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.
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.
Anastrozole and tamoxifen should not be administered together. Clinical and pharmacokinetic results from the ATAC study 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. However, coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen.
The goal of anastrozole therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. 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.
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. 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, exemestane, letrozole, testolactone, vorozole could interfere with biotransformation of DHEA.
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.
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.
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%).
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%.
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.
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). 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.
During the ATAC trial, more patients receiving anastrozole were reported to have hypercholesterolemia compared to those receiving tamoxifen (9% vs. 3.5%, respectively). 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%).
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.
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%).
Hematologic and lymphatic adverse events reported by recipients of anastrozole during clinical trials included anemia (2—5%), leukopenia (2—5%), and lymphedema (10%).
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.
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%).
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.
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.
