Medical Editor: John P. Cunha, DO, FACOEP
What Is Revlimid?
Revlimid (lenalidomide) is a thalidomide analogue indicated for the treatment of patients with anemia and multiple myeloma. Revlimid is also used in patients with myelodysplastic syndrome and may also be used for other purposes not listed. Revlimid is available in generic form.
What Are Side Effects of Revlimid?
Revlimid may cause serious side effects including:
- hives,
- difficulty breathing,
- swelling of your face, lips, tongue, or throat,
- severe skin reaction,
- fever,
- sore throat,
- burning in your eyes,
- skin pain,
- red or purple skin rash that spreads and causes blistering and peeling,
- sudden numbness or weakness,
- severe headache,
- problems with speech or vision,
- shortness of breath,
- swelling or redness in your arm or leg,
- chest pain or pressure,
- pain spreading to your jaw or shoulder,
- sweating,
- chills,
- swollen gums,
- mouth sores,
- skin sores,
- easy bruising,
- unusual bleeding,
- swollen glands,
- low fever,
- rash,
- pain,
- lower back pain,
- blood in your urine,
- little or no urination,
- numbness or tingly feeling around your mouth,
- shortness of breath,
- confusion, and
- fainting
Get medical help right away, if you have any of the symptoms listed above.
Side effects of Revlimid include:
- nausea,
- diarrhea,
- constipation,
- dry or itchy skin,
- runny or stuffy nose,
- muscle or joint pain,
- headache, or
- tiredness
Serious side effects of Revlimid include:
- fetal risk,
- hematologic toxicity,
- deep vein thrombosis,
- pulmonary embolism,
- increased risk of death in people who have chronic lymphocytic leukemia (CLL),
- risk of new cancers (malignancies),
- serious allergic reactions and serious skin reactions,
- worsening of your tumor, and
- thyroid problems
Seek medical care or call 911 at once if you have the following serious side effects:
- Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
- Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheadedness, or passing out;
- Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.
Dosage for Revlimid?
The recommended starting dose of Revlimid is 10 mg daily.
What Drugs, Substances, or Supplements Interact with Revlimid?
Revlimid may interact with other drugs. Tell your doctor all medications and supplements you use.
Revlimid During Pregnancy and Breastfeeding
Revlimid is not recommended for use during pregnancy; it may harm a fetus. Women must avoid pregnancy for at least 4 weeks before beginning Revlimid therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Revlimid 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 while taking Revlimid and for up to 4 weeks after discontinuing Revlimid, even if they have undergone a successful vasectomy.
Additional Information
It is unknown if Revlimid passes into breast milk or how it might affect a nursing infant. Because of the potential for adverse reactions in breastfed infants, breastfeeding during treatment with Revlimid is not recommended.
Our Revlimid (lenalidomide) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
SLIDESHOW
Understanding Cancer: Metastasis, Stages of Cancer, and More See SlideshowGet emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning in your eyes, skin pain, red or purple skin rash that spreads and causes blistering and peeling).
Call your doctor at once if you have:
- signs of a stroke or blood clot--sudden numbness or weakness, severe headache, problems with speech or vision, shortness of breath, swelling or redness in your arm or leg;
- heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, sweating;
- liver problems--upper stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
- low blood cell counts--fever, chills, swollen gums, mouth sores, skin sores, easy bruising, unusual bleeding;
- signs of a tumor getting worse--swollen glands, low fever, rash, or pain; or
- signs of tumor cell breakdown--lower back pain, blood in your urine, little or no urinating; numbness or tingly feeling around your mouth; muscle weakness or tightness; feeling short of breath; confusion, fainting.
Common side effects may include:
- fever, cough, tiredness;
- itching, rash, swelling; or
- nausea, diarrhea, constipation.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
SIDE EFFECTS
The following clinically significant adverse reactions are described in detail in other sections of the prescribing information:
- Embryo-Fetal Toxicity [see BOX WARNING,WARNINGS AND PRECAUTIONS]
- Hematologic Toxicity [see BOX WARNING,WARNINGS AND PRECAUTIONS]
- Venous and Arterial Thromboembolism [see BOX WARNING,WARNINGS AND PRECAUTIONS]
- Increased Mortality in Patients with CLL [see WARNINGS AND PRECAUTIONS]
- Second Primary Malignancies [see WARNINGS AND PRECAUTIONS]
- Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Severe Cutaneous Reactions[see WARNINGS AND PRECAUTIONS]
- Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
- Tumor Flare Reactions [see WARNINGS AND PRECAUTIONS]
- Impaired Stem Cell Mobilization [see WARNINGS AND PRECAUTIONS]
- Thyroid Disorders [see WARNINGS AND PRECAUTIONS]
- Early Mortality in Patients with MCL [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity [see WARNINGS AND PRECAUTIONS]
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 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 Reactionsa | Grade 3/4 Adverse Reactionsb | ||||
| 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) |
| Pyrexiac | 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 painc | 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) | 40 ( 8) | 10 ( 2) | < 1% | < 1% | < 1% |
| Infections and infestations | ||||||
| Bronchitisc | 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 infectionc% f | 69 (13) | 53 ( 10) | 31 ( 6) | < 1% | 8 ( 1) | < 1% |
| Pneumonia[email protected] | 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) |
| Cellulitisc | < 5% | < 5% | < 5% | 8 ( 2) | < 1% | < 1% |
| Sepsis[email protected] | 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 disordersd | ||||||
| Anemia | 233 (44) | 193 (36) | 229 (42) | 97 (18) | 97 (18) | 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% |
| Dyspneac,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) |
| 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) |
| Gout e | < 5% | < 5% | < 5% | 8 ( 2) | 0 ( 0) | 0 ( 0) |
| Diabetes mellitus% e | < 5% | < 5% | < 5% | 8 ( 2) | < 1% | < 1% |
| Hypophosphatemia e | < 5% | < 5% | < 5% | 7 ( 1) | < 1% | < 1% |
| Hyponatremia% e | < 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 f | 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 thrombosisc% | 55 (10) | 39 ( 7) | 22 ( 4) | 30 ( 6) | 20 ( 4) | 15 ( 3) |
| Hypotensionc% | 51 ( 10) | 35 ( 6) | 36 ( 7) | 11 ( 2) | 8 ( 1) | 6 ( 1) |
| Injury, Poisoning, and Procedural Complications | ||||||
| Fall f | 43 ( 8) | 25 ( 5) | 25 ( 5) | < 1% | 6 ( 1) | 6 ( 1) |
| Contusion f | 33 ( 6) | 24 ( 4) | 15 ( 3) | < 1% | < 1% | 0 ( 0) |
| Eye disorders | ||||||
| Cataract | 73 (14) | 31 ( 6) | < 1% | 31 ( 6) | 14 ( 3) | < 1% |
| Cataract subcapsular e | < 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 fibrillationc | 37 ( 7) | 25 ( 5) | 25 ( 5) | 13 ( 2) | 9 ( 2) | 6 ( 1) |
| Myocardial infarction (including acute)c ,e | < 5% | < 5% | < 5% | 10 ( 2) | < 1% | < 1% |
| Renal and Urinary disorders | ||||||
| Renal failure (including acute)[email protected],f | 49 ( 9) | 54 (10) | 37 ( 7) | 28 ( 5) | 33 ( 6) | 29 ( 5) |
| Neoplasms benign, malignant and unspecified (Including cysts and polyps) | ||||||
| Squamous cell carcinomac e | < 5% | < 5% | < 5% | 8 ( 2) | < 1% | 0 ( 0) |
| Basal cell carcinomac e,f | < 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. a 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. b 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. c 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. d 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. e Footnote “a” not applicable. f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome. % - 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 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 |
||||||
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 5 summarizes the adverse reactions reported for the REVLIMID and placebo maintenance treatment arms.
Table 5: 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 a | Grade 3/4 Adverse Reactions b | All Adverse Reactions a | Grade 3/4 Adverse Reactions b | |||||
| 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 c % | 177 ( 79) | 94 ( 43) | 133 ( 59) | 73 ( 33) | 178 ( 61) | 33 ( 12) | 158 ( 54) | 21 ( 8) |
| Thrombocytopenia c % | 162 ( 72) | 101 ( 46) | 84 ( 38) | 67 ( 30) | 69 ( 24) | 29 ( 10) | 38 ( 13) | 8 ( 3) |
| Leukopenia c | 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 c d % | < 1% | 0 ( 0) | 0 ( 0) | 0 ( 0) | 12 ( 4) | < 1% | 7 ( 2) | < 1% |
| Febrile neutropenia c | 39 ( 17) | 34 ( 15) | 39 ( 17) | 34 ( 15) | 7 ( 2) | < 1% | 5 ( 2) | < 1% |
| Infections and infestations# | ||||||||
| Upper respiratory tract infection e | 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* c % | 31 ( 14) | 15 ( 7) | 23 ( 10) | 7 ( 3) | 50 ( 17) | 13 ( 5) | 27 ( 9) | 5 ( 2) |
| Bronchitis c | 10 ( 4) | 9 ( 4) | < 1% | 5 ( 2) | 139 ( 47) | 104 ( 37) | 4 ( 1) | < 1% |
| Nasopharyngitis e | 5 ( 2) | < 1% | 0 ( 0) | 0 ( 0) | 102 ( 35) | 84 ( 30) | < 1% | 0 ( 0) |
| Gastroenteritis c | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 66 ( 23) | 55 ( 20) | 6 ( 2) | 0 ( 0) |
| Rhinitis e | < 1% | 0 ( 0) | 0 ( 0) | 0 ( 0) | 44 ( 15) | 19 ( 7) | 0 ( 0) | 0 ( 0) |
| Sinusitis e | 8 ( 4) | 3 ( 1) | 0 ( 0) | 0 ( 0) | 41 ( 14) | 26 ( 9) | 0 ( 0) | < 1% |
| Influenza c | 8 ( 4) | 5 ( 2) | < 1% | < 1% | 39 ( 13) | 19 ( 7) | 3 ( 1) | 0 ( 0) |
| Lung infection c | 21 ( 9) | < 1% | 19 ( 8) | < 1% | 9 ( 3) | 4 ( 1) | < 1% | 0 ( 0) |
| Lower respiratory tract infection e | 13 ( 6) | 5 ( 2) | 6 ( 3) | 4 ( 2) | 4 ( 1) | 4 ( 1) | 0 ( 0) | < 1% |
| Infection c | 12 ( 5) | 6 ( 3) | 9 ( 4) | 5 ( 2) | 17 ( 6) | 5 ( 2) | 0 ( 0) | 0 ( 0) |
| Urinary tract infection c d e | 9 ( 4) | 5 ( 2) | 4 ( 2) | 4 ( 2) | 22 ( 8) | 17 ( 6) | < 1% | 0 ( 0) |
| Lower respiratory tract infection bacterial d | 6 ( 3) | < 1% | 4 ( 2) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) |
| Bacteremia d | 5 ( 2) | 0 ( 0) | 4 ( 2) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) |
| Herpes zoster c d | 11 ( 5) | 10 ( 5) | 3 ( 1) | < 1% | 29 ( 10) | 25 ( 9) | 6 ( 2) | < 1% |
| Sepsis* c d @ | < 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) |
| Nausea e | 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) |
| Constipation e | 12 ( 5) | 8 ( 4) | 0 ( 0) | 0 ( 0) | 37 ( 13) | 25 ( 9) | < 1% | 0 ( 0) |
| Abdominal pain e | 8 ( 4) | 7 ( 3) | < 1% | 4 ( 2) | 31 ( 11) | 15 ( 5) | < 1% | < 1% |
| Abdominal pain upper e | 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) |
| Pyrexia e | 17 ( 8) | 10 ( 5) | < 1% | < 1% | 60 ( 20) | 26 ( 9) | < 1% | 0 ( 0) |
| Skin and subcutaneous tissue disorders | ||||||||
| Dry skin e | 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 | ||||||||
| Paresthesia e | < 1% | 0 ( 0) | 0 ( 0) | 0 ( 0) | 39 ( 13) | 30 ( 11) | < 1% | 0 ( 0) |
| Peripheral neuropathy* e | 34 ( 15) | 30 ( 14) | 8 ( 4) | 8 ( 4) | 29 ( 10) | 15 ( 5) | 4 ( 1) | < 1% |
| Headache d | 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 d | 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 d | 16 ( 7) | 15 ( 7) | 13 ( 6) | 14 ( 6) | 0 ( 0) | < 1% | 0 ( 0) | 0 ( 0) |
| Musculoskeletal and connective tissue disorders | ||||||||
| Muscle spasms e | 0 ( 0) | < 1% | 0 ( 0) | 0 ( 0) | 98 ( 33) | 43 ( 15) | < 1% | 0 ( 0) |
| Myalgia e | 7 ( 3) | 8 ( 4) | 3 ( 1) | 5 ( 2) | 19 ( 6) | 12 ( 4) | < 1% | < 1% |
| Musculoskeletal pain e | < 1% | < 1% | 0 ( 0) | 0 ( 0) | 19 ( 6) | 11 ( 44) | 0 ( 0) | 0 ( 0) |
| Hepatobiliary disorders | ||||||||
| Hyperbilirubinemia e | 34 ( 15) | 19 ( 9) | 4 ( 2) | < 1% | 4 ( 1) | < 1% | < 1% | 0 ( 0) |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Cough e | 23 ( 10) | 12 ( 5) | 3 ( 1) | < 1% | 80 ( 27) | 56 ( 20) | 0 ( 0) | 0 ( 0) |
| Dyspnea c e | 15 ( 7) | 9 ( 4) | 8 ( 4) | 4 ( 2) | 17 ( 6) | 9 ( 3) | < 1% | 0 ( 0) |
| Rhinorrhea e | 0 ( 0) | 3 ( 1) | 0 ( 0) | 0 ( 0) | 15 ( 5) | 6 ( 2) | 0 ( 0) | 0 ( 0) |
| Pulmonary embolism c d e | 0 ( 0) | 0 ( 0) | 0 ( 0) | 0 ( 0) | 3 ( 1) | 0 ( 0) | < 1% | 0 ( 0) |
| Vascular disorders | ||||||||
| Deep vein thrombosis*c d % | 8 ( 4) | < 1% | 5 ( 2) | < 1% | 7 ( 2) | < 1% | 4 ( 1) | < 1% |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | ||||||||
| Myelodysplastic syndrome c d e | 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. a 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. b 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. c 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. d Footnote “a” not applicable for either study e Footnote “b” not applicable for either study @ -ADRs where at least one resulted in a fatal outcome % - 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) # - All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered listed *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 |
||||||||
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 6, 7, and 8 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.
Table 6: 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 7: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and with a ≥1% Difference in Proportion of Patients with MM between the
| 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 8: Serious Adverse Reactions Reported in ≥1% Patients and with a ≥1% Difference in Proportion of Patients with MM between the
| 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 resulted in a fatal outcome. % - 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). |
||
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 [see BOX WARNING And WARNINGS AND PRECAUTIONS]
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 9: Summary of Adverse Reactions Reported in ≥5% of the REVLIMID Treated Patients in del 5q MDS Clinical Study
| Body System Adverse Reaction a |
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 | 39 | (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) |
| a 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 10: Most Frequently Observed Grade 3 and 4 Adverse Reactions 1 Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study
| Adverse Reactions 2 | 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) |
| 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. 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, cardio-respiratory 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 11 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 11: 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 Reactions1 (N=134) n (%) |
Grade 3/4 Adverse Reactions2 (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 |
| 1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects. 2 -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. % - 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). # - All adverse reactions under Body System of Infections except for rare infections of Public Health interest will be considered listed. + - All adverse reactions under HLT of Rash will be considered listed. |
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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 (14.4)]. 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 ≤ 3x 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 12: 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 1 | Grade 3 / 4 Adverse Reactions 2 | ||
| 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 3,$,% | 13 (7) | 6 (3.3) | 6 (3.4) | 4 (2.2) |
| Sinusitis | 13 (7) | 5 (2.8) | 0 (0) | 0 (0) |
| Urinary tract infection$ | 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 3,$, % | 102 (58) | 40 (22) | 88 (50) | 23 (13) |
| Leukopenia $,% | 36 (20) | 17 (9) | 12 (7) | 3 (1.7) |
| Anemia 3,$ | 28 (16) | 8 (4.4) | 8 (4.5) | 1 (< 1) |
| Thrombocytopenia 3,$,% | 26 (15) | 8 (4.4) | 4 (2.3) | 2 (1.1) |
| Lymphopenia | 8 (4.5) | 14 (8) | 5 (2.8) | 2 (1.1) |
| Febrile Neutropenia 3,$,% | 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 | ||||
| Nervous system disorders | 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 3,$ | 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 3,$ | 2 (1.1) | 1 (< 1) | 2 (1.1) | 0 (0) |
| Gastrointestinal disorders | ||||
| Diarrhea $,% | 55 (31) | 41 (23) | 5 (2.8) | 0 (0) |
| Constipation | 46 (26) | 25 (14) | 0 (0) | 0 (0) |
| Abdominal pain c ,$ | 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 3,$,@,% | 3 (1.7) | 0 (0) | 2 (1.1) | 0 (0) |
| Cardiac disorders | ||||
| Supraventricular tachycardia 3,$ | 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 3,$ | 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. 1 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). 2 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). 3 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. @ - adverse reactions in which at least one resulted in a fatal outcome. % - 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 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. |
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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 [see WARNINGS AND PRECAUTIONS]
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)
DRUG INTERACTIONS
Digoxin
When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUCinf were increased by 14%. Periodically monitor digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, during administration of REVLIMID.
Concomitant Therapies That May Increase The Risk Of Thrombosis
Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID [see WARNINGS AND PRECAUTIONS].
Warfarin
Co-administration of multiple doses of REVLIMID (10 mg/day) with a single dose of warfarin (25 mg) had no effect on the pharmacokinetics of lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin.
Read the entire FDA prescribing information for Revlimid (Lenalidomide)
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