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anastrozole
Drug Monograph
Drug Name | Mechanism of Action and Pharmacokinetics | Indications and Status | Adverse Effects | Dosing | Administration
Guidelines | Special Precautions | Interactions | Recommended Clinical Monitoring | Supplementary Public Funding | References | Disclaimer A ­ Drug Name
anastrozole SYNONYM(S): ZD1033
COMMON TRADE NAME(S): Arimidex® (AstraZeneca)
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B ­ Mechanism of Action and Pharmacokinetics
In estrogen­dependent tumours, estrogen deprivation causes growth arrest and possibly tumour cell death. Aromatase (estrogen synthetase) is an enzyme that catalyses various steps in the conversion of androgen to estrogen and is found in peripheral tissues as well as breast tumours; peripheral conversion is the major source of estrogens in postmenopausal women. Anastrozole is a potent and selective non­steroidal aromatase inhibitor. It significantly lowers serum estradiol concentration and has no detectable effect on the formation of adrenal corticosteroids, aldosterone, and TSH. Patients with estrogen or progesterone receptor positive tumours are more likely to respond to treatment with aromatase inhibitors. Anastrozole does not have progestogenic, androgenic or estrogenic activity.
Absorption
Oral: 80%
Absorption of anastrozole is rapid and maximum plasma level is reached within 2 hours of ingestion. Food decreases the rate but not the overall extent of absorption. Steady state concentration is reached after 7 days of once daily dosing. Pharmacokinetics are linear and do not change with repeated dosing.
Distribution
Widely distributed into tissues.
Cross blood brain barrier? No information found
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PPB Metabolism
40%
Extensively (85%) metabolized in liver (via N­dealkylation, hydroxylation and glucuronidation). No evidence of age or ethnicity effects on pharmacokinetics.
Active metabolites Inactive metabolites Elimination
No
Yes
Elimination mainly by metabolism (85%).
Urine Half­life 11% (unchanged)
50 hours
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C ­ Indications and Status
Health Canada Approvals:
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For hormonal treatment of advanced breast cancer in postmenopausal women. For the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. Approval is based on superior disease­free survival of anastrozole in comparison to tamoxifen; however, overall survival was not significantly different. back to top
D ­ Adverse Effects
Emetogenic potential: Not applicable Extravasation Potential: Not applicable The table below contains adverse effects reported mainly in adjuvant breast cancer with 5­year treatment.
ORGAN SITE
Cardiovascular SIDE EFFECT* (%)
ONSET**
Arterial thromboembolism (2%)
Cardiac ischemia (4%)
Hypertension (13%)
Lymphedema (10%)
D
E
D
E
Venous thromboembolism (3%)
Dermatological Rash (11%) (may be severe)
D
E
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Gastrointestinal Abdominal pain (9%)
I E
Nausea, vomiting (13%)
I E
Weight changes (9%)
General Hematological D
Fatigue (19%)
E
Tumour flare (3%) (reported in metastatic breast cancer patients)
E
Anemia (4%)
D
Leukopenia (<5%)
D
Hepatobiliary ↑ LFTs (rare, may be severe)
D
Hypersensitivity Hypersensitivity (rare)
Infection Infection (9%)
Metabolic / Endocrine ↑ Cholesterol (9%) (increased HDL 7%)
Musculoskeletal I
E
D
Abnormal electrolyte(s) (↑Ca, rare)
E
Carpal tunnel syndrome (<10%)
E
Musculoskeletal pain (36%)
E
Osteoporosis (11%) (may be severe)
Nervous System D
Dizziness (8%)
Headache (10%)
E
E
Insomnia (10%)
E
Mood changes (19%)
Paresthesia (7%)
D
E
Ophthalmic Cataract (6%)
D
Reproductive and breast disorders Endometrial cancer (<1%)
D
Menopausal symptoms (36%)
Vaginal bleeding (6%)
E
E
Respiratory Cough, dyspnea (8%)
E
Vascular Vasculitis (rare)
E
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post­marketing, phase 1 studies, isolated data or anecdotal reports.
Dose­limiting side effects are underlined. ** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
Anastrozole has generally been well tolerated. Most effects are mild or moderate. The most common adverse events are gastrointestinal or musculoskeletal in nature or are expected effects such as hot flashes or vaginal dryness.
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In phase III studies comparing anastrozole versus megestrol acetate as second­line endocrine therapy for advanced breast cancer, the incidence of gastrointestinal symptoms, hot flashes, vaginal dryness and thromboembolic disease were similar among anastrozole and megestrol recipients. However, more patients treated with megestrol acetate reported weight gain as an adverse event compared to patients treated with anastrozole. Anastrozole had statistically significant lower incidences of hot flashes, vaginal bleeding/discharge, endometrial cancer, venous thromboembolism, and ischemic cerebrovascular events than tamoxifen. Joint pain/stiffness and fracture rates were significantly higher in the anastrozole arm
Patients treated with aromatase inhibitors may be at a higher risk for cardiovascular events (especially in patients with pre­existing ischemic heart disease) as well as osteoporosis. In the pivotal phase III trial comparing anastrozole and tamoxifen for adjuvant breast cancer, fracture rates were higher in the anastrozole group while on active treatment, but were not different after treatment completion. Consider calcium and vitamin D supplements in patients taking anastrozole, with the addition of bisphosphonates in patients with existing moderate or high risk fragility fracture/bone mineral density loss. For more information about bone health via dietary and lifestyle measures, see pamphlet on "Bone Health in Post Menopausal Women". Patients should be carefully monitored and treated appropriately.
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E ­ Dosing
Refer to protocol by which patient is being treated.
Adults:
Oral: 1mg Daily
Recommended treatment duration is 5 years in the adjuvant setting. Dosage with Toxicity:
Toxicity
Action
Myelosuppression
No adjustment required
Severe hypercalcemia
Hold; discontinue if recurs
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Dosage with Hepatic Impairment:
Clearance is reduced by 30% in patients with cirrhosis, but plasma levels are within normal range; no adjustment is required in mild to moderate hepatic impairment. Anastrozole has not been studied in patients with severe hepatic impairment ­ use with caution. Dosage with Renal Impairment:
Clearance is reduced by 50% in severe renal impairment. However, renal excretion is a minor route of excretion and no adjustment is required.
Dosage in the elderly:
No adjustment required.
Children:
Safety and efficacy not established.
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F ­ Administration Guidelines
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Oral self­administration; drug available by outpatient prescription. Swallow whole with a glass of water at the same time each day. Missed dose should be taken as soon as possible, but only if there are at least 12 hours before the next dose is due. back to top
G ­ Special Precautions
Other:
Anastrozole is contraindicated in patients with hypersensitivity to the drug or any of its components. Estrogen should not be co­administered. Use with caution in patients with known osteoporosis or risk factors for osteoporosis, in patients with pre­existing cardiovascular disorders, severe liver or renal impairment. Anastrozole has not been studied in patients with brain, leptomeningeal or pulmonary lymphangitic disease. Use of formulations containing lactose should be carefully considered in patients with hereditary galactose intolerance, severe lactase deficiency Any use of the information is subject, at all times, to CCO’s Terms and Conditions.
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or glucose­galactose malabsorption. Although anastrozole is non­teratogenic,non­mutagenic and non­clastogenic, it has shown carcinogenic effects, crosses the placenta and is fetotoxic. It is contraindicated in pregnant or lactating women. Anastrozole is not recommended for use in premenopausal women as safety and efficacy have not been established.
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H ­ Interactions
Antipyrine, cimetidine, tamoxifen and warfarin clinical interaction studies indicate that the co­
administration of anastrozole with other drugs is unlikely to result in clinically significant CYP450 drug interactions. In clinical studies, there was no evidence of an interaction when anastrozole is co­administered with warfarin or bisphosphonates.
AGENT
EFFECT
Tamoxifen
↓ anastrozole concentration (by 27%)
Estrogen­containing herbals, estrogen
↓ estrogen suppression
MECHANISM
Unknown
MANAGEMENT
Do not co­administer since no efficacy or safety benefit. Avoid
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I ­ Recommended Clinical Monitoring
Recommended Clinical Monitoring l
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Bone mineral density for patients at risk; baseline and routine
Clinical toxicity assessment for fatigue, musculoskeletal, estrogen withdrawal symptoms, rash, edema, thromboembolism, cardiovascular, GI and GU effects, etc.; baseline and routine
Grade toxicity using the current NCI­CTCAE (Common Terminology Criteria for Adverse Events) version Suggested Clinical Monitoring l
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Cholesterol and lipid evaluation; baseline and regular
Electrolytes, including calcium; baseline and as clinically indicated
Liver function tests; baseline and as clinically indicated
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J ­ Supplementary Public Funding
ODB Limited Use (ODB Formulary)
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An alternative to tamoxifen for the adjuvant treatment of postmenopausal women with hormone receptor positive breast cancer For the treatment of metastatic breast cancer in hormone receptor positive post­menopausal women back to top
K ­ References
ATAC Trialists Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early­stage breast cancer: 100­month analysis of the ATAC trial. Lancet Oncology 2008; 9(1): 45­53. ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005; 365: 60–2. McEvoy GK, editor.
AHFS Drug Information 2011. Bethesda: American Society of Health­System Pharmacists, p. 918­
23.
Nabholtz JM, Buzdar A, Pollak M et al. Anastrozole is superior to tamoxifen as first line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000 Nov 15;18(22):3758­67. Product Monograph: Arimidex® (anastrozole). AstraZeneca Canada, January 4, 2013.
March 2013: Added public funding info; revised Feb 2013 back to top
L ­ Disclaimer
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up­to­date public funding information.
Any use of the information is subject, at all times, to CCO’s Terms and Conditions.
CCO Formulary - March 2013
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The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary. The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time. Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as­is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability. CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary. back to top
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