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Arimidex

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Arimidex uses


1 INDICATIONS AND USAGE

Arimidex is an aromatase inhibitor indicated for:

1.1 Adjuvant Treatment

Arimidex tablets are indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.

1.2 First-Line Treatment

Arimidex 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

Arimidex tablets are 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 Arimidex tablets.

2 DOSAGE AND ADMINISTRATION

One 1 mg tablet taken once daily

2.1 Recommended Dose

The dose of Arimidex tablet is one 1 mg tablet taken once a day. For patients with advanced breast cancer, Arimidex tablets should be continued until tumor progression. Arimidex tablets can be taken with or without food.

For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial, Arimidex was administered for five years .

No dosage adjustment is necessary for patients with renal impairment or for elderly patients .

2.2 Patients with Hepatic Impairment

No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Arimidex has not been studied in patients with severe hepatic impairment .

3 DOSAGE FORMS AND STRENGTHS

The tablets are white to off-white, round biconvex, film coated tablets, with “AHI” debossing on one side and plain on other side.

1 mg tablets ( 3)

4 CONTRAINDICATIONS

4.1 Pregnancy and Premenopausal Women

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

4.2 Hypersensitivity

Arimidex is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria .

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 Arimidex in the ATAC trial (17% of patients on Arimidex and 10% of patients on tamoxifen). Consider risk and benefits of Arimidex therapy in patients with pre-existing ischemic heart disease .

5.2 Bone Effects

Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving Arimidex had a mean decrease in both lumbar spine and total hip bone mineral density 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 Arimidex .

5.3 Cholesterol

During the ATAC trial, more patients receiving Arimidex were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively) .

6 ADVERSE REACTIONS

Serious adverse reactions with Arimidex occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling .

Common adverse reactions (occurring with an incidence of ≥10%) in women taking Arimidex included: hot flashes, asthenia, arthritis, pain, arthralgia, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, bone pain, peripheral edema, increased cough, dyspnea, pharyngitis and lymphedema.

In the ATAC trial, the most common reported adverse reaction (>0.1%) leading to discontinuation of therapy for both treatment groups was hot flashes, although there were fewer patients who discontinued therapy as a result of hot flashes in the Arimidex group.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.


To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

Adjuvant Therapy

Adverse reaction data for adjuvant therapy are based on the ATAC trial . The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving Arimidex 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.


Body system and adverse reactions by

COSTART COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms.preferred term A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system.


Arimidex 1 mg

(N N=Number of patients receiving the treatment. = 3092)


Tamoxifen 20 mg

(N = 3094)


Body as a whole


Asthenia

575 (19)

544 (18)

Pain

533 (17)

485 (16)

Back pain

321 (10)

309 (10)

Headache

314 (10)

249 (8)

Abdominal pain

271 (9)

276 (9)

Infection

285 (9)

276 (9)

Accidental injury

311 (10)

303 (10)

Flu syndrome

175 (6)

195 (6)

Chest pain

200 (7)

150 (5)

Neoplasm

162 (5)

144 (5)

Cyst

138 (5)

162 (5)

Cardiovascular


Vasodilatation

1104 (36)

1264 (41)

Hypertension

402 (13)

349 (11)

Digestive


Nausea

343 (11)

335 (11)

Constipation

249 (8)

252 (8)

Diarrhea

265 (9)

216 (7)

Dyspepsia

206 (7)

169 (6)

Gastrointestinal disorder

210 (7)

158 (5)

Hemic and lymphatic


Lymphedema

304 (10)

341 (11)

Anemia

113 (4)

159 (5)

Metabolic and nutritional


Peripheral edema

311 (10)

343 (11)

Weight gain

285 (9)

274 (9)

Hypercholesterolemia

278 (9)

108 (3.5)

Musculoskeletal


Arthritis

512 (17)

445 (14)

Arthralgia

467 (15)

344 (11)

Osteoporosis

325 (11)

226 (7)

Fracture

315 (10)

209 (7)

Bone pain

201 (7)

185 (6)

Arthrosis

207 (7)

156 (5)

Joint Disorder

184 (6)

160 (5)

Myalgia

179 (6)

160 (5)

Nervous system


Depression

413 (13)

382 (12)

Insomnia

309 (10)

281 (9)

Dizziness

236 (8)

234 (8)

Anxiety

195 (6)

180 (6)

Paresthesia

215 (7)

145 (5)

Respiratory


Pharyngitis

443 (14)

422 (14)

Cough increased

261 (8)

287 (9)

Dyspnea

234 (8)

237 (8)

Sinusitis

184 (6)

159 (5)

Bronchitis

167 (5)

153 (5)

Skin and appendages


Rash

333 (11)

387 (13)

Sweating

145 (5)

177 (6)

Special Senses


Cataract Specified

182 (6)

213 (7)

Urogenital


Leukorrhea

86 (3)

286 (9)

Urinary tract infection

244 (8)

313 (10)

Breast pain

251 (8)

169 (6)

Breast Neoplasm

164 (5)

139 (5)

Vulvovaginitis

194 (6)

150 (5)

Vaginal Hemorrhage Vaginal Hemorrhage without further diagnosis.


122 (4)

180 (6)

Vaginitis

125 (4)

158 (5)

Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs.


Arimidex

N=3092

(%)


Tamoxifen

N=3094

(%)


Odds-ratio


95% CI


Hot Flashes

1104 (36)

1264 (41)

0.80

0.73 to 0.89

Musculoskeletal Events Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia.


1100 (36)

911 (29)

1.32

1.19 to 1.47

Fatigue/Asthenia

575 (19)

544 (18)

1.07

0.94 to 1.22

Mood Disturbances

597 (19)

554 (18)

1.10

0.97 to 1.25

Nausea and Vomiting

393 (13)

384 (12)

1.03

0.88 to 1.19

All Fractures

315 (10)

209 (7)

1.57

1.30 to 1.88

Fractures of Spine, Hip, or Wrist

133 (4)

91 (3)

1.48

1.13 to 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 to 1.04

Vaginal Bleeding

167 (5)

317 (10)

0.50

0.41 to 0.61

Ischemic Cardiovascular Disease

127 (4)

104 (3)

1.23

0.95 to 1.60

Vaginal Discharge

109 (4)

408 (13)

0.24

0.19 to 0.30

Venous Thromboembolic events

87 (3)

140 (5)

0.61

0.47 to 0.80

Deep Venous Thromboembolic Events

48 (2)

74 (2)

0.64

0.45 to 0.93

Ischemic Cerebrovascular Event

62 (2)

88 (3)

0.70

0.50 to 0.97

Endometrial Cancer Percentages calculated based upon the numbers of patients with an intact uterus at baseline


4 (0.2)

13 (0.6)

0.31

0.10 to 0.94

Ischemic Cardiovascular Events

Between treatment arms in the overall population of 6186 patients, there was no statistical difference in ischemic cardiovascular events (4% Arimidex vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the Arimidex arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the Arimidex arm and 34/3094 (1.1%) patients in the tamoxifen arm.

In women with pre-existing ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on Arimidex and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving Arimidex and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving Arimidex 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 Arimidex 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 Arimidex lowers circulating estrogen levels it may cause a reduction in bone mineral density.

A post-marketing trial assessed the combined effects of Arimidex 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 Arimidex 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 Arimidex 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 Arimidex 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 Arimidex alone had a neutral effect on lipid profile. Combination treatment with Arimidex 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 Arimidex 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 Arimidex had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving Arimidex 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 Arimidex 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 Arimidex -treated patients 317 (10%) versus 167 (5%), respectively.

Patients receiving Arimidex 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

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.


Body system

Adverse Reaction A patient may have had more than 1 adverse event.


Number (%) of subjects


Arimidex

(N=506)


Tamoxifen

(N=511)


Whole body


Asthenia

83 (16)

81 (16)

Pain

70 (14)


73 (14)

Back pain

60 (12)

68 (13)

Headache

47 (9)

40 (8)

Abdominal pain

40 (8)

38 (7)

Chest pain

37 (7)

37 (7)

Flu syndrome

35 (7)

30 (6)

Pelvic pain

23 (5)

30 (6)

Cardiovascular


Vasodilation

128 (25)

106 (21)

Hypertension

25 (5)

36 (7)

Digestive


Nausea

94 (19)

106 (21)

Constipation

47 (9)

66 (13)

Diarrhea

40 (8)

33 (6)

Vomiting

38 (8)

36 (7)

Anorexia

26 (5)

46 (9)

Metabolic and Nutritional


Peripheral edema

51 (10)

41 (8)

Musculoskeletal


Bone pain

54 (11)

52 (10)

Nervous


Dizziness

30 (6)

22 (4)

Insomnia

30 (6)

38 (7)

Depression

23 (5)

32 (6)

Hypertonia

16 (3)

26 (5)

Respiratory


Cough increased

55 (11)

52 (10)

Dyspnea

51 (10)

47 (9)

Pharyngitis

49 (10)

68 (13)

Skin and appendages


Rash

38 (8)

34 (8)

Urogenital


Leukorrhea

9 (2)


31 (6)

Less frequent adverse experiences reported in patients receiving Arimidex 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.


Number (n) and Percentage of Patients


Adverse Reaction A patient may have had more than 1 adverse reaction.


Arimidex

1 mg

(N=506)

n (%)


NOLVADEX

20 mg

(N=511)

n (%)


Depression

23 (5)

32 (6)

Tumor Flare

15 (3)

18 (4)

Thromboembolic Disease Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis.


18 (4)

33 (6)

Venous


5

15

Coronary and Cerebral Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct.


13

19

Gastrointestinal Disturbance

170 (34)

196 (38)

Hot Flushes

134 (26)

118 (23)

Vaginal Dryness

9 (2)

3 (1)

Lethargy

6 (1)

15 (3)

Vaginal Bleeding

5 (1)

11 (2)

Weight Gain

11 (2)

8 (2)

Second-Line Therapy

Arimidex was tolerated in two controlled clinical trials, 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 Arimidex 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:


Adverse Reaction


Arimidex


Arimidex


Megesterol

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)

Other less frequent (2% to 5%) adverse reactions reported in patients receiving Arimidex 1 mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.

Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection

Cardiovascular: Hypertension; thrombophlebitis

Hepatic: Gamma GT increased; SGOT increased; SGPT increased

Hematologic: Anemia; leukopenia

Metabolic and Nutritional: Alkaline phosphatase increased; weight loss

Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving Arimidex. 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.


Arimidex


Arimidex


Megestrol Acetate


1 mg


10 mg


160 mg


(n=262)


(n=246)


(n=253)


Adverse Reaction 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

These adverse reactions are reported voluntarily from a population of uncertain size. Therefore, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The following have been reported in post-approval use of Arimidex:

Hepatobiliary events including increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-GT, and bilirubin; hepatitis

Rash including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome.

Cases of allergic reactions including angioedema, urticaria and anaphylaxis.

Myalgia, trigger finger and hypercalcemia (with or without an increase in parathyroid hormone)

7 DRUG INTERACTIONS

7.1 Tamoxifen

Co-administration of Arimidex and tamoxifen in breast cancer patients reduced Arimidex plasma concentration by 27%. However, the co-administration of Arimidex and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of Arimidex 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 Arimidex.

7.2 Estrogen

Estrogen-containing therapies should not be used with Arimidex as they may diminish its pharmacological action.

7.3 Warfarin

In a study conducted in 16 male volunteers, Arimidex did not alter the exposure, 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 Arimidex 1 mg will affect other drugs as a result of inhibition of cytochrome P450 .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

PREGNANCY CATEGORY X

Arimidex may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Arimidex is contraindicated in women who are or may become pregnant. In animal studies, Arimidex caused pregnancy failure, increased pregnancy loss, and signs of delayed fetal development. There are no studies of Arimidex use in pregnant women. If Arimidex is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and potential risk for pregnancy loss.

In animal reproduction studies, pregnant rats and rabbits received Arimidex during organogenesis at doses equal to or greater than 1 (rats) and 1/3 (rabbits) the recommended human dose on a mg/m 2 basis. In both species, Arimidex 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. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at Arimidex doses that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUC 0-24hr 9 times higher). In rabbits, Arimidex caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m 2 basis .

8.3 Nursing Mothers

It is not known if Arimidex is excreted in human milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for Arimidex 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

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 Arimidex 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 Arimidex 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. 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 Arimidex 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% Arimidex and 2.7% placebo) and headache (7% Arimidex and 0% placebo); all other adverse reactions showed small differences between treatment groups. One patient treated with Arimidex 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 cm 3 in the anastrozole-treated patients and + 5.2 ± 8.0 cm 3 in 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 Arimidex. 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 Arimidex. 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 Arimidex concentration was 1 hr. The mean (range) disposition parameters of Arimidex 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 Arimidex for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetics of Arimidex was similar in boys with pubertal gynecomastia and girls with McCune- Albright Syndrome.

8.5 Geriatric Use

In studies 0030 and 0027, about 50% of patients were 65 or older. Patients ≥ 65 years of age had moderately better tumor response and time to tumor progression than patients < 65 years of age regardless of randomized treatment. In studies 0004 and 0005, 50% of patients were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients.

In the ATAC study, 45% of patients were 65 years of age or older. The efficacy of Arimidex compared to tamoxifen in patients who were 65 years or older (N=1413 for Arimidex and N=1410 for tamoxifen, the hazard ratio for disease-free survival was 0.93 [95% CI: 0.80, 1.08]) was less than efficacy observed in patients who were less than 65 years of age (N=1712 for Arimidex and N=1706 for tamoxifen, the hazard ratio for disease-free survival was 0.79 [95% CI: 0.67, 0.94]).

The pharmacokinetics of Arimidex is not affected by age.

8.6 Renal Impairment

Since only about 10% of Arimidex 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 .

8.7 Hepatic Impairment

The plasma Arimidex 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. Arimidex has not been studied in patients with severe hepatic impairment .

10 OVERDOSAGE

Clinical trials have been conducted with Arimidex, 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 Arimidex 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 Arimidex is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

11 DESCRIPTION

Arimidex tablets for oral administration contain 1 mg of Arimidex, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C 17H 19N 5 and its structural formula is:

Arimidex is an off-white powder with a molecular weight of 293.4. Arimidex has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Arimidex is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.

Each tablet contains as inactive ingredients: lactose monohydrate, magnesium stearate, hypromellose, macrogol, povidone, sodium starch glycolate, and titanium dioxide.

Chemical Structure for Arimidex

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The growth of many cancers of the breast is stimulated or maintained by estrogens.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.

Arimidex is a 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

Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of Arimidex in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection. The recommended daily dose, Arimidex 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with Arimidex 1 mg.

The effect of Arimidex in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women, Arimidex would not be expected to lower estradiol levels in premenopausal women.

Effect on Corticosteroids

In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of Arimidex was assessed by examining effects on corticosteroid synthesis. For all doses, Arimidex did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with Arimidex.

Other Endocrine Effects

In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone was measured; there was no increase in TSH during the administration of Arimidex. Arimidex does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.

12.3 Pharmacokinetics

Absorption

Inhibition of aromatase activity is primarily due to Arimidex, the parent drug. Absorption of Arimidex is rapid and maximum plasma concentrations typically occur within 2 hours of dosing under fasted conditions. Studies with radiolabeled drug have demonstrated that orally administered Arimidex is well absorbed into the systemic circulation. Food reduces the rate but not the overall extent of Arimidex absorption. The mean C max of Arimidex decreased by 16% and the median T max was delayed from 2 to 5 hours when Arimidex was administered 30 minutes after food. The pharmacokinetics of Arimidex are linear over the dose range of 1 to 20 mg, and do not change with repeated dosing. The pharmacokinetics of Arimidex were similar in patients and healthy volunteers.

Distribution

Steady-state plasma levels are approximately 3- to 4-fold higher than levels observed after a single dose of Arimidex. Plasma concentrations approach steady-state levels at about 7 days of once daily dosing. Arimidex is 40% bound to plasma proteins in the therapeutic range.

Metabolism

Metabolism of Arimidex occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of Arimidex have been identified in human plasma and urine. The major circulating metabolite of Arimidex, triazole, lacks pharmacologic activity.

Arimidex inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Arimidex had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of Arimidex to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.

Excretion

Eighty-five percent of radiolabeled Arimidex was recovered in feces and urine. Hepatic metabolism accounts for approximately 85% of Arimidex elimination. Renal elimination accounts for approximately 10% of total clearance. The mean elimination half-life of Arimidex is 50 hours.

Effect of Gender and Age

Arimidex pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age-related effects were seen over the range <50 to >80 years.

Effect of Race

Estradiol and estrone sulfate serum levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of Arimidex daily for 16 days. Arimidex mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.

Effect of Renal Impairment

Arimidex pharmacokinetics have been investigated in subjects with renal impairment. Arimidex renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment compared to controls. Total clearance was only reduced 10%. No dosage adjustment is needed for renal impairment.

Effect of Hepatic Impairment

Arimidex pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of Arimidex was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, these plasma concentrations were still with the range of values observed in normal subjects. The effect of severe hepatic impairment was not studied. No dose adjustment is necessary for stable hepatic cirrhosis.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose-related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUC 0-24 hr levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/m 2 basis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose-related increase in the incidence of ovarian hyperplasia was also observed in female mice. These ovarian changes are considered to be rodent-specific effects of aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50 mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose.

Arimidex has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats).

Oral administration of Arimidex to female rats (from 2 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended human dose on a mg/m 2 basis and 9 times higher than the AUC 0-24 hr found in postmenopausal volunteers at the recommended dose). Pre-implantation loss of ova or fetus was increased at doses equal to or greater than 0.02 mg/kg/day (about one-fifth the recommended human dose on a mg/m 2 basis). Recovery of fertility was observed following a 5-week non-dosing period which followed 3 weeks of dosing. It is not known whether these effects observed in female rats are indicative of impaired fertility in humans.

Multiple-dose studies in rats administered Arimidex for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma Arimidex C ssmax and AUC 0-24 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 Arimidex C ssmax and AUC 0-24 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

Arimidex has been found to cross the placenta following oral administration of 0.1 mg/kg in rats and rabbits (about 1 and 1.9 times the recommended human dose, respectively, on a mg/m 2 basis). Studies in both rats and rabbits at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively (about 1 and 1/3, respectively, the recommended human dose on a mg/m 2 basis), administered during the period of organogenesis showed that Arimidex increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses); effects were dose related in rats. Placental weights were significantly increased in rats at doses of 0.1 mg/kg/day or more.

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 Arimidex C ssmax and AUC 0-24 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, Arimidex caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m 2 basis); there was no evidence of teratogenicity in rabbits administered 0.2 mg/kg/day (about 3 times the recommended human dose on a mg/m 2 basis).

14 CLINICAL STUDIES

14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women

A multicenter, double-blind trial randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with Arimidex 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 (ie, 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 Arimidex 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 Arimidex .

Demographic and other baseline characteristics were similar among the three treatment groups.


Demographic Characteristic


Arimidex

1 mg

(N N=Number of patients randomized to the treatment=3125)


Tamoxifen

20 mg

(N =3116)


Arimidex 1 mg

plus Tamoxifen

20 mg The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up

(N =3125)


Mean age (yrs.)

64.1

64.1

64.3

Age Range (yrs.)

38.1 to 92.8

32.8 to 94.9

37 to 92.2

Age Distribution (%)

<45 yrs.

0.7

0.4

0.5

45 to 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 Includes patients who were estrogen receptor (ER) positive or progesterone receptor (PgR) positive, or both positive


83.5

83.1

84.0

Negative Includes patients with both ER negative and PgR negative receptor status


7.4

8.0

7.0

Other Includes all other combinations of ER and PgR receptor status unknown


8.8

8.6

9.0

Other Treatment (%) prior to Randomization

Mastectomy

47.8

47.3

48.1

Breast conservation Among the patients who had breast conservation, radiotherapy was administered to 95.0% of patients in the Arimidex arm, 94.1% in the tamoxifen arm and 94.5% in the Arimidex plus tamoxifen arm.


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 to 3 (# of nodes)

24.4

24.4

24.3

4 to 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

Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent- to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the Arimidex arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease-free survival was also statistically significantly improved (HR =0.83, 95% CI: 0.73, 0.94, p=0.0049) in the Arimidex arm compared to the tamoxifen arm.

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

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

The survival data with 68 months follow-up is presented in Table 9.

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

The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 8.


Intent-To-Treat Population Patients may fall into more than one category.


Hormone Receptor-Positive Subpopulation


Arimidex

1 mg

(N N=Number of patients randomized=3125)


Tamoxifen

20 mg

(N =3116)


Arimidex

1 mg

(N =2618)


Tamoxifen

20 mg

(N =2598


Number (%) of Patients


Number (%) of Patients


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)

A summary of the study efficacy results is provided in Table 9.


Intent-To-Treat Population


Hormone Receptor-Positive Subpopulation


Arimidex

1 mg

(N=3125)


Tamoxifen

20 mg

(N=3116)


Arimidex

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

0.78 to 0.97

0.0127

0.83

0.73 to 0.94

0.0049

2-sided 95% CI

p-value

Distant Disease-free Survival


500


530

370

394

Hazard ratio

0.94

0.83 to 1.06

0.93

0.80 to 1.07

2-sided 95% CI

Overall Survival


411

420

296

301

Hazard ratio


0.97

0.85 to 1.12

0.97

0.83 to 1.14

2-sided 95% CI

10-year median follow-up Efficacy Results from the ATAC Trial

In a subsequent analysis of the ATAC trial, patients in the two monotherapy arms were followed for a median of 120 months (10 years). Patients received study treatment for a median of 60 months (5 years).


Intent-To-Treat Population


Hormone Receptor-Positive Subpopulation


Arimidex

1 mg

(N=3125)


Tamoxifen

20 mg

(N=3116)


Arimidex

1 mg

(N=2618)


Tamoxifen

20 mg

(N=2598)


Number of Events


Number of Events


Disease-free Survival


953


1022


735

924

Hazard ratio

0.91

0.86

2-sided

95% CI

0.83 to 0.99

0.78 to 0.95

p-value

0.0365

0.0027

Overall Survival


734


747

563

586

Hazard ratio


0.97

0.88 to 1.08

0.95

0.84 to 1.06

2-sided

95% CI

Figure 3 - Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to Arimidex or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat) (a)

a The proportion of patients with 120 months’ follow-up was 29.4%.

Figure 4 - Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to Arimidex or Tamoxifen Monotherapy in the ATAC Trial (b)

bThe proportion of patients with 120 months’ follow-up was 29.8%.

Figure 1 Figure 2 figure 3 figure 4

14.2 First Line Therapy in Postmenopausal Women with Advanced Breast Cancer

Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of Arimidex compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients between the ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of Arimidex once daily or 20 mg of tamoxifen once daily. The primary endpoints for both trials were time to tumor progression, objective tumor response rate, and safety.

Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027.


Number (%) of subjects


Trial 0030


Trial 0027


Receptor status


Arimidex

1 mg

(n=171)


Tamoxifen

20 mg

(n=182)


Arimidex

1 mg

(n=340)


Tamoxifen

20 mg

(n=328)


ER ER=Estrogen receptor and/or PgR PgR=Progesterone receptor


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)

For the primary endpoints, trial 0030 showed that Arimidex had a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression; objective tumor response rates were similar for Arimidex and tamoxifen. Trial 0027 showed that Arimidex and tamoxifen had similar objective tumor response rates and time to tumor progression

Table 12 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints.


End point


Trial 0030


Trial 0027


Arimidex

1 mg

(n=171)


Tamoxifen

20 mg

(n=182)


Arimidex

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

who progressed

114 (67%)

138 (76%)

249 (73%)

247 (75%)

Hazard ratio (LCL LCL=Lower Confidence Limit ) Tamoxifen:Anastrozole


1.42 (1.15)

1.01 (0.87)

2-sided 95% CI CI=Confidence Interval


(1.11, 1.82)

(0.85, 1.20)

p-value Two-sided Log Rank


0.006

0.920

Best objective response rate

Number (%) of subjects

With CR CR=Complete Response + PR PR=Partial Response


36 (21.1%)

31 (17.0%)

112 (32.9%)

107 (32.6%)

Odds Ratio (LCL ) Arimidex:Tamoxifen


1.30 (0.83)

1.01 (0.77)

Figure 5 - Kaplan-Meier probability of time to disease progression for all randomized patients (intent to- treat) in Trial 0030

Figure 6 - Kaplan-Meier probability of time to progression for all randomized patients (intent-to-treat) in Trial 0027

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.

Figure 5 Figure 6

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

Arimidex was studied in two controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER-negative; the ER-negative patients were eligible only if they had a positive response to tamoxifen. Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of Arimidex. or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to Arimidex. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were calculated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated.

Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients entered who had prior tamoxifen therapy for advanced disease (58% in Trial 0004; 57% in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative. In Trial 0005, 58% of patients were ER-positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0004, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases.

Efficacy results from the two studies were similar as presented in Table 13. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters listed in the table below.


Arimidex

1 mg


Arimidex

10 mg


Megestrol

Acetate

160 mg


Trial 0004

( N. America)


(N=128)

(N=130)

(N=128)

Median Follow-up (months) Surviving Patients


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

When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to Arimidex 1 mg and megestrol acetate. There is, in this data, no indication that Arimidex 10 mg is superior to Arimidex 1 mg.


Trials 0004 & 0005

(Pooled Data)


Arimidex

1 mg

N=263


Arimidex

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

Product: 63629-5269

NDC: 63629-5269-1 30 TABLET in a BOTTLE

NDC: 63629-5269-2 20 TABLET in a BOTTLE

NDC: 63629-5269-3 90 TABLET in a BOTTLE

17 PATIENT COUNSELING INFORMATION

“See FDA approved patient labeling.”

17.1 Pregnancy

Patients should be advised that Arimidex may cause fetal harm. They should also be advised that Arimidex is not for use in premenopausal women; therefore, if they become pregnant, they should stop taking Arimidex tablets and immediately contact their doctor.

17.2 Allergic 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 seek medical attention immediately.

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 Arimidex use compared to tamoxifen use. If patients have new or worsening chest pain or shortness of breath they should seek medical attention immediately.

17.4 Bone Effects

Patients should be informed that Arimidex lowers the level of estrogen. This may lead to a loss of the mineral content of bones, which might decrease bone strength. A possible consequence of decreased mineral content of bones is an increase in the risk of fractures.

17.5 Cholesterol

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

17.6 Tickling, Tingling or Numbness

Patients should be informed that if they experience tickling, tingling, or numbness they should notify their health care provider.

17.7 Tamoxifen

Patients should be advised not to take Arimidex with tamoxifen.

17.8 Missed Doses

Inform patients that if they miss a dose, take it as soon as they remember. If it is almost time for their next dose, skip the missed dose and take the next regularly scheduled dose. Patients should not take two doses at the same time.

Manufactured For:

Accord Healthcare, Inc.,

1009 Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No.: 457, 458,

Village – Matoda,

Bavla Road, Ta. - Sanand,

Dist.- Ahmedabad – 382 210.

India.

10 1557 5 654728

Issued June 2014

Patient Information

Arimidex Tablets

(an as' troe zole)

What is the most important information I should know about Arimidex tablet? Arimidex tablets may cause serious side effects including:


Get medical help right away if you have new or worsening chest pain or shortness of breath during treatment with Arimidex tablets.

What is Arimidex tablet?

Arimidex tablet is a prescription medicine used in women after menopause (“the change of life”) for:


Arimidex tablet does not work in women with breast cancer who have not gone through menopause (premenopausal women).

Who should not take Arimidex tablets?

Do not take Arimidex tablet if you:


What should I tell my doctor before taking Arimidex tablets?

Before you take Arimidex tablets, tell your doctor if you:


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


Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Arimidex tablets?


What are the possible side effects of Arimidex tablets?

Arimidex tablets may cause serious side effects including:


Common side effects in women taking Arimidex tablets include:


Arimidex tablets may also cause you to have tickling, tingling or numbness of your skin.

Tell your doctor if you have any side effect that bothers you or that does not go away.


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 Arimidex tablets?


General information about the safe and effective use of Arimidex tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take Arimidex tablets for a condition for which it was not prescribed. Do not give Arimidex tablets to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Arimidex tablets that is written for health professionals.

What are the ingredients in Arimidex tablets?

Active ingredient: Arimidex

Inactive ingredients: lactose monohydrate, magnesium stearate, hypromellose, macrogol, povidone, sodium starch glycolate, and titanium dioxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured For:

Accord Healthcare, Inc.,

1009 Slater Road,

Suite 210-B,

Durham, NC 27703,

USA.

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No.: 457, 458,

Village – Matoda,

Bavla Road, Ta. - Sanand,

Dist.- Ahmedabad – 382 210.

India.

10 1557 5 654728

Issued June 2014

Arimidex 1mg Tablet

Arimidex pharmaceutical active ingredients containing related brand and generic drugs:


Arimidex available forms, composition, doses:


Arimidex destination | category:


Arimidex Anatomical Therapeutic Chemical codes:


Arimidex pharmaceutical companies:


References

  1. Dailymed."ANASTROZOLE TABLET [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ANASTROZOLE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "anastrozole". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Arimidex?

Depending on the reaction of the Arimidex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Arimidex not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Arimidex addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Arimidex, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Arimidex consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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