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Letrozole

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
Brands: Femara

Medically reviewed by Drugs.com on Jan 11, 2021. Written by ASHP.

Introduction

Antineoplastic agent; selective aromatase inhibitor.

Uses for Letrozole

Early-stage Breast Cancer in Postmenopausal Women

Adjuvant treatment in postmenopausal women with early-stage hormone receptor-positive breast cancer. Superior to tamoxifen when each drug was given alone; efficacy of sequential therapy (tamoxifen for 2 years followed by letrozole for 3 years, or vice versa) similar to that of letrozole given for 5 years.

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

Aromatase inhibitors are a treatment of choice for adjuvant hormonal therapy to lower risk of breast cancer recurrence in postmenopausal women with early-stage hormone receptor-positive breast cancer. An aromatase inhibitor-containing regimen is modestly more effective than tamoxifen alone.

ASCO states that most postmenopausal women with early-stage hormone receptor-positive breast cancer should consider receiving an aromatase inhibitor during the course of adjuvant therapy, either as primary (initial) therapy or following 2–3 years of tamoxifen (sequential therapy), for a total of 5 years of adjuvant endocrine therapy. Data also support switching to an aromatase inhibitor following 5 years of adjuvant tamoxifen (extended adjuvant therapy). ASCO states that women who receive extended adjuvant therapy should receive tamoxifen for 5 years followed by an aromatase inhibitor for 3–5 years.

Consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen in postmenopausal women. Fracture, MI, hypercholesterolemia, and arthralgia reported more frequently in patients receiving adjuvant letrozole, whereas thromboembolic events, vaginal bleeding, and endometrial disorders reported more frequently in those receiving adjuvant tamoxifen.

Early-stage Breast Cancer in Premenopausal Women

Use of endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) in combination with ovarian suppression as adjuvant therapy in premenopausal women 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; superior to tamoxifen in producing objective tumor response and delaying tumor progression.

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. Combined therapy with an aromatase inhibitor and lapatinib has not been compared with trastuzumab-containing chemotherapy for treatment of metastatic breast cancer.

In combination with ribociclib for initial treatment of hormone receptor-positive, HER2-negative 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).

Female Infertility

Has been used to induce ovulation in anovulatory women desiring pregnancy. Letrozole is not FDA-labeled for this indication; manufacturer states that the drug is contraindicated in women who may become or are pregnant. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Letrozole Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to meals.

Dosage

Adults

Early-stage Breast Cancer in Postmenopausal Women
Adjuvant Treatment
Oral

2.5 mg once daily. Discontinue if relapse occurs.

Initial adjuvant therapy: Planned duration of treatment in clinical study was 5 years; 73% of patients completed therapy. Optimal duration unknown. In patients who discontinue aromatase inhibitor therapy prior to 5 years, ASCO recommends consideration of tamoxifen to complete the 5-year adjuvant regimen.

Sequential adjuvant therapy: Optimal time to switch from tamoxifen to aromatase inhibitor therapy is unknown. ASCO states that disease-free patients may switch to an aromatase inhibitor after 2–3 years of adjuvant tamoxifen therapy to complete a 5-year sequential adjuvant regimen.

Extended adjuvant therapy: Initiate letrozole after completion of 5 years of adjuvant tamoxifen therapy. Planned duration of letrozole treatment in clinical study was 5 years; 71% of patients completed ≥3 years and 58% completed ≥4.5 years of treatment. ASCO recommends administering an aromatase inhibitor for 3–5 years beyond the initial 5 years of tamoxifen therapy, for a total of 8–10 years of adjuvant endocrine therapy. Optimal duration unknown.

Early-stage Breast Cancer in Premenopausal Women†
Adjuvant Treatment
Oral

2.5 mg once daily for 5 years has been used in combination with ovarian suppression.

In clinical studies, ovarian suppression achieved with goserelin 3.6 mg implanted sub-Q every 4 weeks, leuprolide acetate 3.75 mg by IM injection every 4 weeks, triptorelin 3.75 mg by IM injection every 4 weeks, or surgical or radiation ablation.

Advanced Breast Cancer in Postmenopausal Women
First-line Treatment
Oral

2.5 mg once daily. Continue therapy until tumor progresses.

Second-line Treatment
Oral

2.5 mg once daily. Continue therapy until tumor progresses.

Prescribing Limits

Adults

Early-stage Breast Cancer in Postmenopausal Women
Adjuvant Treatment
Oral

Maximum 5 years of aromatase inhibitor therapy; toxicity beyond 5 years not established.

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

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

Geriatric Patients

No dosage adjustment necessary.

Cautions for Letrozole

Contraindications

  • Pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

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

Warnings/Precautions

Effects on Bone

Postmenopausal women receiving an aromatase inhibitor as adjuvant therapy are at high risk for osteoporosis.

Bone mineral density (BMD) at lumbar spine decreased by 4.1% over 2 years in patients receiving adjuvant letrozole and increased by 0.3% in those receiving tamoxifen; results for hip BMD were similar, but difference was less pronounced. Incidence of osteoporosis (5 versus 3%) and fractures (14 versus 10%) was higher during or after treatment with letrozole versus tamoxifen. Arthralgia (48%), myalgia (10–11%), back pain (9–10%), musculoskeletal pain or stiffness (4–7%), bone pain (6–7%), osteoporosis (11%), and osteopenia (8–10%) occurred at a similar rate in patients receiving letrozole or anastrozole as initial adjuvant therapy.

Hip BMD decreased by 4 or 2% over 2 years in patients receiving extended adjuvant therapy with letrozole or placebo, respectively. Incidence of osteoporosis (14 versus 8%) and fracture (13 versus 8%) was higher during or after treatment with letrozole versus placebo.

Evaluate all postmenopausal women initiating adjuvant aromatase inhibitor therapy for risk of osteoporotic fractures; determine BMD and assess other risk factors for fracture (e.g., age, low body mass index, family history of hip fracture, prior fragility fracture, history of cigarette smoking, excessive alcohol consumption, current or prior corticosteroid use). Closely monitor patients for changes in risk status during therapy, and assess BMD at regular intervals (e.g., every 1–2 years in those with osteopenia or osteoporosis). Consider other potential causes of osteoporosis (e.g., vitamin D deficiency, hyperthyroidism, hyperparathyroidism, hypercalciuria).

Initiate appropriate therapy to prevent further bone loss as clinically indicated. Base decision to initiate antiresorptive therapy (e.g., bisphosphonate, denosumab) on overall risk of fracture and rate of bone loss.

Lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation in alcohol consumption) and supplemental calcium and vitamin D recommended in all women receiving adjuvant letrozole therapy.

Lipid Effects

Hypercholesterolemia reported in 52% of patients receiving letrozole as initial adjuvant therapy, 16% of patients receiving the drug as extended adjuvant therapy, and 3% of patients receiving the drug as second-line therapy for advanced disease.

Hypercholesterolemia (52 versus 29%) and use of antilipemic agents (29 versus 20%) reported more frequently in patients receiving letrozole versus tamoxifen as initial adjuvant therapy. Among patients with normal baseline serum cholesterol concentrations, elevated total cholesterol concentrations reported in 8 or 3% of those receiving letrozole or tamoxifen, respectively. Hypercholesterolemia occurred at a similar rate (7–8%) in patients receiving letrozole or anastrozole as initial adjuvant therapy.

Total cholesterol concentrations, lipoprotein fractions, and use of antilipemic agents were similar in patients receiving extended adjuvant therapy with letrozole versus placebo.

Monitor serum lipid concentrations in patients receiving long-term letrozole therapy.

CNS Effects

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

Hematologic Effects

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 women who are pregnant. 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.

Impairment of Fertility

May impair female and male fertility.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

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.

Pediatric Use

Safety and efficacy not established in children of any age.

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.

Premenopausal Women

Clinical benefit not established in premenopausal women with breast cancer. Contraindicated in premenopausal women.

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.

Common Adverse Effects

Initial adjuvant therapy: Hypercholesterolemia, hot flushes (flashes), arthralgia/arthritis.

Extended adjuvant therapy: Flushing, asthenia, arthralgia, headache, increased sweating, edema, hypercholesterolemia.

Advanced-stage disease: Bone pain, hot flushes, back pain, dyspnea, nausea, arthralgia.

Interactions for Letrozole

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

Specific Drugs

Drug

Interaction

Comments

Antineoplastic agents

No clinical experience with concomitant use to date

Cimetidine

No clinically important effect on letrozole pharmacokinetics

Estrogens

Antagonistic pharmacologic effects

Concomitant use not recommended

Tamoxifen

Decreased plasma letrozole concentrations

Therapeutic effect of letrozole not impaired if used immediately after tamoxifen

Warfarin

No clinically important effects on warfarin pharmacokinetics

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 (Clcr 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.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 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. Lifestyle changes (e.g., weight-bearing exercise, abstinence from smoking, moderation of alcohol consumption) and dietary supplementation with calcium and vitamin D advised. Importance of BMD monitoring.

  • Risk of fetal harm and pregnancy loss. Necessity of advising 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 become pregnant or if pregnancy is suspected during therapy. If pregnancy occurs, advise pregnant women of potential risk to the fetus. Advise patients that letrozole is FDA-labeled for use only in postmenopausal women.

  • Importance of advising 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.)

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

Letrozole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2.5 mg*

Femara

Novartis

Letrozole Tablets

Letrozole Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

Letrozole 2.5 mg (28 film-coated tablets)

Ribociclib succinate 200 mg (of ribociclib) (21, 42, or 63 film-coated tablets)

Kisqali Femara Co-Pack

Novartis

AHFS DI Essentials™. © Copyright 2021, Selected Revisions January 11, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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