• POTENTIAL FOR HUMAN BIRTH DEFECTS
• HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA)
• DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM

• she understands and can reliably carry out instructions.
• she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the RevAssist^SM program.
• she has received and understands both oral and written warnings of the potential risks of taking lenalidomide during pregnancy and of exposing a fetus to the drug.
• she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously, unless continuous abstinence from heterosexual sexual contact is the chosen method. Sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months), or had a bilateral oophorectomy are considered to be females of childbearing potential.
• she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4 weeks prior to beginning lenalidomide therapy, during lenalidomide therapy, during dose interruptions and for 4 weeks after discontinuation of lenalidomide therapy.
• she has had two negative pregnancy tests with a sensitivity of at least 50 mIU/mL, within 10-14 days and 24 hours prior to beginning therapy.
• if the patient is between 12 and 18 years of age, her parent or legal guardian must have read the educational materials and agreed to ensure compliance with the above.

This drug is associated with significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. (SEE DOSAGE AND ADMINISTRATION)

DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM

This drug has demonstrated a significantly increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID^® (lenalidomide) combination therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID^® (lenalidomide) may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

You can get the information about REVLIMID^® and the RevAssist^SM program on the internet at www.REVLIMID.com or by calling the manufacturer’s toll free number 1-888-423-5436.

DESCRIPTION

REVLIMID^®(lenalidomide), a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic and anti-neoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:

3-(4-amino-1-oxo 1,3-dihydro-2H-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.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide possesses anti-neoplastic, immunomodulatory and antiangiogenic properties. Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory 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:

Pharmacokinetic Parameters:

CLINICAL STUDIES

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 cells/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.

The frequency of RBC-transfusion independence was 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.

Multiple Myeloma

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. Section).

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.

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.

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.

INDICATIONS AND USAGE:

REVLIMID^® (lenalidomide) is indicated for the treatment of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

REVLIMID^® (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy.

CONTRAINDICATIONS:

Pregnancy Category X: (See 'BOXED WARNING')

Due to its structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in pregnant women and women capable of becoming pregnant. (See BOXED WARNINGS.) When there is no alternative, females of childbearing potential may be treated with lenalidomide provided adequate precautions are taken to avoid pregnancy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, including at least one highly effective method (e.g., IUD, hormonal contraception, tubal ligation, or partner’s vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating treatment with REVLIMID^® (lenalidomide), during therapy with REVLIMID^® (lenalidomide), during therapy delay, and continuing for 4 weeks following discontinuation of REVLIMID^® (lenalidomide) therapy. If hormonal or IUD contraception is medically contraindicated, two other effective or highly effective methods may be used.

Females of childbearing potential being treated with REVLIMID^® (lenalidomide) should have pregnancy testing (sensitivity of at least 50 mIU/mL). The first test should be performed within 10-14 days and the second test within 24 hours prior to beginning REVLIMID^® (lenalidomide) therapy and then weekly during the first month of REVLIMID^® (lenalidomide), then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy occurs, REVLIMID^® (lenalidomide) must be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician / gynecologist experienced in reproductive toxicity for further evaluation and counseling.

REVLIMID^® (lenalidomide) is contraindicated in any patients who have demonstrated hypersensitivity to the drug or its components.

WARNINGS:

Pregnancy Category X: (See 'BOXED WARNING' and CONTRAINDICATIONS)

REVLIMID^® (lenalidomide) is an analogue of thalidomide. Thalidomide is a known human teratogen that causes life-threatening human birth defects. REVLIMID^® (lenalidomide) may cause fetal harm when administered to a pregnant female. Females of childbearing potential should be advised to avoid pregnancy while on REVLIMID^® (lenalidomide). Two effective contraceptive methods should be used during therapy, during therapy interruptions and for at least 4 weeks after completing therapy.

There are no adequate and well-controlled studies in pregnant females.

Because of this potential toxicity and to avoid fetal exposure to REVLIMID^® (lenalidomide), REVLIMID^® (lenalidomide) is only available under a special restricted distribution program. This program is called "RevAssist^SM".

Lenalidomide has been shown to have an embryocidal effect in rabbits at a dose of 50 mg/kg (approximately 120 times the human dose of 10 mg based on body surface area).

An embryo-fetal development study in rats revealed no teratogenic effects at the highest dose of 500 mg/kg (approximately 600 times the human dose of 10 mg based on body surface area). At 100, 300 or 500 mg/kg/day there was minimal maternal toxicity that included slight, transient, reduction in mean body weight gain and food intake. However this animal model may not adequately address the full spectrum of the potential embryo-fetal developmental effects of lenalidomide.

A pre- and post-natal development study in rats revealed few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 600 times the human dose of 10 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring.

Reproductive effects of lenalidomide have not been thoroughly assessed. The structural similarity of lenalidomide to thalidomide, a known human teratogen, suggests a potential risk to the developing fetus.

HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA):

This drug is associated with significant neutropenia and thrombocytopenia.

Eighty percent of patients with del 5q MDS had to have a dose delay or reduction during the major study for the indication. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14 – 411 days), and the median time to documented recovery was 17 days (range, 2 – 170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8 - 290 days), and the median time to documented recovery was 22 days (range, 5 – 224 days). Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. SeeDOSAGE AND ADMINISTRATION.

In the pooled multiple myeloma studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID^® (lenalidomide) and dexamethasone than in patients treated with dexamethasone alone. SeeADVERSE REACTIONS Table 7. Patients on therapy should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients may require dose interruption and/or dose reduction. SeeDOSAGE AND ADMINISTRATION

DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM:

This drug has demonstrated a significantly increased risk of DVT and PE in patients with multiple myeloma who were treated with REVLIMID^® (lenalidomide) combination therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID^® (lenalidomide) may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors. See ADVERSE REACTIONS Table 7.

PRECAUTIONS:

General:

No formal studies have been conducted in patients with renal impairment. This drug is known to be excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Information for Patients:

Patients should be counseled on lenalidomide’s potential risk of teratogenicity due to its structural similarity to thalidomide. Patients may only acquire a prescription for REVLIMID^® (lenalidomide) therapy through a controlled distribution program (RevAssist^SM) through contracted pharmacies. Female patients of childbearing potential will be educated and counseled on the requirements of the RevAssist^SM program and the precautions to be taken to preclude fetal exposure to REVLIMID^® (lenalidomide). Patients should become familiar with the REVLIMID^® (lenalidomide) RevAssist^SM educational materials, Patient Medication Guide, and direct any questions to their physician or pharmacist prior to starting REVLIMID^® (lenalidomide) therapy.

Laboratory tests:

The MDS clinical study enrolled patients with absolute neutrophil counts (ANC) ≥ 500 cells/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. A complete blood cell count (CBC), including white blood cell count with differential, platelet count, hemoglobin, and hematocrit should be performed weekly for the first 8 weeks of REVLIMID^® (lenalidomide) treatment and monthly thereafter to monitor for cytopenias.

The multiple myeloma studies 1 and 2 enrolled patients with absolute neutrophil counts (ANC) ≥ 1000 cells/mm³, platelet counts ≥ 75,000/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. A CBC should be performed every two weeks for the first three months and at least monthly thereafter to monitor for cytopenias.

Drug Interactions:

Results from human in vitro metabolism studies and nonclinical studies show that REVLIMID^® (lenalidomide) is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions in man.

Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose pharmacokinetics of R- and S- warfarin. Co-administration of single 25-mg dose warfarin had no effect on the pharmacokinetics of total lenalidomide. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant lenalidomide administration.

When digoxin was co-administered with lenalidomide the digoxin AUC was not significantly different, however, the digoxin C_max was 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.

Carcinogenesis, mutagenesis, impairment of fertility:

Carcinogenicity: Carcinogenicity studies with lenalidomide have not been conducted.

Mutagenesis: Lenalidomide did not induce mutation in the Ames test, chromosome aberrations in cultured human peripheral blood lymphocytes, or mutation at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

Fertility: A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 600 times the human dose of 10 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

Pregnancy:

Pregnancy Category X: (See 'BOXED WARNINGS' and CONTRAINDICATIONS)

Because of the structural similarity to thalidomide, a known human teratogen, and the lack of sufficient information regarding lenalidomide’s teratogenic potential, REVLIMID^® (lenalidomide) is contraindicated in females who are or may become pregnant and who are not using the two required types of birth control or who are not continually abstaining from reproductive heterosexual sexual intercourse. REVLIMID^® (lenalidomide) should not be used by females who are pregnant or who could become pregnant while taking the drug. If pregnancy does occur during treatment, the drug should be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician / gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID^® (lenalidomide) should be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

Use in Nursing Mothers:

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:

Safety and effectiveness in pediatric patients below the age of 18 have not been established.

Geriatric Use:

REVLIMID^® (lenalidomide) has been used in del 5q MDS clinical trials in patients up to 95 years of age.

Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

REVLIMID^® (lenalidomide) has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age.

Of the 692 MM patients enrolled in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID^® (lenalidomide)/dexamethasone and placebo/dexamethasone groups. Of the 346 patients who received REVLIMID^® (lenalidomide)/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experienced diarrhea, fatigue, pulmonary embolism, an syncope following use of REVLIMID^® (lenalidomide). No differences in efficacy were observed between patients over 65 years of age and younger patients.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it would be prudent to monitor renal function.

Renal Impairment:

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug is expected to be greater in patients with impaired renal function. Patients with renal insufficiency were excluded from the clinical trials, and those who developed renal insufficiency during the clinical trials had the drug held. Care should be taken in dose selection, and it would be prudent to monitor renal function.

ADVERSE REACTIONS:

Myelodysplastic Syndromes

A total of 148 patients received at least 1 dose of 10 mg lenalidomide in the del 5q MDS clinical study. At least one adverse event was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID^® (lenalidomide). The most frequently reported adverse events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions. (SeePRECAUTIONS)

Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events observed. The next most common adverse events observed were diarrhea (48.6%; 72/148), pruritis (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 4 summarizes the adverse events that were reported in ≥ 5% of the REVLIMID^® (lenalidomide) treated patients in the del 5q MDS clinical study. Table 5 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID^® (lenalidomide). In the single-arm studies conducted, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.

In other clinical studies of REVLIMID^® (lenalidomide) in MDS patients, the following serious adverse events (regardless of relationship to study drug treatment) not described in Table 4 or 5 were reported:

Blood and lymphatic system disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression NOS, coagulopathy, hemolysis NOS, hemolytic anemia NOS, refractory anemia

Cardiac disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure NOS, cardio-respiratory arrest, cardiomyopathy NOS, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia NOS, cardiogenic shock, pulmonary edema NOS, supraventricular arrhythmia NOS, tachyarrhythmia, ventricular dysfunction

Ear and labyrinth disorders: vertigo

Endocrine disorders: Basedow’s disease

Gastrointestinal disorders: gastrointestinal hemorrhage NOS, colitis ischemic, intestinal perforation NOS, rectal hemorrhage, colonic polyp, diverticulitis NOS, dysphagia, gastritis NOS, gastroenteritis NOS, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis NOS, perirectal abscess, small intestinal obstruction NOS, upper gastrointestinal hemorrhage

General disorders and administration site conditions: disease progression NOS, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death

Hepatobiliary disorders: hyperbilirubinemia, cholecystitis acute NOS, cholecystitis NOS, hepatic failure

Immune system disorders: hypersensitivity NOS

Infections and infestations: infection NOS, bacteremia, central line infection, clostridial infection NOS, ear infection NOS, Enterobacter sepsis, fungal infection NOS, herpes viral infection NOS, influenza, kidney infection NOS, Klebsiella sepsis, lobar pneumonia NOS, localized infection, oral infection, Pseudomonas infection NOS, septic shock, sinusitis acute NOS, sinusitis NOS, Staphylococcal infection, urosepsis

Injury, poisoning and procedural complications: femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis NOS, hip fracture, overdose NOS, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture

Investigations: blood creatinine increased, culture NOS negative, hemoglobin decreased, liver function tests NOS abnormal, troponin I increased

Metabolism and nutrition disorders: dehydration, gout, hypernatremia, hypoglycemia NOS

Musculoskeletal and connective tissue disorders: arthritis NOS, arthritis NOS aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate

Neoplasms benign, malignant and unspecified: acute leukemia NOS, acute myeloid leukemia NOS, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma NOS, prostate cancer metastatic

Nervous system disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine NOS, spinal cord compression NOS, subarachnoid hemorrhage NOS, transient ischemic attack

Psychiatric disorders: confusional state

Renal and urinary disorders: renal failure NOS, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass NOS

Reproductive system and breast disorders: pelvic pain NOS

Respiratory, thoracic and mediastinal disorders: bronchitis NOS, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration NOS, wheezing

Skin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosis

Vascular system disorders: deep vein thrombosis, hypotension NOS, aortic disorder, ischemia NOS, thrombophlebitis superficial, thrombosis

Multiple Myeloma

Data were evaluated from 691 patients in two studies who received at least one dose of REVLIMID^® (lenalidomide)/dexamethasone (346 patients) or placebo/dexamethasone (345 patients).

In the REVLIMID^® (lenalidomide) /dexamethasone treatment group, 151 patients (45%) underwent at least one dose interruption with or without a dose reduction of REVLIMID^® (lenalidomide) compared to 21% in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID^® (lenalidomide) /dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse events and Grade 3/4 adverse events were more frequent in patients who received the combination of REVLIMID^®(lenalidomide)/dexamethasone compared to placebo/dexamethasone.

Table 6 summarizes the number and percentage of patients with Grade 1-4 adverse events reported in ≥10% of patients in either treatment group in Studies 1 and 2.

Table 7 summarizes the Grade 3/4 adverse events reported in ≥2% of patients in either treatment group in Studies 1 and 2.

In the pooled analysis, thrombotic or thromboembolic events, including deep vein thrombosis , pulmonary embolism, thrombosis, and intracranial venous sinus thrombosis, were reported more frequently in patients treated with REVLIMID^® (lenalidomide)/dexamethasone combination. The number of patients experiencing a thrombotic event in the combination arm were 43/346 (12%) compared with those in the placebo/dexamethasone arm 14/345 (4%).

In these and other clinical studies of REVLIMID^® (lenalidomide) in patients with multiple myeloma, the following serious adverse events (considered related to study drug treatment) not described in Table 7 were reported:

Blood and lymphatic system disorders: pancytopenia, anemia NOS aggravated

Cardiac disorders: cardiac failure congestive, atrial flutter, pulmonary edema

Endocrine disorders: adrenal insufficiency NOS, acquired hypothyroidism

Eye disorders: blindness

Gastrointestinal disorders: abdominal pain NOS, colitis pseudomembranous, gastritis NOS, gastrointestinal hemorrhage NOS, peptic ulcer hemorrhage, upper gastrointestinal hemorrhage

General disorders and administration site conditions: performance status decreased

Hepatobiliary disorders: hepatic failure, hepatitis toxic

Infections and infestations: bronchopneumonia NOS, cellulitis, Pneumocystis carnii pneumonia, sepsis NOS, bursitis infective NOS, cellulitis staphylococcal, Enterobacter bacteremia, Escherichia sepsis, gastrointestinal infection NOS, herpes zoster, herpes zoster ophthalmic, infection NOS, lung infection NOS, neutropenic sepsis, pneumonia bacterial NOS, pneumonia cytomegaloviral, pneumonia pneumoccal, pneumonia primary atypical, pneumonia staphylococcal, septic shock, streptococcal sepsis, subacute endocarditis, urinary tract infection NOS

Investigations: International normalized ratio increased, weight decreased, blood creatinine increased, body temperature increased, c-reactive protein increased, hemoglobin decreased, white blood cell count decreased

Metabolism and nutrition disorders: dehydration, diabetes mellitus NOS, diabetes with hyperosmolarity, diabetic ketoacidosis

Musculoskeletal and connective tissue disorders: myopathy steroid, back pain, myopathy

Nervous system disorders: dizziness, memory impairment, brain edema, cerebral infarction, cerebral ischemia, cerebrovascular accident, encephalitis NOS, intracranial hemorrhage NOS, intracranial venous sinus thrombosis NOS, leukoencephalopathy, somnolence, tremor

Psychiatric disorders: mental status changes, delirium, delusion NOS, insomnia, psychotic disorder NOS

Renal and urinary disorders: Fanconi syndrome acquired, hematuria, renal failure acute, renal failure NOS, renal tubular necrosis, urinary retention

Respiratory, thoracic and mediastinal disorders: bronchopneumopathy, hypoxia

Skin and subcutaneous tissue disorders: rash NOS, skin desquamation NOS

Vascular system disorders: phlebitis NOS, venous thrombosis NOS limb, circulatory collapse, hypertension NOS, hypotension NOS, orthostatic hypotension, peripheral ischemia

OVERDOSAGE

No cases of overdose have been reported during the clinical studies.

DOSAGE AND ADMINISTRATION

Myelodysplastic Syndromes

The recommended starting dose of REVLIMID^® (lenalidomide) is 10 mg daily with water. Patients should not break, chew or open the capsules. Dosing is continued or modified based upon clinical and laboratory findings.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it would be prudent to monitor renal function.

Multiple Myeloma

The recommended starting dose of REVLIMID^® (lenalidomide) is 25 mg/day with water orally administered as a single 25 mg capsule on Days 1‑21 of repeated 28-day cycles. Patients should not break, chew or open the capsules. The recommended dose of dexamethasone is 40 mg/day 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. Dosing is continued or modified based upon clinical and laboratory findings.

The effect of substituting lesser strengths of REVLIMID^®(lenalidomide) to achieve a 25 mg capsule dose is unknown.

HOW SUPPLIED

REVLIMID^®(lenalidomide) 5 mg, 10 mg, 15 mg and 25 mg capsules will be supplied through the RevAssist^SM program. (SeeINFORMATION FOR PATIENTS)

REVLIMID^® (lenalidomide) is supplied as:

White opaque capsules imprinted “REV” on one half and “5 mg” on the other half in black ink:

5 mg bottles of 30 (NDC 59572-405-30)

5 mg bottles of 100 (NDC 59572-405-00)

Blue/green and pale yellow opaque capsules imprinted “REV” on one half and “10 mg” on the other half in black ink:

10 mg bottles of 30 (NDC 59572-410-30)

10 mg bottles of 100 (NDC 59572-410-00)

Powder blue and white opaque capsules imprinted “REV” on one half and “15 mg” on the other half in black ink:

15 mg bottles of 21 (NDC 59572-415-21)

15 mg bottles of 100 (NDC 59572-415-00)

White opaque capsules imprinted “REV” on one half and “25 mg” on the other half in black ink:

25 mg bottles of 25 (NDC 59572-425-25)

25 mg bottles of 100 (NDC 59572-425-00)

Storage and Dispensing

Dispense no more than a 28-day supply.

Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F). [See USP Controlled Room Temperature].