No

Antineoplastic Agent, Miscellaneous; Aromatase Inhibitor

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

D

Clinical effects on the fetus: 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.

Breast-feeding/lactation: It is not known if letrozole is excreted in breast milk; exercise caution when letrozole is administered to nursing women

Hypersensitivity to letrozole or any of its excipients

Letrozole was not mutagenic in in vitro tests but was observed to be a potential clastogen in in vitro assays. Repeated dosing caused sexual inactivity in females and atrophy in the reproductive tract in males and females at doses of 0.6 mg/kg, 0.1 mg/kg, and 0.03 mg/kg in mice, rats, and dogs, respectively (~1 mg/kg, 0.4 mg/kg, and 0.4 mg/kg the maximum recommended human doses, respectively).

Increases in AST, ALT, and GGT greater than or equal to 5 times the upper limit of normal (ULN) and of bilirubin greater than or equal to 1.5 times the ULN were most often associated with metastatic disease in the liver.

>10%: Gastrointestinal: Nausea

1% to 10%:

Central nervous system: Headache, somnolence, dizziness

Dermatologic: Hot flashes, rash, pruritus

Gastrointestinal: Vomiting, constipation, diarrhea, abdominal pain, anorexia, dyspepsia

Neuromuscular: Arthralgia

Respiratory: Dyspnea, coughing

<1%: Thromboembolic events, vaginal bleeding

No experience with letrozole overdose has been reported. In single-dose studies, the highest dose used was 30 mg, which was well tolerated. Lethality was observed in mice and rats following single oral doses that were greater than or equal to 2000 mg/kg (~4000 to 8000 times the maximum daily doses recommended in humans); death was associated with reduced motor activity, ataxia, and dyspnea. Lethality was observed in cats following single I.V. doses that were greater than or equal to 10 mg/kg (~50 times the maximum daily dose recommended in humans): death was preceded by depressed blood pressure and arrhythmias.

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.

CYP3A3/4 and 2A6 enzyme substrate; CYP2A6 and 2C19 enzyme inhibitor

Nonsteroidal, competitive inhibitor of the aromatase enzyme system which binds to the heme group of aromatase, a cytochrome P-450 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. Approximately 30% of breast cancers are sensitive to this estrogen deprivation.

Absorption: Well absorbed from GI tract; not affected by food

Distribution: V_d: ~1.9 L/kg

Protein binding, plasma: Weakly bound

Metabolism: In the liver to a pharmacologically inactive carbinol metabolite

Half-life: Terminal elimination: ~2 days

Time to steady state plasma concentrations: 2-6 weeks

Elimination: Renally of the glucuronide conjugate of the metabolite; ~90% of letrozole is recovered in urine

Oral (refer to individual protocols):

Dosage adjustment in renal impairment: No dosage adjustment is required in patients with renal impairment if Cl_cr greater than or equal to 10 mL/minute

Dosage adjustment in hepatic impairment: No dosage adjustment is recommended for patients with mild-to-moderate hepatic impairment. Patients with severe impairment of liver function have not been studied; dose patients with severe impairment of liver function with caution.

Clinical/radiologic evidence of tumor regression in advanced breast cancer patients. Until the toxicity has been defined in larger patient populations, monitor the following laboratory tests periodically during therapy: complete blood counts, thyroid function tests, serum electrolytes, serum transaminases, and serum creatinine.

May cause drowsiness or dizziness

None reported

No information available to require special precautions

No effects or complications reported

Take as directed, without regard to food. You may experience nausea, vomiting, or loss of appetite (frequent mouth care, frequent small 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 (boiled milk or yogurt may help); loss of hair (will grow back). Report chest pain, palpitations, or swollen extremities; vaginal bleeding or hot flashes; unusual coughing or difficulty breathing; severe nausea; muscle pain; or skin rash. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Breast-feeding is not recommended.

Tablet: 2.5 mg

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.

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.

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.

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.