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Anastrozole

Pronunciation

Pronunciation

(an AS troe zole)

Index Terms

  • ICI-D1033
  • ZD1033

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Arimidex: 1 mg

Generic: 1 mg

Brand Names: U.S.

  • Arimidex

Pharmacologic Category

  • Antineoplastic Agent, Aromatase Inhibitor

Pharmacology

Potent and selective nonsteroidal aromatase inhibitor. By inhibiting aromatase, the conversion of androstenedione to estrone, and testosterone to estradiol, is prevented, thereby decreasing tumor mass or delaying progression in patients with tumors responsive to hormones. Anastrozole causes an 85% decrease in estrone sulfate levels.

Absorption

Well absorbed; extent of absorption not affected by food

Metabolism

Extensively hepatic (~85%) via N-dealkylation, hydroxylation, and glucuronidation; primary metabolite (triazole) inactive

Excretion

Feces; urine (urinary excretion accounts for ~10% of total elimination, mostly as metabolites)

Onset of Action

Onset of estradiol reduction: 70% reduction after 24 hours; 80% after 2 weeks of therapy

Time to Peak

Plasma: ~2 hours without food; 5 hours with food

Duration of Action

Duration of estradiol reduction: 6 days

Half-Life Elimination

~50 hours

Protein Binding

Plasma: 40%

Special Populations: Renal Function Impairment

Renal clearance is decreased proportionally with CrCl and was approximately 50% lower in those with severe renal function impairment (CrCl less than 30 mL/minute per 1.73 m2); this reduced total body clearance by 10%.

Special Populations: Hepatic Function Impairment

Oral clearance was approximately 30% lower in those with stable hepatic cirrhosis, but plasma concentrations were within normal range.

Use: Labeled Indications

Breast cancer:

First-line treatment of locally-advanced or metastatic breast cancer (hormone receptor-positive or unknown) in postmenopausal women

Adjuvant treatment of early hormone receptor-positive breast cancer in postmenopausal women

Treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy

Off Label Uses

Endometrial or uterine cancers (recurrent or metastatic)

Hormonal agents such as progestational agents or tamoxifen may be used in the management of recurrent or metastatic endometrial cancer. In select patients, aromatase inhibitors, including anastrozole may be considered. A small phase II trial evaluated anastrozole in a group of unselected patients with advanced recurrent or persistent endometrial cancer; the results showed minimal activity of anastrozole [Rose 2000]. A retrospective analysis of patients with uterine leiomyosarcoma suggests that, in patients with low disease burden and an indolent course (who are estrogen- or progesterone-receptor positive), hormone blockade with an aromatase inhibitor such as anastrozole may be considered [O'Cearbhaill 2010]. Additional data is necessary to further define the role of anastrozole in the treatment of these conditions.

Ovarian cancer (recurrent)

Hormonal therapy, including aromatase inhibitors such as anastrozole, may be considered in patients with recurrent ovarian cancer who cannot tolerate or have not responded to other chemotherapy regimens. Data from a small phase II study in patients with ovarian cancer suggests that anastrozole may lead to a response in a small number of patients, and is well tolerated [del Carmen 2003]. Additional data is necessary to further define the role of anastrozole in the treatment of this condition.

Risk reduction for breast cancer in postmenopausal women

Data from a large international, randomized, placebo-controlled, double-blind phase III study (IBIS-II) supports the use of anastrozole in the prevention of breast cancer in high-risk postmenopausal women [Cuzick 2014].

Contraindications

Hypersensitivity to anastrozole or any component of the formulation; use in women who are or may become pregnant

Canadian labeling: Additional contraindications (not in US labeling): Lactating women

Dosing: Adult

Breast cancer, advanced: Postmenopausal females: Oral: 1 mg once daily; continue until tumor progression

Breast cancer, early (adjuvant treatment): Postmenopausal females: Oral: 1 mg once daily.

Duration of therapy: The American Society of Clinical Oncology (ASCO) guidelines for Adjuvant Endocrine Therapy of Hormone-Receptor Positive Breast Cancer (Focused Update) recommend a maximum duration of 5 years of aromatase inhibitor (AI) therapy for postmenopausal women; AIs may be combined with tamoxifen for a total duration of up to 10 years of endocrine therapy. Refer to the guidelines for specific recommendations based on menopausal status and tolerability (Burstein 2014). In a phase III study with another AI (letrozole), treatment with an additional 5 years of AI therapy (for a total of 10 years of AI therapy) demonstrated a significantly improved rate of disease-free survival and a decreased risk of disease recurrence and contralateral breast cancer (when compared to placebo), although overall survival was not significantly different between groups and bone-related adverse events occurred more frequently with letrozole versus placebo (Goss 2016).

Breast cancer, risk reduction (off-label use): Postmenopausal females ≥40 years: Oral: 1 mg once daily for 5 years (Cuzick 2014)

Endometrial or uterine cancer, recurrent or metastatic (off-label use): Oral: 1 mg once daily (Rose 2000)

Ovarian cancer, recurrent (off-label use): Oral: 1 mg once daily until disease progression or unacceptable toxicity (del Carmen 2003)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild to moderate impairment or stable hepatic cirrhosis: No dosage adjustment necessary.

Severe hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Administration

May be administered with or without food.

Storage

Store at 20°C to 25°C (68°F to 77°F).

Drug Interactions

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Estrogen Derivatives: May diminish the therapeutic effect of Anastrozole. Avoid combination

Methadone: Aromatase Inhibitors may increase the serum concentration of Methadone. Monitor therapy

Tamoxifen: May decrease the serum concentration of Anastrozole. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Vasodilatation (25% to 36%), ischemic heart disease (4%; 17% in patients with pre-existing ischemic heart disease), hypertension (2% to 13%), angina pectoris (2%; 12% in patients with pre-existing ischemic heart disease), edema (7% to 11%)

Central nervous system: Fatigue (19%), mood disorder (19%), headache (9% to 18%), pain (11% to 17%), depression (2% to 13%)

Dermatologic: Skin rash (6% to 11%)

Endocrine & metabolic: Hot flash (12% to 36%)

Gastrointestinal: Gastrointestinal distress (29% to 34%), nausea (11% to 20%), vomiting (8% to 13%)

Neuromuscular & skeletal: Weakness (13% to 19%), arthritis (17%), arthralgia (2% to 15%), back pain (10% to 12%), ostealgia (6% to 12%), osteoporosis (11%)

Respiratory: Pharyngitis (6% to 14%), dyspnea (8% to 11%), increased cough (7% to 11%)

1% to 10%:

Cardiovascular: Peripheral edema (5% to 10%), chest pain (5% to 7%), venous thrombosis (2% to 4%; including pulmonary embolism, thrombophlebitis, retinal vein thrombosis), myocardial infarction (1%)

Central nervous system: Insomnia (2% to 10%), dizziness (5% to 8%), paresthesia (5% to 7%), anxiety (2% to 6%), confusion (2% to 5%), drowsiness (2% to 5%), malaise (2% to 5%), nervousness (2% to 5%), carpal tunnel syndrome (3%), hypertonia (3%), cerebrovascular insufficiency (2%), lethargy (1%)

Dermatologic: Alopecia (2% to 5%), pruritus (2% to 5%), diaphoresis (1% to 5%)

Endocrine & metabolic: Hypercholesterolemia (9%), increased serum cholesterol (9%), weight gain (2% to 9%), increased gamma-glutamyl transferase (2% to 5%), weight loss (2% to 5%)

Gastrointestinal: Constipation (7% to 9%), diarrhea (7% to 9%), abdominal pain (6% to 9%), anorexia (5% to 8%), dyspepsia (7%), gastrointestinal disease (7%), xerostomia (4% to 6%)

Genitourinary: Mastalgia (2% to 8%), urinary tract infection (2% to 8%), pelvic pain (5% to 7%), vulvovaginitis (6%), vaginal dryness (1% to 5%), vaginal hemorrhage (1% to 5%), vaginal discharge (4%), vaginitis (4%), leukorrhea (2% to 3%)

Hematologic & oncologic: Lymphedema (10%), breast neoplasm (5%), neoplasm (5%), anemia (2% to 5%), leukopenia (2% to 5%), tumor flare (3%)

Hepatic: Increased serum alkaline phosphatase (2% to 5%), increased serum ALT (2% to 5%), increased serum AST (2% to 5%)

Infection: Infection (2% to 9%)

Neuromuscular & skeletal: Bone fracture (1% to 10%), arthrosis (7%), myalgia (2% to 6%), neck pain (2% to 5%), pathological fracture (2% to 5%)

Ophthalmic: Cataract (6%)

Respiratory: Flu-like symptoms (2% to 7%), sinusitis (2% to 6%), bronchitis (2% to 5%), rhinitis (2% to 5%)

Miscellaneous: Accidental injury (2% to 10%), cyst (5%), fever (2% to 5%)

<1% (Limited to important or life-threatening): Anaphylaxis, angioedema, cerebral infarction, cerebral ischemia, dermal ulcer, endometrial carcinoma, erythema multiforme, hepatitis, hepatomegaly, hypercalcemia, hypersensitivity angiitis (including anaphylactoid purpura [IgA vasculitis]), jaundice, joint stiffness, pulmonary embolism, retinal thrombosis, skin blister, skin lesion, Stevens-Johnson syndrome, tenosynovitis (stenosing), urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Decreased bone mineral density: Due to decreased circulating estrogen levels, anastrozole is associated with a reduction in bone mineral density (BMD); decreases (from baseline) in total hip and lumbar spine BMD have been reported. Patients with preexisting osteopenia are at higher risk for developing osteoporosis (Eastell 2008). When initiating anastrozole treatment, follow available guidelines for bone mineral density management in postmenopausal women with similar fracture risk; concurrent use of bisphosphonates may be useful in patients at risk for fractures.

• Hypercholesterolemia: Elevated total cholesterol levels (contributed to by LDL cholesterol increases) have been reported in patients receiving anastrozole; use with caution in patients with hyperlipidemias. Cholesterol levels should be monitored/managed in accordance with current guidelines for patients with LDL elevations.

Disease-related concerns:

• Hepatic impairment: Plasma concentrations in patients with stable hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Has not been studied in patients with severe hepatic impairment.

• Ischemic disease: Patients with preexisting ischemic cardiac disease have an increased risk for ischemic cardiovascular events.

Special populations:

• Pregnancy: Use is contraindicated in women who are or may become pregnant.

• Premenopausal women: Anastrozole offers no clinical benefit in premenopausal women with breast cancer.

Monitoring Parameters

Bone mineral density; total cholesterol and LDL

Breast cancer risk reduction (off-label use): Bone mineral density at baseline, mammograms, and clinical breast exam at baseline and at least every 2 years (Cuzick, 2014)

Pregnancy Risk Factor

X

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Anastrozole is contraindicated in women who are or may become pregnant (may cause fetal harm if administered during pregnancy). Use in premenopausal women with breast cancer does not provide any clinical benefit.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flushing, nausea, vomiting, joint pain, joint edema, insomnia, cough, pharyngitis, or back pain. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of high calcium (weakness, confusion, fatigue, headache, nausea and vomiting, constipation, or bone pain), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), shortness of breath, excessive weight gain, swelling of arms or legs, severe headache, burning or numbness feeling, angina, abnormal heartbeat, mood changes, severe dizziness, passing out, polyuria, difficult urination, severe loss of strength and energy, enlarged lymph nodes, vaginal bleeding, or vaginitis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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