ࡱ>  bjbj O AA4IIIhTI`##^w#w#w#R$ r$ ~$_______bJe_ )R$R$ ) )_A|Xw#w#`X1X1X1 )"w#w#_X1 )_X1X1f)UpYw#[IB,zWD_`0`We.leYeYT$:%X1&T'$$$__(00$$$` ) ) ) )e$$$$$$$$$ : National PBM Drug Monograph Lenalidomide (Revlimid) Updated June 2009 VHA Pharmacy Benefits Management Services and the Medical Advisory Panel Executive Summary: Efficacy: Lenalidomide is an analogue of thalidomide. It is an immunomodulatory drug that inhibits proinflammatory cytokines, stimulates T-cell proliferation and NK cell activity, has antiangiogenic activity, and pro-apoptotic activity is some cell lines It metabolism has not been fully studied, but 2/3 of the drug is eliminated in the urine. In vitro studies with human liver cell lines indicate that lenalidomide is not affected by, does not inhibit or induce cytochrome P450 isoenzymes and therefore there is little chance for a drug interaction with this metabolizing pathway. Lenalidomide was studied in a single-arm, open label, multicenter study (003) in patients with myelodysplastic syndrome with a del 5q cytogenetic abnormality who were RBC transfusion dependent. In addition, patients had low or intermediate-1 risk IPSS scores. Lenalidomide, given at 10mg daily for 21 days every 28 days or 10mg daily eliminated transfusion dependence in 64% of patients for a median duration of 52 weeks. Lenalidomide was studied in newly diagnosed patients with multiple myeloma in combination with dexamethasone. The same combination was studied in the relapsed and refractory setting. In multiple myeloma, the combination of lenalidomide and low-dose dexamethasone produced increased overall survival compared to lenalidomide plus high-dose dexamethasone in the initial therapy setting in two interim analyses. In the relapsed or refractory myeloma setting, lenalidomide plus dexamethasone demonstrated increased time to progression and overall survival compared to dexamethasone alone. Safety: A large percentage of patients experienced adverse events. The most common adverse events in MDS were neutropenia, thrombocytopenia, and infections. The most serious adverse events were neutropenia, thrombocytopenia, and venous thromboembolic events Up to 80% of patients required at least one dose interruption or dose reduction during therapy A Black Box warning for 1) teratogenicity 2) neutropenia and thrombocytopenia and 3) deep vein thrombosis and pulmonary embolism are contained in the package insert. The combination of lenalidomide plus dexamethasone increases the risk for VTE. The addition of erythropoietin also increases the risk. Assess patients for thrombosis risk and provide antithrombotic therapy as needed. The following recommendations are based on current medical evidence and expert opinion from clinicians. The content of the document is dynamic and will be revised as new clinical data becomes available. The purpose of this document is to assist practitioners in clinical decision-making, to standardize and improve the quality of patient care, and to promote cost-effective drug prescribing. The clinician should utilize this guidance and interpret it in the clinical context of individual patient situations Introduction The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating lenalidomide for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology/Pharmacokinetics,, The mechanism of action of lenalidomide has not been fully characterized. Lenalidomide is a derivative of thalidomide and belongs to the novel class of derivatives known as immunomodulatory drugs. It has immunomodulatory properties through inhibition of proinflammatory cytokines like TNF-, IL-6, and IL-12 and stimulation of T-cell proliferation and NK cell activity and number. Lenalidomide also possess antiangiogenic activity and has demonstrated inhibition of cell proliferation and pro-apoptotic activity in some cell lines. Table #1 Pharmacokinetics ParameterLenalidomideMetabolismNot fully studiedEliminationAbout 2/3 eliminated in urineHalf-life3 hoursProtein BindingBioavailabilityAbsorption is rapid; food does not change the AUC but reduces peak plasma levels Special Populations: 1. Renal Insufficiency: The pharmacokinetics of lenalidomide in MDS patients with renal insufficiency has not been well studied. In multiple myeloma patients, patients with mild renal impairment had a 56% increase in the AUC compared to patients with normal renal function. 2. Hepatic Disease: Pharmacokinetic parameters have not been studied in this population. 3. Age: The effects of age on lenalidomide pharmacokinetics have not been studied. 4. Pediatrics: There is no pharmacokinetic data in patients under the age of 18. 5. Gender: The effects of gender have not been studied. 6. Race: The effects of race on lenalidomide pharmacokinetics have not been studied. FDA Approved Indication(s) and Off-label Uses Treatment of patients with transfusion-dependent anemia due to low- or intermediate-1 risk myelodysplastic syndromes associated with a 5q deletion cytogenetic abnormality (with or without other cytogenetic abnormalities). Lenalidomide, in combination with dexamethasone, is indicated in the treatment of multiple myeloma in patients who have received at least 1 prior chemotherapy regimen.. Off-label use: Transfusion-dependent MDS patients without a 5q deletion cytogenetic abnormality Lenalidomide in combination with low dose dexamethasone and/or other cytotoxic agents in newly diagnosed patients with multiple myeloma Current VA National Formulary Alternatives Myelodysplastic syndrome: Azacitidine given subcutaneously for 7 days every 4 weeks; restricted to criteria for use for all MDS subtypes regardless of cytogenetic abnormalities Multiple Myeloma: Various combination chemotherapy drugs (e.g. melphalan, prednisone, dexamethasone, doxorubicin) Nonformulary Drugs Thalidomide, bortezomib Dosage and Administration Myelodysplastic Syndromes 1. Starting Dose Lenalidomide 10mg orally with water every day. Capsules should not be chewed or opened. Since this drug is excreted by the kidneys, there is a higher risk of adverse reactions in patients with impaired renal function (e.g. the elderly). In these patients, renal function and dose selection should be carefully monitored. 2. Dose Adjustments During Treatment Table #2 If thrombocytopenia develops within 4 weeks of starting at 10mg If baseline platelet count is e"100,000/mcLIf platelets:RecommendationsFall to < 50,000/mcL When they Return to e" 50,000/mcLINTERRUPT lenalidomide therapy RESUME lenalidomide at 5mg every dayIf baseline platelet count is < 100,000/mcLWhen Platelets:RecommendationsFall to 50% of baseline If baseline is e" 60,000/mcL and returns to e" 50,000/mcL If baseline is < 60,000/mcL and returns to e" 30,000/mcLINTERRUPT therapy RESUME lenalidomide at 5mg every day RESUME lenalidomide at 5mg every day Table #3 If thrombocytopenia develops AFTER 4 weeks of starting at 10mg When Platelets:RecommendationsAre < 30,000/mcL or <50,000/mcL requiring platelet transfusions Return to e" 30,000/mcL (without hemostatic failure)INTERRUPT lenalidomide therapy RESUME lenalidomide at 5 mg every day Table #4 If thrombocytopenia develops during treatment with 5mg every day When Platelets:RecommendationsAre < 30,000/mcL or <50,000/mcL requiring platelet transfusions Return to e" 30,000/mcL (without hemostatic failure)INTERRUPT lenalidomide therapy RESUME lenalidomide at 5 mg every OTHER day Table #5 If neutropenia develops within 4 weeks of starting at 10mg If baseline ANC e" 1,000/mcLWhen Neutrophils:RecommendationsFall to < 750/mcL Return to e" 1,000/mcLINTERRUPT lenalidomide therapy RESUME lenalidomide at 5mg every dayIf baseline ANC < 1,000/mcLWhen Neutrophils:RecommendationsFall to < 500/mcL Return to e" 500/mcLINTERRUPT lenalidomide therapy RESUME lenalidomide at 5mg every day Table #6 If neutropenia develops AFTER 4 weeks of starting at 10mg When Neutrophils:Recommendations< 500/mcL for e"7 days or <500/mcL with fever e" 38.5C Return to e" 500/mcLINTERRUPT lenalidomide therapy RESUME lenalidomide at 5mg every day Table #7 If neutropenia develops during treatment with 5mg every day When Neutrophils:Recommendations< 500/mcL for e"7 days or <500/mcL with fever e" 38.5C Return to e" 500/mcLINTERRUPT lenalidomide therapy RESUME lenalidomide at 5mg every OTHER day Multiple Myeloma 1. Starting dose in relapsed/refractory setting is 25 mg/day with water administered as a single capsule days 1-21 of a 28 day cycles. The dose of dexamethasone is 40 mg/day on days 1-4, 9-12, and 17-20 for the first 4 cycles then 40mg/day orally on days 1-4 every 28 days. Please Note: For initial therapy, preliminary data using a low dose of dexamethasone (40mg on D 1, 8, 15, and 22) shows increased survival at 1 year, 18 months, and Overall Survival in an interim analysis with lower rates of VTE, infection, and hyperglycemia compared to the same dose of lenalidomide with standard dose dexamethasone. 2. Dose adjustments during therapy Table #8 Platelet Counts - Thrombocytopenia When Platelets:RecommendationsFall to <30,000/mcL Return to (30,000/mcLInterrupt lenalidomide therapy, monitor CBC weekly. Restart at 15 mg dailyFor each subsequent drop <30,000/mcL Return to (30,000/mcLInterrupt lenalidomide therapy Resume therapy at 5 mg less than the previous dose. Do not go below 5 mg/day and discontinue on 4th or subsequent occurrence Table #9 Neutrophil Counts Neutropenia When Neutrophils:RecommendationsFall to <1000/mcL Return to (1000/mcL and neutropenia is only toxicityInterrupt lenalidomide therapy, add G-CSF, monitor CBC weekly Resume at 25 mg/dayReturn to (1000/mcL and if other toxicityResume at 15 mg/dayFor each subsequent drop <1000/mcL Return to (1000/mcLInterrupt lenalidomide therapy Resume at 5 mg less than the previous dose. Do not go below 5 mg/day and discontinue on 4th or subsequent occurrence. Table #10 e"Grade 3 non-hematological toxicity First occurrenceHold, restart with 5mg ! when d" grade 2Second occurrenceHold, restart with 5mg ! when d" grade 2Third occurrenceHold, restart with 5mg ! when d" grade 2Fourth occurrenceHold, restart with 5mg ! when d" grade 2 Do not go below 5 mg/day Table #11 e"Grade 2 rash, Steven Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), pneumonitis e"Grade 2 rash, SJS, TEN, pneumonitisHold and investigate. Discontinue if SJS, TEN or pneumonitis develops. Table #12 Starting Dose for Renal Impairment CategoryRenal Function (Cockcroft-Gault CLCR)DiseaseMultiple MyelomaMDSModerate ImpairmentCLCR(30 but < 50mL/min10mg every 24 hours5 mg every 24 hoursSevere ImpairmentCLCR <30mL/min (not requiring dialysis)15 mg every 48 hours5 mg every 24 hoursEnd Stage Renal DiseaseCLCR <30mL/min (requiring dialysis)5mgonce daily. On dialysis days give following dialysis.5mg 3 times a week following each dialysis Efficacy Myelodysplastic Syndromes Efficacy Measures Primary Endpoint: RBC transfusion independence for at least 8 consecutive weeks. Secondary Endpoints: Cytogenetic Response e"50% decrease in RBC transfusion requirements Change of hemoglobin concentration from baseline Platelet response Neutrophil response Bone marrow response Duration of response Safety Summary of efficacy findings Study 003 was a single arm, multicenter, phase II trial of lenalidomide in transfusion dependent patients with Myelodysplastic Disease (MDS) with an International Prognostic Scoring System (IPSS)* of low or intermediate-1 risk with an associated del 5q (with or without other cytogenetic abnormalities). Transfusion dependence was defined as 2 or more units of packed RBC units 8 weeks prior to starting study. ECOG Performance Status of 0-2 Exclusions included: Pregnant or lactating females, inability to perform bone marrow aspirate, chronic myelomonocytic leukemia, ANC <500cells/mm3, platelets <50,000/mm3, serum creatinine >2.5gm/dL, serum AST/ALT > 3 X ULN, direct bilirubin >2 mg/dL, prior e" grade 3 allergic reaction/hypersensitivity to thalidomide, anemia due to other causes (iron, folate, or B12 deficiency, autoimmune or hereditary hemolysis, or GI bleed), chronic use of physiologic doses of steroids within 28 days, use of chemotherapy or immunosuppressive drugs for MDS within 28 days Dose: 10mg orally daily on days 1-21 every 28 days (N=45); amended later to continuous dosing regimen of 10mg orally every day (N=103). Dosing was amended based in information from the pilot study (001) that the onset of response was faster with continuous dosing. The median age of patients was 71 years old; 34.5% were male, 96.6% were white, 37.2% had a low IPSS score, 43.9% had a intermediate-1 risk IPSS score, 39.9% had an ECOG PS of 0, 50.7% ECOG PS=1, and 0.9% ECOG PS=2. The median number of units of red blood cells transfused in the 8 weeks prior to starting on the study was 6 with 71% of patients receiving 4 or more units. Table #13 Efficacy Endpoints Outcome10 mg Continuous dosing (N=103)10 mg Synchronous dosing (N=45)Overall (N=148)% Transfusion Independent Overall (95%CI) Low IPSS (95%CI) Intermediate-1 IPSS (95%CI) 68 (58. 76.8) 66.7 (50.5, 80.4) 72.5(56.1, 85.4) 55.6 (40, 70.4) 84.6 (54.6, 98.1) 48 (27, 68.7) 64.2 (55.9, 71.9) 70.9 (57.1, 82.4) 63.1 (50.2, 74.7)Duration of Response Patients Progressed Patients Censored Median (min, max) Updated Data Patients Progressed Patients Censored Median (min,max) 11.4% 88.6 28.5 wks (8.1, 44) 11.8% 88.2 40.7 wks (8.1, 48.1) 11.5% 88.5 30 wks (8.1, 48.1) 28.1% 71.9 52.3 wks (8.1, 74.6)Change in hemoglobin from baseline of e"1 g/dL (95%CI)N/AN/A(N=93) 73.1% (62.9, 81.8)Decrease of e"50% in RBC Transfusion requirements (95%CI) 74.6% (63,84) 72.4% (53, 87) 74% (64,82)Cytogenetic Response % Major Minor(n=72 evaluable) 44% 29 Summary Transfusion independence was consistent in other populations, i.e. isolated 5q deletion vs 5q plus other cytogenetic deletions The rate of RBC-transfusion independence was similar between major cytogenetic responders (95.8%) and minor cytogenetic responders (94.7%) There was no comparator arm (neither best supportive care or placebo) to assess efficacy or safety results Responses based on RBC transfusion independence lasted a minimum of 8 weeks with a median duration of 30 weeks. Updated analysis found a median duration of response of 52 weeks. There were no platelet responses in the FDA analysis of 14 eligible patients Of the 6 patients eligible for neutrophil response, there was one major response Granulocyte CSF was allowed in patients who developed neutropenia or fever and neutropenia. *International Prognostic Scoring System Prognostic VariableScore Value00.51.01.52.0BM blasts (%)<55-10-11-2021-30KaryotypeGoodIntermediatePoorCytopeniasGrade 0/1Grade 2/3Karyotypes: Good=normal; -Y, del(5q), del(20q); Poor=complex e"3 abnormalities or chromosome 7 abnormality; Intermediate= all others Risk group scores Low= 0 Intermediate-1 = 0.5-1.0 Intermediate-2 = 1.5-2.0 High = e"2.5 For further details on the efficacy results of the clinical trials, refer to Appendix on Page 19. Supporting Data Study 001 was an open label, single center trial (phase 2) to evaluate efficacy and safety in patients with MDS who had symptomatic anemia or transfusion dependent anemia with no response to epoetin or high endogenous erythropoietin levels. Patients received lenalidomide at one of 3 doses: 25mg daily, 10 mg daily, or 10 mg daily for 21 days every 28 days. Table#14 Study 001 Results Response25 mg/day N=1310mg/day N=1310mg/d for 21 days N=17Total N=43Erythroid Response Major Minor Total 6 0 6 6 1 7 9 2 11 21(49%) 3 (7%) 24 (56%)Weeks to Response Median SD Range 95.8 2.5-18.5 10.56.4 2-17.5 11.510.3 6-24NA Multiple Myeloma Initial Treatment in Patients Eligible for Transplant Table #15 Efficacy of initial treatment in patients who ARE transplant candidates StudyTreatmentNo. of patientsOutcomesSignificanceRajkumar 2005 Phase II Lacy et al. 2007 Long-term resultsLenalidomide/dexamethasone (Rev/dex) L: 25mg daily D1-21 D: 40mg daily D1-4, 9-12, 17-20 After 4 cycles reduce dexamethasone to 40mg daily D1-4 each month After 4 months continue therapy or transplantN=34Overall Response=31 CR=2 VGPR/nCR=11 PR=18 MR=2 No response=1 TTP=32.4 mo for non-transplant group =not reached for transplant group 2yr Overall Survival No transplant=90% Transplant=92%Rajkumar 2007 Phase III (abstract) Rajkumar 2007 Phase III Update (abstract)Lenalidomide plus high-dose dexamethasone vs lenalidomide plus low-dose dexamethasone L: 25mg/daily D1-21 HighD: 40mg D1-4, 9-12, 17-20 LowD: 40mg D1, 8, 15, 22HighD=223 LowD=222Overall Survival (interim) in favor of L+LowD Similar survival favor for L+LowD in patients <65 yo (65 yo 1 yr survival L+HighD=86% L+LowD=98% Overall Survival (2nd interim) in favor of L+LowD 1yr Survival L+HighD=87% L+LowD=96% 18 month Survival L+HighD=80% L+LowD=91% P<0.001 P=0.015 P=0.004 P<0.001  Summary Lenalidomide plus dexamethasone is an effective treatment for patients who are candidates for stem cell transplantation. Utilization of lower dexamethasone doses in a phase III trial produced an increase in overall survival and one year survival in interim two planned interim analyses versus standard or high dose dexamethasone with significantly lower rates of thromboembolism (6.1% vs. 22.1%), infection (7.5% vs. 15.7%), and hyperglycemia (6.6% vs. 9.7%). The survival advantage for the low dose dexamethasone regimen held true for patients < 65 years old and those ( 65 years old. Initial therapy in patients who are NOT transplant candidates: The combination of lenalidomide plus low-dose dexamethasone may also be used for initial therapy in patients who are not candidates for stem cell transplant. The combination of melphalan, prednisone, and lenalidomide was studied by the Italian Multiple Myeloma Network in a phase I/II trial in patients ( 65 years old. A high proportion of patients achieved a complete or very good partial response. The 1-year event free survival was 92.3% for all patients (95%CI 85.1-99.5) and 95.2% for patients who received the maximally tolerated dose (95%CI 93.2-97.3). Treatment of Relapsed or Refractory Disease Table #16 Treatment of relapsed or refractory multiple myeloma with lenalidomide StudyTreatmentNo. of patientsOutcomesSignificanceSingle AgentRichardson 2002 Phase 1CC-5013 (lenalidomide) 5mg/day, 10mg/day, 25mg/day, and 50mg/day dose escalationN=27DLT at 25mg/d but not at 50mg/d Response of at least a 25% reduction in paraproteins in 71%Richardson 2006 Phase IILenalidomide 30mg/day D1-21 If PD or SD after 2 cycles add dexamethasone 40mg D1-4, 15-18QD dose=67 BID dose=35Overall Response (CR+PR) BID=14% QD=18% Progressive Disease BID=23% QD=18% Dex added in 67% Overall Response BID=22% (no CR) QD=22%Combination TherapyDimopoulos 2007 Phase III MM010 Europe, Israel, AustraliaLenalidomide 25mg D1-21 or placebo Dexamethasone 40mg D1-4, 9-12, 17-20 for first four cycles then 40mg D1-4 of each cycleL+dex=176 Dex=175Time to progression L+dex=11.3 mo Dex=4.7 mo TTP if previous thalidomide therapy L+Dex=8.4 mo Dex=4.6 mo TTP if no previous thalidomide L+Dex=13.5 mo Dex=4.7 mo (Partial response L+Dex=60.2% Dex=24% Overall Survival L+Dex=not reached Dex=20.6 mo P<0.001 HR=2.85 (95%CI 2.16-3.76) P<0.001 P<0.001 P<0.001 P<0.001 HR=0.66 95%CI 0.45-0.96 P=0.03Weber 2007 Phase III MM009 N. AmericaLenalidomide 25mg D1-21 or placebo Dexamethasone 40mg D1-4, 9-12, 17-20 for first four cycles then 40mg D1-4 of each cycleL+dex=177 Dex=176Time to progression L+Dex=11.1 mo Dex=4.7 mo TTP if previous thalidomide L+Dex=8.5 mo Dex=4.1 mo TTP if previous bortezomib L+Dex=10.3 mo Dex=3.3 mo (Partial response L+Dex=61% Dex=19.9% Overall Survival L+Dex=29.6 mo Dex=20.2 mo HR=0.35 95%CI 0.27-0.47 P<0.001 P<0.001 P<0.001 P<0.001 HR=0.44 95%CI 0.3-0.65 P<0.001Wang 2008 Secondary analysis of subgroup data from MM009 and MM010Assess efficacy of lenalidomide plus dexamethasone in patients with prior thalidomide exposureNo prior exposure L+Dex=226 Dex=204 Prior exposure L+Dex=127 Dex=147Overall Response No prior exposure L+Dex=64.6% Dex=27.5% Prior exposure L+Dex=53.5% Dex=14.3% Overall Response No prior vs prior L+Dex 65% vs 55% Dex 28% vs 14% Time to progression No prior exposure L+Dex=13.0 mo Dex=4.7 mo Prior exposure L+Dex=8.4 mo Dex=4.6 mo Progression free survival No prior exposure L+Dex=13.2 mo Dex=4.7mo Prior exposure L+Dex=8.4 mo Dex=4.6 mo  P<0.001 P<0.001 P=0.04 P=0.003 P<0.001 P<0.001 P<0.001 P<0.001 Summary The activity of lenalidomide in relapsed or refractory disease, either alone or in combination, was shown in phase I, II, and III trials with response rates improving from approximately 20-25% with dexamethasone alone to 61% with lenalidomide plus dexamethasone. The two large, identical phase III trials of lenalidomide plus dexamethasone had similar results: higher complete and overall response rates, longer time to progression of disease, and a longer overall survival compared to dexamethasone alone. The combination arm also had an increased rate of neutropenia and venous thromboembolism. A post-hoc analysis of patients previously treated with thalidomide demonstrated similar results in the combination arm. Adverse Events (Safety Data) Table #17 Adverse Events in e"5% of lenalidomide patients System/Organ Class10mg dose Overall %Blood and lymph Thrombocytopenia Neutropenia Anemia Leukopenia Febrile Neutropenia 61.5 58.8 11.5 8.1 5.4Skin Pruritus Rash Dry skin Contusion Night sweats Increased sweating Ecchymosis Erythema 41.9 35.8 14.2 8.1 8.1 6.8 5.4 5.4GI Disorders Diarrhea Constipation Nausea Abdominal pain Vomiting Abdominal pain upper Dry mouth Loose stools 48.6 23.6 23.6 12.2 10.1 8.1 6.8 6.1Respiratory/ thoracic Nasopharyngitis Cough Dyspnea Pharyngitis Epistaxis Exertional dyspnea Rhinitis Bronchitis 23 19.6 16.9 15.5 14.9 6.8 6.8 6.1General Disorders Fatigue Pyrexia Peripheral edema Asthenia Edema Pain Rigors Chest pain 31.1 20.9 20.3 14.9 10.1 6.8 6.1 5.4Musculoskeletal Arthralgia Back pain Muscle cramp Pain in limb Myalgia Peripheral swelling 21.6 20.9 18.2 10.8 8.8 8.1Nervous System Dizziness Headache Hypoasthesia Dysgeusia Peripheral neuropathy 19.6 19.6 6.8 6.1 5.4Infections URT Infection Pneumonia UTI Sinusitis Cellulitis 14.9 11.5 10.8 8.1 5.4Metabolism/nutrition Hypokalemia Anorexia Hypomagnesemia 10.8 10.1 6.1Hepatic Increased alanine aminotransferase 8.1Psychiatric Insomnia Depression 10.1 5.4Vascular Hypertension 6.1Renal and Urinary Dysuria 6.8Cardiac Palpitations 5.4Endocrine Acquired hypothyroidism 6.8There is some data of a relationship to the dose and toxicity; there was more neutropenia, pneumonia, and diarrhea in the continuous dose group vs. the syncopated dose group. There was no difference in anemia, thrombocytopenia, febrile neutropenia, pancytopenic sepsis, and pyrexia. Deaths and Other Serious Adverse Events Myelodysplastic Syndromes Table #18 Most Frequent Grade 3 and 4 Adverse Events Event10mg dose Overall %Neutropenia53.4Thrombocytopenia50Pneumonia7.4Rash6.8Anemia6.1Leukopenia5.4Fatigue4.7Dyspnea4.7Back Pain4.7Febrile Neutropenia4.1Nausea4.1Diarrhea3.4Pyrexia3.4Sepsis2.7Granulocytopenia2.0Pulmonary embolism2.0Multi-organ failure1.4Serious adverse events reported in other clinical trials of lenalidomide: Blood: warm type hemolytic anemia, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia Cardiac: Congestive heart failure, atrial fibrillation, angina, cardiac arrest, cardiomyopathy, myocardial infarction, pulmonary edema, supraventricular arrhythmia, ventricular dysfunction GI: GI hemorrhage, ischemic colitis, intestinal perforation, rectal hemorrhage, dysphagia, gastritis Hepatic: hyperbilirubinemia, cholecystitis Nervous system: cerebrovascular accident, aphasia, cerebellar infarction, TIA Renal: Renal failure, hematuria, azotemia Respiratory: exacerbation of COPD, respiratory failure, exacerbation of dyspnea, interstitial lung disease Table#19 Differences in frequency of Grades 3 and 4 AE in Studies 003 and 002* Organ SystemStudy 003 N=148Study 002 N=215Neutropenia53.4%26.5%Thrombocytopenia50.021.4Infections- All Pneumonia16.2 8.912.1 3.7Rash6.84.2Fatigue4.73.3Pyrexia3.40.9Bleeding, all types2.72.8Pulmonary Embolism Deep Vein Thrombosis2.0 3.50 0.9*Study 002 population did not have a 5q deletion Common Adverse Events The most common adverse events were: thrombocytopenia, neutropenia, diarrhea, and fatigue Tolerability Table #20 Reasons for Discontinuation of lenalidomide Primary reason for discontinuationOverall MDS studies at 10mg (N=395) %Adverse Event19Lack of therapeutic effect14.9Withdrew consent4.6Lost to follow-up0.6Death3.8Protocol violation0.3Other2.3 Dose interrupted or reduced at least once due to an adverse event: 79.7% of patients Second dose interruption or reduction due to an adverse event: 33.8% of patients Multiple Myeloma Table #21 Adverse Events Reported in at least 10% of Patients in 2 Phase III Trials Organ systemLenalidomide/Dex % N=346Placebo/Dex % N=345Blood and lymph Neutropenia Anemia NOS Thrombocytopenia 27.7 24.3 17.1 4.6 17.4 9.9Eye Vision blurred 14.7 10.4GI Disorders Constipation Diarrhea NOS Nausea Dyspepsia Vomiting NOS 38.7 29.2 22.0 13.9 10.1 18.6 24.6 19.1 13.3 8.1General Fatigue Asthenia Pyrexia Edema Peripheral 38.4 23.4 23.1 21.1 37.4 24.9 19.4 18.8Infections Upper Respiratory Tract NOS Pneumonia NOS 13.6 11.3 12.5 7.5Investigations Weight decreased 18.2 13.9Metabolism Hyperglycemia NOS Anorexia Hypokalemia 15.0 13.6 11.3 14.2 8.7 5.2Musculoskeletal Muscle Cramp Back pain Muscle weakness NOS Arthralgia 30.1 15.3 15.0 10.4 20.6 14.2 15.4 14.8Nervous system Headache Dizziness Tremor Dysgeusia Paresthesia 21.4 20.8 19.7 13.3 11.6 21.4 15.4 7.0 9.3 12.5Psychiatric Insomnia 32.1 37.1Respiratory Dyspnea NOS Cough 20.2 14.5 15.4 20.6Skin Rash NOS 15.9 8.1Vascular DVT Pulmonary embolism 7.8 3.2 3.2 0.9 Precautions/Contraindications Black Box Warnings Potential for Human Birth Defects Lenalidomide is an analogue of thalidomide, a known human teratogen that causes severe life-threatening human birth defects. If taken during pregnancy, lenalidomide may cause birth defects or death to an unborn child. Females should be advised to avoid pregnancy while taking lenalidomide. Because of the potential for toxicity, lenalidomide will only be available under a special distribution program to patients, physicians, and pharmacists registered with the program (RevAssist). Before starting therapy, females of child bearing potential should have at least 2 negative pregnancy tests: one within 10-14 days of starting therapy and the second within 24 hours of starting therapy. Breast-feeding is contraindicated. Hematologic Toxicity (Neutropenia and Thrombocytopenia) Patients with 5q deletion Myelodysplastic Syndrome (MDS) have significant neutropenia and thrombocytopenia associated with the use of lenalidomide. Eighty percent of patients required a dose delay or reduction. Thirty-four percent required a second delay or dose reduction. Patients on therapy with del 5q myelodysplastic syndromes should have blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Myeloma patients also need monitoring for hematologic toxicity, every 2 weeks for the first 12 weeks, then monthly. Patients may require dose delay, dose reduction, blood product support, or growth factors. Deep Vein Thrombosis and Pulmonary Embolism Patients with multiple myeloma treated with lenalidomide in combination therapy experienced an increased risk of deep vein thrombosis and pulmonary embolism. Patients and physicians should observe for signs and symptoms of thromboembolism and patients should seek medical care if they develop shortness of breath, chest pain, and arm or leg swelling. It is unknown if prophylactic anticoagulation or antiplatelet therapy lessens t the potential for thromboembolic events. The decision to use prophylactic anticoagulation or antiplatelet therapy should be done thoughtfully after full assessment of the patients risk factors. Skin Rash Skin rash is common with lenalidomide therapy and usually resolves within 2-3 weeks; no interruption of treatment is required, unless severe. Unselective antihistamine, topical steroids or short course of oral prednisone 10mg/day for 2 weeks may relieve symptoms. Rare, fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necorlysis (TEN) have been reported. Discontinue lenalidomide if skin rash e" Grade 2 is exfoliative or bullous, or if SJS or TEN are suspected. Hypersensitivity Pneumonitis Rarely, hypersensitivity pneumonitis-like syndrome has been reported with lenalidomide use. In the case of unexpected respiratory symptoms such as dyspnea on exertion, crackles on physical examination, radiological bilateral ground-glass opacities and non-resolving pneumonia, lenalidomide should be discontinued until further investigation excludes hypersensitivity pneumonitis-like syndrome. Precautions 1. This drug is excreted by the kidneys. The risks of adverse events may be increased in patients with renal impairment, but no studies have been conducted in this population. 2. Patients should be counseled on the risk of teratogenicity, and female patients should be counseled on the precautions to be taken to preclude fetal exposure as set forth in the RevAssist"! educational materials. Contraindications 1. Pregnancy: Category X (Black Box Warning) 2. Hypersensitivity to lenalidomide, to thalidomide, and in patients with grade 3 or 4 thrombocytopenia. It contains lactose and is contraindicated in patients with hereditary lactase/ glucose or galactose disorders. Look-alike / Sound-alike (LA / SA) Error Risk Potential The VA PBM and Center for Medication Safetyis conducting a pilot program which queries a multi-attribute drug product search engine for similar sounding and appearing drug names based on orthographic and phonologic similarities, as well as similarities in dosage form, strength and route of administration. Based on similarity scores as well as clinical judgment, the following drug namesmay be potential sources of drug name confusion: LA/SA for generic name lenalidomide: thalidomide, Leflunomide, leuprolide, finasteride, temozolomide LA/SA for trade name Revlimid: Revatio, Thalomid, Revia Drug Interactions Drug-Drug Interactions 1. Human In vitro metabolism studies and other non-clinical studies show that lenalidomide is not metabolized by, does not inhibit, and does no induce the cytochrome P450 isoenzymes and therefore is unlikely to cause or be subject to P450 drug interactions. 2. Co-administration of multiple 10mg doses of lenalidomide had no effect on single dose pharmacokinetics of R- and S- warfarin. Co-administration of a single 25mg dose of warfarin did not affect the pharmacokinetics of multiple dose lenalidomide. Changes in the INR and PT after warfarin were as expected and not affected by lenalidomide. 3. Co-administration of digoxin with lenalidomide did not change the digoxin AUC, but the Cmax of digoxin was increased 14%. Periodic monitoring of digoxin serum levels, in accordance with clinical judgment, is recommended. Acquisition Costs as of May 18, 2009 Table #22 Acquisition Cost Comparison DrugDoseCost/Day/patient ($)Cost/month (28 days)/patient ($)Lenalidomide25 mg per day196.43-234.214125.03 - 4918.41Lenalidomide15 mg per day224.48-225.534714.08 - 4715.13Lenalidomide10mg per day174.61-188.854889.08 - 5287.80Lenalidomide5mg per day165.79-180.374642.12 - 5050.36 Conclusions Myelodysplastic Syndromes Efficacy: In the ITT analysis of this single-arm, phase II trial, 64.2% of patients were transfusion independent for at least 56 days. Responses were seen in both low risk and intermediate-1 risk patients and in both dosing schemas. Transfusion independence occurred in patients with an isolated del 5q and in patients with del 5q plus other cytogenetic abnormalities. The duration of the response during the study was 30 weeks, with a large percentage of patients censored on the day of analysis. Updated analysis data showed a median duration of response of 52 weeks, suggesting a clinical benefit. Responses were also accompanied by cytogenetic responses in 43% of patients. Safety: A large percentage of patients experienced an adverse event; 79.7% experienced a grade 3 or 4 adverse event. Neutropenia and thrombocytopenia can have rapid onset and resolution is unpredictable. It is difficult to assess if this is due to the drug or the disease or both as there is no comparator. A substantial number of patients required a dose interruption or dose reduction at least once during therapy due to neutropenia or thrombocytopenia. Other important adverse events included infections, bleeding events, diarrhea, rash, pruritus, fatigue, peripheral edema, pyrexia, respiratory symptoms, musculoskeletal symptoms, headache, dizziness, and anorexia. Patients >65 years old experienced a higher frequency of adverse events. Patients with a 5q deletion experienced more neutropenia, thrombocytopenia, and infections than similar patients without a del 5 q, although this data is from two different studies. Approximately 14 deaths are possibly or probably related to drug-induced neutropenia or thrombocytopenia. Multiple Myeloma Efficacy: In patients receiving initial therapy who are candidates for stem cell transplant, the combination of lenalidomide plus dexamethasone demonstrated a good overall response rate in phase II trials. Preliminary data from a large phase III trial of lenalidomide plus standard dose or low dose dexamethasone found benefit from the low-dose dexamethasone combination with lenalidomide with regard to overall survival, 1-year survival, and 18-months survival. The low dose regimen was also better tolerated. The same regimens used for initial therapy in patients who are transplant candidates may be used in patients who are not transplant candidates. In a phase I/II trial looking at the combination of melphalan, prednisone, and lenalidomide, the combination produced good overall response rates. These findings need to be tested in a larger population against a standard melphalan plus prednisone regimen. For relapsed or refractory disease, while single agent lenalidomide produces responses in the range of 20-25%, the combination of lenalidomide plus dexamethasone produces responses in the range of 61%. This was demonstrated in two large identical phase III trials, one international and one in North America. Those trials demonstrated not only improved response rates, but improvement in time to progression and overall survival, independent of prior exposure to thalidomide. Safety: The most common severe toxicities with lenalidomide plus dexamethasone include neutropenia, anemia, thrombocytopenia, and venous thromboembolism. Non-hematologic toxicities include insomnia, fatigue, constipation, muscle cramps, and infections. While peripheral neuropathy has been reported, it is less common than with thalidomide. Lenalidomide is excreted renally, therefore it is expected that accumulation may occur at various levels of decreasing renal function. In a pharmacokinetic study of patients with varying degrees of renal function, but without malignancy, the total and renal clearance of lenalidomide decreased as renal impairment worsened. Subjects with a baseline Creatinine Clearance < 50ml/min had reduced lenalidomide clearance, increased total exposure, and prolonged half-life compared to subjects with baseline Creatinine Clearance (50 ml/min, suggesting dose adjustments for those with the lower clearances. Hemodialysis removed 31% of lenalidomide. . Data from patients receiving lenalidomide plus dexamethasone found an association between the development of (grade 3 myelosuppression in patients with a baseline Creatinine Clearance (40ml/min and the need for dose reduction. While lenalidomide alone as induction or maintenance after chemotherapy is associated with low risk (<5%) of venous thromboembolism, the risk of thromboembolism significantly increased when lenalidomide is used in combination with dexamethasone, doxorubicin, erythropoietin, or multi-agent chemotherapies Risk assessment model and prevention strategies have been proposed, however never in a randomized trial comparing lenalidomide with and without prophylaxis. Anticoagulant prophylaxis is not recommended for patients receiving single-agent lenalidomide. In other circumstances, the incidence seems to be reduced using one of the following strategies: Warfarin A low-dose and full dose strategy has been used to prevent venous thromboembolic events (VTE) in patients taking thalidomide but has not been studied with lenalidomide. In newly diagnosed myeloma patients who were treated with thalidomide and dexamethasone, the risk of venous thromboembolism was effectively reduced by full-dose warfarin, while low-dose-fixed warfarin (1mg/day) was ineffective. Full doses of warfarin might best be avoided in patients with pre-existing thrombocytopenia and/or in patients in whom severe thrombocytopenia is likely to develop due to use of thalidomide or lenalidomide-based combination chemotherapy. In this setting, LMWH is better suited for prevention of VTE due to its short half-life. LMW Heparin The data regarding VTE prevention is inadequate to make recommendations for patients taking thalidomide or lenalidomide. A small series reported on the use of prophylactic LMWH in patients treated with lenalidomide plus standard dose dexamethasone. One of 45 patients developed a VTE (2.2%). LMWH is not an optimal choice in patients with reduced creatinine clearance (<30ml/min) because it may accumulate and increase the bleeding risk. The preferred choice in this situation could therefore be full-dose warfarin. Aspirin In the phase II trial of lenalidomide plus dexamethasone for newly diagnosed patients, there was one thrombotic event when aspirin, dosed at the discretion of the physician, was used as prophylaxis.5 In a Southwest Oncology Group (SWOG) protocol comparing dexamethasone plus placebo to dexamethasone plus lenalidomide, the incidence of VTE was reduced from 75% to 19% with the addition of aspirin 325mg prophylaxis. In a pooled analysis of 125 patients in phase II clinical trials involving lenalidomide, of which 88% received DVT prophylaxis; the most common form was aspirin. VTE events occurred in 8% overall, with an incidence of 12% in patients on high dose steroids and 6% in those on low dose steroids. A risk assessment model (Palumbo et al) based on expert opinion has been proposed by the International Myeloma Working Group for the management of VTE in myeloma patients treated with lenalidomide or thalidomide. Using that model, aspirin would only be recommended for low-risk patients. LMWH or full-dose warfarin would be recommended in the presence of at least two individual or myeloma-related risk factors and in patients who receive chemotherapy plus lenalidomide, independent of the presence of additional risk factors. There is an on-going randomized trial comparing aspirin, warfarin and LMWH for prophylaxis in patients receiving lenalidomide or thalidomide. Updated June 2009. Contact person: Mark C. Geraci, Pharm.D., BCOP Clinical Specialist Appendix Table: Clinical Trials with lenalidomide in MDS Citation Design Analysis type SettingEligibility CriteriaInterventionsPatient Population ProfileEfficacy Results Safety ResultsStudy 003 Single-arm Open label MulticenterInclusion criteria 1. low or intermediate risk-1 IPSS MDS with del 5q cytogenetics 2. RBC transfusion dependent anemia (e"2 units of RBC s in previous 8 weeks) 3. ECOG PS 0-2 4. Women of child bearing years with negative serum or urine pregnancy test agreeing to adequate contraceptive methods Exclusion criteria 1. Pregnant or lactating female 2. unable to aspirate bone marrow 3. proliferative CMML 4. ANC<500, plts<50K, Creatinine >2.5, AST/ALT>3X ULN, D.Bili >2.0 5. Prior e"grade 3 toxicity to thalidomide 6. nutritional anemias 7. epoetin use within 7 days 8. chronic >physiologic doses of steroids Lenalidomide 10mg daily for 21 days , repeat every 28 days (N=45) Amended to: Lenalidomide 10mg daily (N=103)Age, med:=71 Sex: M 34.5% Race: white 96.6% IPSS low: 37.2% IPSS intmed-1: 43.9 IPSS interm-2: 4.1 IPSS High: Missing: 13.5 ECOG 0: 39.5% 1: 50.7 2: 9.4NR =148 Outcome 10mg Overall % Transfusion Independence Low IPSS Inter-1 IPSS 64.2 70.9 63.1 Duration of response Updated 30 wks 52.3 wks Progression % Updates 11.5 28.1 Change in Hgb e"1 73.1% Decrease of e"50% in RBC transfusion req t 74% Cytogenetic responses Major Minor 44% 29 Most common: neutropenia, thrombocytopenia, diarrhea Serious: Neutropenia, thrombocytopenia, pneumonia, rash, fatigue, pulmonary embolism, deep ve(*235AFGhq DKCżxxmx`xmxUxUxh& hIWB*phh& h;65B*phh& h\B*phh& h;6B*phh& hv$B*phh& hCB*phh& h@B*phh& h@5B*phh& hP mOJQJh& hCJh& hP mCJ h& h h& h*B*CJphh& heAOJQJh& hP mOJQJh& h2B*OJQJphh& hBnB*OJQJphh& h[9B*OJQJphh& hh{LB*OJQJphh& h%gB*OJQJphh& h%B*OJQJphh& hP mB*OJQJphh& hCB*OJQJphh& hP m>*B*ph@AK% & 9 Q R l m ! ^`gdugd gdCgdC  & Fgdh{LgdC$ & 8 D P R l m !! 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Potential teratogen 2. neutropenia and thrombocytopenia 3. Deep vein thrombosis and pulmonary embolismStudy 001 Single arm Open label Single CenterInclusion: 1. MDS 2. baseline hemoglobin <10 or transfusion dependent (at leas 4 units PRBCs in 8 weeks) 3. ECOG PS 0-2 4. Adequate renal and hepatic function 5. Adequate birth control for women of childbearing years Exclusion: 1. Myelofibrosis >30% of bone marrow 2. Grade 4 neutropenia or thrombocytopenia 3. Clinically significant pulmonary, CV, endocrine, neurologic, GI, GU disease unrelated to hematologic disorder 4. Pregnant or lactating females 5. ongoing steroid treatment 6. known hep-B surface antigemia 7. bone marrow blasts >30% 8. chromosome abnormalities common to AML ie t(8:21), t(15:17), inv(16) 9. nutritional anemiasLenalidomide 25mg daily Or Lenalidomide 10mg daily Or Lenalidomide 10mg daily for 21 days repeat every 28 daysAge, med: 72 M: 60.5% Race: white 88.4% Del 5q: 30.2% ECOG 0: 44.2% 1: 51.2 2: 4.7 IPSS low: 32.9% Inter-1: 53.5 Inter-2: 9.3 High: 2.3NR=43 Response 25 N=13 10 N=13 10/21 N=17 Total N=43 RBC Maj Min Total 6 0 6 6 1 7 9 2 11 21 3 24 Weeks to response 9 10.5 11.5 Most common: neutropenia and thrombocytopenia Severe myelosuppression was dose dependent. 3 deaths thought to be treatment related: cholecystitis with rupture, splenic infarct in patient with splenomegaly, pneumonia with neutropenia Pruritus in 28% , restricted to scalp Diarrhea in 21% of patients treated for greater than 3 monthsNR, Number randomized. Add abbreviations, other footnotes.     Lenalidomide Monograph June 2009 Updated version may be found at  HYPERLINK "http://www.vapbm.org" www.vapbm.org or vaww.pbm.med.va.gov -  PAGE 1 - STRICTLY CONFIDENTIAL PRE-DECISIONAL DELIBERATION INFORMATION  Monograph  FILENAME LenadlidomideUpdateMono (2).docDRAFTUpdated version may be found at  HYPERLINK "http://www.vapbm.org" www.vapbm.org or vaww.pbm.med.va.gov PAGE 21 References:  Teo SK. Properties of thalidomide and its analogues: implications for anticancer therapy. The AAPS Journal 2005;7(1) Article 3.  Mitsiades CS, Mitsiades N. CC-5013 Celgene. Current Opinions in Investigational Drugs 2004; 5:635-647.  Center for Drug Evaluation and Research Application number 21-880. Medical Review. 2005  List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, et al. Efficacy of lenalidomide in myelodysplastic syndromes. NEJM 2005; 352:549-57.  Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/dex) for newly diagnosed myeloma. Blood 2005;106:4050-4053.  Lacy MQ, Gertz MA, Dispenzieri A, Hayman SR, Geyer S, et al. Long-term results of response to therapy, time to progression and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc 2007;82:1179-1184.  Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, et.al. Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasonen in newly diagnosised multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group (abstract). J Clin Oncol 2007;25:18s.  Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, et al. A randomized trial of lenalidomide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. Blood 2007;110:74.  Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed multiple myeloma: a report from the GIMEMA-Italian Multiple Myeloma Network. J Clin Oncol 2007;25:4459-4465.  Richardson PG< Schlossman RL, Weller E, Hideshima T, Mitsiades C, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002;100:3063-3067.  Richardson PG, Blood E, Mitsiades CS, Jagganath S, Zeldenrust SR, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006;108:3458-3464.  Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau J-L, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Eng J Med 20007;357:2123-32.  Weber DM, Chen C, Niesvizky R, Wang M, Belch A, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Eng J Med 2007;357:2133-42.  Revlimid (lenalidomide) Product Package Insert. Celgene Corporation, Summit, NJ 2006.  Chen N, Lau H, Kong L, Kumar G, Zeldis JB, et al. Pharmacokinetics of lenalidomide in subjects with various degrees of renal impairment and in subjects on hemodialysis. J Clin Pharmacol 2007;47:1466-1475.  Niesvizky R, Naib T, Christos PJ, Jayabalan D, Furst JR, et al. Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-nave patients undergoing front-line lenalidomide and dexamethasone therapy. Br J Haemotol 2007;138:640-643.  Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414-423.  Klein U, Kosely F, hillengab J, Hundemer, Schmitt S, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol 2009;88:67-71.  Zonder JA, Barlogie B, Durie BGM, McCoy J, Crowley J, et al. Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis. Blood 2006;108:403-404.  Menon SP, Rajkumar SV, Lacy M, Falco P, Palumbo A. Thromboembolic events with lenalidomide-based therapy for multiple myeloma. 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