Lenalidomide is a thalidomide analogue indicated for the treatment of patients with: ? Multiple myeloma (MM),in combination with dexamethasone,in patients who have received at least one prior therapy . ? Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities ? Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies,one of which included bortezomib
Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of Lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1α) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM. Immunomodulatory properties of Lenalidomide include increased number and activation of T cells and natural killer (NK) cells leading to direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In MM cells, the combination of Lenalidomide and Dxamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.
Absorption: Lenalidomide is rapidly absorbed following oral administration. Following single and multiple doses of Lenalidomide in patients with MM or MDS, the maximum plasma concentrations occurred between 0.5 and 6 hours post-dose. The single and multiple dose pharmacokinetic disposition of Lenalidomide is linear with AUC and Cmax values increasing proportionally with dose. Multiple doses of Lenalidomide at the recommended dosage does not result in drug accumulation. Administration of a single 25 mg dose of Lenalidomide with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in Cmax. In the trials where the efficacy and safety were established for Lenalidomide, the drug was administered without regard to food intake. Lenalidomide can be administered with or without food. The oral absorption rate of Lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.
Distribution: In vitro [14 C]-Lenalidomide binding to plasma proteins is approximately 30%. Lenalidomide is present in semen at 2 hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration of Lenalidomide 25 mg daily.
Elimination: The mean half-life of Lenalidomide is 3 hours in healthy subjects and 3 to 5 hours in patients with MM, MDS or MCL.
Metabolism: Lenalidomide undergoes limited metabolism. Unchanged Lenalidomide is the predominant circulating component in humans. Two identified metabolites are 5¬ Hydroxy-Lenalidomide and N-Acetyl Lenalidomide; each constitutes less than 5% of parent levels in circulation.
Excretion: Elimination is primarily renal. Following a single oral administration of [14 C]-Lenalidomide 25 mg to healthy subjects, approximately 90% and 4% of the radioactive dose was eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose was excreted as Lenalidomide in the urine within 24 hours. Hydroxy-Lenalidomide and N-Acetyl-Lenalidomide represented 4.6% and 1.8% of the excreted dose, respectively. The renal clearance of Lenalidomide exceeds the glomerular filtration rate.
MM: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles. Recommended dose of dexamethasone is 40 mg once daily on Days 1-4, 9-12,and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg/day orally on Days 1-4 every 28 days . ? MDS: 10 mg once daily . ? MCL: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles ? Continue or modify dosing based on clinical and laboratory findings ? Renal impairment: Adjust starting dose in patients with moderate or severe renal impairment and on dialysis (CLcr<60 mL/min)
Digoxin: When Digoxin was co-administered with multiple doses of Lenalidomide (10 mg/day) the Digoxin Cmax and AUCinf were increased by 14%. Periodic monitoring of Digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of Lenalidomide.
Concomitant Therapies That May Increase the Risk of Thrombosis: Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen-containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving Lenalidomide.
Warfarin: Co-administration of multiple doses of Lenalidomide (10 mg/day) with a single dose of Warfarin (25 mg) had no effect on the pharmacokinetics of Lenalidomide or R- and S-Warfarin. It is not known whether there is an interaction between Dexamethasone and Warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant Warfarin.
EMBRYO-FETAL TOXICITY,HEMATOLOGIC TOXICITY,and VENOUS THROMBOEMBOLISM,Demonstrated hypersensitivity to lenalidomide (4.2,5.5). ? Allergic Reactions,including fatalities: Hypersensitivity,angioedema, Stevens-Johnson syndrome,toxic epidermal necrolysis; discontinue Lenalidomide if reactions are suspected. Do not resume Lenalidomide if these reactions are verified . ? Tumor lysis syndrome (TLS) including fatalities: Monitor patients at risk of TLS (i.e.,those with high tumor burden) and take appropriate precautions . ? Tumor flare reaction: Serious tumor flare reactions have occurred during investigational use of Lenalidomide for chronic lymphocytic leukemia and lymphoma . ? Hepatotoxicity: Hepatic failure including fatalities; monitor liver function. Stop Lenalidomide and evaluate if hepatotoxicity is suspected. ? Second Primary Malignancies (SPM): Higher incidences of SPM were observed in controlled trials of patients with multiple myeloma receiving Lenalidomide .
fatigue, neutropenia,constipation,diarrhea,muscle cramp,anemia,pyrexia, peripheral edema,nausea,back pain,upper respiratory tract infection, dyspnea,dizziness,thrombocytopenia,tremor and rash.
EMBRYO-FETAL TOXICITY,Discontinue drug or nursing taking into consideration importance of drug to the mother
There is no specific experience in the management of Lenalidomide overdose in patients with MM, MDS, or MCL.
Store below 30°C in a dry place. Protect from light. Keep out of the reach of children.
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