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. (See PRECAUTIONS)
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), pruritus (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.
Table 4: Summary of Adverse Events Reported in ≥ 5% of the REVLIMID® (lenalidomide) treated patients in del 5q MDS Clinical Study | NOS, not otherwise specified |
| [a] System organ classes and preferred terms are coded using the MedDRA dictionary. System organ classes and preferred terms are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an AE is counted only once in the AE category. |
| System organ class/Preferred term [a] | 10 mg Overall
(N=148) |
| Patients with at least one adverse event | 148 (100.0) |
| Blood and Lymphatic System Disorders | |
| Thrombocytopenia | 91 (61.5) |
| Neutropenia | 87 (58.8) |
| Anemia NOS | 17 (11.5) |
| Leukopenia NOS | 12 (8.1) |
| Febrile Neutropenia | 8 (5.4) |
| Skin and Subcutaneous Tissue Disorders | |
| Pruritus | 62 (41.9) |
| Rash NOS | 53 (35.8) |
| Dry Skin | 21 (14.2) |
| Contusion | 12 (8.1) |
| Night Sweats | 12 (8.1) |
| Sweating Increased | 10 (6.8) |
| Ecchymosis | 8 (5.4) |
| Erythema | 8 (5.4) |
| Gastrointestinal Disorders | |
| Diarrhea NOS | 72 (48.6) |
| Constipation | 35 (23.6) |
| Nausea | 35 (23.6) |
| Abdominal Pain NOS | 18 (12.2) |
| Vomiting NOS | 15 (10.1) |
| Abdominal Pain Upper | 12 (8.1) |
| Dry Mouth | 10 (6.8) |
| Loose Stools | 9 (6.1) |
| Respiratory, Thoracic and Mediastinal Disorders | |
| Nasopharyngitis | 34 (23.0) |
| Cough | 29 (19.6) |
| Dyspnea NOS | 25 (16.9) |
| Pharyngitis | 23 (15.5) |
| Epistaxis | 22 (14.9) |
| Dyspnea Exertional | 10 (6.8) |
| Rhinitis NOS | 10 (6.8) |
| Bronchitis NOS | 9 (6.1) |
| General Disorders and Administration Site Conditions | |
| Fatigue | 46 (31.1) |
| Pyrexia | 31 (20.9) |
| Edema Peripheral | 30 (20.3) |
| Asthenia | 22 (14.9) |
| Edema NOS | 15 (10.1) |
| Pain NOS | 10 (6.8) |
| Rigors | 9 (6.1) |
| Chest Pain | 8 (5.4) |
| Musculoskeletal and Connective Tissue Disorders | |
| Arthralgia | 32 (21.6) |
| Back Pain | 31 (20.9) |
| Muscle Cramp | 27 (18.2) |
| Pain in Limb | 16 (10.8) |
| Myalgia | 13 (8.8) |
| Peripheral Swelling | 12 (8.1) |
| Nervous System Disorders | |
| Dizziness | 29 (19.6) |
| Headache | 29 (19.6) |
| Hypoesthesia | 10 (6.8) |
| Dysgeusia | 9 (6.1) |
| Peripheral Neuropathy NOS | 8 (5.4) |
| Infections and Infestations | |
| Upper Respiratory Tract Infection NOS | 22 (14.9) |
| Pneumonia NOS | 17 (11.5) |
| Urinary Tract Infection NOS | 16 (10.8) |
| Sinusitis NOS | 12 (8.1) |
| Cellulitis | 8 (5.4) |
| Metabolism and Nutrition Disorders | |
| Hypokalemia | 16 (10.8) |
| Anorexia | 15 (10.1) |
| Hypomagnesemia | 9 (6.1) |
| Investigations | |
| Alanine Aminotransferase Increased | 12 (8.1) |
| Psychiatric Disorders | |
| Insomnia | 15 (10.1) |
| Depression | 8 (5.4) |
| Vascular Disorders | |
| Hypertension NOS | 9 (6.1) |
| Renal and Urinary Disorders | |
| Dysuria | 10 (6.8) |
| Cardiac Disorders | |
| Palpitations | 8 (5.4) |
| Endocrine Disorders | |
| Acquired Hypothyroidism | 10 (6.8) |
Table 5: Most Frequently Observed Grade 3 and 4 Adverse Events [1] Regardless of Relationship to Study Drug Treatment | [1] Adverse events with frequency ≥1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2. |
| [2] Preferred Terms are coded using the MedDRA dictionary. A patient with multiple occurrences of an AE is counted only once in the Preferred Term category. |
| Preferred term [2] | 10 mg
(N=148) |
| Patients with at least one Grade 3/4 AE | 131 (88.5) |
| Neutropenia | 79 (53.4) |
| Thrombocytopenia | 74 (50.0) |
| Pneumonia NOS | 11 (7.4) |
| Rash NOS | 10 (6.8) |
| Anemia NOS | 9 (6.1) |
| Leukopenia NOS | 8 (5.4) |
| Fatigue | 7 (4.7) |
| Dyspnea | 7 (4.7) |
| Back Pain | 7 (4.7) |
| Febrile Neutropenia | 6 (4.1) |
| Nausea | 6 (4.1) |
| Diarrhea NOS | 5 (3.4) |
| Pyrexia | 5 (3.4) |
| Sepsis | 4 (2.7) |
| Dizziness | 4 (2.7) |
| Granulocytopenia | 3 (2.0) |
| Chest Pain | 3 (2.0) |
| Pulmonary Embolism | 3 (2.0) |
| Respiratory Distress | 3 (2.0) |
| Pruritus | 3 (2.0) |
| Pancytopenia | 3 (2.0) |
| Muscle Cramp | 3 (2.0) |
| Respiratory Tract Infection | 2 (1.4) |
| Upper Respiratory Tract Infection | 2 (1.4) |
| Asthenia | 2 (1.4) |
| Multi-organ Failure | 2 (1.4) |
| Epistaxis | 2 (1.4) |
| Hypoxia | 2 (1.4) |
| Pleural Effusion | 2 (1.4) |
| Pneumonitis NOS | 2 (1.4) |
| Pulmonary Hypertension NOS | 2 (1.4) |
| Vomiting NOS | 2 (1.4) |
| Sweating Increased | 2 (1.4) |
| Arthralgia | 2 (1.4) |
| Pain in Limb | 2 (1.4) |
| Headache | 2 (1.4) |
| Syncope | 2 (1.4) |
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 6: Number of Patients with Adverse Events Reported in at Least 10% of Patients in Either Treatment Group in Studies 1 and 2 (Safety Population) | ª See WARNINGS |
| Revlimid/Dex
(N=346) | Placebo/Dex
(N=345) |
| System organ class/Preferred term | n | (%) | n | (%) |
| Subjects with at least one adverse event | 346 | (100.0) | 344 | (99.7) |
| Blood and Lymphatic System Disorders | | | | |
| | | | |
| Neutropenia | 96 | (27.7) | 16 | (4.6) |
| Anemia NOS | 84 | (24.3) | 60 | (17.4) |
| Thrombocytopenia | 59 | (17.1) | 34 | (9.9) |
| Eye Disorders | | | | |
| Vision Blurred | 51 | (14.7) | 36 | (10.4) |
| Gastrointestinal Disorders | | | | |
| Constipation | 134 | (38.7) | 64 | (18.6) |
| Diarrhea NOS | 101 | (29.2) | 85 | (24.6) |
| Nausea | 76 | (22.0) | 66 | (19.1) |
| Dyspepsia | 48 | (13.9) | 46 | (13.3) |
| Vomiting NOS | 35 | (10.1) | 28 | (8.1) |
| General Disorders and Administration Site Conditions | | | | |
| Fatigue | 133 | (38.4) | 129 | (37.4) |
| Asthenia | 81 | (23.4) | 86 | (24.9) |
| Pyrexia | 80 | (23.1) | 67 | (19.4) |
| Edema Peripheral | 73 | (21.1) | 65 | (18.8) |
| Infections and Infestations | | | | |
| Upper Respiratory Tract Infection NOS | 47 | (13.6) | 43 | (12.5) |
| Pneumonia NOS | 39 | (11.3) | 26 | (7.5) |
| Investigations | | | | |
| Weight Decreased | 63 | (18.2) | 48 | (13.9) |
| Metabolism and Nutrition Disorders | | | | |
| Hyperglycemia NOS | 52 | (15.0) | 49 | (14.2) |
| Anorexia | 47 | (13.6) | 30 | (8.7) |
| Hypokalemia | 39 | (11.3) | 18 | (5.2) |
| Musculoskeletal and Connective Tissue Disorders | | | | |
| Muscle Cramp | 104 | (30.1) | 71 | (20.6) |
| Back Pain | 53 | (15.3) | 49 | (14.2) |
| Muscle Weakness NOS | 52 | (15.0) | 53 | (15.4) |
| Arthralgia | 36 | (10.4) | 51 | (14.8) |
| Nervous System Disorders | | | | |
| Headache | 74 | (21.4) | 74 | (21.4) |
| Dizziness | 72 | (20.8) | 53 | (15.4) |
| Tremor | 68 | (19.7) | 24 | (7.0) |
| Dysgeusia | 46 | (13.3) | 32 | (9.3) |
| Paresthesia | 40 | (11.6) | 43 | (12.5) |
| Psychiatric Disorders | | | | |
| Insomnia | 111 | (32.1) | 128 | (37.1) |
| Respiratory, Thoracic and Mediastinal Disorders | | | | |
| Dyspnea NOS | 70 | (20.2) | 53 | (15.4) |
| Cough | 50 | (14.5) | 71 | (20.6) |
| Skin and Subcutaneous Tissue Disorders | | | | |
| Rash NOS | 55 | (15.9) | 28 | (8.1) |
| Vascular Disorders | | | | |
| Deep Vein Thrombosisa | 27 | (7.8) | 11 | (3.2) |
| Pulmonary Embolisma | 11 | (3.2) | 3 | (0.9) |
Table 7 summarizes the Grade 3/4 adverse events reported in ≥2% of patients in either treatment group in Studies 1 and 2.
Table 7: Adverse Events with NCI CTC Grades 3 and 4 Reported In At Least 2% of Patients by Preferred Term and Treatment Group – (Safety Population) | ª See WARNINGS |
| Revlimid/Dex (N=346) | Placebo/Dex (N=345) |
| Grade 3 | Grade 4 | Grade 3 | Grade 4 |
| System organ class/ Preferred term | n (%) | n (%) | n (%) | n (%) |
| Patients with at least one Grade 3 or 4 AE | 225 (65.0) | 25 (7.2) | 186 (53.9) | 31 (9.0) |
| Blood and Lymphatic System Disorders |
| Neutropenia | 60 (17.3) | 13 (3.8) | 8 (2.3) | 2 (0.6) |
| Thrombocytopenia | 31 (9.0) | 4 (1.2) | 16 (4.6) | 3 (0.9) |
| Anemia NOS | 25 (7.2) | 4 (1.2) | 10 (2.9) | 2 (0.6) |
| Leukopenia NOS | 12 (3.5) | 0 (0.0) | 1 (0.3) | 0 (0.0) |
| Lymphopenia | 8 (2.3) | 0 (0.0) | 4 (1.2) | 0 (0.0) |
| Cardiac Disorders |
| Atrial Fibrillation | 9 (2.6) | 1 (0.3) | 2 (0.6) | 1 (0.3) |
| Gastrointestinal Disorders |
| Diarrhea NOS | 8 (2.3) | 0 (0.0) | 2 (0.6) | 0 (0.0) |
| Constipation | 7 (2.0) | 0 (0.0) | 1 (0.3) | 0 (0.0) |
| General Disorders and Administration Site Conditions |
| Fatigue | 20 (5.8) | 1 (0.3) | 13 (3.8) | 0 (0.0) |
| Asthenia | 14 (4.0) | 0 (0.0) | 16 (4.6) | 0 (0.0) |
| Pyrexia | 4 (1.2) | 0 (0.0) | 8 (2.3) | 0 (0.0) |
| Infections and Infestations |
| Pneumonia NOS | 18 (5.2) | 4 (1.2) | 15 (4.3) | 3 (0.9) |
| Metabolism and Nutrition Disorders |
| Hyperglycemia NOS | 22 (6.4) | 4 (1.2) | 19 (5.5) | 7 (2.0) |
| Hypocalcemia | 8 (2.3) | 5 (1.4) | 4 (1.2) | 1 (0.3) |
| Hypokalemia | 9 (2.6) | 1 (0.3) | 5 (1.4) | 0 (0.0) |
| Musculoskeletal and Connective Tissue Disorders |
| Muscle Weakness NOS | 18 (5.2) | 0 (0.0) | 10 (2.9) | 0 (0.0) |
| Nervous System Disorders |
| Syncope | 7 (2.0) | 0 (0.0) | 3 (0.9) | 0 (0.0) |
| Neuropathy NOS | 7 (2.0) | 0 (0.0) | 2 (0.6) | 0 (0.0) |
| Psychiatric Disorders |
| Depression | 9 (2.6) | 0 (0.0) | 5 (1.4) | 1 (0.3) |
| Confusional State | 6 (1.7) | 0 (0.0) | 8 (2.3) | 0 (0.0) |
| Respiratory, Thoracic and Mediastinal Disorders |
| Dyspnea NOS | 6 (1.7) | 3 (0.9) | 7 (2.0) | 1 (0.3) |
| Vascular Disorders |
| Deep Vein Thrombosisa | 23 (6.6) | 1 (0.3) | 9 (2.6) | 1 (0.3) |
| Pulmonary Embolisma | 2 (0.6) | 9 (2.6) | 1 (0.3) | 2 (0.6) |
Thrombotic Events (see WARNINGS)
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 carinii 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 pneumococcal, 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
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