II. History

  1. Thalidomide was originally introduced in the U.S. in the 1950s as a Sedative and Antiemetic in Hyperemesis Gravidarum
    1. Identified as a highly Teratogenic agent and pulled from the U.S. market
    2. More than 10,000 children were born with serious congenital malformations attributed to Thalidomide
  2. Later, in the 1990s, Thalidomide was reinvestigated as an immunomodulatory agent
    1. Thalidomide is a complex drug that spontaneously hydrolyzes to 20 metabolites in vivo
    2. Thalidomide was among the first TNFa agents
    3. Thalidomide has since been approved for Multiple Myeloma and many Autoimmune Conditions
    4. Related drugs, Lenalidomide and Pomalidomide have since been developed

IV. Indications: Thalidomide Analogs

  1. Lenalidomide (Revlimid)
    1. Multiple Myeloma
    2. Myelodysplastic Syndromes (deletion 5q)
    3. Mantle cell Lymphoma
    4. Follicular Lymphoma
    5. Marginal zone Lymphoma
  2. Pomalidomide (Pomalyst)
    1. Multiple Myeloma
    2. AIDS-related Kaposi Sarcoma

V. Contraindications

  1. Pregnancy (black box warning, REMS)
  2. Risk of Venous Thromboembolism (relative contraindication)

VI. Mechanism

  1. Glutamic Acid synthetic derivatives with immunomodulatory and antinflammatory effects
  2. Immunomodulatory effects are related to its binding and blocking the Protein Cereblon
  3. Inhibit Tumor Necrosis Factor alpha (TNFa)
    1. Inhibits activated peripheral Monocytes and their chemotaxis
    2. Inhibits Neutrophil chemotaxis
    3. Inhibits Interleukin and Interferon activity
  4. Inhibits pro-Angiogenesis factors
    1. Vascular Endothelial Growth Factor (VEGF)
    2. Basic Fibroblast Growth Factor (bFGF)
  5. Other effects
    1. Promotes T Cell and Natural Killer (NK) cell activity
    2. Promotes Antibody-dependent cellular cytotoxicity (ADCC)

VII. Medications

  1. Thalidomide (Thalidomid)
  2. Thalidomide Analogs
    1. Lenalidomide (Revlimid)
    2. Pomalidomide (Pomalyst)
      1. Orally Bioavailable derivative of Thalidomide

VIII. Dosing

  1. See other references for disease specific dosing protocols

IX. Pharmacokinetics: Thalidomide

  1. Variable oral Bioavailability
  2. Peak activity 2 to 5 hours after oral dose
  3. Half-Life: 5-7 hours
  4. Renal excretion: 90%

X. Adverse Effects: Thalidomide and Analogs

  1. Highly Teratogenic (see below)
  2. Cardiovascular
    1. Venous Thromboembolism
    2. Ischemic Heart Disease (including Myocardial Infarction)
    3. Cerebrovascular Accident
    4. Orthostatic Hypotension
    5. Bradycardia
  3. Neuropsychiatric effects
    1. Peripheral Neuropathy
    2. Sedation
    3. Headache
    4. Mood change
  4. Endocrine effects
    1. Hypothyroidism
    2. ACTH Stimulation
    3. Hypoglycemia
  5. Hematologic
    1. Neutropenia
    2. Thrombocytopenia
    3. Tumor Lysis Syndrome
    4. Secondary primary malignancy
  6. Other effects
    1. Constipation
    2. Rash (including Stevens-Johnson Syndrome)
    3. Hepatotoxicity (Pomalidomide, Lenalidomide)

XI. Safety

  1. Avoid in Lactation
  2. Avoid in pregnancy (all trimesters, Pregnancy category X)
    1. Use two forms of reliable Contraception
    2. Male patients should use a Condom or abstain from intercourse
  3. Monitoring
    1. Complete Blood Count
    2. Periodic complete Neurologic Exams (every 6 months)
    3. Liver Function Test (Pomalidomide, Lenalidomide)

XII. Drug Interactions

  1. Strong CYP1A2 Inhibitors
    1. Avoid with Pomalidomide
  2. Digoxin
    1. Lenalidomide may increase levels

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Related Studies

Ontology: Thalidomide (C0039736)

Definition (MSH) A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of TUMOR NECROSIS FACTOR-ALPHA from monocytes, and modulates other cytokine action.
Definition (NCI) A synthetic derivative of glutamic acid (alpha-phthalimido-glutarimide) with teratogenic, immunomodulatory, anti-inflammatory and anti-angiogenic properties. Thalidomide acts primarily by inhibiting both the production of tumor necrosis factor alpha (TNF-alpha) in stimulated peripheral monocytes and the activities of interleukins and interferons. This agent also inhibits polymorphonuclear chemotaxis and monocyte phagocytosis. In addition, thalidomide inhibits pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thereby inhibiting angiogenesis.
Definition (NCI_NCI-GLOSS) A drug that is used to treat multiple myeloma in patients who have just been diagnosed, and a painful skin disease related to leprosy. It is also being studied in the treatment of other types of cancer. Thalomid belongs to the family of drugs called angiogenesis inhibitors.
Definition (CSP) piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn due to teratogenic effects; it has been reintroduced and used for a number of immunological and inflammatory disorders.
Definition (PDQ) A synthetic derivative of glutamic acid (alpha-phthalimido-glutarimide) with teratogenic, immunomodulatory, anti-inflammatory and anti-angiogenic properties. Thalidomide acts primarily by inhibiting both the production of tumor necrosis factor alpha (TNF-alpha) in stimulated peripheral monocytes and the activities of interleukins and interferons. This agent also inhibits polymorphonuclear chemotaxis and monocyte phagocytosis. In addition, thalidomide inhibits pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thereby inhibiting angiogenesis. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=42332&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=42332&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C870" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Hazardous or Poisonous Substance (T131) , Organic Chemical (T109)
MSH D013792
SnomedCT 363551007, 78702007, 404878004
English Thalidomide, thalidomide, 1H-Isoindole-1,3(2H)-dione, 2-(2,6-dioxo-3-piperidinyl)-, 2,6-Dioxo-3-phthalimidopiperidine, 2-(2,6-Dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione, 3-Phthalimidoglutarimide, N-(2,6-Dioxo-3-piperidyl)phthalimide, Alpha-Phthalimidoglutarimide, N-Phthaloylglutamimide, N-Phthalylglutamic Acid Imide, Sedalis, hormones thalidomide, thalidomide (medication), THALIDOMIDE, Thalidomide [Chemical/Ingredient], Thalidomide - chemical (substance), Thalidomide - chemical, (+)-Thalidomide, .alpha.-Phthalimidoglutarimide, Phthalimide, N-(2, 6-dioxo-3-piperidyl)-, (-)-, 2, 6-Dioxo-3-phthalimidopiperidine, (-)-Thalidomide, N-Phthalylglutamic acid imide, Phthalimide, N-(2, 6-dioxo-3-piperidyl)-, (+)-, Thalidomide (substance), Thalidomide (product), THAL
Swedish Talidomid
Czech thalidomid
Finnish Talidomidi
Russian TALIDOMID, ТАЛИДОМИД
Japanese サリドマイド, ケバドン, サレド
Polish Contergan, Saptenon, Talidomid
Spanish talidomida - químico, talidomida - químico (sustancia), talidomida (sustancia), talidomida, talidomida (producto), Talidomida
French Thalidomide
German Contergan, Thalidomid
Italian Talidomide
Portuguese Talidomida

Ontology: lenalidomide (C1144149)

Definition (NCI) A thalidomide analog with potential antineoplastic activity. Lenalidomide inhibits TNF-alpha production, stimulates T cells, reduces serum levels of the cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and inhibits angiogenesis. This agent also promotes G1 cell cycle arrest and apoptosis of malignant cells.
Definition (NCI_NCI-GLOSS) A drug that is similar to thalidomide, and is used to treat multiple myeloma and certain types of anemia. It is also being studied in the treatment of other types of cancer. Lenalidomide belongs to the family of drugs called angiogenesis inhibitors.
Definition (PDQ) A thalidomide analog with potential antineoplastic activity. Lenalidomide inhibits TNF-alpha production, stimulates T cells, reduces serum levels of the cytokines vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and inhibits angiogenesis. This agent also promotes G1 cell cycle arrest and apoptosis of malignant cells. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=38564&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=38564&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C2668" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C467567
SnomedCT 421471009, 421737001
English Lenalidomide, Lenalidomide (product), Lenalidomide (substance), lenalidomide, lenalidomide (medication), LENALIDOMIDE, 3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, lenalidomide [Chemical/Ingredient], IMiD-1, 2,6-Piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H- isoindol-2-yl)-, 3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione, IMiD3 cpd
Spanish lenalidomida (sustancia), lenalidomida, lenalidomida (producto)

Ontology: pomalidomide (C2347624)

Definition (NCI_NCI-GLOSS) A substance being studied in the treatment of prostate cancer, multiple myeloma, and other types of cancer. Pomalidomide is a form of the drug thalidomide. It stops the growth of blood vessels, stimulates the immune system, and may kill cancer cells. Pomalidomide is a type of angiogenesis inhibitor and a type of immunomodulatory agent.
Definition (NCI) An orally bioavailable derivative of thalidomide with potential immunomodulating, antiangiogenic and antineoplastic activities. Although its exact mechanism of action has yet to be fully elucidated, pomalidomide appears to inhibit TNF-alpha production, enhance the activity of T cells and natural killer (NK) cells and enhance antibody-dependent cellular cytotoxicity (ADCC). In addition, pomalidomide may inhibit tumor angiogenesis, promote cell cycle arrest in susceptible tumor cell populations, and stimulate erythropoeisis.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C467566
SnomedCT 703789000, 703790009
English pomalidomide, 3-Amino-N-(2,6-dioxo-3-piperidyl)phthalimide, 4-Amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione, 4-Aminothalidomide, POMALIDOMIDE, Pomalidomide, Pomalidomide (product), Pomalidomide (substance)