What are the side effects of Letrozole (Femara)?

Side Effects of Letrozole (Femara)

Letrozole commonly causes musculoskeletal symptoms, bone mineral density loss, and increased fracture risk compared to tamoxifen, while having fewer thromboembolic and gynecological side effects. 1

Common Side Effects

Musculoskeletal Effects

• Arthralgia (joint pain) - affects up to 53% of patients 1
• Myalgia (muscle pain) - affects up to 28% of patients 1
• Musculoskeletal pain - reported in 14-22% of patients 2
• Bone mineral density loss - significant decrease in total hip BMD (-3.6%) and lumbar spine BMD (-5.35%) at 24 months 3
• Increased risk of osteoporosis and bone fractures (14% vs 9% with placebo) 1

Cardiovascular Effects

• Increased risk of grade 3-5 cardiac adverse events compared to tamoxifen 1
• Peripheral edema (5-8% of patients) 2
• Hypertension (5-7% of patients) 2

Vasomotor Symptoms

• Hot flushes (5-6% of patients) 2
• Night sweats 1

Neurological/Psychological Effects

• Headache (7-9%) 2
• Dizziness (3-7%) 2
• Fatigue (3-5%) 2
• Somnolence (2-3%) 2

Gastrointestinal Effects

• Nausea (10-15%) 2
• Vomiting (5-7%) 2
• Constipation (6-9%) 2
• Diarrhea (3-6%) 2
• Abdominal pain (5-9%) 2
• Anorexia (3-5%) 2

Sexual/Reproductive Effects

• Vaginal dryness 1
• Dyspareunia (painful intercourse) 1

Other Effects

• Hypercholesterolemia (3-30%) 2
• Weight gain 1
• Rash (3-5%) 2

Serious but Less Common Side Effects

• Thromboembolic events (less common than with tamoxifen) 1
• Hypersensitivity reactions including anaphylaxis 2
• Hepatic enzyme elevation 2
• Toxic epidermal necrolysis 2
• Erythema multiforme 2

Monitoring and Management

Bone Health

• Baseline and periodic bone mineral density (DEXA) scans 1
• Calcium and vitamin D supplementation 1
• Consider bone-modifying agents for those with significant bone loss 1
• Resistance exercise to help maintain bone density 1

Cardiovascular Health

• Regular blood pressure monitoring 1
• Lipid profile assessment 4
• Management of cardiovascular risk factors 1

Musculoskeletal Symptoms

• NSAIDs or acetaminophen for joint/muscle pain
• Physical activity and exercise
• Consider dose adjustment if symptoms are severe

Clinical Considerations

• Side effect profiles differ significantly between letrozole and tamoxifen:

  • Letrozole: More musculoskeletal symptoms, bone loss, and fracture risk
  • Tamoxifen: More thromboembolic events, endometrial cancer risk, and vaginal bleeding 1

• The BIG 1-98 trial showed higher incidence of bone fractures with letrozole compared to tamoxifen (9.5% vs 6.5%) 1

• Letrozole should not be used in premenopausal women with functioning ovaries 1

• Cognitive effects may occur with letrozole, including memory impairment, though these are less well-documented in human studies 5

• Patients should be counseled about potential side effects before starting therapy and monitored regularly for adverse events during treatment

• Despite these side effects, letrozole has shown superior efficacy in disease-free survival compared to tamoxifen in postmenopausal women with hormone receptor-positive breast cancer 1