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Uses

Breast Cancer

Reduction in the Incidence of Breast Cancer in Women at High Risk

Randomized trials are under way to investigate the use of aromatase inhibitors, such as anastrozole, for reduction in the incidence of breast cancer among women who are at high risk for developing the disease.

Initial or Sequential Adjuvant Therapy for Early-stage Breast Cancer

Anastrozole is used alone as initial (primary) adjuvant therapy in postmenopausal women with early-stage hormone receptor-positive breast cancer. Anastrozole also is used as sequential adjuvant therapy following 2-3 years of adjuvant tamoxifen for early-stage hormone receptor-positive breast cancer in postmenopausal women. Aromatase inhibitors, including anastrozole, currently are considered a treatment of choice for adjuvant hormonal therapy to lower the risk of breast cancer recurrence in postmenopausal women with early-stage hormone receptor-positive breast cancer. Although tamoxifen historically has been the drug of choice for adjuvant hormonal therapy in such patients, results of large, randomized clinical studies indicate that an aromatase inhibitor-containing regimen is modestly more effective than tamoxifen alone. Longer-term follow-up of these studies is needed to further clarify lasting clinical efficacy, effects on survival, and late adverse effects of aromatase inhibitor therapy.

Clinical Trials of Anastrozole as Initial Adjuvant Therapy

In a double-blind, multicenter trial (the Arimidex, Tamoxifen, Alone or in Combination [ATAC] trial), 9366 postmenopausal women with operable breast cancer were randomized to receive anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of anastrozole 1 mg daily and tamoxifen 20 mg daily, as adjuvant therapy for 5 years or until recurrence of disease. About 84% of the patients in each group had hormone receptor-positive (i.e., estrogen receptor-positive, progesterone receptor-positive, or both) breast tumors. The primary end point of the trial was disease-free survival, which was defined as time to occurrence of any of the following events: distant or local recurrence, a contralateral primary breast tumor, or death from any cause.

Analysis of the data at a median follow-up of 68 months when patients had received treatment for a median of 60 months showed that disease-free survival was prolonged in patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio of 0.87 with a 95% confidence interval of 0.78-0.97). The frequency of events observed in patients receiving anastrozole versus tamoxifen was locoregional recurrence in 3.8 versus 4.8%, contralateral breast cancer in 1.1 versus 1.9%, and distant recurrence in 10.4 versus 12% of patients. No difference was observed between the groups for the secondary endpoints of distant disease-free survival and overall survival. Subgroup analysis confirmed that disease-free survival was prolonged with anastrozole versus tamoxifen therapy for patients with hormone receptor-positive tumors, but benefit was less clear in patients who had received previous adjuvant therapy or patients who were 65 years of age or older.

Analysis of the data (both overall and for the subset of patients with hormone receptor-positive tumors) at a median follow-up of 10 years (120 months) showed that the benefit of prolonged disease-free survival was maintained in patients receiving anastrozole, but there was no difference in overall survival between the groups; time to recurrence, time to distant recurrence, and incidence of contralateral breast cancer also were improved in patients receiving anastrozole compared with those receiving tamoxifen. The greatest differences between anastrozole and tamoxifen in time to recurrence, rate of contralateral breast cancer, and disease-free survival were observed during the first 2 years of treatment; between-treatment differences in distant recurrence rates remained similar over 10 years of follow-up. Although recurrence rates for the anastrozole and tamoxifen treatment groups remained different throughout 10 years of follow-up, analyses conducted using data for patients with hormone receptor-positive tumors suggested that the difference between treatments might diminish after 8 years of follow-up. Assessment of quality of life during 5 years of treatment did not show any difference between the anastrozole and tamoxifen groups.

At a median follow-up of 33 months, combination therapy with anastrozole and tamoxifen was not associated with an improvement in disease-free survival compared with tamoxifen alone, and this treatment arm was discontinued.

In the ATAC trial, anastrozole was associated with a higher incidence of joint disorders (including arthritis, arthrosis, and arthralgia), fractures (including fractures of the spine, hip, and wrist), and elevations in serum cholesterol compared with tamoxifen. Postmenopausal women receiving aromatase inhibitors, such as anastrozole, as adjuvant therapy are at high risk for osteoporosis. (See Precautions and Contraindications and Musculoskeletal Effects sections in Cautions for further information on screening and treatment guidelines for osteoporosis in such patients.) Anastrozole was associated with a lower incidence of endometrial cancer, ischemic cerebrovascular events, venous thromboembolic events (including deep venous thrombosis), vaginal discharge, vaginal bleeding, and hot flushes compared with tamoxifen.

Clinical Trials of Anastrozole as Sequential Adjuvant Therapy

In a randomized trial involving 448 postmenopausal women with node-positive, estrogen receptor-positive breast cancer (Italian Tamoxifen Anastrozole [ITA] trial), patients who had received 2-3 years of adjuvant tamoxifen therapy were randomized to receive anastrozole or to continue receiving tamoxifen to complete a total of 5 years of adjuvant therapy. At a median follow-up of 36 months following randomization, those receiving tamoxifen followed by anastrozole had longer event-free survival and disease-free survival but similar overall survival as those receiving 5 years of tamoxifen therapy. Improvements in recurrence-free survival and event-free survival associated with anastrozole therapy were maintained at a median follow-up of 64 months; overall survival was not significantly different between treatment groups.

Analysis of combined data from 2 randomized trials involving a total of 3224 postmenopausal women with hormone-sensitive early-stage breast cancer who had received 2 years of adjuvant therapy with tamoxifen (Austrian Breast and Colorectal Cancer Study Group trial 8 [ABCSG-8] and Arimidex-Nolvadex [ARNO] 95 trial) showed that those receiving anastrozole for the remaining 3 years of adjuvant therapy had a higher rate of event-free survival (96%) compared with those receiving tamoxifen for the entire 5-year period (93%); at the completion of 5 years of endocrine therapy, overall survival did not differ between the groups. Analysis of data from ABCSG-8 alone showed a low overall rate of breast cancer recurrence and a high overall survival rate among patients enrolled in this study (reflecting inclusion in the study of women at low to moderate risk of recurrence) and no significant difference in recurrence-free survival between the 2 adjuvant regimens at a median follow-up of 5 years after initiation of adjuvant endocrine therapy. Analysis of data from the ARNO 95 trial at a median follow-up of 30 months, when patients who previously had received tamoxifen for 2 years had received randomized treatment with anastrozole or tamoxifen for a median of about 27 months, indicated that patients who were switched to anastrozole had prolonged disease-free and overall survival compared with those who continued receiving tamoxifen.

Analysis of pooled data for individual patients from these 3 randomized trials, conducted at a median follow-up of 30 months, suggested that disease-free survival, event-free survival, distant recurrence-free survival, and overall survival are longer in patients who switch to anastrozole following 2-3 years of tamoxifen than in those who remain on tamoxifen for the 5-year duration of adjuvant therapy for hormone receptor-positive early-stage breast cancer.

Clinical Role

Based on data from randomized controlled trials demonstrating prolonged disease-free survival in patients receiving anastrozole- or other aromatase inhibitor-based adjuvant regimens, the American Society of Clinical Oncology (ASCO) states that most postmenopausal women with early-stage hormone receptor-positive breast cancer should consider receiving an aromatase inhibitor (e.g., anastrozole) during the course of adjuvant therapy, either as primary (initial) therapy or following 2-3 years of tamoxifen therapy (sequential therapy), to complete a total of 5 years of adjuvant endocrine therapy. Clinically meaningful differences among the currently available aromatase inhibitors (i.e., anastrozole, exemestane, letrozole) have not been demonstrated to date. Data also support switching to an aromatase inhibitor following 5 years of adjuvant tamoxifen therapy (extended therapy) (see Extended Adjuvant Therapy for Early-stage Breast Cancer under Uses: Breast Cancer). The optimal time for switching from tamoxifen to an aromatase inhibitor is not known. The duration of aromatase inhibitor therapy should not exceed 5 years, since toxicity of long-term (e.g., beyond 5 years) use of aromatase inhibitors, including anastrozole, has not been determined. The optimal duration of adjuvant anastrozole therapy is not known. ASCO states that clinicians should consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen; during the course of adjuvant therapy, patients who are intolerant of one aromatase inhibitor may be switched to a different aromatase inhibitor or to tamoxifen.

The use of a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin) in combination with an aromatase inhibitor, such as anastrozole, as adjuvant therapy in premenopausal women with hormone receptor-positive breast cancer is being investigated in large randomized trials. The use of an aromatase inhibitor as a single agent for adjuvant therapy is not appropriate in premenopausal women with breast cancer because these agents alone are not likely to provide sufficient suppression of ovarian function to be of clinical benefit. Similarly, the use of an aromatase inhibitor as monotherapy for adjuvant therapy for hormone receptor-positive breast cancer in premenopausal women experiencing a chemotherapy-induced disruption in ovarian function is not advised; a substantial number of such patients can expect resumption of ovarian function, and this would likely render therapy with an aromatase inhibitor ineffective.

Extended Adjuvant Therapy for Early-stage Breast Cancer

Based on data from randomized controlled trials demonstrating prolonged disease-free survival in patients receiving aromatase inhibitors, including anastrozole, as extended adjuvant therapy following 5 years of adjuvant tamoxifen therapy, ASCO recommends extended therapy with an aromatase inhibitor (e.g., anastrozole) in postmenopausal women with early-stage hormone receptor-positive breast cancer who complete 5 years of adjuvant tamoxifen therapy. Clinically meaningful differences among the currently available aromatase inhibitors (i.e., anastrozole, exemestane, letrozole) have not been demonstrated to date. Clinicians should consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen. ASCO states that women who receive extended adjuvant therapy should receive a total of 8-10 years of adjuvant endocrine therapy, including 5 years of tamoxifen therapy followed by 3-5 years of aromatase inhibitor therapy. The optimal duration of extended adjuvant therapy is not known, and the toxicity of long-term (e.g., beyond 5 years) use of aromatase inhibitors in this setting has not been determined. Ongoing clinical trials are evaluating whether longer durations of aromatase inhibitor therapy are more effective.

Anastrozole is used as extended adjuvant therapy following adjuvant tamoxifen for hormone receptor-positive early-stage breast cancer in postmenopausal women. In a randomized trial involving 856 postmenopausal women with hormone receptor-positive early-stage breast cancer who remained free of disease after completing 5 years of adjuvant therapy with tamoxifen (47% of whom had also received the aromatase inhibitor aminoglutethimide for the first 2 years of therapy), those receiving 3 years of extended adjuvant therapy with anastrozole had reduced risk of disease recurrence and similar overall survival compared with those who received no further treatment.

First-line Therapy for Advanced Breast Cancer

Anastrozole is used for the first-line treatment of hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women. Data from 2 double-blind, randomized clinical trials indicate that anastrozole is at least as effective as tamoxifen for producing objective tumor response and delaying tumor progression in such patients. In the 2 studies, a total of 1021 patients (age range: 30-92 years) were randomized to receive anastrozole 1 mg once daily or tamoxifen 20 mg once daily for hormone receptor-positive (i.e., estrogen receptor-positive, progesterone receptor-positive, or both) breast tumors or hormone receptor-unknown breast tumors.

Results from trial 0030, a North American study involving 353 patients (about 90% with hormone receptor-positive breast tumors and 10% with hormone receptor-unknown breast tumors), showed a similar objective response rate (about 21 and 17%, respectively) and an increased median time to progression (11.1 versus 5.6 months, respectively) for patients receiving anastrozole compared with those receiving tamoxifen at a median follow-up of about 18 months. In trial 0027, a predominately European study involving 668 patients (about 45% with hormone receptor-positive breast tumors and 55% with hormone receptor-unknown breast tumors), a similar objective response rate (about 33% in both groups) and median time to progression (about 8 months in both groups) were reported at a median follow-up of 19 months in patients receiving anastrozole or tamoxifen.

Conclusions concerning differences in overall survival between the 2 treatments could not be made because of the low number of deaths occurring across treatment groups in either study at the time of data analysis. A later analysis of combined patient data for the 2 studies at a median of 43.7 months of follow-up showed no difference in survival between the treatment groups (death rate: 56%); analysis of pooled data from published studies for first-line, second-line, or subsequent therapy of advanced breast cancer that included these 2 studies suggests that treatment with third-generation aromatase inhibitors, such as anastrozole, as first-line therapy for advanced breast cancer offers a small survival advantage (about 11%) compared with standard hormonal therapy, such as tamoxifen. Analysis of combined data for the 2 studies shows that adverse effects occurred at a similar frequency in patients receiving anastrozole or tamoxifen.

Second-line Therapy for Advanced Breast Cancer

Anastrozole is used for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. The principal goal of therapy in patients with metastatic breast cancer generally has been palliative with an emphasis on extension of survival and improvement in the quality of life. Data from 2 comparative clinical trials suggest that anastrozole is at least as effective as megestrol acetate in postmenopausal women with advanced breast cancer who have had disease progression following tamoxifen therapy for either advanced or early breast cancer. Patients who have estrogen receptor-negative breast cancer and those who fail to respond to tamoxifen therapy rarely have responded to anastrozole.

In 2 well-controlled clinical trials, a total of 764 postmenopausal women with advanced breast cancer which progressed following tamoxifen therapy (for either advanced or early breast cancer) were randomized to receive anastrozole 1 mg or 10 mg daily, or megestrol acetate 40 mg 4 times daily. Most of the patients enrolled had ER-positive tumors; patients with ER-negative disease were eligible only if they previously had responded to tamoxifen (about 5% of the patients in each trial). Some patients also had received previous cytotoxic therapy. The primary efficacy variables were time to progression and objective response rate, and similar results were observed among treatment groups and between the 2 trials.

In trial 0004, a North American study involving 386 patients (about 80% with hormone receptor-positive breast tumors), a median time to progression of 5.7, 5.3, and 5.1 months, respectively, and an objective response rate of 12.5, 10, and 10.2%, respectively, were reported in patients receiving anastrozole 1 mg daily, anastrozole 10 mg daily, and megestrol acetate 40 mg 4 times daily. In trial 0005, a predominately European study involving 378 patients (about 60% with hormone receptor-positive breast tumors), a median time to progression of 4.4, 5.3, and 3.9 months, respectively, and an objective response rate of 12.6, 15.3, and 14.4%, respectively, were reported in patients receiving anastrozole 1 mg daily, anastrozole 10 mg daily, and megestrol acetate 40 mg 4 times daily.

Pooled analysis of data from the 2 trials showed a median time to progression of 4.8, 5.3, and 4.6 months, respectively, and an objective response rate of 12.5, 12.5, and 12.3%, respectively, in patients receiving anastrozole 1 mg daily, anastrozole 10 mg daily, and megestrol acetate 40 mg 4 times daily. Similar efficacy was observed for patients receiving anastrozole 1 mg and megestrol acetate, and there was no evidence of superior efficacy of the 10-mg daily dose of anastrozole compared with the 1-mg daily dose. Analysis of pooled data from published studies for first-line, second-line, or subsequent therapy of advanced breast cancer that included these 2 studies suggests that treatment with third-generation aromatase inhibitors, such as anastrozole, as second-line or subsequent therapy for advanced breast cancer offers a small survival advantage (about 14%) compared with standard hormonal therapy, such as megestrol acetate. Weight gain was reported less frequently with anastrozole (1 mg daily) than with megestrol acetate (40 mg 4 times daily) in these clinical trials.

Anastrozole is used as second-line hormonal therapy in postmenopausal women with estrogen receptor-positive or estrogen receptor-unknown advanced breast cancer. In premenopausal women with hormone receptor-positive advanced breast cancer, ovarian ablation by surgery or external-beam radiation, or suppression of ovarian function with an LHRH agonist, is advised; the use of an LHRH agonist (e.g., goserelin) in combination with an aromatase inhibitor, such as anastrozole, is being investigated. The use of an aromatase inhibitor as single-agent therapy is not appropriate in premenopausal women with breast cancer because these agents alone are not likely to provide sufficient suppression of ovarian function to be of clinical benefit.

Dosage and Administration

Administration

Anastrozole is administered orally.

Food does not affect the absorption of anastrozole, and the drug may be administered without regard to meals.

Dosage

Unlike aminoglutethimide, a less selective aromatase inhibitor, anastrozole is highly selective for suppression of estrogen synthesis, and concomitant corticosteroid replacement therapy is not required.

Because no evidence of altered pharmacokinetics has been observed in women older than 80 years of age compared with women younger than 50 years of age, the manufacturer states that adjustment of anastrozole dosage is not necessary in geriatric patients.

Breast Cancer

Adjuvant Therapy for Early-stage Breast Cancer

For adjuvant therapy in the treatment of early-stage, hormone receptor-positive breast cancer in postmenopausal women, the recommended dosage of anastrozole is 1 mg daily. The optimal duration of therapy is unknown. In a large, randomized clinical trial (the ATAC trial), the duration of anastrozole therapy was 5 years. Because adherence to adjuvant anastrozole therapy may decrease during the first year of therapy and further diminish over time, communication with the patient and interventions to improve compliance should be considered.

The American Society of Clinical Oncology (ASCO) states that an aromatase inhibitor (e.g., anastrozole) may be administered to postmenopausal women with early-stage, hormone receptor-positive breast cancer as initial adjuvant therapy and continued for a total of 5 years or may be administered following initial tamoxifen therapy as part of a sequential adjuvant regimen. The optimal time to switch from tamoxifen to aromatase inhibitor therapy is not known; however, based on clinical trials conducted to date, ASCO recommends that patients who are disease-free may be switched to an aromatase inhibitor after 2-3 years of tamoxifen therapy to complete a 5-year sequential adjuvant regimen. In patients who initially receive an aromatase inhibitor but discontinue therapy prior to 5 years, ASCO states that consideration should be given to administering tamoxifen to complete the 5-year adjuvant regimen. ASCO recommends that patients who receive an extended adjuvant regimen receive an aromatase inhibitor (e.g., anastrozole) for 3-5 years beyond the initial 5 years of tamoxifen therapy, to complete a total of 8-10 years of adjuvant endocrine therapy.

First-line Therapy for Advanced Breast Cancer

For the first-line treatment of hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women, the recommended dosage of anastrozole is 1 mg daily. Anastrozole therapy should be continued until tumor progression is evident.

Second-line Therapy for Advanced Breast Cancer

For the second-line treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy, the recommended dosage of anastrozole is 1 mg daily. Anastrozole therapy should be continued until tumor progression is evident.

Dosage in Renal and Hepatic Impairment

Reduction in renal clearance does not affect total body clearance of anastrozole since only about 10% of the drug is excreted unchanged in urine. Therefore, adjustment of anastrozole dosage is not required in patients with renal impairment.

The manufacturer states that no dosage adjustment is required in patients with mild to moderate hepatic impairment or stable hepatic cirrhosis. Anastrozole has not been studied in patients with severe hepatic impairment.

Cautions

The incidence of adverse effects is based on data from randomized trials of postmenopausal women receiving anastrozole 1 mg daily for breast cancer as initial adjuvant therapy (3092 patients, median duration of treatment: 60 months), as first-line therapy (506 patients), or as second-line therapy (262 patients). Unless the type of therapy (based on stage of breast cancer) is specified, incidence rates reflect the experience of all these patients receiving the drug. Unless otherwise noted, these adverse effects occurred at a similar rate in patients receiving treatments being compared with anastrozole (i.e., tamoxifen as adjuvant therapy for early breast cancer or as initial treatment for advanced breast cancer, and megestrol acetate as second-line therapy for advanced breast cancer).

In the ATAC trial in patients with early-stage breast cancer, the most frequent adverse effects of anastrozole were hot flushes (flashes), asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema, and lymphedema. The most common adverse effect resulting in discontinuance of either anastrozole or tamoxifen in this trial was hot flushes, although fewer patients discontinued therapy because of hot flushes in the anastrozole group. Serious treatment-related adverse events were reported less frequently during treatment in patients receiving anastrozole compared with those receiving tamoxifen, but occurred at similar rates during posttreatment follow-up. At a median follow-up of 10 years, safety results for the ATAC trial were similar to results reported during earlier analyses. The total number of deaths occurring during or following treatment was similar in the 2 treatment groups, although more deaths were related to breast cancer in the tamoxifen group than in the anastrozole group.

In patients with advanced breast cancer, the most frequent adverse effects of anastrozole are hot flushes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis, and peripheral edema. Anastrozole generally was well tolerated in patients with advanced breast cancer receiving the drug as second-line therapy in clinical trials; less than 3.3% of patients (compared with 4% for patients receiving megestrol acetate) withdrew from the clinical trials because of adverse effects. Less common adverse effects (i.e., those reported in 2-5% of patients) that occurred in patients receiving anastrozole as second-line therapy were similar to those observed in patients receiving the drug as first-line therapy in clinical trials.

Cardiovascular Effects

Thromboembolic Events and Ischemic Disease

Among patients receiving adjuvant therapy, venous thromboembolic events occurred less frequently in patients receiving anastrozole than in those receiving tamoxifen (3 versus 5%); this included deep venous thrombosis (2% of patients in each treatment group). Ischemic cerebrovascular events also occurred less frequently in patients receiving anastrozole compared with those receiving tamoxifen (2 versus 3%). Ischemic cardiovascular events were reported in similar proportions of patients receiving anastrozole or tamoxifen (4 versus 3%). Angina pectoris or myocardial infarction was reported in 2.3 or 1.2%, respectively, of those receiving adjuvant therapy with anastrozole compared with 1.6 or 1.1%, respectively, of those receiving tamoxifen. In the subset of patients with preexisting ischemic heart disease, ischemic cardiovascular events were reported in 17% of patients receiving anastrozole compared with 10% of those receiving tamoxifen; angina pectoris or myocardial infarction was reported in 11.6 or 0.9%, respectively of those receiving anastrozole compared with 5.2 or 3.2%, respectively, of those receiving tamoxifen. At a median follow-up of 10 years (median adjuvant treatment duration of 5 years), cardiovascular events in patients receiving adjuvant anastrozole or tamoxifen therapy were consistent with the known safety profiles of the drugs.

Among patients receiving anastrozole as first-line therapy, thromboembolic disease was reported in 18 patients (4%), with 5 patients experiencing venous thrombosis (including pulmonary embolus, thrombophlebitis, and retinal vein thrombosis) and 13 patients experiencing coronary and/or cerebral thrombosis (including myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia, and cerebral infarct).

Among patients receiving anastrozole as second-line therapy, thromboembolic disease was reported in 3%, and thrombophlebitis occurred in 2-5%.

Vasomotor Symptoms

Among patients receiving adjuvant therapy, hot flushes (flashes) occurred less frequently in patients receiving anastrozole than in those receiving tamoxifen (36 versus 41%). Among patients receiving anastrozole as first-line or second-line therapy, hot flushes occurred in 26 or 13%, respectively.

Effects on Lipoproteins

Among patients receiving adjuvant therapy in the ATAC trial, increased serum cholesterol concentrations were reported more frequently in patients receiving anastrozole compared with those receiving tamoxifen (9 versus 3.5%). However, in another clinical trial, no clinically important changes in concentrations of total, high-density lipoprotein (HDL)-, or low-density lipoprotein (LDL)-cholesterol or concentrations of triglycerides were observed from baseline to 12 months in patients receiving anastrozole alone or in conjunction with risedronate.

Among patients receiving anastrozole as second-line therapy, mean total serum cholesterol concentrations increased by 19 mg/dL (0.5 mmol/L); increases in LDL cholesterol have been shown to contribute to these elevations.

Other Cardiovascular Effects

Vasodilation was reported in 36 or 25% of patients receiving anastrozole as adjuvant or first-line therapy, respectively. Hypertension occurred in 13% and lymphedema and peripheral edema each occurred in 10% of patients receiving anastrozole as adjuvant therapy. Among patients receiving anastrozole as first-line or second-line therapy, peripheral edema was reported in 10 or 5%, respectively, and hypertension was reported in about 5%. Edema occurred in 7% of patients receiving anastrozole as second-line therapy.

Genitourinary Effects

Among patients receiving adjuvant therapy, vaginal bleeding and vaginal discharge occurred less frequently in patients receiving anastrozole than in those receiving tamoxifen (5 versus 10% and 4 versus 13%, respectively). Endometrial cancer also was reported less frequently in patients receiving anastrozole than in those receiving tamoxifen (0.2 versus 0.6%).(Also see Cautions: Mutagenicity and Carcinogenicity.) Vulvovaginitis was reported in 6% of patients and vaginal hemorrhage (without further diagnosis) and vaginitis each were reported in 4% of patients receiving anastrozole as adjuvant therapy. In a subprotocol assessing quality of life during 5 years of treatment in the ATAC trial, analysis of gynecologic symptoms and sexual function showed that anastrozole was associated with less vaginal discharge but more vaginal dryness, pain on intercourse, and loss of sexual interest than tamoxifen; no difference in overall quality of life was detected between the groups. In another subprotocol assessing occurrence of endometrial disorders in a small subset of patients enrolled in the ATAC trial, endometrial abnormalities (mainly polyps) were reported after 6 years of follow-up in 12 or 20% of patients receiving anastrozole or tamoxifen, respectively; fewer patients receiving anastrozole appeared to require medical intervention for endometrial abnormalities (1.4 versus 9.8%). Most abnormalities occurred within the first year of treatment.

Among patients receiving anastrozole as first-line or second-line therapy, pelvic pain occurred in 5%, vaginal bleeding or hemorrhage occurred in 1 or 2%, respectively, and vaginal dryness was reported in 2%.

Breast pain and urinary tract infection each occurred in up to 8% of patients receiving anastrozole. Leukorrhea was reported in 3% of patients receiving anastrozole as adjuvant therapy and 2% of patients receiving the drug as first-line therapy.

Musculoskeletal Effects

Among patients receiving adjuvant therapy, adverse musculoskeletal effects (e.g., joint symptoms including joint disorder, arthritis, arthrosis, and arthralgia) and fractures occurred more frequently in patients receiving anastrozole than in those receiving tamoxifen (36 versus 29% and 10 versus 7%, respectively); this included fractures of the spine, hip, and wrist (4 versus 3%). Arthritis, arthralgia, and arthrosis occurred in 17, 15, and 7%, respectively, of patients receiving anastrozole as adjuvant therapy; osteoporosis, bone pain, and joint disorder were reported in 11, 7, and 6%, respectively. Myalgia occurred in 6% of patients receiving anastrozole as adjuvant therapy. In clinical trials, carpal tunnel syndrome occurred more frequently in patients receiving anastrozole than in those receiving tamoxifen (2.5 versus 0.7%).

A syndrome consisting of arthralgia and other symmetrical bone and joint symptoms (e.g., pain, stiffness, achiness) that are not associated with other manifestations of rheumatologic disorders has been reported in patients receiving aromatase inhibitors. Symptoms generally resolve within 8-10 weeks following discontinuance of therapy.

Because anastrozole lowers circulating estrogen concentrations, it may cause a reduction in bone mineral density (BMD). Analysis of data at 12 and 24 months from a substudy of the ATAC trial showed that whereas mean values for lumbar spine and total hip BMD (compared with baseline) decreased in patients receiving anastrozole, these values increased in those receiving tamoxifen. For patients receiving adjuvant therapy with anastrozole, the rate of bone loss at the lumbar spine slowed at 2-5 years compared with the change measured from baseline to 2 years, but the rate of bone loss at the hip did not slow over the 5-year period. Analysis of the data at 5 years indicated accelerated bone loss at the lumbar spine and the hip in patients receiving anastrozole, compared with a slight increase in BMD in the lumbar spine but not in the hip in patients receiving tamoxifen. Among women who had normal BMD at baseline, none developed osteoporosis after 5 years of anastrozole therapy, but osteopenia was more frequent in these patients than in those receiving tamoxifen (17 versus 3%).

Analysis of data from the ATAC study at a median follow-up of 10 years (median adjuvant treatment duration of 5 years) showed that the cumulative incidence of all first fractures (both serious and nonserious, occurring either during or after treatment) was higher in the anastrozole group compared with the tamoxifen group (15 versus 11%). Fractures were reported more frequently during treatment in patients receiving anastrozole compared with those receiving tamoxifen; however, after completion of treatment, the incidence of fractures was similar between groups.

Postmenopausal women receiving anastrozole as adjuvant therapy are at high risk for osteoporosis. All postmenopausal women initiating adjuvant therapy with an aromatase inhibitor should be evaluated for risk of osteoporotic fractures. Screening with dual energy radiographic absorptiometry (DXA) to determine the BMD of the hip and spine should be performed in conjunction with assessment of other risk factors for fracture (e.g., age, low body mass index, family history of hip fracture, prior fragility fracture, history of cigarette smoking, excessive alcohol consumption, current or prior corticosteroid use). Patients should be monitored closely for changes in risk status during therapy, and BMD should be assessed at regular intervals (e.g., every 1-2 years in those with osteopenia or osteoporosis). Other potential causes of osteoporosis (e.g., vitamin D deficiency, hyperthyroidism, hyperparathyroidism, hypercalciuria) should be considered. Appropriate therapy to prevent further bone loss should be initiated as clinically indicated. The decision to initiate therapy with an antiresorptive agent (e.g., a bisphosphonate, denosumab) should be based on overall risk of fracture and rate of bone loss. All women receiving adjuvant therapy with anastrozole should be advised to adopt lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation in alcohol consumption) and dietary supplementation with calcium and vitamin D to reduce the risk of osteoporosis.

Among patients receiving first-line therapy, there was no evidence of an increased incidence of fracture in patients receiving anastrozole compared with those receiving tamoxifen. Tumor flare was reported in 3% of such patients.

Among patients receiving anastrozole as first-line or second-line therapy, bone pain was reported in 11 or 6%, respectively. Myalgia, arthralgia, pathologic fracture, and neck pain each were reported in 2-5% of patients receiving anastrozole as second-line therapy, which was similar to experience in those receiving the drug as first-line therapy.

Back pain occurred in 10-12% of patients receiving anastrozole. Joint pain and stiffness also have been reported in patients receiving anastrozole. Joint pain (commonly affecting the hands, knees, hips, lower back, or shoulders) and stiffness, particularly early morning stiffness, have been reported within 2 months of initiation of therapy in patients receiving anastrozole as second-line therapy; none of these patients had a history of arthritis or arthralgia associated with menopause, prior chemotherapy, or hormone therapy. In a small number of patients experiencing severe arthralgia, symptoms resolved with discontinuance of the drug. Trigger finger has been reported in less than 1% of patients receiving anastrozole.

GI Effects

Among patients receiving anastrozole as adjuvant therapy, nausea and vomiting were reported in 13%. Dyspepsia and unspecified GI disorder each occurred in 7% of such patients.

Among patients receiving anastrozole as first-line or second-line therapy, GI disturbance was reported in 34 or 29%, nausea in 19 or 16%, vomiting in 8 or 9%, and anorexia in 5 or 7%, respectively.

Among patients receiving second-line therapy, diarrhea occurred more frequently in patients receiving anastrozole than in those receiving megestrol acetate (8 versus 3%). Dry mouth was reported in 6% of such patients.

Diarrhea occurred in 8-9%, and abdominal pain and constipation each occurred in 7-9% of patients receiving anastrozole.

Respiratory Effects

Pharyngitis occurred in 14, 10, and 6% of patients receiving anastrozole as adjuvant, first-line, or second-line therapy, respectively. Increased cough was reported in 8-11%, and dyspnea was reported in 8-10% of patients receiving anastrozole. Sinusitis occurred in 6% and bronchitis in 5% of patients receiving anastrozole as adjuvant therapy. Sinusitis, bronchitis, and rhinitis each were reported in 2-5% of patients receiving anastrozole as second-line therapy, which was similar to experience in those receiving the drug as first-line therapy.

Nervous System Effects

Among patients receiving anastrozole as adjuvant therapy, mood disturbance was reported in 19%, depression in 13%, insomnia in 10%, and anxiety in 6%. Among patients receiving anastrozole as first-line or second-line therapy, depression occurred in 5% and insomnia occurred in about 5-6%. Headache occurred in 9-13% and dizziness in 6-8% of patients receiving anastrozole. Paresthesia occurred in 7 or 5% of patients receiving anastrozole as adjuvant or second-line therapy, respectively.

Somnolence, confusion, anxiety, and nervousness each were reported in 2-5% of patients receiving anastrozole as second-line therapy, which was similar to experience in those receiving the drug as first-line therapy. Hypertonia occurred in 3% of patients receiving anastrozole as first-line therapy.

Dermatologic Effects

Rash occurred in 11, 8, or 6% of patients receiving anastrozole as adjuvant, first-line, or second-line therapy, respectively. Sweating occurred in 5 or 2% of patients receiving anastrozole as adjuvant or second-line therapy, respectively. Hair thinning, alopecia, and pruritus each were reported in 2-5% of patients receiving anastrozole as second-line therapy, which was similar to experience in those receiving the drug as first-line therapy.

Mucocutaneous disorders, including erythema multiforme and Stevens-Johnson syndrome, have been reported in patients receiving anastrozole.

Metabolic Effects

Weight gain occurred in 9% of patients receiving anastrozole as adjuvant therapy and in 2% of those receiving anastrozole as first-line or second-line therapy. Among patients receiving second-line therapy, weight gain occurred less frequently in patients receiving anastrozole than in those receiving megestrol acetate (2 versus 12%). Weight loss was reported in 2-5% of patients receiving anastrozole as second-line therapy, which was similar to experience in those receiving the drug as first-line therapy.

Hepatic Effects

Increased serum concentrations of γ-glutamyltransferase (GGT), AST, ALT, and alkaline phosphatase were reported in 2-5% of patients receiving anastrozole as second-line therapy, which was similar to experience in those receiving the drug as first-line therapy. During postmarketing surveillance, increased serum concentrations of AST, ALT, or alkaline phosphatase have been reported in up to 10% of patients receiving anastrozole; hepatitis and increased serum concentrations of GGT and bilirubin have been reported in less than 1% of patients.

Hematologic Effects

Anemia occurred in 4% of patients receiving anastrozole as adjuvant therapy. Anemia and leukopenia each were reported in 2-5% of patients receiving anastrozole as second-line therapy, which was similar to experience in those receiving the drug as first-line therapy.

Infectious Complications

Among patients receiving anastrozole as adjuvant therapy, infection was reported in 9%. Infection was reported in 2-5% of patients receiving anastrozole as second-line therapy, which was similar to experience in those receiving the drug as first-line therapy.

Ocular Effects

Cataracts were reported in 6% of patients receiving anastrozole as adjuvant therapy. Retinal hemorrhage has been reported in patients receiving anastrozole as adjuvant therapy.

Sensitivity Reactions

Systemic allergic reactions, including angioedema, urticaria, and anaphylaxis, have been reported in patients receiving anastrozole.

Other Adverse Effects

Fatigue/asthenia occurred in 16-19%, pain (nonspecific) in 11-17%, and chest pain (nonspecific) in 5-7% of patients receiving anastrozole. Accidental injury was reported in 10% of patients receiving anastrozole as adjuvant therapy and in 2-5% of patients receiving anastrozole as first-line or second-line therapy. Flu syndrome was reported in up to 7% of patients receiving anastrozole. Cyst occurred in 5% of patients receiving anastrozole as adjuvant therapy. Lethargy was reported in 1% of patients receiving anastrozole as first-line therapy. Fever and malaise each were reported in 2-5% of patients receiving anastrozole as second-line therapy, which was similar to experience in those receiving the drug as first-line therapy.

Precautions and Contraindications

Anastrozole currently is indicated for use in the treatment of breast cancer in postmenopausal women only. Anastrozole is not recommended for use in premenopausal women because safety and efficacy have not been established in this patient population.

Postmenopausal women with breast cancer receiving adjuvant therapy with an aromatase inhibitor, such as anastrozole, are at high risk for osteoporosis. Postmenopausal women initiating such therapy should undergo screening to determine BMD and be evaluated for other risk factors for osteoporotic fractures. Patients should be monitored closely for changes in risk status during therapy, and BMD should be assessed at regular intervals. Appropriate therapy to prevent further bone loss should be initiated as clinically indicated. All women receiving adjuvant therapy with anastrozole should be advised to adopt lifestyle changes (e.g., weight-bearing exercise) and dietary supplementation with calcium and vitamin D to reduce the risk of osteoporosis.(Also see Cautions: Musculoskeletal Effects.)

The effect of anastrozole on lipid metabolism has not been fully established, and serum lipoprotein concentrations should be monitored in patients receiving long-term therapy with the drug.

Because an increased incidence of ischemic cardiovascular events has been observed in women with preexisting ischemic heart disease who received anastrozole as adjuvant therapy, risks and benefits of the drug should be considered in patients with ischemic heart disease.

Anastrozole is contraindicated in patients with known hypersensitivity to the drug or any component of the commercially available formulation.

Pediatric Precautions

Efficacy of anastrozole for the treatment of pubertal gynecomastia in adolescent males and for the treatment of progressive precocious puberty associated with McCune-Albright syndrome in girls has not been established.

Results of a randomized, double-blind, placebo-controlled trial in 80 adolescent males 11-18 years of age with pubertal gynecomastia failed to establish efficacy of anastrozole (1 mg daily for 6 months) in reducing gynecomastia or relieving breast pain. Serum estradiol concentrations were reduced by 15.4 or 4.5% in patients receiving anastrozole or placebo, respectively. Patients receiving anastrozole were more likely to experience treatment-related adverse effects (16.3 versus 8.1%), and the difference was related mainly to higher rates of acne and headache in those receiving anastrozole. One patient discontinued anastrozole therapy because of testicular enlargement.

Results of a noncomparative open-label trial of anastrozole (1 mg daily for 12 months) in 28 girls (2 to less than 10 years of age) with McCune-Albright syndrome and progressive precocious puberty showed no reduction from baseline in the frequency of vaginal bleeding days or in the rate of increase in bone age and no clinically important changes in Tanner staging, mean ovarian or uterine volume, or mean predicted adult height. A small reduction in growth rate was observed; however, because the study was uncontrolled, it is unclear whether this effect was related to anastrozole or to other confounding factors (e.g., variations in endogenous estrogen levels commonly observed in patients with McCune-Albright syndrome). Adverse effects (i.e., nausea, acne, extremity pain, increased aminotransferase concentrations, allergic dermatitis) were reported in 18% of patients.

Pharmacokinetics of anastrozole were similar in adolescent males with pubertal gynecomastia and in girls with McCune-Albright syndrome, and the elimination half-life in these pediatric populations (about 47 hours) was similar to that observed in postmenopausal women with breast cancer.

Geriatric Precautions

Among patients receiving anastrozole as adjuvant therapy for early-stage breast cancer in the ATAC trial, 45% were 65 years of age or older. Subgroup analysis showed that anastrozole did not provide the same benefit for disease-free survival in women 65 years of age or older (hazard ratio of 0.93 with a 95% confidence interval of 0.8-1.08) that it provided in postmenopausal women younger than 65 years of age (hazard ratio of 0.79 with a 95% confidence interval of 0.67-0.94).

Among patients receiving anastrozole as first-line or second-line therapy in clinical trials, about 50% were 65 years of age or older. No difference in efficacy was observed for geriatric patients (65 years or older) compared with younger patients receiving anastrozole as second-line therapy for advanced breast cancer; moderately greater efficacy was observed for geriatric patients (65 years or older) receiving either anastrozole or tamoxifen as first-line therapy for advanced breast cancer.

Mutagenicity and Carcinogenicity

Mutagenicity

In vitro tests, including the Ames and E. coli bacterial tests and the CHO-K1 gene mutation assay, have not shown anastrozole to be mutagenic. In addition, the drug was not shown to be clastogenic in the in vitro chromosome aberration test in human lymphocytes or in the in vivo micronucleus test in rats.

Carcinogenicity

At a median duration of treatment of 60 months, a lower incidence of endometrial cancer (0.2 versus 0.6%) was observed in patients receiving anastrozole versus tamoxifen as adjuvant therapy in a large, randomized trial; neoplasm and breast neoplasm each were reported as an adverse event in 5% of patients in each treatment group. At a median follow-up of 10 years, the incidence of endometrial cancer remained lower in patients who had received anastrozole compared with those who had received tamoxifen for a median of 60 months (0.2 versus 0.8%); the cumulative incidence of new primary cancers was similar (14%) in each treatment group.

Anastrozole has shown carcinogenic activity in animal models. In rats administered anastrozole 1-25 mg/kg daily (about 10-243 times the daily maximum recommended human dose on a mg/m basis) by oral gavage for up to 2 years, an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps was observed in females and an increased incidence of thyroid adenoma was observed in males receiving the high dose. In female rats, a dose-related increase in the incidence of ovarian and uterine hyperplasia was observed. Area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24h) values in rats receiving anastrozole 25 mg/kg daily were 110-125 times higher than AUC0-24h values in postmenopausal individuals receiving the recommended dose of the drug.

In mice, oral doses of anastrozole 5-50 mg/kg daily (about 24-243 times the daily maximum recommended human dose on a mg/m basis) for up to 2 years resulted in an increased incidence of benign ovarian stromal, epithelial, and granulosa cell tumors in female mice at all dosage levels and an increased incidence of lymphosarcoma in male and female mice at the high dose. In female mice, a dose-related increase in the incidence of ovarian hyperplasia also was observed; the ovarian changes observed are considered to be rodent-specific effects of aromatase inhibition, and the clinical importance of these effects to humans is unknown. AUC values in mice receiving anastrozole 50 mg/kg daily were 35-40 times higher than AUC values in postmenopausal individuals receiving the recommended dosage of the drug.

Pregnancy, Fertility, and Lactation

Pregnancy

Anastrozole is contraindicated in women who are or may become pregnant (i.e., premenopausal women) since the drug can cause fetal toxicity when administered to pregnant women and clinical benefits of anastrozole therapy in premenopausal women with breast cancer have not been established. If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus and the potential risk for loss of the pregnancy.

Adequate, well-controlled studies of anastrozole in pregnant women have not been conducted. Anastrozole has been shown to cross the placenta in rats and rabbits receiving oral doses of 0.1 mg/kg (approximately 1 and 1.9 times the recommended human dose, respectively, on a mg/m basis). Increased pregnancy loss (increased preimplantation and/or postimplantation loss, increased resorption, and decreased numbers of live fetuses) was demonstrated in rats and rabbits receiving anastrozole dosages equal to or exceeding 0.1 and 0.02 mg/kg daily, respectively (about one and one-third times the recommended human dosage, respectively, on a mg/m basis), during the period of organogenesis; in rats, this effect was dose-related. In rats receiving dosages equal to or exceeding 0.1 mg/kg daily, placental weights were increased.

In rats, anastrozole dosages of 1 mg/kg daily (which produced steady-state peak plasma anastrozole concentrations and AUC0-24h values that were 19 and 9 times higher, respectively, than those observed in healthy postmenopausal women receiving the recommended dose) resulted in fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights). In rats, no evidence of teratogenicity was observed at dosages of up to 1 mg/kg daily. In rabbits, anastrozole dosages equal to or exceeding 1 mg/kg daily (about 16 times the recommended human dosage on a mg/m basis) caused pregnancy failure. No evidence of teratogenicity was observed in rabbits receiving anastrozole 0.2 mg/kg daily (about 3 times the recommended human dosage on a mg/m basis).

Fertility

Impairment of fertility and effects on the reproductive organs associated with anastrozole have been demonstrated in animal studies. In female rats, oral administration of anastrozole at a dosage of 1 mg/kg daily (about 10 times the recommended human dosage on a mg/m basis and resulting in an AUC0-24h about 9 times higher than that observed in postmenopausal women receiving the recommended dose) from 2 weeks before mating to pregnancy day 7 caused a high incidence of infertility and reduced numbers of viable pregnancies. Preimplantation loss of ova or fetus was increased at dosages equal to or exceeding 0.02 mg/kg daily (about one-fifth the recommended human dosage on a mg/m basis). Recovery of fertility was observed following a 5-week nondosing period that followed 3 weeks of dosing. Whether the effects observed in rats are indicative of impaired fertility in humans receiving anastrozole is not known.

In multiple-dose studies in rats, anastrozole dosages equal to or exceeding 1 mg/kg daily for 6 months (which resulted in steady-state peak plasma anastrozole concentrations and AUC0-24h values that were 19 and 9 times higher, respectively, than those observed in healthy postmenopausal humans receiving the recommended dosage) resulted in hypertrophy of the ovaries and development of follicular cysts. In multiple-dose studies in dogs receiving anastrozole dosages equal to or exceeding 1 mg/kg daily for 6 months (which produced steady-state peak plasma anastrozole concentrations and AUC0-24h values that were 22 and 16 times higher, respectively, than those observed in postmenopausal women receiving the recommended dosage), hyperplastic uteri were observed. The relationship between the reproductive effects observed in animals and possible effects of the drug on fertility in humans is not known.

Lactation

It is not known whether anastrozole is distributed into milk. Because many drugs are distributed into milk and because tumorigenic effects of anastrozole have been observed in animals and anastrozole has the potential to cause serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Selective Estrogen Receptor Modulators

The concomitant use of selective estrogen receptor modulators (e.g., tamoxifen, raloxifene) and aromatase inhibitors, such as anastrozole, is not recommended.

Data from a subprotocol of the ATAC trial indicate that concomitant use of anastrozole and tamoxifen does not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen, its principal active metabolite. The mean plasma anastrozole concentration was reduced by an average of 27% in patients receiving tamoxifen and anastrozole versus anastrozole alone, but analysis of blood samples from a different subprotocol of the ATAC trial demonstrates similar degrees of suppression of plasma estradiol concentrations for anastrozole alone and in combination with tamoxifen. Although the clinical importance of this pharmacokinetic interaction is uncertain, combination therapy did not demonstrate greater efficacy than use of tamoxifen alone, and the concomitant use of anastrozole and tamoxifen is not recommended.

Because this pharmacokinetic interaction may occur with similar agents and reduce plasma concentrations of anastrozole, the concomitant use of other selective estrogen receptor modulators (e.g., raloxifene) is not recommended. Among women receiving anastrozole who require drug therapy for osteoporosis, the use of an oral bisphosphonate, rather than raloxifene, is advised.

Estrogens

Because estrogens may diminish the pharmacologic action of anastrozole, the drugs should not be used concomitantly.

Drugs Metabolized by Hepatic Microsomal Enzymes

Anastrozole has been shown to inhibit in vitro metabolic reactions catalyzed by cytochrome P-450 (CYP) isoenzymes 1A2, 2C8/9, and 3A4, but only at relatively high concentrations. Anastrozole did not inhibit CYP isoenzyme 2A6 or 2D6 in human liver microsomes, and the drug did not alter the pharmacokinetics of antipyrine. In addition, anastrozole did not alter systemic exposure (as measured by peak plasma concentrations and area under the concentration-time curve [AUC]) or anticoagulant effects of either R- or S-warfarin. It is considered unlikely that anastrozole, when administered at the recommended dosage, will result in clinically important interactions with drugs metabolized by CYP enzymes.

Pharmacokinetics

The pharmacokinetics of anastrozole are linear over the dose range of 1-20 mg and are not altered with repeated dosing. The pharmacokinetic disposition of anastrozole is similar in female patients with breast cancer and in healthy postmenopausal women.

Absorption

Anastrozole is rapidly and well absorbed into systemic circulation following oral administration; peak plasma concentrations generally are attained within 2 hours when the drug is administered in the fasted state. Plasma concentrations approach steady state after about 7 days of once-daily dosing, and steady-state concentrations are approximately 3-4 times higher than concentrations achieved after a single dose of the drug.

Food reduces the rate but does not affect the extent of oral absorption of anastrozole. When anastrozole was administered 30 minutes after food, the mean peak plasma concentration of the drug was decreased by 16% and the median time to peak plasma concentration was delayed by 3 hours.

Distribution

Within the therapeutic plasma concentration range, anastrozole is 40% bound to plasma proteins.

It is not known whether anastrozole crosses the placenta in humans; however, the drug has been shown to cross the placenta in rats and rabbits.(See Cautions: Pregnancy, Fertility, and Lactation.)

It is not known whether anastrozole is distributed into milk in humans.

Elimination

A mean terminal elimination half-life of approximately 50 hours has been reported.

Anastrozole is extensively metabolized in the liver. Hepatic metabolism accounts for about 85% of the elimination of anastrozole, with renal excretion accounting for only about 10% of total clearance. Studies with radiolabeled drug have shown that about 85% of an orally administered dose is recovered in urine and feces.

Metabolism of anastrozole occurs via N-dealkylation, hydroxylation, and glucuronidation. Three metabolites of anastrozole have been identified in human plasma and urine: triazole, a glucuronide conjugate of anastrozole, and a glucuronide conjugate of hydroxyanastrozole. Triazole, the major circulating metabolite of anastrozole, lacks pharmacologic activity, and the aromatase-inhibiting activity of anastrozole results principally from the parent drug.

Among healthy postmenopausal women and female patients with breast cancer, no age-related differences in pharmacokinetics of anastrozole have been observed in women older than 80 years of age compared with women younger than 50 years of age.

The apparent oral clearance of anastrozole was reduced by approximately 30% in individuals with stable hepatic cirrhosis related to alcohol abuse compared with controls with normal hepatic function. However, plasma anastrozole concentrations observed in individuals with hepatic cirrhosis were within the range of concentrations observed in normal individuals across all clinical trials.

Although the renal clearance of anastrozole decreases proportionally with creatinine clearance and is reduced by about 50% in individuals with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m) compared with controls, total body clearance of anastrozole is reduced by only 10% in patients with severe renal impairment.

Steady-state minimum plasma concentrations averaged 25.7 and 30.4 ng/mL, respectively, in white and Japanese postmenopausal women receiving anastrozole 1 mg daily for 16 days; serum estradiol and estrone sulfate concentrations were similar between the groups.

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