Letrozole (letrozole)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Letrozole, an aromatase inhibitor, is an antineoplastic agent.
Letrozole, a benzyltriazole derivative, is a selective, nonsteroidal aromatase inhibitor. Letrozole differs structurally from aminoglutethimide but shares the pharmacologic activity of competitive aromatase inhibition; although both drugs are selective nonsteroidal inhibitors, letrozole is more potent and selective on a molar basis. Competitive aromatase inhibitors also have been referred to as type II inhibitors of the enzyme.
Like anastrozole, letrozole is a triazole derivative. The N-4 nitrogen of the triazole ring, which coordinates with the heme iron atom of the aromatase enzyme complex, is thought to be responsible for the high affinity of the drug for the estrogen synthetase enzyme.
The growth of some breast cancers is stimulated or maintained by estrogens; in these cancers, decreasing estrogen levels or inhibiting estrogen effects can lead to decreased tumor mass or delayed cancer progression. In postmenopausal women, estrogens are primarily produced through the action of aromatase enzymes, which convert adrenal androgens (e.g., androstenedione, testosterone) to estrone and estradiol. Letrozole selectively inhibits synthesis of estrogens via inhibition of the aromatase enzyme; it does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.
Suppression of plasma concentrations of estradiol, estrone, and estrone sulfate by 75-95% from baseline, with maximal suppression achieved within 2-3 days, has been observed in postmenopausal women with advanced breast cancer receiving daily letrozole doses of 0.1-5 mg. Suppression was dose-related, and letrozole doses equal to or exceeding 0.5 mg resulted in suppression to estrone and estrone sulfate concentrations below the lower limit of detection in many cases. Suppression of serum estrogen concentrations was maintained throughout treatment in all patients receiving daily letrozole doses equal to or exceeding 0.5 mg.
Letrozole is rapidly and completely absorbed from the GI tract following oral administration. Steady-state plasma concentrations of the drug are reached in 2-6 weeks in patients receiving letrozole 2.5 mg daily. Letrozole exhibits slightly nonlinear pharmacokinetics with repeated administration of 2.5 mg daily, with steady-state plasma concentrations 1.5-2 times higher than predicted based on plasma concentrations measured after a single dose.
However, continuous accumulation of letrozole does not occur, and steady-state concentrations are maintained over extended periods of daily drug administration. Food does not affect the oral absorption of the drug.
Letrozole is weakly bound to plasma proteins. It has a terminal elimination half-life of about 2 days. The primary elimination pathway of letrozole consists of slow metabolism in the liver to a pharmacologically inactive carbinol metabolite (4,4'-methanol-bisbenzonitrile) followed by renal excretion of the glucuronide conjugate of this metabolite.
Formation of the carbinol metabolite is mediated by cytochrome P-450 (CYP) isoenzymes 3A4 and 2A6, and formation of the ketone analog of the carbinol metabolite is mediated by isoenzyme 2A6.
Following oral administration of radiolabeled letrozole, 90% of the administered dose was excreted in the urine. Of the radiolabeled drug recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% consisted of 2 unidentified metabolites, and 6% was unchanged drug.
Age-related differences in pharmacokinetics over the range of 35 years of age to greater than 80 years of age have not been observed in patients receiving letrozole in clinical trials. Age-related differences between adults and children or race-related differences in the pharmacokinetics of letrozole have not been evaluated.
USES: This medication is used to treat certain types of breast cancer (such as hormone-receptor-positive breast cancer) in women after menopause. Letrozole is also used to help prevent the cancer from returning. Some breast cancers are made to grow faster by a natural hormone called estrogen.
Letrozole decreases the amount of estrogen the body makes and helps to slow or reverse the growth of these breast cancers.
Generic name: letrozole
Pronunciation: (LET-tro-zole)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Letrozole
Indications
The following indications are listed for Letrozole:
- Early Breast Cancer Hormone Receptor Positive And Postmenopausal
- Hormone Receptor Positive Postmenopausal Advanced Breast Cancer
- Hormone Receptor Positive Postmenopausal Early Breast Cancer After Adjuvant Tamoxifen
Dosing
No dosing information is available for this tab.
Letrozole is administered orally. Food does not affect the absorption of letrozole, and the drug may be administered without regard to meals.
Commercially available letrozole tablets should be stored at a controlled room temperature of 20-25degreesC (excursions permitted between 15-30degreesC).
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Letrozole is a substrate of cytochrome P-450 (CYP) 3A4 and CYP2A6. Letrozole has been shown to inhibit CYP2A6 and CYP2C19 in human liver microsomes, but the clinical significance of this is not known.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Pregnancy.
*Known hypersensitivity to letrozole or any ingredient in the formulation.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects (occurring in greater than 20% of patients) are hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, increased sweating, bone pain, and musculoskeletal effects.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
The manufacturer states that safety and efficacy of letrozole in pediatric patientshave not been established.
Adverse effects on bone (bone maturation, BMD) and neuroendocrine and reproductive development disorders of the hypothalamic-pituitary axis were reported following administration of letrozole 0.003-0.3 mg/kg daily in young rats (exposures less than that expected at the recommended human adult dosage) for 12 weeks beginning on postnatal day 7.
Letrozole is contraindicated in women who are pregnant since the drug can cause fetal toxicity when administered to pregnant women. The manufacturer states that a pregnancy test should be performed prior to initiation of letrozole therapy in females of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving the drug and for at least 3 weeks after discontinuance of the drug. If letrozole is administered during pregnancy or if the patient becomes pregnant while receiving the drug, inform the patient of the potential hazard to the fetus.
Spontaneous abortion and congenital birth defects have been reported during postmarketing experience when the drug was used in pregnant women; however, postmarketing reports on letrozole use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. In animal reproduction studies, letrozole administered to pregnant rats and rabbits during organogenesis was associated with increased pregnancy loss (increased postimplantation loss, increased resorption, and decreased number of live fetuses) and teratogenicity (skeletal and renal malformations) at dosages approximately 0.1 times the maximum recommended human dosage on a mg/m2 basis.
It is not known whether letrozole is distributed into human milk or if the drug has any effects on nursing infants or on milk production. Because many drugs are distributed into milk and because impaired reproductive performance has been observed in male offspring of lactating rats and letrozole has the potential to cause serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding during letrozole therapy and for at least 3 weeks after discontinuance of the drug.
The manufacturer makes no specific dosage recommendations for geriatric patients.
In the clinical trial evaluating letrozole as initial adjuvant therapy for early-stage breast cancer, 36% of patients were 65 years of age or older at enrollment, while 12% were 75 years of age or older. Adverse effects generally occurred more frequently in geriatric patients regardless of their assigned study treatment; however, no overall differences in safety and efficacy of letrozole versus tamoxifen were observed between geriatric patients and younger adults.
In the clinical trial evaluating letrozole as extended adjuvant therapy for early-stage breast cancer, 41% of patients were 65 years of age or older at enrollment, while 12% were 75 years of age or older. Although no overall differences in safety or efficacy were observed between geriatric patients and younger adults, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.
In clinical trials evaluating letrozole as first-line or second-line therapy for advanced or metastatic breast cancer, about one-third of patients were 70 years of age or older (median age: 64-65 years). Among patients receiving letrozole as first-line therapy in a clinical trial, higher response rate and longer time to tumor progression were observed in geriatric patients (70 years or older) compared with younger patients.
ICD codes
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Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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