II. History
- Thalidomide was originally introduced in the U.S. in the 1950s as a Sedative and Antiemetic in Hyperemesis Gravidarum
- Identified as a highly Teratogenic agent and pulled from the U.S. market
- More than 10,000 children were born with serious congenital malformations attributed to Thalidomide
- Later, in the 1990s, Thalidomide was reinvestigated as an immunomodulatory agent
- Thalidomide is a complex drug that spontaneously hydrolyzes to 20 metabolites in vivo
- Thalidomide was among the first TNFa agents
- Thalidomide has since been approved for Multiple Myeloma and many Autoimmune Conditions
- Related drugs, Lenalidomide and Pomalidomide have since been developed
III. Indications: Thalidomide
-
Autoimmune Conditions
- Erythema Nodosum leprosum
- Crohn Disease
- Malignancy
- Transplant
- Infectious Disease
- Mycobacterial infection
- HIV Wasting Syndrome
- Miscellaneous Conditions
- Severe recurrent Aphthous Stomatitis
- Hereditary Hemorrhagic Telangiectasia.
IV. Indications: Thalidomide Analogs
- Lenalidomide (Revlimid)
- Multiple Myeloma
- Myelodysplastic Syndromes (deletion 5q)
- Mantle cell Lymphoma
- Follicular Lymphoma
- Marginal zone Lymphoma
- Pomalidomide (Pomalyst)
- Multiple Myeloma
- AIDS-related Kaposi Sarcoma
V. Contraindications
- Pregnancy (black box warning, REMS)
- Risk of Venous Thromboembolism (relative contraindication)
VI. Mechanism
- Glutamic Acid synthetic derivatives with immunomodulatory and antinflammatory effects
- Immunomodulatory effects are related to its binding and blocking the Protein Cereblon
- Inhibit Tumor Necrosis Factor alpha (TNFa)
- Inhibits activated peripheral Monocytes and their chemotaxis
- Inhibits Neutrophil chemotaxis
- Inhibits Interleukin and Interferon activity
- Inhibits pro-Angiogenesis factors
- Vascular Endothelial Growth Factor (VEGF)
- Basic Fibroblast Growth Factor (bFGF)
- Other effects
- Promotes T Cell and Natural Killer (NK) cell activity
- Promotes Antibody-dependent cellular cytotoxicity (ADCC)
VII. Medications
- Thalidomide (Thalidomid)
- Thalidomide Analogs
- Lenalidomide (Revlimid)
- Pomalidomide (Pomalyst)
- Orally Bioavailable derivative of Thalidomide
VIII. Dosing
- See other references for disease specific dosing protocols
IX. Pharmacokinetics: Thalidomide
- Variable oral Bioavailability
- Peak activity 2 to 5 hours after oral dose
- Half-Life: 5-7 hours
- Renal excretion: 90%
X. Adverse Effects: Thalidomide and Analogs
- Highly Teratogenic (see below)
- Cardiovascular
- Neuropsychiatric effects
- Peripheral Neuropathy
- Sedation
- Headache
- Mood change
- Endocrine effects
- Hypothyroidism
- ACTH Stimulation
- Hypoglycemia
- Hematologic
- Neutropenia
- Thrombocytopenia
- Tumor Lysis Syndrome
- Secondary primary malignancy
- Other effects
- Constipation
- Rash (including Stevens-Johnson Syndrome)
- Hepatotoxicity (Pomalidomide, Lenalidomide)
XI. Safety
- Avoid in Lactation
- Avoid in pregnancy (all trimesters, Pregnancy category X)
- Use two forms of reliable Contraception
- Male patients should use a Condom or abstain from intercourse
- Monitoring
- Complete Blood Count
- Periodic complete Neurologic Exams (every 6 months)
- Liver Function Test (Pomalidomide, Lenalidomide)
XII. Drug Interactions
- Strong CYP1A2 Inhibitors
- Avoid with Pomalidomide
-
Digoxin
- Lenalidomide may increase levels
XIII. Resources
- Thalidomide (StatPearls)
- Thalidomide (DailyMed)
- Lenalidomide (DailyMed)
- Pomalidomide (DailyMed)