Drug: Arimidex

ARIMIDEX (anastrozole) tablets for oral administration contain 1 mg of anastrozole, 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 C17H19N5 and its structural formula is: Anastrozole is an off-white powder with a molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile. Each tablet contains as inactive ingredients: lactose, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide.

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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. Clinical Trials Experience Adjuvant Therapy Adverse reaction data for adjuvant therapy are based on the ATAC trial [see Clinical Studies]. 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. 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* ARIMIDEX 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) * 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*
  ARIMIDEX
N=3092 (%) Tamoxifen
N=3094 (%) Odds-ratio 95% CI Hot Flashes 1104 (36) 1264 (41) 0.80 0.73 -0.89 Musculoskeletal Events'1 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 * 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% 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 (ARIMIDEX 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 (ARIMIDEX+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 Results are consistent with the previous analyses. Serious adverse reactions were similar between ARIMIDEX (50%) and tamoxifen (51%).
  • Cardiovascular events were consistent with the known safety profiles of ARIMIDEX and tamoxifen.
  • The cumulative incidences of all first fractures (both serious and non-serious, occurring either during or after treatment) was higher in the ARIMIDEX 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 ARIMIDEX 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 ARIMIDEX 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 ARIMIDEX 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 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) * A patient may have had more than 1 adverse event. Less frequent adverse experiences reported in patients receiving ARIMIDEX 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
Adverse Reaction* Number (n) and Percentage of Patients 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† 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 ARIMIDEX was tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the ARIMIDEX-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: Table 5 :Number (N) and Percentage of Patients with Adverse Reactions in Trials 0004 and 0005
Adverse Reaction* ARIMIDEX 1 mg
(N=262) ARIMIDEX 10 mg
(N=246) Megestrol Acetate 160 mg
(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 ARIMIDEX 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 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. Table 6 : Number (n) and Percentage of Patients with Pre-specified Adverse Reactions in Trials 0004 and 0005
Adverse Reaction Group ARIMIDEX1 mg
(N=262) ARIMIDEX10 mg
(N=246) Megestrol Acetate160 mg
(N=253) 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) 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 [see CONTRAINDICATIONS]
  • Myalgia, trigger finger and hypercalcemia (with or without an increase in parathyroid hormone)
Read the Arimidex (anastrozole) Side Effects Center for a complete guide to possible side effectsLearn More »

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Recommended Dose The dose of ARIMIDEX is one 1 mg tablet taken once a day. For patients with advanced breast cancer, ARIMIDEX should be continued until tumor progression. ARIMIDEX 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 [see Clinical Studies]. No dosage adjustment is necessary for patients with renal impairment or for elderly patients [see Use In Specific Populations]. 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 [see Use in Specific Populations].

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Tamoxifen Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the co-administration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of 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 [see Clinical Studies]. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole. Estrogen Estrogen-containing therapies should not be used with ARIMIDEX as they may diminish its pharmacological action. Warfarin In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by C max and AUC) and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R-and S-warfarin. 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 [see CLINICAL PHARMACOLOGY]. Read the Arimidex Drug Interactions Center for a complete guide to possible interactions Learn More »

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Adjuvant Treatment ARIMIDEX is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. First-Line Treatment ARIMIDEX is 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 ARIMIDEX is 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.

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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 [see Use in Specific Populations]. 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 [see ADVERSE REACTIONS] Last reviewed on RxList: 5/23/2014
This monograph has been modified to include the generic and brand name in many instances.

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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.

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Dosage Forms And Strengths The tablets are white, biconvex, film-coated containing 1 mg of anastrozole. The tablets are impressed on one side with a logo consisting of a letter “A” (upper case) with an arrowhead attached to the foot of the extended right leg of the “A” and on the reverse with the tablet strength marking “Adx 1”. Storage And Handling These tablets are supplied in bottles of 30 tablets (NDC 0310-0201-30). Storage Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850. Revised: May 2014 Last reviewed on RxList: 5/23/2014
This monograph has been modified to include the generic and brand name in many instances.

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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 [see ADVERSE REACTIONS] 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 (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 ARIMIDEX [see ADVERSE REACTIONS]. 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) [see ADVERSE REACTIONS]. Patient Counseling Information See FDA approved patient labeling (PATIENT INFORMATION). 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 and immediately contact their doctor. Allergic (Hypersensitivity) Reactions Patients should be informed of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to seek medical attention immediately. 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. 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. Cholesterol Patients should be informed that an increased level of cholesterol might be seen while receiving ARIMIDEX. Tickling, Tingling or Numbness Patients should be informed that if they experience tickling, tingling, or numbness they should notify their health care provider. Tamoxifen Patients should be advised not to take ARIMIDEX with Tamoxifen. 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/m² basis) 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 AUC0-24 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/m² 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 anastrozole 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/m² basis and 9 times higher than the AUC0-24 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/m² 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 anastrozole for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax 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 anastrozole Cssmax and AUC0-24 hr that were 22 times and 16 times higher than the respective values found in postmenopausal women at the recommended dose). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in premenopausal women. Use In Specific Populations Pregnancy Pregnancy Category X [see CONTRAINDICATIONS] 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, anastrozole 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 anastrozole during organogenesis at doses equal to or greater than 1 (rats) and 1/3 (rabbits) the recommended human dose on a mg/m² basis. In both species, anastrozole 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 anastrozole 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, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m² basis [see Animal Toxicology and/or Pharmacology]. Nursing Mothers It is not known if anastrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 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 (primary efficacy analysis). 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 ARIMIDEX-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 cm³ in the ARIMIDEX-treated patients and + 5.2 ± 8.0 cm³ 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 anastrozole concentration was 1 hr. The mean (range) disposition parameters of anastrozole in pediatric patients were described by a CL/F of 1.54 L/h (0.77-4.53 L/h) and V/F of 98.4 L (50.7-330.0 L). The terminal elimination half-life was 46.8 h, which was similar to that observed in postmenopausal women treated with anastrozole for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetics of anastrozole was similar in boys with pubertal gynecomastia and girls with McCune-Albright Syndrome. 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 anastrozole are not affected by age. Renal Impairment Since only about 10% of anastrozole is excreted unchanged in the urine, the renal impairment does not influence the total body clearance. Dosage adjustment in patients with renal impairment is not necessary [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Hepatic Impairment The plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Therefore, dosage adjustment is also not necessary in patients with stable hepatic cirrhosis. ARIMIDEX has not been studied in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 5/23/2014
This monograph has been modified to include the generic and brand name in many instances.

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