Usage
Thalidomide is prescribed for:
- Multiple myeloma (in combination with dexamethasone) in newly diagnosed patients ineligible for high-dose chemotherapy.
- Erythema nodosum leprosum (ENL), a painful skin condition related to leprosy.
Pharmacological Classification: Immunomodulatory agent, antineoplastic agent, and anti-angiogenic agent.
Mechanism of Action: Thalidomide’s mechanism is complex and not fully understood. It inhibits angiogenesis (formation of new blood vessels), modulates immune system function (including T-cell and cytokine activity), and directly affects myeloma cell growth and survival.
Alternate Names
Thalidomide has no widely used alternate names.
Brand Names: Thalomid®
How It Works
Pharmacodynamics: Thalidomide exerts anti-inflammatory, immunomodulatory, anti-angiogenic and antineoplastic effects. It inhibits TNF-alpha production, alters cytokine profiles, suppresses angiogenesis, and induces myeloma cell apoptosis.
Pharmacokinetics:
- Absorption: Well-absorbed orally.
- Metabolism: Extensive non-hepatic metabolism via spontaneous hydrolysis.
- Elimination: Primarily renal excretion, with a half-life of 4-6 hours. Not significantly metabolized by CYP enzymes.
Mode of Action: At the molecular level, thalidomide binds to cereblon, a protein involved in ubiquitin ligase activity. This interaction leads to the degradation of specific proteins crucial for myeloma cell survival and angiogenesis.
Dosage
Standard Dosage
Adults:
- Multiple Myeloma: 200 mg orally once daily at bedtime (at least 1 hour after the evening meal).
- ENL: 100-300 mg orally once daily, preferably at bedtime. Higher doses (up to 400 mg/day) may be used in severe cases or if previous high doses were required. Tapering is recommended after the active reaction subsides.
Children:
Use in children under 12 is generally not recommended due to limited safety and efficacy data. In some cases, for children 12 and older, dosing must be determined by the doctor based on the specific condition and patient characteristics.
Special Cases:
- Elderly Patients (over 75 years): A lower starting dose of 100 mg/day is recommended for multiple myeloma due to increased risk of adverse effects.
- Patients with Renal Impairment: No specific dose adjustments are available. Close monitoring is required.
- Patients with Hepatic Dysfunction: No specific dose adjustments are available. Close monitoring is required.
- Patients with Comorbid Conditions: Dose adjustment may be needed, especially in patients with a history of thromboembolic events. Thromboprophylaxis should be considered.
Clinical Use Cases
Thalidomide is not typically used in the context of intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
Dose adjustments are made based on tolerability and the presence of side effects. Dose reductions or interruptions may be necessary for neuropathy, skin rash, or other adverse reactions.
Side Effects
Common Side Effects:
- Drowsiness/somnolence
- Fatigue
- Constipation
- Peripheral neuropathy (numbness, tingling, pain in hands and feet)
- Dizziness
Rare but Serious Side Effects:
- Venous thromboembolism (deep vein thrombosis, pulmonary embolism)
- Severe peripheral neuropathy
- Neutropenia
- Stevens-Johnson syndrome/toxic epidermal necrolysis
- Angioedema/anaphylaxis
Long-Term Effects:
- Persistent peripheral neuropathy
Adverse Drug Reactions (ADR):
The most serious ADRs include thromboembolic events, severe allergic reactions (angioedema, anaphylaxis), and severe skin reactions (SJS/TEN).
Contraindications
- Pregnancy (absolute contraindication due to severe teratogenic effects)
- Hypersensitivity to thalidomide or related drugs (lenalidomide, pomalidomide)
Drug Interactions
- CNS Depressants: Additive sedative effects.
- Hormonal Contraceptives: Not recommended due to increased risk of thromboembolism.
- CYP450 Interactions: Not a major substrate or inhibitor of CYP enzymes. However, some interactions may occur through other metabolic pathways (e.g., increased metabolism of aminophylline).
- Other Interactions: Numerous interactions are possible. Always check for potential drug interactions before prescribing.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: X (Contraindicated). Thalidomide is a potent teratogen.
- Breastfeeding: Contraindicated as thalidomide is excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: Immunomodulatory, anti-angiogenic, antineoplastic.
- Side Effects: Drowsiness, fatigue, constipation, peripheral neuropathy, thromboembolism.
- Contraindications: Pregnancy, hypersensitivity.
- Drug Interactions: CNS depressants, hormonal contraceptives.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 200 mg/day for multiple myeloma, 100-300 mg/day for ENL.
- Monitoring Parameters: Complete blood count, neurological examination, signs of thromboembolism.
Popular Combinations
- Thalidomide + Dexamethasone (for multiple myeloma)
- Thalidomide + Melphalan + Prednisone (for multiple myeloma)
Precautions
- General Precautions: Pregnancy testing (for women of childbearing potential), monitoring for neuropathy and thromboembolism.
- Specific Populations: Strict pregnancy prevention measures for both men and women, dose reduction in elderly patients.
- Lifestyle Considerations: Avoid alcohol and activities requiring alertness due to drowsiness.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Thalidomide?
A: For multiple myeloma, 200 mg/day orally. For ENL, 100-300 mg/day orally. Adjust for age and comorbidities.
Q2: What are the most serious side effects of Thalidomide?
A: Venous thromboembolism, severe peripheral neuropathy, and severe allergic/skin reactions (e.g., SJS/TEN).
Q3: Can Thalidomide be used during pregnancy?
A: Absolutely not. Thalidomide is a potent teratogen and is contraindicated during pregnancy.
Q4: How does Thalidomide work in multiple myeloma?
A: It inhibits angiogenesis, modulates the immune system, and directly targets myeloma cells for apoptosis.
Q5: What are the common drug interactions with Thalidomide?
A: CNS depressants and hormonal contraceptives. Numerous other interactions exist. Always check for potential interactions.
Q6: How should peripheral neuropathy caused by Thalidomide be managed?
A: Dose reduction or discontinuation may be necessary. Symptomatic treatment can be provided.
Q7: What precautions are necessary for male patients taking Thalidomide?
A: Thalidomide is present in semen. Strict contraception is essential, even if the male partner has had a vasectomy.
Q8: What is the role of Thalidomide in treating ENL?
A: It reduces inflammation and suppresses the painful skin manifestations of ENL.
A: Primarily through spontaneous hydrolysis, not by CYP enzymes.
Q10: What is the standard duration of Thalidomide treatment for multiple myeloma?
A: Up to 12 cycles of 6 weeks each when used in combination with other agents.
