole ANASTROZOLE 1 mg

Inactive Ingredients

Ingredient Name Strength
lactose monohydrate
MAGNESIUM STEARATE
HYPROMELLOSES
POLYETHYLENE GLYCOLS
povidone
SODIUM STARCH GLYCOLATE TYPE A POTATO
titanium dioxide

Product Characteristics

Color Size Imprint Code Shape
WHITE 6 mm AN;1 ROUND

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:43063-383-15 15 in 1 BOTTLE, PLASTIC

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA079220 2010-06-28


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Be sure to consult your doctor before taking any medication!
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