What are the adverse effects of Thalidomide (generic name)?

Thalidomide Adverse Effects

Thalidomide causes serious and potentially life-threatening adverse effects, with the most critical being teratogenicity (absolute contraindication in pregnancy), venous thromboembolism (15.3% grade 3-4), and peripheral neuropathy (10.4% grade 3-4), requiring mandatory prophylactic anticoagulation and regular neurological monitoring. 1

Major Adverse Effects by Category

Hematologic and Thrombotic Complications

Venous Thromboembolism (VTE)

• Grade 3-4 VTE occurs in 15.3% of patients receiving thalidomide/dexamethasone 1
• Risk increases dramatically when combined with high-dose dexamethasone or chemotherapy (>30% in some combinations) 1, 2
• DVT typically occurs within the first months of treatment, more frequent in newly diagnosed patients with high tumor burden 2
• Prophylactic anticoagulation is mandatory when thalidomide is combined with dexamethasone 1
• Low-molecular-weight heparin (LMWH) is superior to warfarin or aspirin for DVT prophylaxis 1
• Arterial thromboembolism can occur, including myocardial infarction and stroke, though less common than venous events 3, 2

Hematologic Toxicity

• Generally mild compared to other agents 2
• Neutropenia significantly less common than with lenalidomide (0.6% vs 14.6% grade 3-4) 1

Neurological Toxicity

Peripheral Neuropathy

• Grade 3-4 peripheral neuropathy occurs in 10.4% of patients on thalidomide/dexamethasone 1
• Occurs in approximately 50% of patients receiving thalidomide plus dexamethasone and chemotherapy 2
• May be irreversible, especially after high cumulative doses 1
• Frequency ranges from 25-42% in pediatric studies 1
• Monitor for tingling, paresthesia, and numbness at 6-monthly intervals with careful neurological examination and vibration sensitivity assessment 1
• Led to drug discontinuation in 30-60% of patients after 2-4 years in maintenance therapy 1

Central Nervous System Effects

• Somnolence is common and dose-dependent 1, 4
• Vertigo/somnolence requiring drug suspension (documented in pediatric cases) 1
• Agitation/hallucinations requiring discontinuation 1
• Sedation occurs in approximately 10% of patients 1

Gastrointestinal Effects

• Constipation is common and dose-dependent 1, 4, 2
• Gastrointestinal disturbance 1

Dermatologic Reactions

• Rash is common 1, 4
• Stevens-Johnson syndrome (rare but serious) 4
• Toxic epidermal necrolysis 5

Teratogenicity

This is the most devastating adverse effect:

• Thalidomide is absolutely contraindicated during pregnancy 1, 6
• Causes severe and life-threatening birth defects including amelia (absence of limbs), phocomelia (short limbs), bone hypoplasticity, external ear abnormalities, facial palsy, eye abnormalities, and congenital heart defects 6
• Mortality at or shortly after birth occurs in approximately 40% of affected infants 6
• Mandatory contraception is required for all patients of childbearing potential 1
• Any suspected fetal exposure must be reported to FDA MedWatch (1-800-FDA-1088) and REMS Call Center (1-888-423-5436) 6

Other Significant Adverse Effects

Fatigue and Constitutional Symptoms

• Fatigue is common and dose-dependent 1, 4, 2
• Malaise 4
• Pyrexia 2
• Pain 2

Less Common but Serious

• Peripheral edema 4
• Elevated liver enzymes 4
• Osteonecrosis of jaw 2

Dose-Dependent Toxicity Profile

• Doses ≤200 mg/day are generally better tolerated 4
• Incidence and severity of adverse events directly related to dose and duration of therapy 4
• Nonhematologic side effects are high and dose-dependent 2

Clinical Management Algorithms

For Multiple Myeloma Patients

1. Initiate prophylactic anticoagulation immediately when starting thalidomide/dexamethasone 1
2. Baseline neurological assessment before starting therapy 1
3. Monitor for VTE symptoms especially in first 4 months 2
4. Neurological examination every 6 months including vibration sensitivity 1
5. Consider dose reduction to 50 mg daily if peripheral neuropathy develops 1

For Pediatric Crohn's Disease

• Starting dose: 50 mg daily for adolescents, 2 mg/kg for young children 1
• Reserved only for very selected cohort who are anti-TNF responders but lost response or intolerant 1
• 6-monthly neurological and psychological examination mandatory 1
• Contraception mandatory when appropriate 1

Critical Pitfalls to Avoid

• Never use thalidomide without prophylactic anticoagulation when combined with dexamethasone or chemotherapy 1
• Do not ignore early neurological symptoms—peripheral neuropathy may become irreversible 1, 4
• Do not use in pregnancy under any circumstances 1, 6
• Do not assume aspirin alone is adequate for VTE prophylaxis—LMWH is superior 1
• Prolonged exposure may induce resistance and reduce overall survival 2