Adjuvant Treatment
Anastrozole tablets are indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.
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.
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.
Anastrozole Dosage and Administration
Recommended Dose
The dose of Anastrozole is one 1 mg tablet taken once a day. For patients with advanced breast cancer, Anastrozole should be continued until tumor progression. Anastrozole 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)]
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)]
Dosage Forms and Strengths
Anastrozole tablets 1 mg are white, round, convex, film-coated, debossed SZ on one side and 171 on the reverse side.
Contraindications
Pregnancy and Premenopausal Women
Anastrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Anastrozole is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies in pregnant women using Anastrozole. If Anastrozole 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. [see USE IN SPECIFIC POPULATIONS (8.1)]
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)]
Warnings and Precautions
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)]
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 [see ADVERSE REACTIONS (6.1)].
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)].
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, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, pain, 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.
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.
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Body system and adverse reactions by COSTART† preferred term | Anastrozole 1 mg (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) |
N=Number of patients receiving the treatment.
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).
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Anastrozole N=3092 (%) | Tamoxifen N=3094 (%) | Odds-ratio | 95% CI | |
| Hot Flashes | 1104 (36) | 1264 (41) | 0.80 | 0.73 − 0.89 |
| Musculoskeletal Events† | 1100 (36) | 911 (29) | 1.32 | 1.19 − 1.47 |
| Fatigue/Asthenia | 575 (19) | 544 (18) | 1.07 | 0.94 − 1.22 |
| Mood Disturbances | 597 (19) | 554 (18) | 1.10 | 0.97 − 1.25 |
| Nausea and Vomiting | 393 (13) | 384 (12) | 1.03 | 0.88 − 1.19 |
| All Fractures | 315 (10) | 209 (7) | 1.57 | 1.30 − 1.88 |
| Fractures of Spine, Hip, or Wrist | 133 (4) | 91 (3) | 1.48 | 1.13 − 1.95 |
| Wrist/Colles’ fractures | 67 (2) | 50 (2) | ||
| Spine fractures | 43 (1) | 22 (1) | ||
| Hip fractures | 28 (1) | 26 (1) | ||
| Cataracts | 182 (6) | 213 (7) | 0.85 | 0.69 − 1.04 |
| Vaginal Bleeding | 167 (5) | 317 (10) | 0.50 | 0.41 − 0.61 |
| Ischemic Cardiovascular Disease | 127 (4) | 104 (3) | 1.23 | 0.95 − 1.60 |
| Vaginal Discharge | 109 (4) | 408 (13) | 0.24 | 0.19 − 0.30 |
| Venous Thromboembolic events | 87 (3) | 140 (5) | 0.61 | 0.47 − 0.80 |
| Deep Venous Thromboembolic Events | 48 (2) | 74 (2) | 0.64 | 0.45 − 0.93 |
| Ischemic Cerebrovascular Event | 62 (2) | 88 (3) | 0.70 | 0.50 − 0.97 |
| Endometrial Cancer‡ | 4 (0.2) | 13 (0.6) | 0.31 | 0.10 − 0.94 |
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.
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.
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Body system Adverse Reaction* | Number (%) of subjects | |
Anastrozole (n=506) | Tamoxifen (n=511) | |
| Whole body | ||
| Asthenia | 83 (16) | 81 (16) |
| Pain | 70 (14) | 73 (14) |
| Back pain | 60 (12) | 68 (13) |
| Headache | 47 (9) | 40 (8) |
| Abdominal pain | 40 (8) | 38 (7) |
| Chest pain | 37 (7) | 37 (7) |
| Flu syndrome | 35 (7) | 30 (6) |
| Pelvic pain | 23 (5) | 30 (6) |
| Cardiovascular | ||
| Vasodilation | 128 (25) | 106 (21) |
| Hypertension | 25 (5) | 36 (7) |
| Digestive | ||
| Nausea | 94 (19) | 106 (21) |
| Constipation | 47 (9) | 66 (13) |
| Diarrhea | 40 (8) | 33 (6) |
| Vomiting | 38 (8) | 36 (7) |
| Anorexia | 26 (5) | 46 (9) |
| Metabolic and Nutritional | ||
| Peripheral edema | 51 (10) | 41 (8) |
| Muscoloskeletal | ||
| Bone pain | 54 (11) | 52 (10) |
| Nervous | ||
| Dizziness | 30 (6) | 22 (4) |
| Insomnia | 30 (6) | 38 (7) |
| Depression | 23 (5) | 32 (6) |
| Hypertonia | 16 (3) | 26 (5) |
| Respiratory | ||
| Cough increased | 55 (11) | 52 (10) |
| Dyspnea | 51 (10) | 47 (9) |
| Pharyngitis | 49 (10) | 68 (13) |
| Skin and appendages | ||
| Rash | 38 (8) | 34 (8) |
| Urogenital | ||
| Leukorrhea | 9 (2) | 31 (6) |
Less frequent adverse experiences reported in patients receiving Anastrozole 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.
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| Number (n) and Percentage of Patients | ||
Adverse Reaction* | Anastrozole 1 mg (n=506) n (%) | NOLVADEX20 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) |
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