Can Lenalidomide cause plasma cell myeloma?

ADVERSE REACTIONS The following clinically significant adverse reactions are described in detail in other sections of the prescribing information: Embryo-Fetal Toxicity [see Boxed Warning , Warnings and Precautions ( 5.1 , 5.2 )] Hematologic Toxicity [see Boxed Warning , Warnings and Precautions ( 5.3 )] Venous and Arterial Thromboembolism [see Boxed Warning , Warnings and Precautions ( 5.4 )] Increased Mortality in Patients with CLL [see Warnings and Precautions ( 5.5 )] Second Primary Malignancies [see Warnings and Precautions ( 5.6 )] Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions ( 5.7 )] Hepatotoxicity [see Warnings and Precautions ( 5.8 )] Severe Cutaneous Reactions [see Warnings and Precautions ( 5.9 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.10 )] Tumor Flare Reactions [see Warnings and Precautions ( 5.11 )] Impaired Stem Cell Mobilization [see Warnings and Precautions ( 5.12 )] Thyroid Disorders [see Warnings and Precautions ( 5.13 )] Early Mortality in Patients with MCL [see Warnings and Precautions ( 5.14 )] Hypersensitivity [see Warnings and Precautions ( 5.15 )] MM: Most common adverse reactions (≥20%) include diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor ( 6.1 ). MDS: Most common adverse reactions (>15%) include thrombocytopenia, neutropenia, diarrhea, pruritus, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, pharyngitis, and epistaxis ( 6.1 ). Non-Hodgkin’s Lymphoma (NHL: MCL): Most common adverse reactions (≥15%) included neutropenia, thrombocytopenia, anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia, cough, upper respiratory tract infection, and rash ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed MM – Lenalidomide Capsules Combination Therapy: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of lenalidomide with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7). In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18. In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of lenalidomide were infection events (28.8%); overall, the median time to the first dose interruption of lenalidomide was 7 weeks. The most common adverse reactions leading to dose reduction of lenalidomide in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of lenalidomide was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of lenalidomide were infection events (3.4%). In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous. Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms. Table 4: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Rd Continuous or Rd18 Arms* Body System Adverse Reaction All Adverse Reactions a Grade 3/4 Adverse Reactions b Rd Continuous (N=532) Rd18 (N=540) MPT (N=541) Rd Continuous (N=532) Rd18 (N=540) MPT (N=541) General disorders and administration site conditions Fatigue % 173 (33) 177 (33) 154 (28) 39 (7) 46 (9) 31 (6) Asthenia 150 (28) 123 (23) 124 (23) 41 (8) 33 (6) 32 (6) Pyrexia c 114 (21) 102 (19) 76 (14) 13 (2) 7 (1) 7 (1) Non-cardiac chest pain f 29 (5) 31 (6) 18 (3) <1% < 1% < 1% Gastrointestinal disorders Diarrhea 242 (45) 208 (39) 89 (16) 21 (4) 18 (3) 8 (1) Abdominal pain %f 109 (20) 78 (14) 60 (11) 7 (1) 9 (2) < 1% Dyspepsia f 57 (11) 28 (5) 36 (7) <1% < 1% 0 (0) Musculoskeletal and connective tissue disorders Back pain c 170 (32) 145 (27) 116 (21) 37 (7) 34 (6) 28 (5) Muscle spasms f 109 (20) 102 (19) 61 (11) < 1% < 1% < 1% Arthralgia f 101 (19) 71 (13) 66 (12) 9 (2) 8 (1) 8 (1) Bone pain f 87 (16) 77 (14) 62 (11) 16 (3) 15 (3) 14 (3) Pain in extremity f 79 (15) 66 (12) 61 (11) 8 (2) 8 (1) 7 (1) Musculoskeletal pain f 67 (13) 59 (11) 36 (7) < 1% < 1% < 1% Musculoskeletal chest pain f 60 (11) 51 (9) 39 (7) 6 (1) < 1% < 1% Muscular weakness f 43 (8) 35 (6) 29 (5) < 1% 8 (1) < 1% Neck pain f 40 (8) 19 (4) 10 (2) < 1% < 1% < 1% Infections and infestations Bronchitis c 90 (17) 59 (11) 43 (8) 9 (2) 6 (1) < 1% Nasopharyngitis f 80 (15) 54 (10) 33 (6) 0 (0) 0 (0) 0 (0) Urinary tract infection f 76 (14) 63 (12) 41 (8) 8 (2) 8 (1) < 1% Upper respiratory tract infection c% f 69 (13) 53 (10) 31 (6) < 1% 8 (1) < 1% Pneumonia c@ 93 (17) 87 (16) 56 (10) 60 (11) 57 (11) 41 (8) Respiratory tract infection % 35 (7) 25 (5) 21 (4) 7 (1) < 1% < 1% Influenza f 33 (6) 23 (4) 15 (3) < 1% < 1% 0 (0) Gastroenteritis f 32 (6) 17 (3) 13 (2) 0 (0) < 1% < 1% Lower respiratory tract infection 29 (5) 14 (3) 16 (3) 10 (2) < 1% < 1% Rhinitis f 29 ( 5) 24 (4) 14 (3) 0 (0) 0 (0) 0 (0) Cellulitis c < 5% < 5% < 5% 8 (2) < 1% < 1% Sepsis c@ 33 (6) 26 (5) 18 (3) 26 (5) 20 (4) 13 (2) Nervous system disorders Headache f 75 (14) 52 (10) 56 (10) < 1% < 1% < 1% Dysgeusia f 39 (7) 45 (8) 22 (4) < 1% 0 (0.0) < 1% Blood and lymphatic system disorders d Anemia 233 (44) 193 (36) 229 (42) 97 (18) 85 (16) 102 (19) Neutropenia 186 (35) 178 (33) 328 (61) 148 (28) 143 (26) 243 (45) Thrombocytopenia 104 (20) 100 (19) 135 (25) 44 (8) 43 (8) 60 (11) Febrile neutropenia 7 (1) 17 (3) 15 (3) 6 (1) 16 (3) 14 (3) Pancytopenia < 1% 6 (1) 7 (1) < 1% < 1% < 1% Respiratory, thoracic and mediastinal disorders Cough f 121 (23) 94 (17) 68 (13) < 1% < 1% < 1% Dyspnea c,e 117 (22) 89 (16) 113 (21) 30 (6) 22 (4) 18 (3) Epistaxis f 32 (6) 31 (6) 17 (3) < 1% < 1% 0 (0) Oropharyngeal pain f 30 (6) 22 (4) 14 (3) 0 (0) 0 (0) 0 (0) Dyspnea exertional e 27 (5) 29 (5) < 5% 6 (1) < 1% 0 (0) Metabolism and nutrition disorders Decreased appetite 123 (23) 115 (21) 72 (13) 14 (3) 7 (1) < 1% Hypokalemia % 91 (17) 62 (11) 38 (7) 35 (7) 20 (4) 11 (2) Hyperglycemia 62 (12) 52 (10) 19 (4) 28 (5) 23 (4) 9 (2) Hypocal

WARNINGS AND PRECAUTIONS Increased Mortality: serious and fatal cardiac adverse reactions occurred in patients with CLL treated with lenalidomide capsules ( 5.5 ). Second Primary Malignancies (SPM): Higher incidences of SPM were observed in controlled trials of patients with MM receiving lenalidomide capsules ( 5.6 ). Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue ( 5.7 ). Hepatotoxicity: Hepatic failure including fatalities; monitor liver function. Stop lenalidomide capsules and evaluate if hepatotoxicity is suspected ( 5.8 ). Severe Cutaneous Reactions: Discontinue lenalidomide for severe reactions ( 5.9 ). Tumor lysis syndrome (TLS) including fatalities: Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions ( 5.10 ). Tumor flare reaction: Serious tumor flare reactions, including fatal reactions, have occurred during investigational use of lenalidomide capsules for chronic lymphocytic leukemia and lymphoma ( 5.11 ). Impaired Stem Cell mobilization: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with lenalidomide has been reported. Consider early referral to transplant center ( 5.12 ). Early mortality in MCL: Higher rate of early deaths have occurred in patients with MCL ( 5.14 ). Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue lenalidomide for angioedema and anaphylaxis ( 5.15 ). 5.1 Embryo-Fetal Toxicity Lenalidomide is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes life-threatening human birth defects or embryo-fetal death [see Use in Specific Populations ( 8.1 )] . An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. Lenalidomide capsules are only available through the Lenalidomide REMS program [see Warnings and Precautions ( 5.2 )] . Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning lenalidomide capsules therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with lenalidomide capsules, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10 to 14 days and the second test within 24 hours prior to prescribing lenalidomide therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles [see Use in Specific Populations ( 8.3 )] . Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide capsules and for up to 4 weeks after discontinuing lenalidomide capsules, even if they have undergone a successful vasectomy. Male patients taking lenalidomide capsules must not donate sperm and for up to 4 weeks after discontinuing lenalidomide capsules [see Use in Specific Populations ( 8.3 )] . Blood Donation Patients must not donate blood during treatment with lenalidomide capsules and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to lenalidomide. 5.2 Lenalidomide REMS Program Because of the embryo-fetal risk [see Warnings and Precautions ( 5.1 )] , lenalidomide capsules are available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the Lenalidomide REMS program. Required components of the Lenalidomide REMS program include the following: Prescribers must be certified with the Lenalidomide REMS program by enrolling and complying with the REMS requirements. Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations ( 8.3 )] and males must comply with contraception requirements [see Use in Specific Populations ( 8.3 )] . Pharmacies must be certified with the Lenalidomide REMS program, must only dispense to patients who are authorized to receive lenalidomide capsules and comply with REMS requirements. Further information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity Lenalidomide capsules can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking lenalidomide capsules should have their complete blood counts assessed periodically as described below [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )] . Monitor complete blood counts (CBC) in patients taking lenalidomide capsules in combination with dexamethasone for MM every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration ( 2.1 )] . In trials for another indication, Grade 3 or 4 neutropenia was reported in up to 59% of lenalidomide capsules-treated patients and Grade 3 or 4 thrombocytopenia in up to 38% of lenalidomide capsules-treated patients. Monitor complete blood counts (CBC) in patients taking lenalidomide capsules for MDS weekly for the first 8 weeks and at least monthly thereafter. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14 to 411 days), and the median time to documented recovery was 17 days (range, 2 to 170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8 to 290 days), and the median time to documented recovery was 22 days (range, 5 to 224 days) [see Boxed Warning and Dosage and Administration ( 2.2 )] . Monitor complete blood counts (CBC) in patients taking lenalidomide capsules for MCL weekly for the first cycle (28 days), every 2 weeks during cycles 2 to 4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous and Arterial Thromboembolism Venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with lenalidomide. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with MM after at least one prior therapy who were treated with lenalidomide and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Th