Brand name: Femara
Drug class: Antiestrogens
- Aromatase Inhibitors
VA class: AN900
Chemical name: 4,4′-(1H-1,2,4-triazol-1-ylmethylene)bis-benzonitrile
Molecular formula: C₁₇H₁₁N₅
CAS number: 112809-51-5

Medically reviewed by Drugs.com on May 25, 2023. Written by ASHP.

Introduction

Antineoplastic agent; selective aromatase inhibitor.

Uses for Letrozole

Initial, Sequential, or Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer

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

Extended adjuvant treatment in postmenopausal women with early-stage breast cancer who have received 5 years of adjuvant tamoxifen therapy. Efficacy of letrozole as extended adjuvant therapy based on analysis of disease-free survival in patients receiving the drug for a median of 5 years.

ASCO states that postmenopausal women with node-positive hormone receptor-positive breast cancer should be offered extended adjuvant endocrine therapy with one of the following: aromatase inhibitor therapy for up to a total of 10 years; tamoxifen for 10 years; tamoxifen for 5 years, then an aromatase inhibitor for 5 years; or tamoxifen for 2–3 years, then an aromatase inhibitor for 7–8 years. Women with node-negative breast cancer may also be offered extended adjuvant endocrine therapy for up to a total of 10 years, but benefits are likely narrower due to lower risk for recurrence.

Consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen; during the course of adjuvant therapy, patients who are intolerant of one treatment may be switched to a different treatment.

Adjuvant Therapy for Early-Stage Breast Cancer in Premenopausal Women

Use of endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) in combination with ovarian suppression^{† [off-label]} as adjuvant therapy in premenopausal women^{† [off-label]} with early-stage hormone receptor-positive breast cancer may be considered a reasonable choice (accepted).

Advanced Breast Cancer in Postmenopausal Women

First-line therapy for hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women.

Second-line therapy for advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy (e.g., tamoxifen).

In combination with lapatinib for treatment of hormone receptor-positive metastatic breast cancer that overexpresses the human epidermal growth factor receptor type 2 (HER2) protein in postmenopausal women who are candidates for hormonal therapy.

In combination with ribociclib for initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women.

According to ASCO, combination therapy with a nonsteroidal aromatase inhibitor (e.g., letrozole, anastrozole) and a cyclin-dependent kinase (CDK) 4/6 inhibitor should be offered first line to postmenopausal patients with treatment-naive hormone receptor-positive metastatic breast cancer; for some patients, monotherapy with an aromatase inhibitor may be appropriate. Choice of second-line hormonal therapy should take into account prior treatment exposure and response to previous endocrine therapy; options for second-line therapy include tamoxifen, an aromatase inhibitor, or fulvestrant with or without everolimus.

Advanced Breast Cancer in Pre-/Perimenopausal Women and Men

In combination with ribociclib and a gonadotropin-releasing hormone (GnRH) agonist for the initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in adult patients, including pre-/perimenopausal women and men.

For first-line treatment of most premenopausal women, ASCO recommends combination therapy with a nonsteroidal aromatase inhibitor (e.g., letrozole, anastrozole) and a CDK 4/6 inhibitor, in conjunction with chemical ovarian function suppression. Ovarian suppression or ablation in combination with hormonal therapy should be offered to premenopausal women with metastatic hormone receptor-positive breast cancer; patients without prior exposure to hormonal therapy may be treated with tamoxifen or ovarian suppression/ablation alone, but combination therapy is preferred. In men with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer, ASCO recommends endocrine therapy (i.e., tamoxifen, an aromatase inhibitor combined with a GnRH agonist, or fulvestrant) first line except in cases of visceral crisis or rapidly progressing disease; as in women, CDK 4/6 inhibitors may be used with endocrine therapy.

Related/similar drugs

Enhertu, Trodelvy, tamoxifen, Arimidex, paclitaxel, Taxol, Femara

Letrozole Dosage and Administration

General

Pretreatment Screening

• Perform pregnancy testing in females of reproductive potential prior to starting letrozole.

Patient Monitoring

• Consider bone density and serum cholesterol monitoring during therapy.

Dispensing and Administration Precautions

• To avoid medication errors, the Institute for Safe Medication Practices (ISMP) recommends that prescribers communicate both the brand and generic names for letrozole on the prescription order form.

Administration

Oral Administration

Administer orally once daily without regard to meals.

Dosage

Adults

Breast Cancer

> Initial, Sequential, or Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer

Oral

2.5 mg once daily. Discontinue if relapse occurs.

Initial adjuvant therapy: Median duration of treatment in clinical study was 5 years. Optimal duration unknown.

Extended adjuvant therapy: Initiate letrozole after completion of 5 years of adjuvant tamoxifen therapy. Median duration of letrozole treatment in clinical study was 5 years; 71% of patients completed ≥3 years and 58% completed ≥4.5 years of treatment. Optimal duration unknown.

ASCO states that postmenopausal women with node-positive hormone receptor-positive early breast cancer should be offered extended adjuvant endocrine therapy with one of the following: aromatase inhibitor therapy for up to a total of 10 years; tamoxifen for 10 years; tamoxifen for 5 years, then an aromatase inhibitor for 5 years; or tamoxifen for 2–3 years, then an aromatase inhibitor for 7–8 years. Women with node-negative breast cancer may also be offered extended adjuvant endocrine therapy for up to a total of 10 years, although benefits are likely narrower due to lower risk for recurrence.

Adjuvant Therapy for Early-stage Breast Cancer in Premenopausal Women† [off-label]

Oral

2.5 mg once daily for 5 years has been used in combination with ovarian suppression^{† [off-label]}.

Advanced Breast Cancer in Postmenopausal Women

Oral

2.5 mg once daily. Continue therapy until tumor progresses.

Advanced Breast Cancer in Pre-/Perimenopausal Women and Men

Oral

2.5 mg once daily in combination with ribociclib. These patients should also be treated with a luteinizing hormone-releasing hormone (LHRH) according to current clinical practice standards.

Special Populations

Hepatic Impairment

Cirrhosis and severe hepatic impairment (Child-Pugh class C): Decrease dosage to 2.5 mg every other day.

Mild to moderate hepatic impairment: No dosage adjustment recommended.

Renal Impairment

Cl_cr ≥10 mL/minute: No dosage adjustment necessary.

Geriatric Patients

No dosage adjustment necessary.

Cautions for Letrozole

Contraindications

• Pregnancy.

• Known hypersensitivity to letrozole or any ingredient in the formulation.

Warnings/Precautions

Bone Effects

May cause reduction in bone mineral density (BMD). In the adjuvant studies, decreases in BMD at the lumbar spine and hip were greater among patients receiving letrozole compared to patients receiving tamoxifen. Osteoporosis and fractures occurred more frequently among patients receiving letrozole compared to patients receiving tamoxifen.

Consider BMD monitoring in patients receiving letrozole.

Cholesterol

Hypercholesterolemia and use of antilipemic agents reported more frequently in patients receiving letrozole versus tamoxifen as initial adjuvant therapy.

Consider cholesterol monitoring in patients receiving letrozole.

Hepatic Impairment

Patients with cirrhosis and severe hepatic impairment experienced twice the exposure to letrozole as healthy volunteers with normal liver function. Dosage reduction recommended in this population.

Effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels not determined.

Fatigue and Dizziness

Fatigue, dizziness, and somnolence reported. Caution advised when driving or using machinery.

Laboratory Test Abnormalities

Moderate decreases in lymphocyte counts observed in some patients, but of uncertain clinical importance and transient in about half of those affected.

Thrombocytopenia reported but causality is unclear.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryotoxic, fetotoxic, and teratogenic in animals. Contraindicated in pregnancy. Test for pregnancy prior to initiation of the drug. Advise females of reproductive potential to use effective contraceptive methods during therapy and for ≥3 weeks after discontinuance of the drug. If used during pregnancy or patient becomes pregnant, apprise of fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm. Embryotoxic, fetotoxic, and teratogenic in animals. Spontaneous abortion and congenital birth defects reported during postmarketing experience in pregnant women, but data are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes.

Contraindicated in pregnancy. Test for pregnancy prior to initiation of the drug. If used during pregnancy or patient becomes pregnant, apprise of fetal hazard.

Lactation

Not known whether letrozole is distributed into human milk; effects on nursing infant and milk production also unknown. Discontinue nursing during therapy and for ≥3 weeks after drug discontinuance.

Females and Males of Reproductive Potential

May cause fetal harm. Contraindicated in pregnancy. Test for pregnancy prior to initiation of the drug. Advise females of reproductive potential to use effective contraceptive methods during therapy and for ≥3 weeks after discontinuance of the drug.

May impair female and male fertility.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Initial adjuvant therapy in postmenopausal women: 36% of study patients were ≥65 years of age and 12% were ≥75 years of age. Adverse effects generally more common 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.

Extended adjuvant therapy in postmenopausal women: 41% of study patients were ≥65 years of age and 12% were ≥75 years of age. No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

First- and second-line treatment in postmenopausal women: Median patient age in all studies was 64–65 years; one-third were ≥70 years of age. In the first-line clinical study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients <70 years of age.

Hepatic Impairment

Dosage reduction recommended in patients with cirrhosis and severe hepatic impairment. Effect of hepatic impairment on drug exposure in noncirrhotic cancer patients with increased bilirubin concentrations not determined.

Renal Impairment

Letrozole pharmacokinetics not altered in individuals with varying renal function. No dosage adjustment is necessary in patients with Cl_cr ≥10 mL/minute.

Common Adverse Effects

Adverse effects occurring in >20% of patients: hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, increased sweating, bone pain, and musculoskeletal effects.

Drug Interactions

Metabolized by CYP3A4 and CYP2A6. Inhibits CYP2A6 and, to a lesser extent, CYP2C19 in vitro.

Specific Drugs

Letrozole Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed after oral administration.

Onset

Plasma estradiol, estrone, and estrone sulfate reduced by 75–95% within 2–3 days with daily dosages of 0.1–5 mg.

Duration

Estrogen suppression maintained throughout therapy in patients receiving ≥0.5 mg daily.

Food

Food does not affect absorption.

Distribution

Extent

Not known if distributed into milk.

Plasma Protein Binding

Weakly bound.

Elimination

Metabolism

Principally metabolized to inactive carbinol metabolite by CYP3A4 and CYP2A6.

Elimination Route

Excreted in urine as glucuronide of carbinol metabolite (≥75%), unidentified metabolites (about 9%), and unchanged drug (6%).

Half-life

2 days.

Special Populations

Renal function did not affect the pharmacokinetics of a single 2.5-mg dose in adults with varying renal function. Renal impairment (Cl_cr 20–50 mL/minute) did not affect steady-state plasma concentrations in patients with advanced breast cancer.

AUC was increased twofold and clearance was decreased in adults with cirrhosis and severe hepatic impairment (Child-Pugh class C); higher letrozole concentrations are expected in breast cancer patients with severe hepatic impairment compared with patients with normal liver function.

AUC was increased (37%) in adults with moderate hepatic impairment (e.g., cirrhosis, Child-Pugh class A and B); drug exposure was within range observed in patients without hepatic impairment.

No age-related differences in pharmacokinetics observed in patients ranging from 35 to >80 years of age. Age-related differences between adults and children or race-related differences in the pharmacokinetics of letrozole not evaluated.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

• Selectively inhibits conversion of androgens to estrogens.

• Decreased serum and tumor concentrations of estrogen inhibit breast tumor growth and delay disease progression.

• Does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.

Advice to Patients

• Risk of dizziness, fatigue, or somnolence; use caution when driving or operating machinery.

• Risk of osteoporosis. Monitor bone mineral density (BMD).

• Risk of fetal harm and pregnancy loss. Advise females of reproductive potential to use effective contraception during letrozole therapy and for ≥3 weeks after the last dose. Importance of women informing clinicians immediately if they become pregnant or if pregnancy is suspected during therapy. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

• Advise women to avoid breast-feeding while receiving letrozole and for ≥3 weeks following discontinuance of therapy.

• Risk of male or female infertility.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Reload page with references included

Frequently asked questions

• How long do letrozole side effects last?
• What happens when you stop taking letrozole?
• When is the best time of day to take letrozole?
• How many cycles of letrozole are needed to get pregnant?
• Is letrozole a form of chemotherapy?
• Does letrozole affect blood sugar levels?
• When will I ovulate after taking letrozole?
• How do you take letrozole for fertility?
• How does Femara affect your period?

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