Anastrozole

Class: Antiestrogens
- Aromatase Inhibitors
VA Class: AN900
Chemical Name: α,α,α′,α′-Tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-benzenediacetonitrile
Molecular Formula: C₁₇H₁₉N₅
CAS Number: 120511-73-1
Brands: Arimidex

Medically reviewed by Drugs.com on Jan 11, 2021. Written by ASHP.

Introduction

Antineoplastic agent; selective aromatase inhibitor (type II).

Uses for Anastrozole

Early-stage Breast Cancer in Postmenopausal Women

Initial (primary) adjuvant therapy in postmenopausal women with early-stage hormone receptor-positive breast cancer.

Sequential adjuvant therapy† following 2–3 years of adjuvant tamoxifen for early-stage hormone receptor-positive breast cancer in postmenopausal women.

Extended adjuvant therapy† following 5 years of adjuvant tamoxifen for early-stage hormone receptor-positive breast cancer in postmenopausal women.

Aromatase inhibitors are a treatment of choice for adjuvant hormonal therapy to lower risk of breast cancer recurrence in postmenopausal women with early-stage hormone receptor-positive breast cancer. An aromatase inhibitor-containing regimen is modestly more effective than tamoxifen alone.

ASCO states that most postmenopausal women with early-stage hormone receptor-positive breast cancer should consider receiving an aromatase inhibitor during the course of adjuvant therapy, either as primary (initial) therapy or following 2–3 years of tamoxifen (sequential therapy), for a total of 5 years of adjuvant endocrine therapy. Data also support switching to an aromatase inhibitor following 5 years of adjuvant tamoxifen (extended adjuvant therapy). ASCO states that women who receive extended adjuvant therapy should receive tamoxifen for 5 years followed by an aromatase inhibitor for 3–5 years.

Consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen. Joint disorders (arthritis, arthrosis, arthralgia), fractures, and elevated cholesterol reported more frequently in patients receiving adjuvant anastrozole, whereas adverse gynecologic effects (endometrial cancer, vaginal discharge, vaginal bleeding), hot flushes, ischemic cerebrovascular events, and venous thromboembolism reported more frequently in those receiving adjuvant tamoxifen.

Early-stage Breast Cancer in Premenopausal Women

Use of endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) in combination with ovarian suppression† as adjuvant therapy in premenopausal women† with early-stage hormone receptor-positive breast cancer may be considered a reasonable choice (accepted).

Advanced Breast Cancer in Postmenopausal Women

First-line therapy for hormone receptor-positive (i.e., estrogen receptor-positive, progesterone receptor-positive, or both) or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women.

Second-line therapy for advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Usually ineffective in patients with estrogen receptor-negative breast cancer and those who fail tamoxifen therapy.

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

Has been used for reduction in the incidence of breast cancer† in women at high risk for developing the disease.

Anastrozole Dosage and Administration

General

Administration of corticosteroid replacement therapy not necessary. (See Actions.)

Administration

Oral Administration

Administer orally once daily without regard to meals.

Dosage

Adults

Breast Cancer

Adjuvant Therapy for Early-stage Breast Cancer in Postmenopausal Women

Oral

1 mg once daily.

Initial adjuvant therapy: Optimum duration unknown; duration of therapy in clinical study was 5 years. In patients who discontinue aromatase inhibitor therapy prior to 5 years, ASCO recommends consideration of tamoxifen to complete the 5-year adjuvant regimen.

Sequential adjuvant therapy†: Optimal time to switch from tamoxifen to aromatase inhibitor therapy is unknown. ASCO states that disease-free patients may switch to an aromatase inhibitor after 2–3 years of adjuvant tamoxifen therapy to complete a 5-year sequential adjuvant regimen.

Extended adjuvant therapy†: 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.

Adjuvant Therapy for Early-stage Breast Cancer in Premenopausal Women†

Oral

Dosage of 1 mg once daily has been used in combination with ovarian suppression†.

In clinical studies, ovarian suppression achieved with goserelin 3.6 mg implanted sub-Q every 4 weeks, leuprolide acetate 3.75 mg by IM injection every 4 weeks, triptorelin 3.75 mg by IM injection every 4 weeks, or surgical or radiation ablation.

First-line Therapy for Advanced Breast Cancer in Postmenopausal Women

Oral

1 mg once daily. Continue therapy until tumor progresses.

Second-line Therapy for Advanced Breast Cancer in Postmenopausal Women

Oral

1 mg once daily. Continue therapy until tumor progresses.

Prescribing Limits

Adults

Breast Cancer

Adjuvant Treatment of Early-stage Breast Cancer in Postmenopausal Women

Oral

Maximum 5 years of aromatase inhibitor therapy; toxicity beyond 5 years not established.

Special Populations

Hepatic Impairment

Dosage adjustment not required in patients with mild to moderate hepatic impairment or stable hepatic cirrhosis. (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe hepatic impairment.

Renal Impairment

Dosage adjustment not required. (See Special Populations under Pharmacokinetics.)

Geriatric Patients

Dosage adjustment not required. (See Special Populations under Pharmacokinetics.)

Cautions for Anastrozole

Contraindications

Known hypersensitivity to anastrozole or any ingredient in the formulation.

Warnings/Precautions

Ischemic Cardiovascular Effects

Increased incidence of ischemic cardiovascular events (e.g., angina pectoris) reported in patients with preexisting ischemic heart disease; consider risks and benefits of therapy in these patients.

Effects on Bone

Postmenopausal women receiving an aromatase inhibitor as adjuvant therapy are at high risk for osteoporosis.

Bone mineral density (BMD) at lumbar spine and hip decreased in patients receiving anastrozole and increased in those receiving tamoxifen as initial (primary) adjuvant therapy. Incidence of fractures was higher with anastrozole versus tamoxifen during treatment, but not following completion of treatment.

Evaluate all postmenopausal women initiating adjuvant aromatase inhibitor therapy for risk of osteoporotic fractures; determine BMD and assess 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). Closely monitor patients for changes in risk status during therapy, and assess BMD at regular intervals (e.g., every 1–2 years in those with osteopenia or osteoporosis). Consider other potential causes of osteoporosis (e.g., vitamin D deficiency, hyperthyroidism, hyperparathyroidism, hypercalciuria).

Initiate appropriate therapy to prevent bone loss as clinically indicated. Base decision to initiate antiresorptive therapy (e.g., bisphosphonate, denosumab) on overall risk of fracture and rate of bone loss.

Lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation in alcohol consumption) and supplemental calcium and vitamin D recommended in all women receiving adjuvant anastrozole therapy.

Lipid Effects

Increases in total serum cholesterol reported during therapy; consider monitoring serum cholesterol.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryotoxic and fetotoxic in animals. Test for pregnancy prior to initiation of the drug. Advise females of reproductive potential to use effective contraceptive methods during therapy and for ≥3 weeks after discontinuance of the drug. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Sensitivity Reactions

Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria) reported rarely.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether anastrozole or its metabolites are distributed into human milk; effects on nursing infant and milk production also unknown. Discontinue nursing during therapy and for 2 weeks after drug discontinuance.

Pediatric Use

Has been used in clinical studies of adolescent boys 11–18 years of age with pubertal gynecomastia† and in girls 2 to <10 years of age with McCune-Albright syndrome and progressive precocious puberty†; however, efficacy not established for these indications.

Geriatric Use

For adjuvant treatment of hormone receptor-positive early-stage breast cancer, efficacy (e.g., disease-free survival benefit) in women ≥65 years of age was less than efficacy observed in postmenopausal women <65 years of age.

No substantial differences in efficacy for patients ≥65 years of age relative to younger adults when used as second line therapy for advanced breast cancer; moderately greater efficacy observed for patients ≥65 years of age when used as first-line therapy for locally advanced or metastatic breast cancer.

Hepatic Impairment

Not studied in patients with severe hepatic impairment.

Common Adverse Effects

Initial adjuvant therapy: Vasodilation, hot flushes (flashes), fatigue/asthenia, mood disturbance, pain, arthritis, arthralgia.

Advanced-stage disease: GI disturbance (e.g., nausea), hot flushes, vasodilation, nausea, asthenia.

Interactions for Anastrozole

Inhibits CYP1A2, 2C8/9, and 3A4 in vitro, but only at relatively high concentrations. Does not inhibit CYP2A6 or CYP2D6 in vitro. Pharmacokinetic interaction unlikely with drugs metabolized by CYP isoenzymes at recommended dosages.

Specific Drugs

Drug	Interaction	Comment
Antipyrine	Pharmacokinetic interaction unlikely
Estrogens	Antagonistic pharmacologic effects	Concomitant use not recommended
Raloxifene	Possible decreased plasma anastrozole concentrations	Concomitant use not recommended Oral bisphosphonate (rather than raloxifene) is recommended if osteoporosis therapy is required
Tamoxifen	Possible decreased plasma anastrozole concentrations; concomitant use does not improve efficacy	Concomitant use not recommended
Warfarin	No clinically important effects on anticoagulant activity or pharmacokinetics of warfarin

Anastrozole Pharmacokinetics

Absorption

Bioavailability

Rapidly and well absorbed after oral administration, with peak plasma concentrations usually attained within 2 hours under fasting conditions.

Steady-state plasma concentrations achieved in about 7 days.

Onset

Serum estradiol concentrations reduced by approximately 70% within 24 hours of a 1-mg dose and by approximately 80% after 14 days of daily dosing.

Duration

Suppression of serum estradiol concentrations maintained for up to 6 days after discontinuance of daily anastrozole administration.

Food

Food reduces rate but does not affect extent of absorption.

Distribution

Extent

Anastrozole crosses the placenta in animals; not known whether anastrozole crosses the placenta in humans.

Not known whether anastrozole is distributed into milk.

Plasma Protein Binding

40%.

Elimination

Metabolism

Undergoes N-dealkylation, hydroxylation, and glucuronidation in the liver to multiple, pharmacologically inactive, metabolites.

Elimination Route

Hepatic metabolism (85%) and renal excretion (10%).

Half-life

Approximately 50 hours.

Special Populations

No evidence of altered pharmacokinetics observed in women >80 years of age compared with women <50 years of age.

Individuals with severe renal impairment (Cl_cr <30 mL/minute): Renal clearance decreased by approximately 50%, but total body clearance decreased by only 10%.

Individuals with stable hepatic cirrhosis (related to alcohol abuse): Clearance reduced by approximately 30% compared with those with normal hepatic function; however, plasma concentrations within range compared with individuals with normal hepatic function.

Stability

Storage

Oral

Tablets

20–25°C.

Actions

Selectively inhibits conversion of androgens to estrogens.
Decreased serum and tumor concentrations of estrogen inhibit breast tumor growth and delay disease progression.
Does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.

Advice to Patients

Importance of providing patient with a copy of the manufacturer’s patient information.
Risk of osteoporosis. Lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation of alcohol consumption) and dietary supplementation with calcium and vitamin D advised. Importance of BMD monitoring.
Risk of fetal harm if used during pregnancy. Necessity of advising females of reproductive potential to use effective contraception during anastrozole therapy and for ≥3 weeks after the last dose. Importance of women informing clinicians immediately if they become pregnant or pregnancy is suspected during therapy. If pregnancy occurs, advise pregnant women of potential risk to the fetus.
Importance of advising women to avoid breast-feeding while receiving anastrozole and for 2 weeks following discontinuance of therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., estrogens, raloxifene, tamoxifen), and OTC drugs, as well as any concomitant illnesses.
Increased risk of ischemic cardiovascular events in patients with preexisting ischemic heart disease.
Importance of immediately informing clinician if manifestations of a serious allergic reaction (e.g., swelling of face, lips, tongue, and/or throat; difficulty in swallowing and/or breathing) occur.
Risk of hypercholesterolemia. Importance of lipoprotein monitoring.
Risk of carpal tunnel syndrome. Importance of informing clinician if tickling, tingling, or numbness occurs.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name