Introduction
Femara (letrozole) is a third-generation, nonsteroidal aromatase inhibitor used primarily in the treatment of hormone receptor-positive breast cancer in postmenopausal women. It represents a significant advancement in endocrine therapy for breast cancer, offering improved specificity and potency compared to earlier generations of aromatase inhibitors.
Mechanism of Action
Femara exerts its therapeutic effect through competitive inhibition of the aromatase enzyme complex. This enzyme system, located primarily in adipose tissue, breast tissue, and the ovaries, is responsible for the conversion of androgens (androstenedione and testosterone) to estrogens (estrone and estradiol). By blocking this conversion, Femara significantly reduces circulating estrogen levels in postmenopausal women by 75-95%, creating an estrogen-deprived environment that inhibits the growth of estrogen-dependent breast cancer cells.
Indications
FDA-approved indications include:
- Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
- Extended adjuvant treatment of early breast cancer following 5 years of tamoxifen therapy
- First-line treatment of postmenopausal women with hormone receptor-positive or unknown, locally advanced or metastatic breast cancer
- Treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy
Dosage and Administration
Standard dosing: 2.5 mg orally once daily, with or without food Special populations:- Renal impairment: No dosage adjustment necessary for mild to moderate impairment
- Hepatic impairment: No dosage adjustment necessary for mild to moderate impairment; use with caution in severe hepatic impairment
- Geriatric patients: No dosage adjustment required
- Premenopausal women: Not indicated due to lack of efficacy
Pharmacokinetics
Absorption: Rapidly and completely absorbed after oral administration; bioavailability 99.9% Distribution: Volume of distribution approximately 1.9 L/kg; 60% plasma protein bound Metabolism: Extensively metabolized in liver via CYP3A4 and CYP2A6 to inactive metabolites Elimination: Primarily renal excretion (90%) as glucuronide conjugates; elimination half-life approximately 2 days Steady state: Achieved in 2-6 weeks of daily dosingContraindications
- Premenopausal women
- Pregnancy or women of childbearing potential not using adequate contraception
- Patients with known hypersensitivity to letrozole or any component of the formulation
- Patients with severe hepatic impairment (Child-Pugh Class C)
Warnings and Precautions
Bone effects: Increased risk of osteoporosis and fractures; baseline bone density assessment recommended with periodic monitoring Cardiovascular: Increased incidence of hypercholesterolemia; monitor lipid profiles periodically Hepatic impairment: Use with caution in severe impairment CNS effects: May cause dizziness and fatigue; caution patients about driving or operating machinery Pregnancy: Category D - can cause fetal harm; contraindicated in pregnancyDrug Interactions
Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin): May decrease letrozole concentrations Tamoxifen: Coadministration may reduce letrozole efficacy; avoid concurrent use Estrogen-containing therapies: May diminish therapeutic effect; contraindicated CYP2C19 inhibitors: Potential increase in letrozole concentrations (clinical significance unknown)Adverse Effects
Very common (>10%):- Hot flashes (20-35%)
- Arthralgia (20-25%)
- Fatigue (15-20%)
- Hypercholesterolemia (15-20%)
- Headache (10-15%)
- Nausea (8-10%)
- Bone pain (7-9%)
- Weight increase (5-7%)
- Depression (5-7%)
- Osteoporosis (5-6%)
- Peripheral edema (4-5%)
- Cardiovascular events (myocardial infarction, angina)
- Thromboembolic events
- Hepatic toxicity
- Severe cutaneous reactions
Monitoring Parameters
Baseline:- Complete blood count
- Comprehensive metabolic panel (including liver function tests)
- Lipid profile
- Bone mineral density scan
- Pregnancy test in appropriate patients
- Regular assessment of bone mineral density (every 1-2 years)
- Lipid profile every 6-12 months
- Liver function tests every 3-6 months
- Regular assessment of treatment response and disease status
- Monitoring for signs of disease progression
- Assessment of musculoskeletal symptoms
- Hot flash severity and frequency
- Joint pain and stiffness
- Mood changes
- Fatigue levels
Patient Education
Key points to discuss:- Take medication exactly as prescribed at the same time each day
- Report any new or worsening bone pain, joint stiffness, or mobility issues
- Notify healthcare provider immediately if pregnancy is suspected
- Regular weight-bearing exercise and adequate calcium/vitamin D intake are important for bone health
- Report any chest pain, shortness of breath, or leg swelling
- Regular follow-up appointments are essential for monitoring treatment effectiveness and side effects
- Do not take any estrogen-containing products or supplements
- Use caution when driving or operating machinery until effects on alertness are known
- Report any signs of depression or mood changes
- Maintain regular cholesterol monitoring as advised by healthcare provider
References
1. FDA Prescribing Information: Femara (letrozole) tablets 2. Early Breast Cancer Trialists' Collaborative Group. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352. 3. Mouridsen H, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21(11):2101-2109. 4. Coombes RC, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081-1092. 5. National Comprehensive Cancer Network (NCCN) Guidelines: Breast Cancer Version 3.2023 6. Perez EA. Safety profiles of aromatase inhibitors in the adjuvant setting. Clin Breast Cancer. 2006;7(1):50-54.