5 mg, 10 mg, 15 mg and 25 mg capsules
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2 H -isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:
3-(4-amino-1-oxo 1,3-dihydro-2 H -isoindol-2-yl) piperidine-2,6-dione
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.
REVLIMID® (lenalidomide) is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for oral administration. Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 5 mg and 25 mg capsule shell contains gelatin, titanium dioxide and black ink. The 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink.
Mechanism of Action
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide possesses antineoplastic, immunomodulatory and antiangiogenic properties. Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the secretion of antiinflammatory cytokines from peripheral blood mononuclear cells. Lenalidomide inhibited cell proliferation with varying effectiveness (IC50s) in some but not all cell lines. Of cell lines tested, lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) but was much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and other cell lines without chromosome 5 deletions. Lenalidomide inhibited the growth of multiple myeloma cells from patients, as well as MM.1S cells (a human multiple myeloma cell line), by inducing cell cycle arrest and apoptosis.
Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.
Pharmacokinetics and Drug Metabolism
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. Co‑administration with food does not alter the extent of absorption (AUC) but does reduce the maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of lenalidomide is linear. Cmax and AUC increase proportionately with increases in dose. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.
Pharmacokinetic sampling in myelodysplastic syndromes (MDS) patients was not performed. In multiple myeloma patients maximum plasma concentrations occurred between 0.5 and 4.0 hours post-dose both on Days 1 and 28. AUC and Cmax values increase proportionally with dose following single and multiple doses. Exposure (AUC) in multiple myeloma patients is 57% higher than in healthy male volunteers.
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%.
Metabolism and Excretion:
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. The process exceeds the glomerular filtration rate and therefore is partially or entirely active. Half‑life of elimination is approximately 3 hours.
Patients with Renal Insufficiency: The pharmacokinetics of lenalidomide were studied in patients with renal impairment due to nonmalignant conditions. In this study, 5 patients with mild renal function impairment (creatinine clearance 57-74 mL/min), 6 patients with moderate renal function impairment (creatinine clearance 33-46 mL/min), 6 patients with severe renal function impairment (creatinine clearance 17-29 mL/min), and 6 patients with end stage renal disease requiring dialysis were administered a single oral 25-mg dose of REVLIMID® (lenalidomide). As a control group comparator, 7 healthy subjects of similar age with normal renal function (creatinine clearance 83-145 mL/min) were also administered a single oral 25-mg dose of REVLIMID® (lenalidomide). As creatinine clearance decreased from mild to severe impairment, half-life increased and drug clearance decreased linearly. Patients with moderate and severe renal impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) given a single, 25-mg dose of lenalidomide had an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 40% of the administered dose was removed from the body during a single dialysis session.
Adjustment of the starting dose of REVLIMID® (lenalidomide) is recommended in patients with moderate or severe (CLcr < 60 mL/min) renal impairment and in patients on dialysis. See DOSAGE AND ADMINISTRATION.
In multiple myeloma patients, those patients with mild renal impairment had an AUC 56% greater than those with normal renal function.
Patients with Hepatic Disease: The pharmacokinetics of lenalidomide in patients with hepatic impairment have not been studied.
Age: The effects of age on the pharmacokinetics of lenalidomide have not been studied.
Pediatric: No pharmacokinetic data are available in patients below the age of 18 years.
Gender: The effects of gender on the pharmacokinetics of lenalidomide have not been studied.
Race: Pharmacokinetic differences due to race have not been studied.
Myelodysplastic Syndromes (MDS) with a Deletion 5q Cytogenetic Abnormality
The efficacy and safety of REVLIMID® (lenalidomide) were evaluated in patients with transfusion dependent anemia in Low- or Intermediate-1- risk MDS with a 5q (q31-33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at a dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an open-label, single-arm, multi-center study. The major study was not designed nor powered to prospectively compare the efficacy of the 2 dosing regimens. Sequential dose reductions to 5 mg daily and 5 mg every other day, as well as dose delays, were allowed for toxicity.
This major study enrolled 148 patients who had RBC transfusion dependent anemia. RBC-transfusion dependence was defined as having received ≥ 2 units of RBCs within 8 weeks prior to study treatment. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 500/mm3, platelet counts ≥ 50,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3.0 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2.0 mg/dL. Granulocyte colony-stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia. Baseline patient and disease-related characteristics are summarized in Table 1.
Table 1: Baseline Demographic and Disease-Related Characteristics
|[a] IPSS Risk Category: Low (combined score = 0), Intermediate-1 (combined score = 0.5 to 1.0), Intermediate-2 (combined score = 1.5 to 2.0), High (combined score ≥ 2.5); Combined score = (Marrow blast score + Karyotype score + Cytopenia score)|
|[b] French-American-British (FAB) classification of MDS.|
| Age (years) |
| Min, Max||37.0, 95.0|
| Gender || n || (%) |
| Race || n || (%) |
| Duration of MDS (years) |
| Min, Max||0.1, 20.7|
| Del 5 (q31-33) Cytogenetic Abnormality || n || (%) |
| Other cytogenetic abnormalities||37||(25.2)|
| IPSS Score [a] || n || (%) |
| Low (0)||55||(37.2)|
| Intermediate-1 (0.5-1.0)||65||(43.9)|
| Intermediate-2 (1.5-2.0)||6||(4.1)|
| High (≥2.5)||2||(1.4)|
| FAB Classification [b] from central review || n || (%) |
The frequency of RBC-transfusion independence was assessed using criteria modified from the International Working Group (IWG) response criteria for MDS. RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period.
Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The median duration from the date when RBC transfusion independence was first declared (i.e., the last day of the 56-day RBC transfusion-free period) to the date when an additional transfusion was received after the 56-day transfusion-free period among the 99 responders was 44 weeks (range of 0 to >67 weeks).
Ninety percent of patients who achieved a transfusion benefit did so by completion of three months in the study.
RBC-transfusion independence rates were unaffected by age or gender.
The dose of REVLIMID® (lenalidomide) was reduced or interrupted at least once due to an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose reduction or interruption was 21 days (mean, 35.1 days; range, 2-253 days), and the median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2-265 days). A second dose reduction or interruption due to adverse events was required in 50 (33.8%) of the 148 patients. The median interval between the first and second dose reduction or interruption was 51 days (mean, 59.7 days; range, 15-205 days) and the median duration of the second dose interruption was 21 days (mean, 26 days; range, 2-148 days).
Granulocyte colony-stimulating factors were permitted for patients who developed neutropenia or fever in association with neutropenia.
Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and safety of REVLIMID® (lenalidomide). These multicenter, multinational, double-blind, placebo-controlled studies compared REVLIMID® (lenalidomide) plus oral pulse high-dose dexamethasone therapy to dexamethasone therapy alone, in patients with multiple myeloma who had received at least one prior treatment.
In both studies, patients in the REVLIMID® (lenalidomide)/dexamethasone group took 25 mg of REVLIMID® (lenalidomide) orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22 to 28 of each 28‑day cycle. Patients in the placebo/dexamethasone group took 1 placebo capsule on Days 1 to 28 of each 28‑day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28‑day cycle for the first 4 cycles of therapy.
The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of each 28‑day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue until disease progression.
In both studies, dose adjustments were allowed based on clinical and laboratory findings. Sequential dose reductions to 15 mg daily, 10 mg daily and 5 mg daily were allowed for toxicity. (See DOSAGE AND ADMINISTRATION)
Table 2 summarizes the baseline patient and disease characteristics in the two studies. In both studies, baseline demographic and disease-related characteristics were comparable between the REVLIMID® (lenalidomide)/dexamethasone and placebo/dexamethasone groups.
Table 2: Baseline Demographic and Disease-Related Characteristics - Studies 1 and 2
| Study 1 || Study 2 |
| REVLIMID/Dex |
| Placebo/Dex |
| REVLIMID/Dex |
| Placebo/Dex |
| Patient Characteristics |
| Min,Max||36,86||37, 85||33, 84||40, 82|
| Male||102 (60%)||101 (59%)||104 (59%)||103 (59%)|
| Female||68 (40%)||70 (41%)||72 (41%)||72 (41%)|
| White||134 (79%)||143 (84%)||172 (98%)||175 (100%)|
| Other||36 (21%)||28 (16%)||4 (2%)||0 (0%)|
|ECOG Performance Status 0-1||151 (89%)||163 (95%)||150 (85%)||144 (82%)|
| Disease Characteristics |
|Baseline Multiple Myeloma Stage (Durie-Salmon)|
|Baseline Creatinine (mg/dL)|
| Min,Max||0.4, 2.6||0.5, 2.4||0.3, 2.3||0.5, 2.3|
| Median ||3.7||3.3||3.4||3.3|
| Min,Max||1.1, 45||1.3, 15.2||1.0, 14.4||1.3, 25.3|
| Number of Prior Therapies |
|No. of Prior Antimyeloma Therapies|
| Types of Prior Therapies |
|Stem Cell Transplantation||60%||60%||56%||54%|
The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease.
Preplanned interim analyses of both studies showed that the combination of REVLIMID® (lenalidomide)/dexamethasone was significantly superior to dexamethasone alone for TTP. The studies were unblinded to allow patients in the placebo/dexamethasone group to receive treatment with the REVLIMID® (lenalidomide)/dexamethasone combination.
Table 3 summarizes TTP and response rates based on the best response assessments for Studies 1 and 2.
Table 3: Summary of Efficacy Analysis — Studies 1 and 2
|1 NE, Not estimable due to short follow-up.|
|2 Hazard Ratio of Revlimid/Dexamethasone to Placebo/Dexamethasone|
|3 The p-value is based on a one-tailed unstratified log rank test.|
| Study 1 || Study 2 |
| REVLIMID/Dex |
| Placebo/Dex |
| REVLIMID/Dex |
| Placebo/Dex |
| TTP |
|115 (68)||61 (36)||133 (76)||78 (45)|
|Median TTP in|
|0.356 [0.257, 0.494]||0.392 [0.274, 0.562]|
| Response |
|14 (8)||1 (1)||14 (8)||1 (1)|
(RR/PR) n (%)
|76 (44)||27 (16)||76 (43)||33 (19)|
|90 (53)||28 (16)||90 (51)||34 (19)|
|5.5 [3.3, 9.1]||4.3 [2.7, 7.0]|
Figures 1 and 2 depict the Kaplan-Meier estimates of TTP in Studies 1 and 2, respectively.
Figure 1: Kaplan-Meier Estimate of Time to Progression - Study 1
The median duration of Study 1 follow-up was 20.1 weeks.
Figure 2: Kaplan-Meier Estimate of Time to Progression - Study 2
The median duration of Study 2 follow-up was 22.3 weeks.