Anastrozole

ANASTROZOLE — anastrozole tablet
Rising Pharmaceuticals, Inc.

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

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

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

2.2 Patients with Hepatic Impairment

No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anastrozole tablets have not been studied in patients with severe hepatic impairment. [See Use in Specific Populations (8.7)]

3 DOSAGE FORMS AND STRENGTHS

The tablets are white to off-white, round, 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

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 increase 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. Consider bone mineral density monitoring in patients treated with anastrozole tablets [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)].

5.4 Embryo-Fetal Toxicity

Based on finding from animal studies and its mechanism of action, anastrozole tablets 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/m2 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 tablets 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 tablets occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling [see Adverse Reactions, (6.2)].

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

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

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

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 tablets 1 mg and tamoxifen 20 mg, respectively. Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1.

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

Body system and adverse reactions by COSTART preferred 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)

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


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

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

Anastrozole 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

* Patients with multiple events in the same category are counted only once in that category.
† Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia.
‡ Percentages calculated based upon the numbers of patients with an intact uterus at baseline.

Ischemic Cardiovascular Events

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

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

Bone Mineral Density Findings

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

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

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

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

Cholesterol

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

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

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

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

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

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

Other Adverse Reactions

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

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

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

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



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

Results are consistent with the previous analyses. Serious adverse reactions were similar between anastrozole tablets (50%) and tamoxifen (51%).

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

First-Line Therapy
Adverse reactions occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 3.

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

Body system Adverse Reaction* Number (%) of subjects
Anastrozole Tablets (N=506) Tamoxifen (N=511)
Whole body
Asthenia 83 (16) 81 (16)
Pain 70 (14) 73 (14)
Back pain 60 (12) 68 (13)
Headache 47 (9) 40 (8)
Abdominal pain 40 (8) 38 (7)
Chest pain 37 (7) 37 (7)
Flu syndrome 35 (7) 30 (6)
Pelvic pain 23 (5) 30 (6)
Cardiovascular
Vasodilation 128 (25) 106 (21)
Hypertension 25 (5) 36 (7)
Digestive
Nausea 94 (19) 106 (21)
Constipation 47 (9) 66 (13)
Diarrhea 40 (8) 33 (6)
Vomiting 38 (8) 36 (7)
Anorexia 26 (5) 46 (9)
Metabolic and Nutritional
Peripheral edema 51 (10) 41 (8)
Musculoskeletal
Bone pain 54 (11) 52 (10)
Nervous
Dizziness 30 (6) 22 (4)
Insomnia 30 (6) 38 (7)
Depression 23 (5) 32 (6)
Hypertonia 16 (3) 26 (5)
Respiratory
Cough increased 55 (11) 52 (10)
Dyspnea 51 (10) 47 (9)
Pharyngitis 49 (10) 68 (13)
Skin and appendages
Rash 38 (8) 34 (8)
Urogenital
Leukorrhea 9 (2) 31 (6)

*A patient may have had more than 1 adverse event.


Less frequent adverse experiences reported in patients receiving anastrozole tablets l mg in either Trial 0030 or Trial 0027 were similar to those reported for second-line therapy.

Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 pre-specified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups.
Table 4- Number of Patients with Pre-specified Adverse Reactions in Trials 0030 and 0027

Number (n) and Percentage of Patients
Adverse Reaction* Anastrozole 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)

*A patient may have had more than 1 adverse reaction. †Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis. ‡Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct.

Second-Line Therapy

Anastrozole tablets were tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the anastrozole tablets-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse reaction. The principal adverse reaction more common with anastrozole tablets than megestrol acetate was diarrhea. Adverse reactions reported in greater than 5% of the patients in any of the treatment groups in these two controlled clinical trials, regardless of causality, are presented below:

Table 5 – Number (n) and Percentage of Patients with Adverse Reactions in Trials 0004 and 0005

Adverse Reaction* 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)

*A patient may have had more than one adverse reaction.Other less frequent (2% to 5%) adverse reactions reported in patients receiving anastrozole tablets l mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality.

Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection
Cardiovascular: Hypertension; thrombophlebitis
Hepatic: Gamma GT increased; SGOT increased; SGPT increased
Hematologic: Anemia; leukopenia
Metabolic and Nutritional: Alkaline phosphatase increased; weight loss Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving anastrozole tablets. Increases in LDL cholesterol have been shown to contribute to these changes.
Musculoskeletal: Myalgia; arthralgia; pathological fracture
Nervous: Somnolence; confusion; insomnia; anxiety; nervousness
Respiratory: Sinusitis; bronchitis; rhinitis
Skin and Appendages: Hair thinning (alopecia); pruritusUrogenital: Urinary tract infection; breast pain The incidences of the following adverse event 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 flashes, and vaginal dryness. These six groups, and the adverse reactions captured in the groups, were prospectively defined. The results are shown in the table below.

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

Anastrozole Tablets 1 mg Anastrozole Tablets 10 mg Megestrol Acetate 160 mg
(N=262) (N=246) (N=253)
Adverse Reaction Group n (%) n (%) n (%)
GastrointestinalDisturbance 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)

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