- 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. Last updated on Oct 16, 2017.
Uses for Letrozole
Adjuvant treatment in postmenopausal women with early-stage hormone receptor-positive breast cancer.1 39 40 41 Superior to tamoxifen when each drug was given alone;1 40 52 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.39 52
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.9 41 An aromatase inhibitor-containing regimen is modestly more effective than tamoxifen alone.9 41
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.41 Data also support switching to an aromatase inhibitor following 5 years of adjuvant tamoxifen (extended adjuvant therapy).41 ASCO states that women who receive extended adjuvant therapy should receive tamoxifen for 5 years followed by an aromatase inhibitor for 3–5 years.41
Consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen.41 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.1 39 40
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.1 9 18 20
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.44 49 53 Combined therapy with an aromatase inhibitor and lapatinib has not been compared with trastuzumab-containing chemotherapy for treatment of metastatic breast cancer.49
Has been used to induce ovulation† in anovulatory women desiring pregnancy.d Letrozole is not FDA-labeled for this indication;e manufacturer states that the drug is contraindicated in women who may become or are pregnant.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Letrozole Dosage and Administration
Administer orally once daily without regard to meals.1
Adjuvant Treatment of Early-stage Breast CancerOral
Initial adjuvant therapy: Planned duration of treatment in clinical study was 5 years; 73% of patients completed therapy.1 Optimal duration unknown.1 In patients who discontinue aromatase inhibitor therapy prior to 5 years, ASCO recommends consideration of tamoxifen to complete the 5-year adjuvant regimen.41
Sequential adjuvant therapy: Optimal time to switch from tamoxifen to aromatase inhibitor therapy is unknown.41 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.41
Extended adjuvant therapy: Initiate letrozole after completion of 5 years of adjuvant tamoxifen therapy.1 25 41 Planned duration of letrozole treatment in clinical study was 5 years;1 25 71% of patients completed ≥3 years and 58% completed ≥4.5 years of treatment.1 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.41 Optimal duration unknown.1 25
First-line Treatment of Locally Advanced or Metastatic Breast CancerOral
Second-line Treatment of Advanced Breast CancerOral
Adjuvant Treatment of Early-stage Breast CancerOral
Cirrhosis and severe hepatic impairment (Child-Pugh class C): Decrease dosage to 2.5 mg every other day.1
Mild to moderate hepatic impairment: No dosage adjustment recommended.1
Clcr ≥10 mL/minute: No dosage adjustment necessary.1
No dosage adjustment necessary.1
Cautions for Letrozole
Premenopausal women.1 (See Premenopausal Women under Cautions.)
Pregnancy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm.1 Embryotoxic, fetotoxic, and teratogenic in animals.1 Contraindicated in women who are or may become pregnant (i.e., premenopausal women).1 If inadvertently used during pregnancy or patient becomes pregnant, apprise of fetal hazard.1 Women who are perimenopausal or recently have become postmenopausal should use adequate contraception until postmenopausal state is fully established.1
Effects on Bone
Postmenopausal women receiving an aromatase inhibitor as adjuvant therapy are at high risk for osteoporosis.29
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.1 Incidence of osteoporosis (5 versus 3%) and fractures (14 versus 10%) was higher during or after treatment with letrozole versus tamoxifen.1
Hip BMD decreased by 4 or 2% over 2 years in patients receiving extended adjuvant therapy with letrozole or placebo, respectively.1 Incidence of osteoporosis (14 versus 8%) and fracture (13 versus 8%) was higher during or after treatment with letrozole versus placebo.1
Evaluate all postmenopausal women initiating adjuvant aromatase inhibitor therapy for risk of osteoporotic fractures;70 71 73 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).70 71 73 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).1 70 71 73 Consider other potential causes of osteoporosis (e.g., vitamin D deficiency, hyperthyroidism, hyperparathyroidism, hypercalciuria).70 71 73
Initiate appropriate therapy to prevent further bone loss as clinically indicated.71 Base decision to initiate antiresorptive therapy (e.g., bisphosphonate, denosumab) on overall risk of fracture and rate of bone loss.70 71 72 73
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.25 29 37 70 71 72 73
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.1
Hypercholesterolemia (52 versus 29%) and use of antilipemic agents (25 versus 16%) reported more frequently in patients receiving letrozole versus tamoxifen as initial adjuvant therapy.1 Among patients with normal baseline serum cholesterol concentrations, elevated total cholesterol concentrations reported in 8 or 3% of those receiving letrozole or tamoxifen, respectively.1
Moderate decreases in lymphocyte counts observed in some patients, but of uncertain clinical importance and transient in about half of those affected.1
Thrombocytopenia reported but causality is unclear.1
Category X.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Not known whether letrozole is distributed into human milk; discontinue nursing or the drug.1
Safety and efficacy not established in children of any age.1
Initial adjuvant therapy: 36% of study patients were ≥65 years of age and 12% were ≥75 years of age.1 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.1
Extended adjuvant therapy: 41% of study patients were ≥65 years of age and 12% were ≥75 years of age.1 No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1
First- and second-line treatment: Median patient age in all studies was 64–65 years; one-third were ≥70 years of age.1 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.1
Dosage reduction recommended in patients with cirrhosis and severe hepatic impairment.1 Effect of hepatic impairment on drug exposure in noncirrhotic cancer patients with increased bilirubin concentrations not determined.1
Common Adverse Effects
Initial adjuvant therapy: Hypercholesterolemia, hot flushes (flashes), arthralgia/arthritis.1
Extended adjuvant therapy: Flushing, asthenia, arthralgia, headache, increased sweating, edema, hypercholesterolemia.1
Advanced-stage disease: Bone pain, hot flushes, back pain, dyspnea, nausea, arthralgia.1
Interactions for Letrozole
No clinical experience with concomitant use to date1
No clinically important effect on letrozole pharmacokinetics1
Antagonistic pharmacologic effectsb
Concomitant use not recommendedb
Decreased plasma letrozole concentrations1
Therapeutic effect of letrozole not impaired if used immediately after tamoxifen1
No clinically important effects on warfarin pharmacokinetics1
Rapidly and completely absorbed after oral administration.1
Plasma estradiol, estrone, and estrone sulfate reduced by 75–95% within 2–3 days with daily dosages of 0.1–5 mg.1
Estrogen suppression maintained throughout therapy in patients receiving ≥0.5 mg daily.1
Food does not affect absorption.1
Not known if distributed into milk.1
Plasma Protein Binding
Principally metabolized to inactive carbinol metabolite by CYP3A4 and CYP2A6.1
Excreted in urine as glucuronide of carbinol metabolite (≥75%), unidentified metabolites (about 9%), and unchanged drug (6%).1
Renal function did not affect the pharmacokinetics of a single 2.5-mg dose in adults with varying renal function.1 Renal impairment (Clcr 20–50 mL/minute) did not affect steady-state plasma concentrations in patients with advanced breast cancer.1
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.1
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.1
25°C (may be exposed to 15–30°C).1
Advice to Patients
Risk of dizziness, fatigue, or somnolence; use caution when driving or operating machinery.1
Risk of osteoporosis.1 29 Life-style changes (e.g., weight-bearing exercise, abstinence from smoking, moderation of alcohol consumption) and dietary supplementation with calcium and vitamin D advised.25 29 37 Importance of BMD monitoring.1 71 73
Risk of fetal harm if used during pregnancy.1 Necessity for perimenopausal or recently postmenopausal women to use adequate contraception until postmenopausal state is fully established.1 Contraindicated in premenopausal women.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
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.
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
AHFS DI Essentials™. © Copyright 2019, Selected Revisions October 16, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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