REVLIMID SIDE EFFECTS
- Generic Name: lenalidomide
- Brand Name: Revlimid
- Drug Class: Antineoplastics, Angiogenesis Inhibitor
SIDE EFFECTS
The following clinically significant adverse reactions are described in detail in other sections of the prescribing information:
- Embryo-Fetal Toxicity
- Hematologic Toxicity
- Venous and Arterial Thromboembolism
- Increased Mortality in Patients with CLL
- Second Primary Malignancies
- Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone
- Hepatotoxicity
- Severe Cutaneous Reactions
- Tumor Lysis Syndrome
- Tumor Flare Reactions
- Impaired Stem Cell Mobilization
- Thyroid Disorders
- Early Mortality in Patients with MCL
- Hypersensitivity
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
REVLIMID Combination Therapy
Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID 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 REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID 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 1 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.
Table 1: 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† | Grade 3/4 Adverse Reactions‡ | ||||
| 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¶ | 114 (21) | 102 (19) | 76 (14) | 13 ( 2) | 7 ( 1) | 7 ( 1) |
| Non-cardiac chest pain# | 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§ # | 109 (20) | 78 (14) | 60 (11) | 7 ( 1) | 9 ( 2) | < 1% |
| Dyspepsia# | 57 (11) | 28 ( 5) | 36 ( 7) | <1% | <1% | 0 ( 0) |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain¶ | 170 (32) | 145 (27) | 116 (21) | 37 ( 7) | 34 ( 6) | 28 ( 5) |
| Muscle spasms# | 109 (20) | 102 (19) | 61 (11) | < 1% | < 1% | < 1% |
| Arthralgia# | 101 (19) | 71 (13) | 66 (12) | 9 ( 2) | 8 ( 1) | 8 ( 1) |
| Bone pain# | 87 (16) | 77 (14) | 62 (11) | 16 ( 3) | 15 ( 3) | 14 ( 3) |
| Pain in extremity# | 79 (15) | 66 (12) | 61 (11) | 8 ( 2) | 8 ( 1) | 7 ( 1) |
| Musculoskeletal pain# | 67 (13) | 59 (11) | 36 ( 7) | < 1% | < 1% | < 1% |
| Musculoskeletal chest pain# | 60 (11) | 51 ( 9) | 39 ( 7) | 6 ( 1) | < 1% | < 1% |
| Muscular weakness# | 43 ( 8) | 35 ( 6) | 29 ( 5) | < 1% | 8 ( 1) | < 1% |
| Neck pain# | 40 ( 8) | 19 ( 4) | 10 ( 2) | < 1% | < 1% | < 1% |
| Infections and infestations | ||||||
| Bronchitis¶ | 90 (17) | 59 (11) | 43 ( 8) | 9 ( 2) | 6 ( 1) | < 1% |
| Nasopharyngitis# | 80 (15) | 54 (10) | 33 ( 6) | 0 ( 0) | 0 ( 0) | 0 ( 0) |
| Urinary tract infection# | 76 (14) | 63 (12) | 41 ( 8) | 8 ( 2) | 8 ( 1) | < 1% |
| Upper respiratory tract infection¶§ # | 69 (13) | 53 ( 10) | 31 ( 6) | < 1% | 8 ( 1) | < 1% |
| Pneumonia¶ Þ | 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# | 33 ( 6) | 23 ( 4) | 15 ( 3) | < 1% | < 1% | 0 ( 0) |
| Gastroenteritis# | 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# | 29 ( 5) | 24 ( 4) | 14 ( 3) | 0 ( 0) | 0 ( 0) | 0 ( 0) |
| Cellulitis¶ | < 5% | < 5% | < 5% | 8 ( 2) | < 1% | < 1% |
| Sepsis¶ Þ | 33 ( 6) | 26 ( 5) | 18 ( 3) | 26 ( 5) | 20 ( 4) | 13 ( 2) |
| Nervous system disorders | ||||||
| Headache# | 75 (14) | 52 ( 10) | 56 (10) | < 1% | < 1% | < 1% |
| Dysgeusia# | 39 ( 7) | 45 ( 8) | 22 ( 4) | < 1% | 0 ( 0.0) | < 1% |
| Blood and lymphatic system disordersß | ||||||
| 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# | 121 (23) | 94 (17) | 68 (13) | < 1% | < 1% | < 1% |
| Dyspnea¶,à | 117 (22) | 89 (16) | 113 (21) | 30 ( 6) | 22 ( 4) | 18 ( 3) |
| Epistaxis# | 32 ( 6) | 31 ( 6) | 17 ( 3) | < 1% | < 1% | 0 ( 0) |
| Oropharyngeal pain# | 30 ( 6) | 22 ( 4) | 14 ( 3) | 0 ( 0) | 0 ( 0) | 0 ( 0) |
| Dyspnea exertionalà | 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) |
| Hypocalcemia | 57 (11) | 56 (10) | 31 ( 6) | 23 ( 4) | 19 ( 4) | 8 ( 1) |
| Dehydration§ | 25 ( 5) | 29 ( 5) | 17 ( 3) | 8 ( 2) | 13 ( 2) | 9 ( 2) |
| Goutà | < 5% | < 5% | < 5% | 8 ( 2) | 0 ( 0) | 0 ( 0) |
| Diabetes mellitus§ à | < 5% | < 5% | < 5% | 8 ( 2) | < 1% | < 1% |
| Hypophosphatemiaà | < 5% | < 5% | < 5% | 7 ( 1) | < 1% | < 1% |
| Hyponatremia§ à | < 5% | < 5% | < 5% | 7 ( 1) | 13 ( 2) | 6 ( 1) |
| Skin and subcutaneous tissue disorders | ||||||
| Rash | 139 (26) | 151 (28) | 105 (19) | 39 ( 7) | 38 ( 7) | 33 ( 6) |
| Pruritus# | 47 ( 9) | 49 ( 9) | 24 ( 4) | < 1% | < 1% | < 1% |
| Psychiatric disorders | ||||||
| Insomnia | 147 (28) | 127 (24) | 53 ( 10) | < 1% | 6 ( 1) | 0 ( 0) |
| Depression | 58 (11) | 46 ( 9) | 30 ( 6) | 10 ( 2) | < 1% | < 1% |
| Vascular disorders | ||||||
| Deep vein thrombosis¶§ | 55 (10) | 39 ( 7) | 22 ( 4) | 30 ( 6) | 20 ( 4) | 15 ( 3) |
| Hypotension¶§ | 51 ( 10) | 35 ( 6) | 36 ( 7) | 11 ( 2) | 8 ( 1) | 6 ( 1) |
| Injury, Poisoning, and Procedural Complications | ||||||
| Fall# | 43 ( 8) | 25 ( 5) | 25 ( 5) | < 1% | 6 ( 1) | 6 ( 1) |
| Contusion# | 33 ( 6) | 24 ( 4) | 15 ( 3) | < 1% | < 1% | 0 ( 0) |
| Eye disorders | ||||||
| Cataract | 73 (14) | 31 ( 6) | < 1% | 31 ( 6) | 14 ( 3) | < 1% |
| Cataract subcapsularà | < 5% | < 5% | < 5% | 7 ( 1) | 0 ( 0) | 0 ( 0) |
| Investigations | ||||||
| Weight decreased | 72 (14) | 78 (14) | 48 ( 9) | 11 ( 2) | < 1% | < 1% |
| Cardiac disorders | ||||||
| Atrial fibrillation¶ | 37 ( 7) | 25 ( 5) | 25 ( 5) | 13 ( 2) | 9 ( 2) | 6 ( 1) |
| Myocardial infarction (including acute)¶ ,à |
< 5% | < 5% | < 5% | 10 ( 2) | < 1% | < 1% |
| Renal and Urinary disorders | ||||||
| Renal failure (including acute)¶Þ,# | 49 ( 9) | 54 (10) | 37 ( 7) | 28 ( 5) | 33 ( 6) | 29 ( 5) |
| Neoplasms benign, malignant and unspecified (Including cysts and polyps) | ||||||
| Squamous cell carcinoma¶ à | < 5% | < 5% | < 5% | 8 ( 2) | < 1% | 0 ( 0) |
| Basal cell carcinoma¶ à,# | < 5% | < 5% | < 5% | < 1% | < 1% | 0 ( 0) |
| Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. * Adverse reactions included in combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis † All treatment-emergent adverse events in at least 5% of subjects in the Rd Continuous or Rd18 Arms and at least a 2% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. ‡ All grade 3 or 4 treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. § adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). ¶ Serious treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. # Footnote “‡” not applicable. Þ adverse reactions in which at least one resulted in a fatal outcome. ß Preferred terms for the blood and lymphatic system disorders body system were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. à Footnote “†” not applicable. |
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Newly Diagnosed MM
REVLIMID Maintenance Therapy Following Auto-HSCT
Data were evaluated from 1018 patients in two randomized trials who received at least one dose of REVLIMID 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity. The mean treatment duration for REVLIMID treatment was 30.3 months for Maintenance Study 1 and 24.0 months for Maintenance Study 2 (overall range across both studies from 0.1 to 108 months). As of the cut-off date of 1 Mar 2015, 48 patients (21%) in the Maintenance Study 1 REVLIMID arm were still on treatment and none of the patients in the Maintenance Study 2 REVLIMID arm were still on treatment at the same cut-off date
The adverse reactions listed from Maintenance Study 1 included events reported post-transplant (completion of high-dose melphalan /auto-HSCT), and the maintenance treatment period. In Maintenance Study 2, the adverse reactions were from the maintenance treatment period only. In general, the most frequently reported adverse reactions (more than 20% in the REVLIMID arm) across both studies were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm and pyrexia. The most frequently reported Grade 3 or 4 reactions (more than 20% in the REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm.
For REVLIMID, the most common adverse reactions leading to dose interruption were hematologic events (29.7%, data available in Maintenance Study 2 only). The most common adverse reaction leading to dose reduction of REVLIMID were hematologic events (17.7%, data available in Maintenance Study 2 only). The most common adverse reactions leading to discontinuation of REVLIMID were thrombocytopenia (2.7%) in Maintenance Study 1 and neutropenia (2.4%) in Maintenance Study 2.
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.
Table 2 summarizes the adverse reactions reported for the REVLIMID and placebo maintenance treatment arms.
Table 2: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the REVLIMID Vs Placebo Arms*
| Body System Adverse Reaction |
Maintenance Study 1 | Maintenance Study 2 | ||||||
| All Adverse Reactions† | Grade 3/4 Adverse Reactions |
All Adverse Reactions† | Grade 3/4 Adverse Reactions‡ |
|||||
| REVLIMID (N=224) n (%) |
Placebo (N=221) n (%) |
REVLIMID (N=224) n (%) |
Placebo (N=221) n (%) |
REVLIMID (N=293) n (%) |
Placebo (N=280) n (%) |
REVLIMID (N=293) n (%) |
Placebo (N=280) n (%) |
|
| Blood and lymphatic system disorders | ||||||||
| Neutropenia§ ¶ | 177 ( 79) | 94 ( 43) | 133 ( 59) | 73 ( 33) | 178 ( 61) | 33 ( 12) | 158 ( 54) | 21 ( 8) |
| Thrombocytopenia§ ¶ | 162 ( 72) | 101 ( 46) | 84 ( 38) | 67 ( 30) | 69 ( 24) | 29 ( 10) | 38 ( 13) | 8 ( 3) |
| Leukopenia§ | 51 ( 23) | 25 ( 11) | 45 ( 20) | 22 ( 10) | 93 ( 32) | 21 ( 8) | 71 ( 24) | 5 ( 2) |
| Anemia | 47 ( 21) | 27 ( 12) | 23 ( 10) | 18 ( 8) | 26 ( 9) | 15 ( 5) | 11 ( 4) | 3 ( 1) |
| Lymphopenia | 40 ( 18) | 29 ( 13) | 37 ( 17) | 26 ( 12) | 13 ( 4) | 3 ( 1) | 11 ( 4) | < 1% |
| Pancytopenia§ # ¶ | < 1% | 0 ( 0) | 0 ( 0) | 0 ( 0) | 12 ( 4) | < 1% | 7 ( 2) | < 1% |
| Febrile neutropenia§ | 39 ( 17) | 34 ( 15) | 39 ( 17) | 34 ( 15) | 7 ( 2) | < 1% | 5 ( 2) | < 1% |
| Infections and infestationsÞ | ||||||||
| Upper respiratory tract infectionß |
60 ( 27) | 35 ( 16) | 7 ( 3) | 9 ( 4) | 32 ( 11) | 18 ( 6) | < 1% | 0 ( 0) |
| Neutropenic infection |
40 ( 18) | 19 ( 9) | 27 ( 12) | 14 ( 6) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) |
| Pneumonias* § ¶ | 31 ( 14) | 15 ( 7) | 23 ( 10) | 7 ( 3) | 50 ( 17) | 13 ( 5) | 27 ( 9) | 5 ( 2) |
| Bronchitis§ | 10 ( 4) | 9 ( 4) | < 1% | 5 ( 2) | 139 ( 47) | 104 ( 37) | 4 ( 1) | < 1% |
| Nasopharyngitisß | 5 ( 2) | < 1% | 0 ( 0) | 0 ( 0) | 102 ( 35) | 84 ( 30) | < 1% | 0 ( 0) |
| Gastroenteritis§ | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 66 ( 23) | 55 ( 20) | 6 ( 2) | 0 ( 0) |
| Rhinitisß | < 1% | 0 ( 0) | 0 ( 0) | 0 ( 0) | 44 ( 15) | 19 ( 7) | 0 ( 0) | 0 ( 0) |
| Sinusitisß | 8 ( 4) | 3 ( 1) | 3 ( 1) | 3 ( 1) | 41 ( 14) | 26 ( 9) | 0 ( 0) | < 1% |
| Influenza§ | 8 ( 4) | 5 ( 2) | < 1% | < 1% | 39 ( 13) | 19 ( 7) | 3 ( 1) | 0 ( 0) |
| Lung infection§ | 21 ( 9) | < 1% | 19 ( 8) | < 1% | 9 ( 3) | 4 ( 1) | < 1% | 0 ( 0) |
| Lower respiratory tract infectionß |
13 ( 6) | 5 ( 2) | 6 ( 3) | 4 ( 2) | 4 ( 1) | 4 ( 1) | 0 ( 0) | < 1% |
| Infection§ | 12 ( 5) | 6 ( 3) | 9 ( 4) | 5 ( 2) | 17 ( 6) | 5 ( 2) | 0 ( 0) | 0 ( 0) |
| Urinary tract infection§ # ß |
9 ( 4) | 5 ( 2) | 4 ( 2) | 4 ( 2) | 22 ( 8) | 17 ( 6) | < 1% | 0 ( 0) |
| Lower respiratory tract infection bacterial# |
6 ( 3) | < 1% | 4 ( 2) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) |
| Bacteremia# | 5 ( 2) | 0 ( 0) | 4 ( 2) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) |
| Herpes zoster§ # | 11 ( 5) | 10 ( 5) | 3 ( 1) | < 1% | 29 ( 10) | 25 ( 9) | 6 ( 2) | < 1% |
| Sepsis* § # à | < 1% | < 1% | 0 ( 0) | 0 ( 0) | 6 ( 2) | < 1% | 4 ( 1) | < 1% |
| Gastrointestinal disorders | ||||||||
| Diarrhea | 122 ( 54) | 83 ( 38) | 22 ( 10) | 17 ( 8) | 114 ( 39) | 34 ( 12) | 7 ( 2) | 0 ( 0) |
| Nauseaß | 33 ( 15) | 22 ( 10) | 16 ( 7) | 10 ( 5) | 31 ( 11) | 28 ( 10) | 0 ( 0) | 0 ( 0) |
| Vomiting | 17 ( 8) | 12 ( 5) | 8 ( 4) | 5 ( 2) | 16 ( 5) | 15 ( 5) | < 1% | 0 ( 0) |
| Constipationß | 12 ( 5) | 8 ( 4) | 0 ( 0) | 0 ( 0) | 37 ( 13) | 25 ( 9) | < 1% | 0 ( 0) |
| Abdominal painß | 8 ( 4) | 7 ( 3) | < 1% | 4 ( 2) | 31 ( 11) | 15 ( 5) | < 1% | < 1% |
| Abdominal pain upperß |
0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 20 ( 7) | 12 ( 4) | < 1% | 0 ( 0) |
| General disorders and administration site conditions | ||||||||
| Asthenia | 0 ( 0) | < 1% | 0 ( 0) | 0 ( 0) | 87 ( 30) | 53 ( 19) | 10 ( 3) | < 1% |
| Fatigue | 51 ( 23) | 30 ( 14) | 21 ( 9) | 9 ( 4) | 31 ( 11) | 15 ( 5) | 3 ( 1) | 0 ( 0) |
| Pyrexiaß | 17 ( 8) | 10 ( 5) | < 1% | < 1% | 60 ( 20) | 26 ( 9) | < 1% | 0 ( 0) |
| Skin and subcutaneous tissue disorders | ||||||||
| Dry skinß | 9 ( 4) | 4 ( 2) | 0 ( 0) | 0 ( 0) | 31 ( 11) | 21 ( 8) | 0 ( 0) | 0 ( 0) |
| Rash | 71 ( 32) | 48 ( 22) | 11 ( 5) | 5 ( 2) | 22 ( 8) | 17 ( 6) | 3 ( 1) | 0 ( 0) |
| Pruritus | 9 ( 4) | 4 ( 2) | 3 ( 1) | 0 ( 0) | 21 ( 7) | 25 ( 9) | < 1% | 0 ( 0) |
| Nervous system disorders | ||||||||
| Paresthesiaß | < 1% | 0 ( 0) | 0 ( 0) | 0 ( 0) | 39 ( 13) | 30 ( 11) | < 1% | 0 ( 0) |
| Peripheral neuropathy* ß |
34 ( 15) | 30 ( 14) | 8 ( 4) | 8 ( 4) | 29 ( 10) | 15 ( 5) | 4 ( 1) | < 1% |
| Headache# | 11 ( 5) | 8 ( 4) | 5 ( 2) | < 1% | 25 ( 9) | 21 ( 8) | 0 ( 0) | 0 ( 0) |
| Investigations | ||||||||
| Alanine aminotransferase increased |
16 ( 7) | 3 ( 1) | 8 ( 4) | 0 ( 0) | 5 ( 2) | 5 ( 2) | 0 ( 0) | < 1% |
| Aspartate aminotransferase increased# |
13 ( 6) | 5 ( 2) | 6 ( 3) | 0 ( 0) | < 1% | 5 ( 2) | 0 ( 0) | 0 ( 0) |
| Metabolism and nutrition disorders | ||||||||
| Hypokalemia | 24 ( 11) | 13 ( 6) | 16 ( 7) | 12 ( 5) | 12 ( 4) | < 1% | < 1% | 0 ( 0) |
| Dehydration | 9 ( 4 ) | 5 ( 2) | 7 ( 3) | 3 ( 1) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) |
| Hypophosphatemia# | 16 ( 7) | 15 ( 7) | 13 ( 6) | 14 ( 6) | 0 ( 0) | < 1% | 0 ( 0) | 0 ( 0) |
| Musculoskeletal and connective tissue disorders | ||||||||
| Muscle spasmsß | 0 ( 0) | < 1% | 0 ( 0) | 0 ( 0) | 98 ( 33) | 43 ( 15) | < 1% | 0 ( 0) |
| Myalgiaß | 7 ( 3) | 8 ( 4) | 3 ( 1) | 5 ( 2) | 19 ( 6) | 12 ( 4) | < 1% | < 1% |
| Musculoskeletal painß |
< 1% | < 1% | 0 ( 0) | 0 ( 0) | 19 ( 6) | 11 ( 44) | 0 ( 0) | 0 ( 0) |
| Hepatobiliary disorders | ||||||||
| Hyperbilirubinemiaß | 34 ( 15) | 19 ( 9) | 4 ( 2) | < 1% | 4 ( 1) | < 1% | < 1% | 0 ( 0) |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Coughß | 23 ( 10) | 12 ( 5) | 3 ( 1) | < 1% | 80 ( 27) | 56 ( 20) | 0 ( 0) | 0 ( 0) |
| Dyspnea§ ß | 15 ( 7) | 9 ( 4) | 8 ( 4) | 4 ( 2) | 17 ( 6) | 9 ( 3) | < 1% | 0 ( 0) |
| Rhinorrheaß | 0 ( 0) | 3 ( 1) | 0 ( 0) | 0 ( 0) | 15 ( 5) | 6 ( 2) | 0 ( 0) | 0 ( 0) |
| Pulmonary embolism§ # ß |
0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 3 ( 1) | 0 ( 0) | < 1% | 0 ( 0) |
| Vascular disorders | ||||||||
| Deep vein thrombosis*§ # ¶ |
8 ( 4) | < 1% | 5 ( 2) | < 1% | 7 ( 2) | < 1% | 4 ( 1) | < 1% |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | ||||||||
| Myelodysplastic syndrome§ # ß |
5 ( 2) | 0 ( 0) | < 1% | 0 ( 0) | 3 ( 1) | 0 ( 0) | < 1% | 0 ( 0) |
| Note: Adverse Events (AEs) are coded to Body System /Adverse Reaction using MedDRA v15.1. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. * Adverse Reactions for combined ADR terms (based on relevant TEAE PTs included in Maintenance Studies 1 and 2 [per MedDRA v 15.1]): Pneumonias Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis Sepsis: Bacterial sepsis, Pneumococcal sepsis, Sepsis, Septic shock, Staphylococcal sepsis Peripheral neuropathy: Neuropathy peripheral, Peripheral motor neuropathy, Peripheral sensory neuropathy, Polyneuropathy Deep vein thrombosis: Deep vein thrombosis, Thrombosis, Venous thrombosis † All treatment-emergent AEs in at least 5% of patients in the REVLIMID Maintenance group and at least 2% higher frequency (%) than the Placebo Maintenance group. ‡ All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. § All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. ¶ ADRs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # Footnote “†” not applicable for either study Þ All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered listed ß Footnote “‡” not applicable ‡ for either study à ADRs where at least one resulted in a fatal outcome |
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After At Least One Prior Therapy For MM
Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).
In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.
Tables 3, 4, and 5 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.
Table 3: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients with MM between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups
| Body System Adverse Reaction |
REVLIMID/Dex (N=353) n (%) |
Placebo/Dex (N=350) n (%) |
| Blood and lymphatic system disorders | ||
| Neutropenia* | 149 (42) | 22 ( 6) |
| Anemia† | 111 (31) | 83 (24) |
| Thrombocytopenia† | 76 (22) | 37 (11) |
| Leukopenia | 28 ( 8) | 4 ( 1) |
| Lymphopenia | 19 ( 5) | 5 ( 1) |
| General disorders and administration site conditions | ||
| Fatigue | 155 (44) | 146 (42) |
| Pyrexia | 97 (27) | 82 (23) |
| Peripheral edema | 93 (26) | 74 (21) |
| Chest pain | 29 ( 8) | 20 ( 6) |
| Lethargy | 24 ( 7) | 8 ( 2) |
| Gastrointestinal disorders | ||
| Constipation | 143 (41) | 74 (21) |
| Diarrhea† | 136 (39) | 96 (27) |
| Nausea† | 92 (26) | 75 (21) |
| Vomiting† | 43 (12) | 33 ( 9) |
| Abdominal pain† | 35 ( 10) | 22 ( 6) |
| Dry mouth | 25 ( 7) | 13 ( 4) |
| Musculoskeletal and connective tissue disorders | ||
| Muscle cramp | 118 (33) | 74 (21) |
| Back pain | 91 (26) | 65 (19) |
| Bone pain | 48 (14) | 39 (11) |
| Pain in limb | 42 (12) | 32 ( 9) |
| Nervous system disorders | ||
| Dizziness | 82 (23) | 59 (17) |
| Tremor | 75 (21) | 26 ( 7) |
| Dysgeusia | 54 (15) | 34 ( 10) |
| Hypoesthesia | 36 (10) | 25 ( 7) |
| Neuropathya | 23 ( 7) | 13 ( 4) |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 83 (24) | 60 (17) |
| Nasopharyngitis | 62 (18) | 31 ( 9) |
| Pharyngitis | 48 (14) | 33 ( 9) |
| Bronchitis | 40 (11) | 30 ( 9) |
| Infectionsb and infestations | ||
| Upper respiratory tract infection | 87 (25) | 55 (16) |
| Pneumonia† | 48 (14) | 29 ( 8) |
| Urinary tract infection | 30 ( 8) | 19 ( 5) |
| Sinusitis | 26 ( 7) | 16 ( 5) |
| Skin and subcutaneous system disorders | ||
| Rashc | 75 (21) | 33 ( 9) |
| Sweating increased | 35 ( 10) | 25 ( 7) |
| Dry skin | 33 ( 9) | 14 ( 4) |
| Pruritus | 27 ( 8) | 18 ( 5) |
| Metabolism and nutrition disorders | ||
| Anorexia | 55 (16) | 34 ( 10) |
| Hypokalemia | 48 (14) | 21 ( 6) |
| Hypocalcemia | 31 ( 9) | 10 ( 3) |
| Appetite decreased | 24 ( 7) | 14 ( 4) |
| Dehydration | 23 ( 7) | 15 ( 4) |
| Hypomagnesemia | 24 ( 7) | 10 ( 3) |
| Investigations | ||
| Weight decreased | 69 (20) | 52 (15) |
| Eye disorders | ||
| Blurred vision | 61 (17) | 40 (11) |
| Vascular disorders | ||
| Deep vein thrombosis* | 33 ( 9) | 15 ( 4) |
| Hypertension | 28 ( 8) | 20 ( 6) |
| Hypotension | 25 ( 7) | 15 ( 4) |
Table 4: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and with a ≥1% Difference in Proportion of Patients with MM between the REVLIMID/dexamethasone and Placebo/dexamethasone groups
| Body System Adverse Reaction |
REVLIMID/Dex (N=353) n (%) |
Placebo/Dex (N=350) n (%) |
| Blood and lymphatic system disorders | ||
| Neutropenia* | 118 (33) | 12 ( 3) |
| Thrombocytopenia† | 43 (12) | 22 ( 6) |
| Anemia† | 35 ( 10) | 20 ( 6) |
| Leukopenia | 14 ( 4) | < 1% |
| Lymphopenia | 10 ( 3) | 4 ( 1) |
| Febrile neutropenia* | 8 ( 2) | 0 ( 0) |
| General disorders and administration site conditions | ||
| Fatigue | 23 ( 7) | 17 ( 5) |
| Vascular disorders | ||
| Deep vein thrombosis* | 29 ( 8) | 12 ( 3) |
| Infections and infestations | ||
| Pneumonia† | 30 ( 8) | 19 ( 5) |
| Urinary tract infection | 5 ( 1) | < 1% |
| Metabolism and nutrition disorders | ||
| Hypokalemia | 17 ( 5) | 5 ( 1) |
| Hypocalcemia | 13 ( 4) | 6 ( 2) |
| Hypophosphatemia | 9 ( 3) | 0 ( 0) |
| Respiratory, thoracic and mediastinal disorders | ||
| Pulmonary embolism† | 14 ( 4) | < 1% |
| Respiratory distress† | 4 ( 1) | 0 ( 0) |
| Musculoskeletal and connective tissue disorders | ||
| Muscle weakness | 20 ( 6) | 10 ( 3) |
| Gastrointestinal disorders | ||
| Diarrhea† | 11 ( 3) | 4 ( 1) |
| Constipation | 7 ( 2) | < 1% |
| Nausea† | 6 ( 2) | < 1% |
| Cardiac disorders | ||
| Atrial fibrillation† | 13 ( 4) | 4 ( 1) |
| Tachycardia | 6 ( 2) | < 1% |
| Cardiac failure congestive† | 5 ( 1) | < 1% |
| Nervous system disorders | ||
| Syncope | 10 ( 3) | < 1% |
| Dizziness | 7 ( 2) | < 1% |
| Eye disorders | ||
| Cataract | 6 ( 2) | < 1% |
| Cataract unilateral | 5 ( 1) | 0 ( 0) |
| Psychiatric disorder | ||
| Depression | 10 ( 3) | 6 ( 2) |
Table 5: Serious Adverse Reactions Reported in ≥1% Patients and with a ≥1% Difference in Proportion of Patients with MM between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups
| Body System Adverse Reaction |
REVLIMID/Dex (N=353) n (%) |
Placebo/Dex (N=350) n (%) |
| Blood and lymphatic system disorders | ||
| Febrile neutropenia* | 6 ( 2) | 0 ( 0) |
| Vascular disorders | ||
| Deep vein thrombosis* | 26 ( 7) | 11 ( 3) |
| Infections and infestations | ||
| Pneumonia† | 33 ( 9) | 21 ( 6) |
| Respiratory, thoracic, and mediastinal disorders | ||
| Pulmonary embolism† | 13 ( 4) | < 1% |
| Cardiac disorders | ||
| Atrial fibrillation† | 11 ( 3) | < 1% |
| Cardiac failure congestive† | 5 ( 1) | 0 ( 0) |
| Nervous system disorders | ||
| Cerebrovascular accident† | 7 ( 2) | < 1% |
| Gastrointestinal disorders | ||
| Diarrhea† | 6 ( 2) | < 1% |
| Musculoskeletal and connective tissue disorders | ||
| Bone pain | 4 ( 1) | 0 ( 0) |
| For Tables 6, 7 and 8 above: * adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). † adverse reactions in which at least one resulted in a fatal outcome. |
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Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.
Venous And Arterial Thromboembolism
VTE and ATE are increased in patients treated with REVLIMID.
Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).
Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively.
Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/ dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively.
Other Adverse Reactions
After At Least One Prior Therapy for MM
In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported:
Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia
Cardiac disorders: bradycardia, myocardial infarction, angina pectoris
Endocrine disorders: hirsutism
Eye disorders: blindness, ocular hypertension
Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia
General disorders and administration site conditions: malaise
Investigations: liver function tests abnormal, alanine aminotransferase increased
Nervous system disorders: cerebral ischemia
Psychiatric disorders: mood swings, hallucination, loss of libido
Reproductive system and breast disorders: erectile dysfunction
Respiratory, thoracic and mediastinal disorders: cough, hoarseness
Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation
Myelodysplastic Syndromes
A total of 148 patients received at least 1 dose of 10 mg REVLIMID in the del 5q MDS clinical study. At least one adverse reaction was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID. The most frequently reported adverse reactions were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.
Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse reactions. The next most common adverse reactions observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 9 summarizes the adverse reactions that were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID. In the single-arm studies conducted, it is often not possible to distinguish adverse reactions that are drug-related and those that reflect the patient’s underlying disease.
Table 6: Summary of Adverse Reactions Reported in ≥ 5% of the REVLIMID Treated Patients in del 5q MDS Clinical Study
| Body System Adverse Reaction* |
10 mg Overall (N=148) |
| Patients with at least one adverse reaction | 148 (100) |
| Blood and Lymphatic System Disorders | |
| Thrombocytopenia | 91 (61) |
| Neutropenia | 87 (59) |
| Anemia | 17 (11) |
| Leukopenia | 12 (8) |
| Febrile Neutropenia | 8 (5) |
| Skin and Subcutaneous Tissue Disorders | |
| Pruritus | 62 (42) |
| Rash | 53 (36) |
| Dry Skin | 21 (14) |
| Contusion | 12 (8) |
| Night Sweats | 12 (8) |
| Sweating Increased | 10 (7) |
| Ecchymosis | 8 (5) |
| Erythema | 8 (5) |
| Gastrointestinal Disorders | |
| Diarrhea | 72 (49) |
| Constipation | 35 (24) |
| Nausea | 35 (24) |
| Abdominal Pain | 18 (12) |
| Vomiting | 15 (10) |
| Abdominal Pain Upper | 12 (8) |
| Dry Mouth | 10 (7) |
| Loose Stools | 9 (6) |
| Respiratory, Thoracic and Mediastinal Disorders | |
| Nasopharyngitis | 34 (23) |
| Cough | 29 (20) |
| Dyspnea | 25 (17) |
| Pharyngitis | 23 (16) |
| Epistaxis | 22 (15) |
| Dyspnea Exertional | 10 (7) |
| Rhinitis | 10 (7) |
| Bronchitis | 9 (6) |
| General Disorders and Administration Site Conditions | |
| Fatigue | 46 (31) |
| Pyrexia | 31 (21) |
| Edema Peripheral | 30 (20) |
| Asthenia | 22 (15) |
| Edema | 15 (10) |
| Pain | 10 (7) |
| Rigors | 9 (6) |
| Chest Pain | 8 (5) |
| Musculoskeletal and Connective Tissue Disorders | |
| Arthralgia | 32 (22) |
| Back Pain | 31 (21) |
| Muscle Cramp | 27 (18) |
| Pain in Limb | 16 (11) |
| Myalgia | 13 (9) |
| Peripheral Swelling | 12 (8) |
| Nervous System Disorders | |
| Dizziness | 29 (20) |
| Headache | 29 (20) |
| Hypoesthesia | 10 (7) |
| Dysgeusia | 9 (6) |
| Peripheral Neuropathy | 8 (5) |
| Infections and Infestations | |
| Upper Respiratory Tract Infection | 22 (15) |
| Pneumonia | 17 (11) |
| Urinary Tract Infection | 16 (11) |
| Sinusitis | 12 (8) |
| Cellulitis | 8 (5) |
| Metabolism and Nutrition Disorders | |
| Hypokalemia | 16 (11) |
| Anorexia | 15 (10) |
| Hypomagnesemia | 9 (6) |
| Investigations | |
| Alanine Aminotransferase Increased | 12 (8) |
| Psychiatric Disorders | |
| Insomnia | 15 (10) |
| Depression | 8 (5) |
| Renal and Urinary Disorders | |
| Dysuria | 10 (7) |
| Vascular Disorders | |
| Hypertension | 9 ( 6) |
| Endocrine Disorders | |
| Acquired Hypothyroidism | 10 (7) |
| Cardiac Disorders | |
| Palpitations | 8 (5) |
| * Body System and adverse reactions are coded using the MedDRA dictionary. Body System and adverse reactions are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. |
|
Table 7: Most Frequently Observed Grade 3 and 4 Adverse Reactions Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study
| Adverse Reactions† | 10 mg (N=148) |
| Patients with at least one Grade 3/4 AE | 131 (89) |
| Neutropenia | 79 (53) |
| Thrombocytopenia | 74 (50) |
| Pneumonia | 11 (7) |
| Rash | 10 (7) |
| Anemia | 9 (6) |
| Leukopenia | 8 (5) |
| Fatigue | 7 (5) |
| Dyspnea | 7 (5) |
| Back Pain | 7 (5) |
| Febrile Neutropenia | 6 (4) |
| Nausea | 6 (4) |
| Diarrhea | 5 (3) |
| Pyrexia | 5 (3) |
| Sepsis | 4 (3) |
| Dizziness | 4 (3) |
| Granulocytopenia | 3 (2) |
| Chest Pain | 3 (2) |
| Pulmonary Embolism | 3 (2) |
| Respiratory Distress | 3 (2) |
| Pruritus | 3 (2) |
| Pancytopenia | 3 (2) |
| Muscle Cramp | 3 (2) |
| Respiratory Tract Infection | 2 (1) |
| Upper Respiratory Tract Infection | 2 (1) |
| Asthenia | 2 (1) |
| Multi-organ Failure | 2 (1) |
| Epistaxis | 2 (1) |
| Hypoxia | 2 (1) |
| Pleural Effusion | 2 (1) |
| Pneumonitis | 2 (1) |
| Pulmonary Hypertension | 2 (1) |
| Vomiting | 2 (1) |
| Sweating Increased | 2 (1) |
| Arthralgia | 2 (1) |
| Pain in Limb | 2 (1) |
| Headache | 2 (1) |
| Syncope | 2 (1) |
| * Adverse reactions with frequency ≥1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2. † Adverse reactions are coded using the MedDRA dictionary. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. |
|
In other clinical studies of REVLIMID in MDS patients, the following serious adverse reactions (regardless of relationship to study drug treatment) not described in Table 9 or 10 were reported:
Blood and lymphatic system disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia, refractory anemia
Cardiac disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardiorespiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, ventricular dysfunction
Ear and labyrinth disorders: vertigo
Endocrine disorders: Basedow’s disease
Gastrointestinal disorders: gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage
General disorders and administration site conditions: disease progression, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death
Hepatobiliary disorders: hyperbilirubinemia, cholecystitis, acute cholecystitis, hepatic failure
Immune system disorders: hypersensitivity
Infections and infestations: infection bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection NOS, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis, Staphylococcal infection, urosepsis
Injury, poisoning and procedural complications: femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture, overdose, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture
Investigations: blood creatinine increased, hemoglobin decreased, liver function tests abnormal, troponin I increased
Metabolism and nutrition disorders: dehydration, gout, hypernatremia, hypoglycemia
Musculoskeletal and connective tissue disorders: arthritis, arthritis aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate
Neoplasms benign, malignant and unspecified: acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma, prostate cancer metastatic
Nervous system disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, spinal cord compression, subarachnoid hemorrhage, transient ischemic attack
Psychiatric disorders: confusional state
Renal and urinary disorders: renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass
Reproductive system and breast disorders: pelvic pain
Respiratory, thoracic and mediastinal disorders: bronchitis, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration, wheezing
Skin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosis
Vascular system disorders: deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosis
Mantle Cell Lymphoma
In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years.
Table 8 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse reactions, and 51 patients (38%) underwent at least one dose reduction due to adverse reactions. Twenty-six patients (19%) discontinued treatment due to adverse reactions.
Table 8: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma
| Body System Adverse Reaction |
All Adverse Reactions* (N=134) n (%) |
Grade 3/4 Adverse Reactions† (N=134) n (%) |
| General disorders and administration site conditions | ||
| Fatigue | 45 (34) | 9 (7) |
| Pyrexia‡ | 31 (23) | 3 (2) |
| Edema peripheral | 21 (16) | 0 |
| Asthenia‡ | 19 (14) | 4 (3) |
| General physical health deterioration | 3 (2) | 2 (1) |
| Gastrointestinal disorders | ||
| Diarrhea‡ | 42 (31) | 8 (6) |
| Nausea‡ | 40 (30) | 1 (<1) |
| Constipation | 21 (16) | 1 (<1) |
| Vomiting‡ | 16 (12) | 1 (<1) |
| Abdominal pain‡ | 13 (10) | 5 ( 4) |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 18 (13) | 2 (1) |
| Muscle spasms | 17 (13) | 1 (<1) |
| Arthralgia | 11 (8) | 2 (1) |
| Muscular weakness‡ | 8 (6) | 2 ( 1) |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 38 (28) | 1 (<1) |
| Dyspnea‡ | 24 (18) | 8 (6) |
| Pleural Effusion | 10 (7) | 2 (1) |
| Hypoxia | 3 (2) | 2 (1) |
| Pulmonary embolism | 3 (2) | 2 ( 1) |
| Respiratory distress‡ | 2 (1) | 2 (1) |
| Oropharyngeal pain | 13 (10) | 0 |
| Infections and infestations | ||
| Pneumonia§ ‡ | 19 (14) | 12 (9) |
| Upper respiratory tract infection | 17 (13) | 0 |
| Cellulitis‡ | 3 (2) | 2 (1) |
| Bacteremia‡ | 2 (1) | 2 (1) |
| Staphylococcal sepsis‡ | 2 (1) | 2 (1) |
| Urinary tract infection‡ | 5 (4) | 2 (1) |
| Skin and subcutaneous tissue disorders | ||
| Rash¶ | 30 (22) | 2 (1) |
| Pruritus | 23 (17) | 1 (<1) |
| Blood and lymphatic system disorders | ||
| Neutropenia | 65 (49) | 58 (43) |
| Thrombocytopenia# ‡ | 48 (36) | 37 (28) |
| Anemia‡ | 41 (31) | 15 (11) |
| Leukopenia‡ | 20 (15) | 9 (7) |
| Lymphopenia | 10 ( 7) | 5 (4) |
| Febrile neutropenia‡ | 8 (6) | 8 (6) |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 19 (14) | 1 (<1) |
| Hypokalemia | 17 (13) | 3 (2) |
| Dehydration‡ | 10 (7) | 4 (3) |
| Hypocalcemia | 4 (3) | 2 (1) |
| Hyponatremia | 3 (2) | 3 (2) |
| Renal and urinary disorders | ||
| Renal failure‡ | 5 (4) | 2 (1) |
| Vascular disorders | ||
| Hypotension§ ‡ | 9 (7) | 4 (3) |
| Deep vein thrombosis‡ | 5 (4) | 5 (4) |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | ||
| Tumor flare | 13 (10) | 0 |
| Squamous cell carcinoma of skin‡ | 4 (3) | 4 (3) |
| Investigations | ||
| Weight decreased | 17 (13) | 0 |
| # – All adverse reactions under Body System of Infections except for rare infections of Public Health interest will be considered listed. * MCL trial AEs – All treatment emergent AEs with ≥10% of subjects. † MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects. ‡ MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects. § Adverse reactions where at least one resulted in a fatal outcome. ¶ All adverse reactions under HLT of Rash will be considered listed. # Adverse reactions where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases). |
||
The following adverse reactions which have occurred in other indications including another MCL study and not described above have been reported (1%-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma.
Cardiac disorder: Cardiac failure
Ear and labyrinth disorders: Vertigo
General disorders and administration site conditions: Chills
Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes
Musculoskeletal and connective tissue disorders: Pain in extremity
Nervous system disorders: Dysgeusia, headache, neuropathy peripheral, lethargy
Psychiatric disorders: Insomnia
Skin and subcutaneous tissue disorders: Dry skin, night sweats
The following serious adverse reactions not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma.
Blood and lymphatic system disorders: Neutropenia
Cardiac disorder: Myocardial infarction (including acute MI), supraventricular tachycardia
Infections and infestations: Clostridium difficile colitis, sepsis
Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma
Respiratory, thoracic, and mediastinal disorders: Chronic obstructive pulmonary disease, pulmonary embolism
Follicular Lymphoma or Marginal Zone Lymphoma
The safety of REVLIMID/ rituximab was evaluated in 398 patients with either previously treated follicular lymphoma or marginal zone lymphoma in two clinical trials; AUGMENT (N=176) and MAGNIFY (N=222) [see Clinical Studies]. Subjects were 18 years or older in age, had an ECOG PS ≤2, ANC ≥1,000 cells/mm3 and platelets≥ 75,000/mm3 (unless secondary to bone marrow involvement by lymphoma), hemoglobin ≥8g/dL, AST and ALT ≤ 3× ULN (unless documented liver involvement with lymphoma, and creatinine clearance of ≥ 30mL/min. Subjects with active HIV, hepatitis B or C were not eligible.
In the AUGMENT trial, patients received REVLIMID 20 mg daily by mouth on days 1 – 21 of each 28 day cycle with rituximab 375 mg/m2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n=176) or placebo with rituximab 375 mg/m2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n=180) for up to 12 cycles. In the MAGNIFY trial, patients received REVLIMID 20 mg by mouth daily, days 1-21 of each 28 day cycle with rituximab 375 mg/m2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 3, 5, 7, 9 and 11 in the induction phase of the trial (n=222). In the AUGMENT trial, 88.1% of patients completed at least 6 cycles of REVLIMID/rituximab, and 71% of patients completed 12 cycles. In the ongoing MAGNIFY trial as of May 1, 2017, 62.2% of patients completed at least 6 cycles of REVLIMID/rituximab, and 30.6% of patients completed 12 cycles.
Across both clinical trials (AUGMENT and MAGNIFY), patients had a median age of 64.5 years (26 to 91); 49% were male; and 81% were White.
Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID/rituximab. Fatal adverse reactions (1 each) included cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. Serious adverse reactions occurred in 26% of patients receiving REVLIMID/rituximab in AUGMENT and 29% in MAGNIFY. The most frequent serious adverse reaction that occurred in ≥ 2.5% of patients in the REVLIMID/rituximab arm was febrile neutropenia (3%). Permanent discontinuation of REVLIMID or rituximab due to an adverse reaction occurred in 14.6% of patients in the REVLIMID/rituximab arm. The most common adverse reaction (in at least 1%) requiring permanent discontinuation of REVLIMID or rituximab was neutropenia (4.8%).
The most common adverse reactions occurring in at least 20% of subjects were; neutropenia (48%), fatigue (37%), diarrhea (32%), constipation (27%), nausea (21%), and cough (20%).
Table 9: All Grade Adverse Reactions ( ≥5%) or Grade 3/4 Adverse Reactions ( ≥1%) in Patients with FL and MZL with a Difference Between Arms of >1% When Compared to Control Arm in AUGMENT Trial
| Body System Adverse Reaction‡ |
All Adverse Reactions* | Grade 3 / 4 Adverse Reactions† | ||
| REVLIMID + Rituximab Arm (N=176) n (%) |
Rituximab + Placebo (Control Arm) (N=180) n (%) |
REVLIMID + Rituximab Arm (N=176) n (%) |
Rituximab + Placebo (Control Arm) (N=180) n (%) |
|
| Infections and infestations | ||||
| Upper respiratory tract infection | 32 (18) | 23 (13) | 2 (1.1) | 4 (2.2) |
| Influenza§ | 17 (10) | 8 (4.4) | 1 (< 1) | 0 (0) |
| Pneumonia¶,#,§ | 13 (7) | 6 (3.3) | 6 (3.4) | 4 (2.2) |
| Sinusitis | 13 (7) | 5 (2.8) | 0 (0) | 0 (0) |
| Urinary tract infection# | 13 (7) | 7 (3.9) | 1 (< 1) | 1 (< 1) |
| Bronchitis | 8 (4.5) | 6 (3.3) | 2 (1.1) | 0 (0) |
| Gastroenteritis# | 6 (3.4) | 4 (2.2) | 2 (1.1) | 0 (0) |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | ||||
| Tumor flare# | 19 (11) | 1 (< 1) | 1 (< 1) | 0 (0) |
| Blood and lymphatic disorders | ||||
| Neutropenia¶,#,§ | 102 (58) | 40 (22) | 88 (50) | 23 (13) |
| Leukopenia#,§ | 36 (20) | 17 (9) | 12 (7) | 3 (1.7) |
| Anemia¶,§ | 28 (16) | 8 (4.4) | 8 (4.5) | 1 (< 1) |
| Thrombocytopenia¶,#,§ | 26 (15) | 8 (4.4) | 4 (2.3) | 2 (1.1) |
| Lymphopenia | 8 (4.5) | 14 (8) | 5 (2.8) | 2 (1.1) |
| Febrile Neutropenia¶,#,§ | 5 (2.8) | 1 (< 1) | 5 (2.8) | 1 (< 1) |
| Metabolism and nutrition disorders | ||||
| Decreased Appetite | 23 (13) | 11 (6) | 2 (1.1) | 0 (0) |
| Hypokalemia§ | 14 (8) | 5 (2.8) | 4 (2.3) | 0 (0) |
| Hyperuricemia | 10 (6) | 8 (4.4) | 1 (< 1) | 1 (< 1) |
| Nervous system disorders | ||||
| Headache | 26 (15) | 17 (9) | 1 (< 1) | 0 (0) |
| Dizziness | 15 (9) | 9 (5) | 0 (0) | 0 (0) |
| Vascular disorders | ||||
| Hypotension§ | 9 (5) | 1 (< 1) | 1 (< 1) | 0 (0) |
| Thromboembolic events a,# |
8 (4.5) | 2 (1.1) | 4 (2.3) | 2 (1.1) |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough b | 43 (24) | 35 (19) | 1 (< 1) | 0 (0) |
| Dyspnea# | 19 (11) | 8 (4.4) | 2 (1.1) | 1 (< 1) |
| Oropharyngeal pain | 10 (6) | 8 (4.4) | 0 (0) | 0 (0) |
| Pulmonary Embolism¶,# |
4 (2.3) | 1 (< 1) | 4 (2.3) | 1 (< 1) |
| Chronic obstructive pulmonary disease# |
3 (1.7) | 0 (0) | 2 (1.1) | 0 (0) |
| Respiratory failure¶,# | 2 (1.1) | 1 (< 1) | 2 (1.1) | 0 (0) |
| Gastrointestinal disorders | ||||
| Diarrhea#,§ | 55 (31) | 41 (23) | 5 (2.8) | 0 (0) |
| Constipation | 46 (26) | 25 (14) | 0 (0) | 0 (0) |
| Abdominal painc ,# | 32 (18) | 20 (11) | 2 (1.1) | 0 (0) |
| Vomiting# | 17 (10) | 13 (7) | 0 (0) | 0 (0) |
| Dyspepsia | 16 (9) | 5 (2.8) | 0 (0) | 0 (0) |
| Stomatitis | 9 (5) | 7 (3.9) | 0 (0) | 0 (0) |
| Skin and subcutaneous tissue disorders | ||||
| Rash #,d | 39 (22) | 14 (8) | 5 (2.8) | 2 (1.1) |
| Pruritus #,e | 36 (20) | 9 (5) | 2 (1.1) | 0 (0) |
| Dry skin | 9 (5) | 6 (3.3) | 0 (0) | 0 (0) |
| Dermatitis acneiform | 8 (4.5) | 0 (0) | 2 (1.1) | 0 (0) |
| Musculoskeletal and connective tissue disorders | ||||
| Muscle Spasms | 23 (13) | 9 (5) | 1 (< 1) | 1 (< 1) |
| Pain in Extremity# | 8 (4.5) | 9 (5) | 2 (1) | 0 (0) |
| Renal disorders | ||||
| Acute Kidney Injury¶,#,Þ,§ | 3 (1.7) | 0 (0) | 2 (1.1) | 0 (0) |
| Cardiac disorders | ||||
| Supraventricular tachycardia¶,# |
2 (1.1) | 0 (0) | 2 (1.1) | 0 (0) |
| General disorders and administration site conditions | ||||
| Fatigue | 38 (22) | 33 (18) | 2 (1.1) | 1 (< 1) |
| Pyrexia¶,# | 37 (21) | 27 (15) | 1 (< 1) | 3 (1.7) |
| Asthenia#,§ | 24 (14) | 19 (11) | 2 (1.1) | 1 (< 1) |
| Edema Peripheral# | 23 (13) | 16 (9) | 0 (0) | 0 (0) |
| Chills | 14 (8) | 8 (4.4) | 0 (0) | 0 (0) |
| Malaise | 13 (7) | 10 (6) | 0 (0) | 0 (0) |
| Influenza like illness | 9 (5) | 7 (3.9) | 0 (0) | 0 (0) |
| Psychiatric disorders | ||||
| Insomnia | 14 (8) | 11 (6) | 0 (0) | 0 (0) |
| Investigations | ||||
| Alanine Aminotransferase Increased |
18 (10) | 15 (8) | 3 (1.7) | 1 (< 1) |
| WBC count decreased |
16 (9) | 13 (7) | 5 (2.8) | 2 (1.1) |
| Lymphocyte count decreased |
12 (7) | 12 (7) | 6 (3.4) | 2 (1.1) |
| Blood bilirubin increased |
10 (6) | 0 (0) | 0 (0) | 0 (0) |
| Weight Decreased | 12 (7) | 2 (1.1) | 0 (0) | 0 (0) |
| Note: Adverse reactions are coded to body system/adverse reaction using MedDRA 21. A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse reaction. * All treatment-emergent AEs in at least 5% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). † All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). ‡ Adverse Reactions for combined ADR terms (based on relevant TEAE PTs [per MedDRA version 21.0]): a “Thromboembolic events” combined term includes the following PTs: pulmonary embolism, deep vein thrombosis, cerebrovascular accident, embolism, and thrombosis. b “Cough” combined AE term includes the following PTs: cough and productive cough. c “Abdominal pain” combined AE term includes the following PTs: abdominal pain and abdominal pain upper. d “Rash” combined AE term includes the following PTs: rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, and rash generalized. e “Pruritus” combined AE term includes the following PTs: pruritus, pruritus generalized, rash pruritic, and pruritus allergic. § adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). ¶ All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). # Serious ADR reported. Þ adverse reactions in which at least one resulted in a fatal outcome. |
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Postmarketing Experience
The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Endocrine disorders: Hypothyroidism, hyperthyroidism
Hepatobiliary disorders: Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient abnormal liver laboratory tests
Immune system disorders: Angioedema, anaphylaxis, acute graft-versus-host disease (following allogeneic hematopoietic transplant), solid organ transplant rejection
Infections and infestations: Viral reactivation (such as hepatitis B virus and herpes zoster), progressive multifocal leukoencephalopathy (PML)
Neoplasms benign, malignant and unspecified (including cysts and polyps): Tumor lysis syndrome, tumor flare reaction
Respiratory, thoracic and mediastinal disorders: Pneumonitis
Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)
SRC: NLM .