LENALIDOMIDE — 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg capsules

Lenalidomide is an immunomodulatory drug (IMiD) and a structural analogue of thalidomide that was first approved by the U.S. FDA in 2005. It has since become a cornerstone of treatment for multiple myeloma and other hematologic malignancies, demonstrating significantly improved efficacy and a more favorable adverse effect profile compared to its predecessor thalidomide. Lenalidomide is available only through a restricted distribution program (REMS in the US, similar programs globally) due to its proven teratogenicity in animal studies and structural similarity to thalidomide, a known human teratogen.

Mechanism of action: Lenalidomide exerts its effects through multiple mechanisms. It binds directly to cereblon (CRBN), a component of the E3 ubiquitin ligase complex, thereby modulating the ubiquitination and subsequent degradation of specific substrate proteins. In multiple myeloma cells, lenalidomide targets the transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos) for proteasomal degradation, leading to direct anti-proliferative and pro-apoptotic effects. It also enhances T-cell and natural killer (NK) cell immune function by co-stimulating T-cells and increasing IL-2 and IFN-γ production.

Clinical efficacy: In multiple myeloma, lenalidomide in combination with dexamethasone significantly improved overall survival compared to dexamethasone alone in patients with relapsed/refractory disease. For newly diagnosed transplant-ineligible patients, the FIRST trial demonstrated superior progression-free and overall survival with continuous lenalidomide-dexamethasone (Rd) compared to melphalan-prednisone-thalidomide (MPT). As maintenance therapy following autologous stem cell transplantation, lenalidomide has been shown to nearly double median progression-free survival. In myelodysplastic syndromes with isolated del(5q), lenalidomide induces transfusion independence in approximately 67% of patients.

Pharmacokinetics: Lenalidomide is rapidly absorbed after oral administration, with peak plasma concentrations reached in approximately 0.5 to 4 hours. It has a mean elimination half-life of approximately 3 hours and is primarily excreted unchanged in the urine (approximately 90%). Renal function significantly affects drug exposure, requiring dose adjustment based on creatinine clearance.

• Pregnancy. Lenalidomide can cause fetal harm and is contraindicated in females who are pregnant.
• Demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide or any component of the formulation.

• Digoxin: Lenalidomide may increase digoxin Cmax and AUC. Monitor digoxin plasma levels periodically.
• Erythropoietin stimulating agents (ESAs): Concomitant use may increase risk of thrombosis.
• Estrogen-containing therapies: May increase risk of thrombosis.
• Warfarin and other anticoagulants: Increased bleeding risk; monitor INR closely.
• CYP450 substrates: Lenalidomide does not significantly inhibit or induce CYP450 enzymes, making major CYP-mediated interactions unlikely.

• Pregnancy: FDA Category X. Contraindicated. Women of reproductive potential must use two forms of effective contraception for at least 4 weeks before, during, and for 4 weeks after treatment.
• Lactation: It is unknown if lenalidomide is excreted in human milk. Advise women not to breastfeed during treatment and for at least 4 weeks after last dose due to potential for serious adverse reactions in nursing infants.
• Pediatric use: Safety and efficacy not established in pediatric patients.
• Geriatric use: No overall differences in safety or efficacy observed, but greater sensitivity cannot be ruled out.
• Renal impairment: Lenalidomide is primarily excreted unchanged in urine. Dose adjustment is required based on creatinine clearance (CrCl). For moderate renal impairment (CrCl 30-60 mL/min), reduce dose. For severe renal impairment (CrCl <30 mL/min), further dose reduction required; not requiring dialysis may receive 5 mg once daily.
• Hepatic impairment: No dedicated studies; use with caution and monitor liver function.

• Multiple myeloma (combination therapy): 25 mg once daily on Days 1-21 of repeated 28-day cycles, in combination with dexamethasone.
• Multiple myeloma (maintenance post-auto-HSCT): 10 mg once daily continuously on Days 1-28 of 28-day cycles. After 3 cycles, may increase to 15 mg if tolerated.
• Myelodysplastic syndromes (del 5q): 10 mg once daily on Days 1-21 of repeated 28-day cycles.
• Mantle cell lymphoma: 25 mg once daily on Days 1-21 of repeated 28-day cycles.
• Follicular lymphoma / Marginal zone lymphoma: 20 mg once daily on Days 1-21 of repeated 28-day cycles for up to 12 cycles, in combination with rituximab.
• Dose adjustments: For hematologic toxicity, dose interruption and reduction guidelines vary by indication and severity (see full prescribing information). For renal impairment, adjust starting dose based on CrCl.
• Administration: Swallow capsules whole with water. Do not open, break, or chew. Take at about the same time each day, with or without food. If a dose is missed and less than 12 hours have elapsed, take it as soon as remembered; if more than 12 hours, skip the missed dose.

• Symptoms: Overdose experience limited; expected to include exaggerated adverse reactions (severe neutropenia, thrombocytopenia, rash).
• Management: No specific antidote. Discontinue lenalidomide, provide supportive care, monitor vital signs and CBC. Hemodialysis may remove lenalidomide (approximately 30% in 4 hours).