Letrozole

Pronunciation

(LET roe zole)

U.S. Brand Names

Femara®

Generic Available

Canadian Brand Names

Femara®

Use

First-line treatment of hormone receptor positive or hormone receptor unknown, locally advanced, or metastatic breast cancer in postmenopausal women; treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy; extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy

Pregnancy Risk Factor

Pregnancy Implications

Letrozole may cause fetal harm when administered to pregnant women. Letrozole is embryotoxic and fetotoxic when administered to rats. There are no studies in pregnant women and letrozole is indicated for postmenopausal women.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to letrozole or any component of the formulation; pregnancy

Warnings/Precautions

Dose-related effects on hematologic or chemistry parameters have not been observed. Increases in transaminases

5 times the upper limit of normal and of bilirubin

1.5 times the upper limit of normal were most often, but not always, associated with metastatic liver disease. For use in postmenopausal women only.

Adverse Reactions

Note: Percentages reported with first- and second-line treatment of breast cancer.

>10%:

Cardiovascular: Hot flushes (5% to 19%)

Central nervous system: Headache (8% to 12%), fatigue (6% to 13%)

Gastrointestinal: Nausea (13% to 17%)

Neuromuscular & skeletal: Musculoskeletal pain, bone pain (22%), back pain (18%), arthralgia (8% to 16%)

Respiratory: Dyspnea (7% to 18%), cough (5% to 13%)

2% to 10%:

Cardiovascular: Chest pain (3% to 8%), peripheral edema (5%), hypertension (5% to 8%)

Central nervous system: Pain (5%), insomnia (7%), dizziness (3% to 5%), somnolence (2% to 3%), depression (<5%), anxiety (<5%), vertigo (<5%)

Dermatologic: Rash (4% to 5%), alopecia (<5%), pruritus (1% to 2%)

Endocrine & metabolic: Breast pain (7%), hypercholesterolemia (3%), hypercalcemia (<5%)

Gastrointestinal: Vomiting (7%), constipation (6% to 10%), diarrhea (5% to 8%), abdominal pain (5% to 6%), anorexia (3% to 5%), dyspepsia (3% to 4%), weight loss (7%), weight gain (2%)

Neuromuscular & skeletal: Weakness (4% to 6%)

Miscellaneous: Flu (6%)

<2%: Angina, cardiac ischemia, coronary artery disease, hemiparesis, hemorrhagic stroke, bilirubin increased, transaminases increased, lymphopenia, MI, portal vein thrombosis, pulmonary embolism, thrombocytopenia, thrombophlebitis, thrombotic stroke, transient ischemic attack, vaginal bleeding, venous thrombosis

Postmarketing and/or case reports: Blurred vision, hepatic enzymes increased

Overdosage/Toxicology

Firm recommendations for treatment are not possible; emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are appropriate.

Drug Interactions

Substrate (minor) of CYP2A6, 3A4; Inhibits CYP2A6 (strong), 2C19 (weak)

CYP2A6 substrates: Letrozole may increase the levels/effects of CYP2A6 substrates. Example substrates include dexmedetomidine and ifosfamide.

Stability

Store at 15°C to 30°C (59°F to 86°F)

Mechanism of Action

Competitive inhibitor of the aromatase enzyme system which binds to the heme group of aromatase, a cytochrome P450 enzyme which catalyzes conversion of androgens to estrogens (specifically, androstenedione to estrone and testosterone to estradiol). This leads to inhibition of the enzyme and a significant reduction in plasma estrogen levels. Does not affect synthesis of adrenal or thyroid hormones, aldosterone, or androgens.

Pharmacodynamics/Kinetics

Absorption: Well absorbed; not affected by food

Distribution: Vd: ~1.9 L/kg

Protein binding, plasma: Weak

Metabolism: Hepatic via CYP3A4 and CYP2A6 to an inactive carbinol metabolite

Half-life elimination: Terminal: ~2 days

Time to steady state, plasma: 2-6 weeks

Excretion: Urine (6% as unchanged drug, 75% as glucuronide carbinol metabolite)

Dosage

Oral (refer to individual protocols): Adults: Breast cancer: 2.5 mg once daily

Elderly: No dosage adjustments required

Dosage adjustment in renal impairment: No dosage adjustment is required in patients with renal impairment if Clcr 10 mL/minute

Dosage adjustment in hepatic impairment:

Mild-to-moderate impairment: No adjustment recommended

Severe impairment: Child-Pugh class C: 2.5 mg every other day

Monitoring Parameters

Monitor periodically during therapy: complete blood counts, thyroid function tests; serum electrolytes, transaminases, and creatinine; bone density

Dietary Considerations

May be taken without regard to meals. Calcium and vitamin D supplementation are recommended.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed, without regard to food. You may experience nausea, vomiting, hot flashes, or loss of appetite (frequent mouth care, small, frequent meals, chewing gum, or sucking lozenges may help); musculoskeletal pain or headache (mild analgesics may offer relief); sleepiness, fatigue, or dizziness (use caution when driving, climbing stairs, or engaging in tasks that require alertness until response to drug is known); constipation (increased exercise, or dietary fruit or fluids may help); diarrhea (buttermilk, boiled milk, or yogurt may help); or loss of hair (will grow back). Report chest pain, pressure, palpitations, or swollen extremities; weakness, severe headache, numbness, or loss of strength in any part of the body; difficulty speaking; vaginal bleeding; unusual signs of bleeding or bruising; respiratory difficulty; severe nausea; or muscle pain; or skin rash. For use in postmenopausal women only.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause drowsiness or dizziness

Mental Health: Effects on Psychiatric Treatment

None reported

Oncology: Emetic Potential

Low (10% to 30%)

Dosage Forms

Tablet: 2.5 mg

References

Bisagni G, Cocconi G, Scaglione F, et al, "Letrozole, a New Oral Nonsteroidal Aromatase Inhibitor in Treating Postmenopausal Patients With Advanced Breast Cancer. A Pilot Study," Ann Oncol , 1996, 7(1):99-102.

Boeddinghaus IM and Dowsett M, "Comparative Clinical Pharmacology and Pharmacokinetic Interactions of Aromatase Inhibitors," J Steroid Biochem Mol Biol , 2001, 79(1-5):85-91.

Buzdar AU, Robertson JF, Eiermann W, et al, "An Overview of the Pharmacology and Pharmacokinetics of the Newer Generation Aromatase Inhibitors Anastrozole, Letrozole, and Exemestane," Cancer , 2002, 95(9):2006-16.

Cunnick GH and Mokbel K, "Aromatase Inhibitors," Curr Med Res Opin , 2001, 17(3):217-22.

Ingle JN, Johnson PA, Suman VJ, et al, "A Randomized Phase II Trial of Two Dosage Levels of Letrozole as Third-Line Hormonal Therapy for Women With Metastatic Breast Carcinoma," Cancer , 1997, 80(2):218-24.

Lamb HM and Adkins JC, "Letrozole. A Review of its Use in Postmenopausal Women With Advanced Breast Cancer," Drugs , 1998, 56(6):1125-40.

Lipton A, Demers LM, Harvey HA, et al. "Letrozole (CGS 20267). A Phase I Study of a New Potent Oral Aromatase Inhibitor of Breast Cancer," Cancer , 1995, 75(8):2132-8.

Lonning PE, "Aromatase Inhibition for Breast Cancer Treatment," Acta Oncol , 1996, 35(Suppl 5):38-43.

Mays-Holland T, "Drug Update: Letrozole: A New Aromatase Inhibitor for Metastatic Breast Cancer," Cancer Pract , 1998, 6(6):349-52.

Njar VC and Brodie AM, "Comprehensive Pharmacology and Clinical Efficacy of Aromatase Inhibitors," Drugs , 1999, 58(2):233-55.

Shaw HS and Ellis MJ, "Letrozole in the Treatment of Breast Cancer," Expert Opin Pharmacother , 2002, 3(5):607-17.

Trunet PF, Bhatnagar AS, Chaudri HA, et al, "Letrozole (CGS 20267), a New Oral Aromatase Inhibitor for the Treatment of Advanced Breast Cancer in Postmenopausal Patients," Acta Oncol , 1996, 35(Suppl 5):15-8.

International Brand Names

Fecinole® (AR); Femara® (AR, AT, AU, BE, BR, CA, CH, CL, CO, CR, CZ, DE, DO, EC, ES); Fémara® (FR); Femara® (GB, GT, HN, HR, HU, ID, IE, IL, IT, NL, NZ, PA, PL, PT, RO, RU, SG, SV, TH, TR, YU); Femar® (DK, FI, NO, SE); Trozet® (IN)

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