DESCRIPTION

 MECHANISM OF ACTION

• Nonsteroidal, competitive inhibitor of aromatase. Nearly 200-fold more potent than aminoglutethimide.

• Inhibits synthesis of estrogens by inhibiting the conversion of adrenal androgens (androstenedione and testosterone) to estrogens (estrone, estrone sulfate, and estradiol). Serum estradiol levels are suppressed by 90% within 14 days and nearly completely suppressed after 6 weeks of therapy.

• No inhibitory effect on adrenal corticosteroid biosynthesis

ABSORPTION

Rapidly and completely absorbed after oral administration. Food does not interfere with oral absorption.

DISTRIBUTION

Significant uptake in peripheral tissues and in breast cancer cells.

INDICATIONS

1. First-line treatment of postmenopausal women with hormone-receptor- positive or hormone-receptor-unknown locally advanced or metastatic breast cancer.

2. Second-line treatment of postmenopausal women with advanced breast cancer after progression on antiestrogen therapy.

3. Adjuvant treatment of postmenopausal women with hormone-receptor- positive early-stage breast cancer.

4. Extended adjuvant treatment of early-stage breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy.

DOSAGE RANGE

1. Metastatic disease: 2.5 mg PO qd until disease progression

2. Adjuvant setting: 2.5 mg PO qd until disease relapse

DRUG INTERACTION 1

Phenytoin and other drugs that stimulate the liver microsomal CYP3A4 enzymes, including carbamazepine, rifampin, phenobarbital, and St. John’s Wort. These drugs may increase the rate of metabolism of letrozole, resulting in its inactivation and lower effective drug levels.

DRUG INTERACTION 2

Drugs that inhibit the liver microsomal CYP3A4 enzymes, including ketoconazole, itraconazole, erythromycin, and clarithromycin. These drugs may decrease the rate of metabolism of letrozole, resulting in increased drug levels and potentially increased toxicity.

DRUG INTERACTION 3

Warfarin—Patients receiving coumarin-derived anticoagulants should be closely monitored for alterations in their clotting parameters (PT and INR) and/or bleeding, as letrozole may inhibit the metabolism of warfarin by the liver P450 system. The dose of warfarin may require careful adjustment in the presence of letrozole therapy.

DRUG INTERACTION Ł

Clopidogrel (Plavix)—Letrozole therapy may reduce the clinical efficacy of clopidogrel, as it is an inhibitor of CYP2C19, which is required for activation of clopidogrel.

SPECIAL CONSIDERATIONS

1. Letrozole is indicated only for postmenopausal women. Efficacy in premenopausal women has not been established, and there may be an increased risk of benign ovarian tumors and cystic ovarian disease in this              population.

2. Use with caution in patients with abnormal liver function. Monitor liver function at baseline and periodically during therapy. The dose should be reduced by 50% in patients with cirrhosis and severe hepatic dysfunction. In this setting, the recommended dose is 2.5 mg PO every other day.

3. No need for glucocorticoid and/or mineralocorticoid replacement.

4. Closely monitor women with osteoporosis or at risk of osteoporosis by performing bone densitometry at the start of therapy and at regular intervals. Treatment or prophylaxis for osteoporosis should be initiated when appropriate.

5. Letrozole can be taken with or without food.

6. Pregnancy category D. Breastfeeding should be avoided.

TOXICITY 1.

Mild musculoskeletal pains and arthralgias are the most common adverse events.

TOXICITY 2

Headache and fatigue.

TOXICITY 3

Mild nausea with less frequent vomiting and anorexia.

TOXICITY Ł

Hot flashes occur in less than 10% of patients.

TOXICITY 5

Mild elevation in serum transaminases and serum bilirubin. Most often seen in patients with established metastatic disease in the liver.

TOXICITY 6

Thromboembolic events are rarely observed.

SPECIFICATION