Usage
Lenalidomide is prescribed for the treatment of several hematological malignancies:
- Multiple Myeloma (MM): In combination with dexamethasone or other drugs for newly diagnosed and relapsed/refractory MM. Also used as maintenance therapy after autologous hematopoietic stem cell transplantation (auto-HSCT).
- Myelodysplastic Syndromes (MDS): Specifically for patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality.
- Mantle Cell Lymphoma (MCL): In patients whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.
- Follicular Lymphoma (FL) and Marginal Zone Lymphoma (MZL): In combination with rituximab for previously treated FL and MZL.
Pharmacological Classification: Immunomodulatory agent, antineoplastic agent.
Mechanism of Action: Lenalidomide has multiple mechanisms of action, including direct cytotoxic effects on tumor cells, immunomodulatory effects (enhancing T-cell and natural killer cell activity), anti-angiogenic effects (inhibiting blood vessel formation), and altering cytokine production.
Alternate Names
International Nonproprietary Name (INN): Lenalidomide
Brand Names: Revlimid
How It Works
Pharmacodynamics: Lenalidomide’s effects are mediated through multiple mechanisms, primarily by binding to cereblon, a component of an E3 ubiquitin ligase complex. This interaction leads to the ubiquitination and degradation of two transcription factors, Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for the survival of myeloma cells. It also enhances T-cell and NK cell activity against myeloma cells, inhibits angiogenesis, and modulates cytokine production.
Pharmacokinetics:
- Absorption: Well-absorbed orally. Food may slightly delay but does not significantly affect overall absorption.
- Metabolism: Primarily metabolized by CYP enzymes, predominantly CYP1A2, with minor contributions from CYP2J2 and CYP3A4. A small amount is also metabolized by hydrolysis.
- Elimination: Primarily eliminated renally as unchanged drug and metabolites. Half-life is approximately 40 hours.
Mode of action: Lenalidomide binds to cereblon, leading to targeted ubiquitination and degradation of specific proteins within myeloma cells (IKZF1, IKZF3), leading to apoptosis. It also affects immune cell function and inhibits angiogenesis.
Elimination Pathways: Predominantly renal excretion of both unchanged drug and metabolites.
Dosage
Standard Dosage
Adults:
- Multiple Myeloma (Newly diagnosed, ineligible for auto-HSCT): 25 mg orally once daily on days 1-21 of repeated 28-day cycles in combination with dexamethasone.
- Multiple Myeloma (Maintenance after auto-HSCT): 10 mg orally once daily continuously (days 1-28 of repeated 28-day cycles). May increase to 15 mg daily after 3 cycles if tolerated.
- MDS (del 5q): 10 mg orally once daily on days 1-21 of repeated 28-day cycles.
- MCL (Relapsed/Refractory): 25 mg orally once daily on days 1-21 of repeated 28-day cycles.
- FL and MZL (Previously treated): 20 mg orally once daily on days 1-21 of repeated 28-day cycles for up to 12 cycles in combination with rituximab.
Children: Not recommended. Safety and efficacy not established.
Special Cases:
- Elderly Patients: Dose adjustments of dexamethasone may be necessary. Close monitoring recommended.
- Patients with Renal Impairment: Dose adjustments are required based on creatinine clearance (CrCl). See specific guidelines based on indication.
- Patients with Hepatic Dysfunction: No specific dose adjustments are routinely recommended, but caution is advised. Close monitoring is necessary.
- Patients with Comorbid Conditions: Considerations should be given for patients with pre-existing conditions like diabetes, cardiovascular disease, and history of thromboembolic events.
Clinical Use Cases
Lenalidomide 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 necessary based on renal function, hematologic toxicity (neutropenia, thrombocytopenia), and other adverse effects. Detailed dose reduction guidelines are available in prescribing information and should be followed.
Side Effects
Common Side Effects
Neutropenia, thrombocytopenia, fatigue, diarrhea, constipation, nausea, vomiting, rash, pruritus, muscle cramps, peripheral neuropathy, and infections.
Rare but Serious Side Effects
Tumor lysis syndrome, severe allergic reactions (angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis), thromboembolic events (deep vein thrombosis, pulmonary embolism), second primary malignancies (e.g., AML, MDS).
Long-Term Effects
Risk of second primary malignancies, peripheral neuropathy.
Adverse Drug Reactions (ADR)
Tumor lysis syndrome, severe allergic reactions, thromboembolic events, and severe myelosuppression.
Contraindications
- Pregnancy.
- Hypersensitivity to lenalidomide or its components.
Drug Interactions
Lenalidomide interacts with numerous medications. Consult detailed drug interaction resources for a complete list. Notable interactions include:
- Digoxin: Increased digoxin levels.
- Warfarin: No clinically significant interaction.
- Estrogen-containing therapies: Increased risk of thrombosis.
- CYP3A4 inducers/inhibitors: May affect lenalidomide metabolism.
Pregnancy and Breastfeeding
- Pregnancy: Contraindicated. Known teratogen. Strict pregnancy prevention measures are required.
- Breastfeeding: Not recommended.
Drug Profile Summary
- Mechanism of Action: Binds to cereblon, leading to degradation of IKZF1 and IKZF3, affecting myeloma cell survival and immune function.
- Side Effects: Neutropenia, thrombocytopenia, fatigue, rash, thromboembolic events.
- Contraindications: Pregnancy, hypersensitivity.
- Drug Interactions: Numerous, including digoxin and estrogen-containing therapies.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended while breastfeeding.
- Dosage: Varies depending on indication; dose adjustments based on renal function and other factors.
- Monitoring Parameters: Complete blood counts (CBCs) with differential, renal function tests, coagulation parameters.
Popular Combinations
- Lenalidomide + Dexamethasone (Multiple myeloma)
- Lenalidomide + Rituximab (Follicular lymphoma and Marginal zone lymphoma)
- Lenalidomide + Bortezomib + Dexamethasone (Multiple myeloma)
Precautions
- General Precautions: Renal and hepatic function, CBC monitoring.
- Specific Populations: Stringent pregnancy prevention measures for females of reproductive potential and male patients.
- Lifestyle Considerations: No specific lifestyle restrictions, but advise patients on managing fatigue and gastrointestinal side effects.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Lenalidomide?
A: Dosage varies depending on the indication and patient-specific factors such as renal function. Consult detailed dosing guidelines and adjust according to individual patient needs.
Q2: What are the most common side effects of lenalidomide?
A: Neutropenia, thrombocytopenia, fatigue, diarrhea/constipation, rash, and increased risk of infections.
Q3: How should lenalidomide be administered?
A: Orally, once daily, with or without food. Capsules should be swallowed whole and not crushed or chewed.
Q4: What are the absolute contraindications for lenalidomide?
A: Pregnancy and known hypersensitivity to lenalidomide.
Q5: What are the key drug interactions with lenalidomide?
A: Numerous drug interactions exist. Notable interactions include digoxin and estrogen-containing therapies. Consult a drug interaction resource for a comprehensive list.
Q6: How does lenalidomide affect pregnancy and breastfeeding?
A: Contraindicated in pregnancy due to teratogenic effects. Breastfeeding is not recommended.
Q7: What are the important monitoring parameters for patients on lenalidomide?
A: Complete blood counts (CBCs) with differential, renal function tests, and coagulation parameters should be monitored regularly.
A: Primarily metabolized by CYP1A2 and eliminated renally.
Q9: Can lenalidomide be used in elderly patients?
A: Yes, but with careful monitoring and potential dose adjustments, particularly for dexamethasone when used in combination.
Q10: What are the potential long-term side effects of lenalidomide?
A: Risk of second primary malignancies and peripheral neuropathy.
