General Information: Anastrozole is a nonsteroidal aromatase inhibitor. Anastrozole is highly potent and specific for aromatase, and represents the fourth generation of aromatase inhibitors. Anastrozole significantly suppresses serum estradiol levels, and it offers an alternative to tamoxifen in postmenopausal women with breast cancer. Unlike aminoglutethimide, an early aromatase inhibitor, anastrozole does not inhibit adrenal steroid synthesis. Patients taking anastrozole, therefore, do not require glucocorticoid or mineralocorticoid replacement therapy. Anastrozole causes less weight gain than megestrol and may offer a survival advantage over megestrol in women with advanced breast cancer. Aromatase inhibitors are considered to be a standard of therapy and drug class of choice for the treatment of early breast cancer in postmenopausal women with hormone-receptor positive disease. The American Society of Clinical Oncology recommends that all postmenopausal women with hormone receptor-positive early breast cancer receive adjuvant aromatase inhibitor therapy. Options include 5 years of an aromatase inhibitor or sequential therapy with 2—3 years or 5 years of tamoxifen followed by 2—3 years or 5 years of an aromatase inhibitor.1 Long-term data indicate that the improvements in disease-free survival persist for the 5 years during treatment and after drug discontinuation (see Dosage).23
Although not FDA-approved, several studies have shown that anastrozole further improves disease-free survival when used sequentially after 2—3 years of tamoxifen when compared to patients taking tamoxifen for 5 years.45
Anastrozole was initially FDA-approved for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed during tamoxifen therapy in December 1995. In September 2000, the FDA approved anastrozole for the first-line treatment of postmenopausal women with advanced or metastatic breast cancer. Approval for the adjuvant treatment of early breast cancer in postmenopausal women with hormone receptor positive disease was received in September 2002.
Mechanism of Action: Anastrozole inhibits aromatase, the enzyme that catalyzes the final step in estrogen production. Anastrozole is an oral, competitive, non-steroidal inhibitor of aromatase and is less likely to exhibit agonist or antagonist steroidal properties.6 The formation of adrenal corticosteroids or aldosterone is not affected by anastrozole; only serum estradiol concentrations are affected by anastrozole. In postmenopausal women, the principal source of circulating estrogens is from the conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase in peripheral tissues. Inhibition of aromatase may result in a more complete estrogen block than surgical ablation. Extraglandular sites are more amenable to aromatase inhibition by anastrozole than are premenopausal ovaries. Inhibiting the biosynthesis of estrogens is one way to deprive the tumor of estrogens and to restrict tumor growth. Estradiol plasma concentrations decrease about 80% from the baseline with continued dosing of anastrozole.7 Aromatase inhibitors might also inhibit estrogen production at the tumor cell. However, tumor production of estradiol may be insignificant because aromatase activity appears to be low.8 Anastrozole has little or no effect on CNS, autonomic, or neuromuscular function.
Pharmacokinetics: Anastrozole is administered orally. Pharmacokinetics are linear, even with repeated dosing. Hepatic metabolism accounts for approximately 85% of elimination. Within 72 hours, about 60% of a dose is excreted in the urine as metabolites and only 10% as unchanged drug. Three metabolites have been identified in plasma and urine, and there are several unidentified minor metabolites. No pharmacological activity has been attributed to triazole, the main circulating metabolite. The other known metabolites are a glucuronide conjugate of hydroxy-anastrozole and a glucuronide conjugate of anastrozole. Anastrozole has a terminal elimination half-life of about 50 hours.
Per the manufacturer, it is unlikely that anastrozole administered at the recommended dose will inhibit the metabolism of cytochrome P450-mediated drugs given concomitantly. High concentrations inhibited metabolic reactions catalyzed by cytochromes P450 (CYP) 1A2, 2C8/9, and 3A4. It did not inhibit CYP2A6 or the polymorphic CYP2D6 in human liver microsomes.9
Route-Specific Pharmacokinetics: Oral Route: Anastrozole is well absorbed and distributed throughout the systemic circulation (85% bioavailability). Maximum plasma concentrations occur within 2 hours.7 Plasma concentrations approach steady-state levels by about the seventh day of once-daily dosing.
Special Populations: Hepatic Impairment: Although hepatic cirrhosis reduces apparent oral clearance of anastrozole, no dosage adjustments are needed because plasma concentrations remain within the same range as for patients without hepatic disease.
Renal Impairment: Renal clearance of anastrozole does decrease proportionally with creatinine clearance, but overall this has very little effect on total body clearance. No dosage adjustments are therefore necessary for patients with impaired renal function.
Indications: Anastrozole is commonly indicated and prescribed for: treatment of advanced or metastatic carcinoma in the breast of postmenopausal women; adjunctive therapy in the treatment of early carcinoma in the breast of postmenopausal women; and treatment of excessive estrogen production in men. It is typically found in capsule or tablet forms of .25 mg, .5 mg, and 1 mg. The effects of Anastrozole can be very substantial, with a daily dose of 1 mg (commonly one tablet).
Contraindications/Precautions: Your health care provider needs to know if you have any of these conditions: heart disease, circulation problems, a history of stroke or blood clot, severe liver disease, high cholesterol, osteoporosis, or low bone mineral density. Anastrozole may not work as well if you take it together with tamoxifen or an estrogen medication (such as hormone replacement therapy, estrogen creams, or birth control pills, injections, implants, skin patches, and vaginal rings). You may need to keep taking anastrozole for up to 5 years.
In general, anastrozole should not be used in premenopausal females; anastrozole may not be able to inhibit the formation of estrogen from the ovaries and therefore is not expected to be effective, although it has been used successfully in the treatment of uterine leiomyomata in premenopausal women.10 Hormone replacement therapy (i.e., exogenous estrogens) should not be administered concurrently with anastrozole.
Hepatic cirrhosis due to alcohol abuse reduces apparent oral clearance of anastrozole by about 30%. Anastrozole should be used with caution in patients with mild to moderate hepatic impairment, and patients should be closely monitored for adverse effects. However, no dosage adjustments are recommended for patients with hepatic disease because plasma anastrozole concentrations remain within the range of those seen in normal patients. No studies have been conducted in patients with severe hepatic impairment.
Consideration should be given to monitoring patients for signs and symptoms of osteoporosis, including decreased bone mineral density (BMD), during treatment with anastrozole, especially in patients with pre-existing osteoporosis, osteopenia, or risk factors for the development of osteoporosis. After a median follow-up of 68 months in the ATAC trial, the odds of bone fractures in patients taking anastrozole were significantly increased compared to patients taking tamoxifen (11% for anastrozole vs. 7.7% for tamoxifen, OR 1.49, 95% CI 1.25—1.77, P < 0.0001).2 Similarly, in the combined analysis of the ABCSG trial 8 and the ARNO 95 trials, after a median follow-up of 36 months, the odds of bone fractures in patients taking anastrozole were significantly increased (2% for anastrozole vs. 1% for tamoxifen, OR 2.14, 95% CI 1.14—4.17, P = 0.015).11
Anastrozole should be used with caution in women with pre-existing ischemic cardiac disease. In the ATAC trial, women with pre-existing ischemic heart disease had an increased incidence of ischemic cardiovascular events (17% of patients receiving anastrozole versus 4% of patients in the overall study population).
Safety and efficacy of anastrozole in children have not been established.
Anastrozole is classified as FDA pregnancy risk category X.12 It is contraindicated for use in women who are pregnant or may become pregnant. Anastrozole may cause fetal harm when administered to pregnant women and offers no clinical benefit when administered to premenopausal women with breast cancer. Animal studies indicate that anastrozole increases pregnancy loss, both pre- and postimplantation. It crosses the placenta and causes fetal harm, including delayed fetal development, but there has been no evidence of teratogenicity. There have been no adequate studies in pregnant women, and anastrozole is only approved for the treatment of postmenopausal women, and should generally not be used in females of childbearing potential. If pregnancy occurs, however, while the patient is receiving anastrozole, she should be warned about the possible risk to the fetus and possible loss of pregnancy.
It is not known whether anastrozole is excreted into breast 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 breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. Anastrozole is contraindicated in pre-menopausal females, so use during lactation would not be expected.12 This list may not include all possible contraindications.
Pregnancy: Anastrozole is classified as FDA pregnancy risk category X.12 It is contraindicated for use in women who are pregnant or may become pregnant. Anastrozole may cause fetal harm when administered to pregnant women and offers no clinical benefit when administered to premenopausal women with breast cancer. Animal studies indicate that anastrozole increases pregnancy loss, both pre- and postimplantation. It crosses the placenta and causes fetal harm, including delayed fetal development, but there has been no evidence of teratogenicity. There have been no adequate studies in pregnant women, and anastrozole is only approved for the treatment of postmenopausal women, and should generally not be used in females of childbearing potential. If pregnancy occurs, however, while the patient is receiving anastrozole, she should be warned about the possible risk to the fetus and possible loss of pregnancy.
Breast-feeding: It is not known whether anastrozole is excreted into breast 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 breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. Anastrozole is contraindicated in pre-menopausal females, so use during lactation would not be expected.12
Interactions: NOTE: High concentrations of anastrozole inhibited metabolic reactions catalyzed by cytochromes P450 (CYP) 1A2, 2C8/9, and 3A4. Anastrozole did not inhibit CYP2A6 or the polymorphic CYP2D6 in human liver microsomes. Per the manufacturer, it is unlikely that anastrozole administered at the recommended dose will inhibit the metabolism of cytochrome P450-mediated drugs given concomitantly.13
In a study in male volunteers (n=16), anastrozole did not alter the warfarin pharmacokinetics (Cmax or AUC), and did not alter warfarin anticoagulant activity as measured by prothrombin time, activated partial thromboplastin time, and thrombin time of both R- and S-warfarin.13
Anastrozole and tamoxifen should not be administered together. Clinical and pharmacokinetic results from the ATAC study 14 demonstrate that concurrent administration of anastrozole and tamoxifen results in a reduction of anastrozole plasma levels by 27% compared to those achieved with anastrozole alone.13 However, coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen.13
The goal of anastrozole therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers.13 Anastrozole should not be given concurrently with any estrogens or estrogen-containing products, including combined oral contraceptives, as these could interfere with the pharmacologic action of anastrozole. In addition, in women receiving long-term aromatase inhibitor therapy, atrophic vaginitis due to estrogen suppression is common; atrophic vaginitis due to aromatase inhibitor therapy is sometimes treated with vaginal estrogen as the systemic exposure of estrogen from vaginal preparations is thought to be low. In a recent study of 7 women on aromatase inhibitor therapy, estrogen concentrations rose significantly after the addition of vaginally administered estrogen for atrophic vaginitis. Estrogen concentrations increased from a mean baseline level of < 5 pmol/l to 72 pmol/l at 2 weeks and to < 35 pmol/l at 4 weeks. Although the study was small, estrogen concentrations rose significantly in 6/7 patients. Clinicians should be aware that serum estrogen concentrations may increase with the use of vaginal estrogen preparations; alternative treatments for atrophic vaginitis in patients taking aromatase inhibitors should be considered.15
Androstenedione is an important metabolic precursor for androgens and estrogens in both males and females. Androstenedione supplements should not be given concurrently with any aromatase inhibitors, as androstenedione could interfere with the pharmacologic action of the aromatase inhibitor. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) could interfere with biotransformation of androstenedione in both males and females; the enzyme aromatase converts androstenedione to estrone.
Prasterone, dehydroepiandrosterone, DHEA is converted via hydrosteroid dehydrogenases and aromatase into androstenedione, testosterone, and estradiol by peripheral tissues.16 Prasterone or DHEA supplements should not be given concurrently with any aromatase inhibitors, as DHEA could interfere with the pharmacologic action of the aromatase inhibitor and compromise aromatase inhibitor effectiveness. Conversely, aromatase inhibitors (e.g., aminoglutethimide, anastrozole,13 exemestane,17 letrozole,18 testolactone,19 vorozole could interfere with biotransformation of DHEA.
Adverse Reactions/Side Effects: Numbness; tingling; cold feeling; or weakness in your hand or wrist; problems with your fingers while gripping; hot flashes; joint pain or stiffness; depression; mood changes; sleep problems (insomnia); cough; sore throat; thinning hair; mild nausea; vomiting; back pain; bone pain
Hot flashes (11—36%) were the most commonly reported adverse reaction associated with anastrozole during clinical trials. Other commonly reported adverse reactions during controlled trials included vaginal irritation (i.e., dryness) (1—2%), vaginal bleeding (1—5%), vaginal discharge (4%), vaginitis (4%), and vulvovaginitis (6%). Vaginal bleeding occurs primarily during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.12
Gastrointestinal/digestive adverse reactions occurred in up to one-third of patients receiving anastrozole during clinical trials. These reactions included abdominal pain (6—9%), anorexia (5—8%), constipation (7—9%), diarrhea (7—9%), dyspepsia (7%), nausea (11—20%), vomiting (8—13%), and xerostomia or dry mouth (4—6%). Weight gain was reported in 2—9% of patients taking anastrozole, but occurred less frequently than with megestrol (12%). Additionally, 2—5% of anastrozole recipients also experienced weight loss and elevated hepatic enzymes, with or without jaundice (< 0.01%). Elevations in hepatic enzymes, primarily serum gamma glutamyl transferase (GGT), were observed in patients with liver metastases receiving anastrozole or megestrol. These changes were likely due to the progression of liver disease in these patients, but other contributing factors cannot be ruled out. Hepatitis and hyperbilirubinemia have been reported during post-marketing use of anastrozole with an estimated incidence of >= 0.1% to < 1%. Due to the voluntary nature of post-market reports, neither a definitive incidence nor causal relationship can be established.12
Nervous system adverse reactions associated with the use of anastrozole during clinical trials include anxiety (2—6%), confusion (2—5%), depression (2—13%), dizziness (5—8%), drowsiness (2—5%), headache (7—18%), hypertonia (3%), insomnia (2—10%), lethargy (1%), malaise (2—5%), nervousness (2—5%), and paresthesias (5—7%).12
Administration of anastrozole has been associated with the development of thromboembolic events. Thromboembolism was reported in 2—4% of patients treated with anastrozole during clinical trials. The incidence of anastrozole-associated thrombosis was less than that reported with tamoxifen (2—6%) or megestrol (5%). Specific cases included angina (2.3—11.6%), cerebrovascular accident (stroke) specifically cerebral ischemia and cerebral infarct (2%), myocardial infarction (0.9—1.2%), myocardial ischemia (< 4%), pulmonary embolism (< 4%), retinal thrombosis (< 4%), and thrombo-phlebitis (2—5%). In the ATAC trial, women with pre-existing ischemic cardiac disease had a 17% incidence of ischemic cardiac events. In this patient population, angina occurred in 11.6% and myocardial infarction in 0.9%.12
Musculoskeletal reactions are some of the more common adverse events experienced by recipients of anastrozole therapy (36%). During clinical trials, patients receiving anastrozole reported symptoms including arthralgia (2—15%), arthritis (17%), arthrosis (7%), asthenia (13—19%), back pain (10—12%), bone pain (6—11%), breast pain (2—8%), carpal tunnel syndrome (2.5%), chest pain (unspecified) (5—7%), fatigue (19%), myalgia (2—6%), neck pain (2—5%), and pelvic pain (5%). Additionally, episodes of trigger finger have been reported during post-marketing use by 0.1—1% of anastrozole recipients. Due to the voluntary nature of post-market reports, neither a definitive incidence nor causal relationship with anastrozole can be established.12
Osteoporosis has been reported as an adverse event to anastrozole, but causality has not been determined. Data from clinical trials indicate that musculoskeletal events and bone fractures are significantly more common in patients receiving anastrozole (36% and 10%, respectively) versus tamoxifen (29% and 7%, respectively). The anatomical sites with the greatest increase in fracture incidence were wrist fractures (2%), spine fractures (1%), and hip fractures (1%). Of note, long-term data indicate that fracture rates were not different after anastrozole or tamoxifen discontinuation (median follow-up 100 months).3 Similarly, in the combined analysis of the ABCSG trial 8 and the ARNO 95 trials, after a median follow-up of 36 months, the odds of bone fractures in patients taking anastrozole were significantly increased (2% for anastrozole vs. 1% for tamoxifen, OR 2.14, 95% CI 1.14—4.17, P=0.015).11 Health care professionals are advised to consider bone mineral density testing prior to and during anastrozole therapy in those patients at risk of developing osteoporosis.12
During the ATAC trial, more patients receiving anastrozole were reported to have hypercholesterolemia compared to those receiving tamoxifen (9% vs. 3.5%, respectively).14 Other anastrozole-associated adverse events affecting the cardiovascular system included edema (7—11%), hypertension (2—13%), peripheral edema (5—10%), and peripheral vasodilation (25—36%).12
Dermatologic adverse events have been associated with anastrozole therapy. During clinical trials, patients treated with anastrozole experiences symptoms including alopecia (2—5%), diaphoresis (1—5%), pruritus (2—5%), and rash (unspecified) (6—11%). Additionally, rare cases (< 1 in 10,000 patients or < 0.01%) of serious anastrozole-induced skin reactions (e.g., skin lesion, skin ulcer, and skin blister) have also occurred. During post-market use, anaphylaxis, angioedema, erythema multiforme, Stevens-Johnson syndrome and urticaria were reported by anastrozole recipients. Due to the voluntary nature of post-market reports, neither a frequency nor a definitive causal relationship to anastrozole can be established.12
During clinical trials, the incidence of infections in patients receiving treatment with anastrozole was 2—9%. Reports identified the specific infection sites as bronchitis (2—5%), influenza (2—7%), pharyngitis (6—14%), sinusitis (2—6%), and urinary tract infections (2—8%). Symptoms reported by anastrozole recipients and potentially related to an infection included cough (7—11%), dyspnea (8—11%), fever (2—5%), leukorrhea (2—3%), and rhinitis (2—5%).12
Hematologic and lymphatic adverse events reported by recipients of anastrozole during clinical trials included anemia (2—5%), leukopenia (2—5%), and lymphedema (10%).12
There are currently no studies in pregnant humans; however, use of anastrozole in rats and rabbits has resulted in pregnancy failure, increased fetal abortion, and signs of delayed fetal development or teratogenesis. In both rats and rabbits, increased pregnancy loss was described as an increase in pre- and post-implantation loss, increased resorption, and decreased number of live fetuses. Additionally, adverse fetal effects associated with anastrozole included incomplete ossification and decreased fetal body weight. Use of anastrozole is contraindicated in pregnant women.12
Other adverse events associated with the use of anastrozole during clinical trials include accidental injury (2—10%), cataracts (6%), development of a cyst or neoplasm (5%), and tumor flare (3%).12
Hypercalcemia (with or without an increase in parathyroid hormone) has been reported in post-marketing use. Due to the voluntary nature of post-market reports, neither a definitive incidence nor causal relationship with anastrozole can be established.9
This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.
Storage: Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.
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- 10. Varelas FK, Papanicolaou AN, Vavasti-Christaki N, et al. The effect of anastrazole on symptomatic uterine leiomyomata. Obstet Gynecol 2007;110:643-9.
- 11. Jakesz R, JOnat W, Gnant M, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005;366:455-62.
- 12. Arimidex (anastrozole) package insert. Wilmington DE: AstraZeneca Pharmaceuticals LP; 2009 Apr.
- 13. Arimidex® (anastrozole) package insert. Wilmington DE: AstraZeneca Pharmaceuticals LP; 2002 Oct.
- 14. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomise
- 15. Kendall A, Dowsett M, Folkerd E, et al. Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol 2006;17:584—7.
- 16. Kroboth PD, Slalek FS, Pittenger AL et al. DHEA and DHEA-S: a review. J Clin Pharmacol 1999;39:327—48.
- 17. Aromasin® (exemestane) package insert. Kalamazoo MI: Pharmacia & Upjohn Company; 2005 Oct.
- 18. Femara® (letrozole) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2003 Feb.
- 19. Teslac (testolactone) package insert. Princeton, NJ: Mead-Johnson Oncology Products, Bristol-Myers Squibb, Co.; 1998 Dec.