Anastrozole

ANASTROZOLE- anastrozole tablet
Bryant Ranch Prepack

Chemical Structure for anastrozoleFigure 1Figure 2figure 3figure 4Figure 5Figure 6

1 Anastrozole Indications and Usage

1.1 Adjuvant Treatment

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

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

Anastrozole 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 anastrozole tablets.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

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

For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial, anastrozole was administered for five years [see Clinical Studies ( 14.1)].

No dosage adjustment is necessary for patients with renal impairment or for elderly patients [see Use in Specific Populations ( 8.6)].

2.2 Patients with Hepatic Impairment

No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anastrozole has 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 to off-white, round biconvex, film coated tablets, with “AHI” debossing on one side and plain on other side.

4 CONTRAINDICATIONS

Hypersensitivity

Anastrozole is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria [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 in the ATAC trial (17% of patients on anastrozole and 10% of patients on tamoxifen). Consider risk and benefits of anastrozole therapy in patients with pre-existing ischemic heart disease [see Adverse Reactions ( 6.1)].

5.2 Bone Effects

Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Consider bone mineral density monitoring in patients treated with anastrozole [see Adverse Reactions ( 6.1)] .

5.3 Cholesterol

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

5.4 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, anastrozole can cause fetal harm when administered to a pregnant woman. Anastrozole caused embryo-fetal toxicities in rats at maternal exposure that were 9 times the human clinical exposure, based on area under the curve (AUC). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m 2 basis. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with anastrozole and for at least 3 weeks after the last dose [see Use in Specific Populations ( 8.1, 8.3) and Clinical Pharmacology ( 12.1)].

6 ADVERSE REACTIONS

Serious adverse reactions with anastrozole occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling [see Adverse Reactions ( 6.2)].

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

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

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

6.1 Clinical Trials Experience

Adjuvant Therapy

Adverse reaction data for adjuvant therapy are based on the ATAC trial [see Clinical Studies (14.1)]. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and tamoxifen 20 mg, respectively.

Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1.

Table 1 — Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment, or within 14 days of the end of treatment in the ATAC trial *

Body system and adverse reactions by

COSTART preferred term

Anastrozole 1 mg

(N § = 3092)

Tamoxifen 20 mg

(N § = 3094)

*
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 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)

Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see Table 2).

Table 2 — Number of Patients with Pre-specified Adverse Reactions in ATAC Trial *

Anastrozole

N=3092

(%)

Tamoxifen

N=3094

(%)

Odds-ratio

95% CI

*
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

Hot Flashes

1104 (36)

1264 (41)

0.80

0.73 to 0.89

Musculoskeletal Events

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

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% anastrozole vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the anastrozole arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the anastrozole arm and 34/3094 (1.1%) patients in the tamoxifen arm.

In women with pre-existing ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on anastrozole and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving anastrozole and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving anastrozole and 8/249 (3.2%) patients receiving tamoxifen.

Bone Mineral Density Findings

Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline.

Because anastrozole lowers circulating estrogen levels it may cause a reduction in bone mineral density.

A post-marketing trial assessed the combined effects of anastrozole and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor-positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates. Bisphosphonate treatment preserved bone density in most patients at risk of fracture.

Postmenopausal women with early breast cancer scheduled to be treated with anastrozole should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.

Cholesterol

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

A post-marketing trial also evaluated any potential effects of anastrozole on lipid profile. In the primary analysis population for lipids (anastrozole alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months.

In secondary population for lipids (anastrozole+risedronate), there also was no clinically significant change in LDL-C and HDL-C from baseline to 12 months.

In both populations for lipids, there was no clinically significant difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months compared with baseline.

In this trial, treatment for 12 months with anastrozole alone had a neutral effect on lipid profile. Combination treatment with anastrozole and risedronate also had a neutral effect on lipid profile.

The trial provides evidence that postmenopausal women with early breast cancer scheduled to be treated with anastrozole should be managed using the current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations.

Other Adverse Reactions

Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving tamoxifen [209 (7%)].

Patients receiving anastrozole had a higher incidence of carpal tunnel syndrome [78 (2.5%)] compared with patients receiving tamoxifen [22 (0.7%)].

Vaginal bleeding occurred more frequently in the tamoxifen-treated patients versus the anastrozole -treated patients 317 (10%) versus 167 (5%), respectively.

Patients receiving anastrozole had a lower incidence of hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen.

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

  • Results are consistent with the previous analyses.
  • Serious adverse reactions were similar between anastrozole (50%) and tamoxifen (51%).
  • Cardiovascular events were consistent with the known safety profiles of anastrozole and tamoxifen.
  • The cumulative incidences of all first fractures (both serious and non-serious, occurring either during or after treatment) was higher in the anastrozole group (15%) compared to the tamoxifen group (11%). This increased first fracture rate during treatment did not continue in the post-treatment follow-up period.
  • The cumulative incidence of new primary cancers was similar in the anastrozole group (13.7%) compared to the tamoxifen group (13.9%). Consistent with the previous analyses, endometrial cancer was higher in the tamoxifen group (0.8%) compared to the anastrozole group (0.2%).
  • The overall number of deaths (during or off-trial treatment) was similar between the treatment groups. There were more deaths related to breast cancer in the tamoxifen than in the anastrozole treatment group.

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