Lenalidomide
WARNINGS:
POTENTIAL FOR HUMAN BIRTH DEFECTS
HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA)
DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM
POTENTIAL FOR HUMAN BIRTH DEFECTS
WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS
LENALIDOMIDE IS AN ANALOGUE OF THALIDOMIDE. THALIDOMIDE IS A KNOWN HUMAN TERATOGEN THAT CAUSES SEVERE LIFE-THREATENING HUMAN BIRTH DEFECTS. IF LENALIDOMIDE IS TAKEN DURING PREGNANCY, IT MAY CAUSE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. FEMALES SHOULD BE ADVISED TO AVOID PREGNANCY WHILE TAKING REVLIMID® (lenalidomide).
Special Prescribing Requirements
BECAUSE OF THIS POTENTIAL TOXICITY AND TO AVOID FETAL EXPOSURE TO REVLIMID® (lenalidomide), REVLIMID® (lenalidomide) IS ONLY AVAILABLE UNDER A SPECIAL RESTRICTED DISTRIBUTION PROGRAM. THIS PROGRAM IS CALLED "RevAssist®." UNDER THIS PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM CAN PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, REVLIMID® (lenalidomide) MUST ONLY BE DISPENSED TO PATIENTS WHO ARE REGISTERED AND MEET ALL THE CONDITIONS OF THE RevAssist® PROGRAM.
PLEASE SEE THE FOLLOWING INFORMATION FOR PRESCRIBERS, FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS RESTRICTED DISTRIBUTION PROGRAM.
RevAssist® PROGRAM DESCRIPTION
Prescribers
REVLIMID® (lenalidomide) can be prescribed only by licensed prescribers who are registered in the RevAssist® program and understand the potential risk of teratogenicity if lenalidomide is used during pregnancy.
Effective contraception must be used by female patients of childbearing potential for at least 4 weeks before beginning REVLIMID® (lenalidomide) therapy, during REVLIMID® (lenalidomide) therapy, during dose interruptions and for 4 weeks following discontinuation of REVLIMID® (lenalidomide) therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal naturally for at least 24 consecutive months. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method. Females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature females who have not undergone a hysterectomy, have not had a bilateral oophorectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be females of childbearing potential.
Before prescribing REVLIMID® (lenalidomide), females of childbearing potential should have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL). The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID® (lenalidomide). A prescription for REVLIMID® (lenalidomide) for a female of childbearing potential must not be issued by the prescriber until negative pregnancy tests have been verified by the prescriber.
Male Patients: It is not known whether lenalidomide is present in the semen of patients receiving the drug. Therefore, males receiving REVLIMID® (lenalidomide) must always use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy.
Once treatment has started and during dose interruptions, pregnancy testing for females of childbearing potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her pregnancy test or in her menstrual bleeding. REVLIMID® (lenalidomide) treatment must be discontinued during this evaluation.
Pregnancy test results should be verified by the prescriber and the pharmacist prior to dispensing any prescription.
If pregnancy does occur during REVLIMID® (lenalidomide) treatment, REVLIMID® (lenalidomide) must be discontinued immediately.
Any suspected fetal exposure to REVLIMID® (lenalidomide) should be reported to the FDA via the MedWatch number at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Female Patients
REVLIMID® (lenalidomide) should be used in females of childbearing potential only when the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is unable to become pregnant while on lenalidomide therapy):
she understands and can reliably carry out instructions.
she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the RevAssist® program.
she has received and understands both oral and written warnings of the potential risks of taking lenalidomide during pregnancy and of exposing a fetus to the drug.
she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously, unless continuous abstinence from heterosexual sexual contact is the chosen method. Sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months), or had a bilateral oophorectomy are considered to be females of childbearing potential.
she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4 weeks prior to beginning lenalidomide therapy, during lenalidomide therapy, during dose interruptions and for 4 weeks after discontinuation of lenalidomide therapy.
she has had two negative pregnancy tests with a sensitivity of at least 50 mIU/mL, within 10-14 days and 24 hours prior to beginning therapy.
if the patient is between 12 and 18 years of age, her parent or legal guardian must have read the educational materials and agreed to ensure compliance with the above.
Male Patients
REVLIMID® (lenalidomide) should be used in sexually active males when the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS:
he understands and can reliably carry out instructions.
he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the RevAssist program.
he has received and understands both oral and written warnings of the potential risks of taking lenalidomide and exposing a fetus to the drug.
he has received both oral and written warnings of the risk of possible contraception failure and that it is unknown whether lenalidomide is present in semen. He has been instructed that he must always use a latex condom during any sexual contact with females of childbearing potential, even if he has undergone a successful vasectomy.
he acknowledges, in writing, his understanding of these warnings and of the need to use a latex condom during any sexual contact with females of childbearing potential, even if he has undergone a successful vasectomy. Females of childbearing potential are considered to be sexually mature females who have not undergone a hysterectomy, have not had a bilateral oophorectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at any time in the preceding 24 consecutive months).
if the patient is between 12 and 18 years of age, his parent or legal guardian must have read the educational materials and agreed to ensure compliance with the above.
HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA)
This drug is associated with significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. (See DOSAGE AND ADMINISTRATION)
DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM
This drug has demonstrated a significantly increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID® (lenalidomide) combination therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID® (lenalidomide) may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient's underlying risk factors.
You can get the information about REVLIMID® (lenalidomide) and the RevAssist® program on the internet at www.REVLIMID.com or by calling the manufacturer's toll free number 1-888-423-5436.
DRUG DESCRIPTION
REVLIMID® (lenalidomide), a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:
Chemical Structure of Lenalidomide
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.
REVLIMID® (lenalidomide) is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for oral administration. Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The 5 mg and 25 mg capsule shell contains gelatin, titanium dioxide and black ink. The 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink.
INDICATIONS
REVLIMID® (lenalidomide) is indicated for the treatment of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
REVLIMID® (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy.
DOSAGE AND ADMINISTRATION
Myelodysplastic Syndromes
The recommended starting dose of REVLIMID® (lenalidomide) is 10 mg daily with water. Patients should not break, chew or open the capsules. Dosing is continued or modified based upon clinical and laboratory findings.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it would be prudent to monitor renal function.
Dose Adjustments During Treatment
Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows:
Platelet counts
If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily
When Platelets Recommended Course
Fall to < 50,000/mcL Interrupt REVLIMID® treatment
Return to ? 50,000/mcL Resume REVLIMID® at 5 mg daily
Fall to 50% of the baseline value Interrupt REVLIMID® treatment
If baseline ? 60,000/mcL and returns to ? 50,000/mcL Resume REVLIMID® at 5 mg daily
If baseline < 60,000/mcL and returns to ? 30,000/mcL Resume REVLIMID® at 5 mg daily
If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily
< 30,000/mcL or < 50,000/mcL and platelet transfusions Interrupt REVLIMID® treatment
Return to ? 30,000/mcL (without hemostatic failure) Resume REVLIMID® at 5 mg daily
Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows:
If thrombocytopenia develops during treatment at 5 mg daily
When Platelets Recommended Course
< 30,000/mcL or < 50,000/mcL and platelet transfusions Interrupt REVLIMID® treatment
Return to ? 30,000/mcL (without hemostatic failure) Resume REVLIMID® at 5 mg every other day
Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows:
Neutrophil counts (ANC)+
If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily
If baseline ANC ? 1,000/mcL
When Neutrophils Recommended Course
Fall to < 750/mcL Interrupt REVLIMID® treatment
Return to ? 1,000/mcL Resume REVLIMID® at 5 mg daily
If baseline ANC < 1,000/mcL
When Neutrophils Recommended Course
Fall to < 500/mcL Interrupt REVLIMID® treatment
Return to ? 500/mcL Resume REVLIMID® at 5 mg daily
If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily
< 500/mcL for ? 7 days or < 500/mcL associated with fever ( ? 38.5°C) Interrupt REVLIMID® treatment
Return to ? 500/mcL Resume REVLIMID® at 5 mg daily
Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows:
If neutropenia develops during treatment at 5 mg daily
When Neutrophils Recommended Course
< 500/mcL for ? 7 days or < 500/mcL associated with fever ( ? 38.5°C) Interrupt REVLIMID® treatment
Return to ? 500/mcL Resume REVLIMID® at 5 mg every other day
+Absolute neutrophil count
Multiple Myeloma
The recommended starting dose of REVLIMID® (lenalidomide) is 25 mg/day with water orally administered as a single 25 mg capsule on Days 1-21 of repeated 28-day cycles. Patients should not break, chew or open the capsules. The recommended dose of dexamethasone is 40 mg/day on Days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg/day orally on Days 1-4 every 28 days. Dosing is continued or modified based upon clinical and laboratory findings.
The effect of substituting lesser strengths of REVLIMID® (lenalidomide) to achieve a 25 mg capsule dose is unknown.
Dose Adjustments During Treatment
Dose modification guidelines, as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to lenalidomide.
Platelet counts
Thrombocytopenia
When Platelets Recommended Course
Fall to < 30,000/mcL Interrupt REVLIMID® treatment, follow CBC weekly
Return to ? 30,000/mcL Restart REVLIMID® at 15 mg daily
For each subsequent drop < 30,000/mcL Interrupt REVLIMID® treatment
Return to ? 30,000/mcL Resume REVLIMID® at 5 mg less than the previous dose. Do not dose below 5 mg daily
Neutrophil counts (ANC)
Neutropenia
When Neutrophils Recommended Course
Fall to < 1000/mcL Interrupt REVLIMID® treatment, add G-CSF, follow CBC weekly
Return to ? 1,000/mcL and neutropenia is the only toxicity Resume REVLIMID® at 25 mg daily
Return to ? 1,000/mcL and if other toxicity Resume REVLIMID® at 15 mg daily
For each subsequent drop < 1,000/mcL Interrupt REVLIMID® treatment
Return to ? 1,000/mcL Resume REVLIMID® at 5 mg less than the previous dose. Do not dose below 5 mg daily
Starting Dose Adjustment for Renal Impairment
Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID® (lenalidomide) are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to nonmalignant conditions, lenalidomide starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min, and dialysis patients with creatinine clearances less than 7 mL/min, have not been studied. The recommendations for initial starting doses for patients with multiple myeloma (MM) and myelodysplastic syndromes (MDS) are as follows:
Starting Dose Adjustment for Renal ImpairmentCategory Renal Function (Cockcroft-Gault CLcr) Disease
Multiple Myeloma Myelodysplastic Syndromes
Moderate Renal Impairment 30 ? CLcr < 60 mL/min 10 mg Every 24 hours 5 mg Every 24 hours
Severe Renal Impairment CLcr < 30 ml/min (not requiring dialysis) 15 mg Every 48 hours 5 mg Every 48 hours
End Stage Renal Disease CLcr < 30 mL/min (requiring dialysis) 5 mg Once daily. Ondialysis days the dose should be administered following dialysis 5 mg3 times a week following each dialysis
After initiation of REVLIMID® (lenalidomide) therapy, subsequent REVLIMID® (lenalidomide) dose modification should be based on individual patient treatment tolerance, as described elsewhere in this section.
Other Grade 3/4 Toxicities
For other Grade 3/4 toxicities judged to be related to lenalidomide, hold treatment and restart at next lower dose level when toxicity has resolved to ? Grade 2.
SIDE EFFECTS
Myelodysplastic Syndromes
A total of 148 patients received at least 1 dose of 10 mg lenalidomide in the del 5q MDS clinical study. At least one adverse event was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID® (lenalidomide). The most frequently reported adverse events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions. (See PRECAUTIONS)
Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events observed. The next most common adverse events observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 4 summarizes the adverse events that were reported in ? 5% of the REVLIMID® (lenalidomide) treated patients in the del 5q MDS clinical study. Table 5 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID® (lenalidomide). In the single-arm studies conducted, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient's underlying disease.
Table 4: Summary of Adverse Events Reported in ? 5% of the REVLIMID® (lenalidomide) Treated Patients in del 5q MDS Clinical StudySystem organ class/Preferred term [a] 10 mg Overall
(N= 148)
Patients with at least one adverse event 148 (100.0)
Blood and Lymphatic System Disorders
Thrombocytopenia 91 (61.5)
Neutropenia 87 (58.8)
Anemia NOS 17 (11.5)
Leukopenia NOS 12 (8.1)
Febrile Neutropenia 8 (5.4)
Skin and Subcutaneous Tissue Disorders
Pruritus 62 (41.9)
Rash NOS 53 (35.8)
Dry Skin 21 (14.2)
Contusion 12 (8.1)
Night Sweats 12 (8.1)
Sweating Increased 10 (6.8)
Ecchymosis 8 (5.4)
Erythema 8 (5.4)
Gastrointestinal Disorders
Diarrhea NOS 72 (48.6)
Constipation 35 (23.6)
Nausea 35 (23.6)
Abdominal Pain NOS 18 (12.2)
Vomiting NOS 15 (10.1)
Abdominal Pain Upper 12 (8.1)
Dry Mouth 10 (6.8)
Loose Stools 9 (6.1)
Respiratory, Thoracic and Mediastinal Disorders
Nasopharyngitis 34 (23.0)
Cough 29 (19.6)
Dyspnea NOS 25 (16.9)
Pharyngitis 23 (15.5)
Epistaxis 22 (14.9)
Dyspnea Exertional 10 (6.8)
Rhinitis NOS 10 (6.8)
Bronchitis NOS 9 (6.1)
General Disorders and Administration Site Conditions
Fatigue 46 (31.1)
Pyrexia 31 (20.9)
Edema Peripheral 30 (20.3)
Asthenia 22 (14.9)
Edema NOS 15 (10.1)
Pain NOS 10 (6.8)
Rigors 9 (6.1)
Chest Pain 8 (5.4)
Musculoskeletal and Connective Tissue Disorders
Arthralgia 32 (21.6)
Back Pain 31 (20.9)
Muscle Cramp 27 (18.2)
Pain in Limb 16 (10.8)
Myalgia 13 (8.8)
Peripheral Swelling 12 (8.1)
Nervous System Disorders
Dizziness 29 (19.6)
Headache 29 (19.6)
Hypoesthesia 10 (6.8)
Dysgeusia 9 (6.1)
Peripheral Neuropathy NOS 8 (5.4)
Infections and Infestations
Upper Respiratory Tract Infection NOS 22 (14.9)
Pneumonia NOS 17 (11.5)
Urinary Tract Infection NOS 16 (10.8)
Sinusitis NOS 12 (8.1)
Cellulitis 8 (5.4)
Metabolism and Nutrition Disorders
Hypokalemia 16 (10.8)
Anorexia 15 (10.1)
Hypomagnesemia 9 (6.1)
Investigations
Alanine Aminotransferase Increased 12 (8.1)
Psychiatric Disorders
Insomnia 15 (10.1)
Depression 8 (5.4)
Vascular Disorders
Hypertension NOS 9 ( 6.1)
Renal and Urinary Disorders
Dysuria 10 (6.8)
Cardiac Disorders
Palpitations 8 (5.4)
Endocrine Disorders
Acquired Hypothyroidism 10 (6.8)
NOS, not otherwise specified
[a] System organ classes and preferred terms are coded using the MedDRA dictionary. System organ classes and preferred terms are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an AE is counted only once in the AE category.
Table 5: Most Frequently Observed Grade 3 and 4 Adverse Events[1] Regardless of Relationship to Study Drug TreatmentPreferred term [2] 10 mg
(N=148)
Patients with at least one Grade 3/4 AE 131 (88.5)
Neutropenia 79 (53.4)
Thrombocytopenia 74 (50.0)
Pneumonia NOS 11 (7.4)
Rash NOS 10 (6.8)
Anemia NOS 9 (6.1)
Leukopenia NOS 8 (5.4)
Fatigue 7 (4.7)
Dyspnea 7 (4.7)
Back Pain 7 (4.7)
Febrile Neutropenia 6 (4.1)
Nausea 6 (4.1)
Diarrhea NOS 5 (3.4)
Pyrexia 5 (3.4)
Sepsis 4 (2.7)
Dizziness 4 (2.7)
Granulocytopenia 3 (2.0)
Chest Pain 3 (2.0)
Pulmonary Embolism 3 (2.0)
Respiratory Distress 3 (2.0)
Pruritus 3 (2.0)
Pancytopenia 3 (2.0)
Muscle Cramp 3 (2.0)
Respiratory Tract Infection 2 (1.4)
Upper Respiratory Tract Infection 2 (1.4)
Asthenia 2 (1.4)
Multi-organ Failure 2 (1.4)
Epistaxis 2 (1.4)
Hypoxia 2 (1.4)
Pleural Effusion 2 (1.4)
Pneumonitis NOS 2 (1.4)
Pulmonary Hypertension NOS 2 (1.4)
Vomiting NOS 2 (1.4)
Sweating Increased 2 (1.4)
Arthralgia 2 (1.4)
Pain in Limb 2 (1.4)
Headache 2 (1.4)
Syncope 2 (1.4)
[1] Adverse events with frequency ? 1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2.
[2] Preferred Terms are coded using the MedDRA dictionary. A patient with multiple occurrences of an AE is counted only once in the Preferred Term category.
In other clinical studies of REVLIMID® (lenalidomide) in MDS patients, the following serious adverse events (regardless of relationship to study drug treatment) not described in Table 4 or 5 were reported:
Blood and lymphatic system disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression NOS, coagulopathy, hemolysis NOS, hemolytic anemia NOS, refractory anemia
Cardiac disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure NOS, cardio-respiratory arrest, cardiomyopathy NOS, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia NOS, cardiogenic shock, pulmonary edema NOS, supraventricular arrhythmia NOS, tachyarrhythmia, ventricular dysfunction
Ear and labyrinth disorders: vertigo
Endocrine disorders: Basedow's disease
Gastrointestinal disorders: gastrointestinal hemorrhage NOS, colitis ischemic, intestinal perforation NOS, rectal hemorrhage, colonic polyp, diverticulitis NOS, dysphagia, gastritis NOS, gastroenteritis NOS, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis NOS, perirectal abscess, small intestinal obstruction NOS, upper gastrointestinal hemorrhage
General disorders and administration site conditions: disease progression NOS, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death
Hepatobiliary disorders: hyperbilirubinemia, cholecystitis acute NOS, cholecystitis NOS, hepatic failure
Immune system disorders: hypersensitivity NOS
Infections and infestations: infection NOS, bacteremia, central line infection, clostridial infection NOS, ear infection NOS, Enterobacter sepsis, fungal infection NOS, herpes viral infection NOS, influenza, kidney infection NOS, Klebsiella sepsis, lobar pneumonia NOS, localized infection, oral infection, Pseudomonas infection NOS, septic shock, sinusitis acute NOS, sinusitis NOS, Staphylococcal infection, urosepsis
Injury, poisoning and procedural complications:femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis NOS, hip fracture, overdose NOS, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture
Investigations: blood creatinine increased, culture NOS negative, hemoglobin decreased, liver function tests NOS abnormal, troponin I increased
Metabolism and nutrition disorders: dehydration, gout, hypernatremia, hypoglycemia NOS
Musculoskeletal and connective tissue disorders: arthritis NOS, arthritis NOS aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate
Neoplasms benign, malignant and unspecified:acute leukemia NOS, acute myeloid leukemia NOS, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma NOS, prostate cancer metastatic
Nervous system disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine NOS, spinal cord compression NOS, subarachnoid hemorrhage NOS, transient ischemic attack
Psychiatric disorders: confusional state
Renal and urinary disorders: renal failure NOS, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass NOS
Reproductive system and breast disorders:pelvic pain NOS
Respiratory, thoracic and mediastinal disorders: bronchitis NOS, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration NOS, wheezing
Skin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosis
Vascular system disorders: deep vein thrombosis, hypotension NOS, aortic disorder, ischemia NOS, thrombophlebitis superficial, thrombosis
Multiple Myeloma
Data were evaluated from 691 patients in two studies who received at least one dose of REVLIMID® (lenalidomide)/dexamethasone (346 patients) or placebo/dexamethasone (345 patients).
In the REVLIMID® (lenalidomide)/dexamethasone treatment group, 151 patients (45%) underwent at least one dose interruption with or without a dose reduction of REVLIMID® (lenalidomide) compared to 21% in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID® (lenalidomide)/dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse events and Grade 3/4 adverse events were more frequent in patients who received the combination of REVLIMID® (lenalidomide)/dexamethasone compared to placebo/dexamethasone.
Table 6 summarizes the number and percentage of patients with Grade 1-4 adverse events reported in ? 10% of patients in either treatment group in Studies 1 and 2.
Table 6: Number of Patients with Adverse Events Reported in at Least 10% of Patients in Either Treatment Group in Studies 1 and 2 (Safety Population)System organ class/Preferred term Revlimid/Dex
(N=346) Placebo/Dex
(N=345)
n (%) n (%)
Subjects with at least one adverse event 346 (100.0) 344 (99.7)
Blood and Lymphatic System Disorders
Neutropenia 96 (27.7) 16 (4.6)
Anemia NOS 84 (24.3) 60 (17.4)
Thrombocytopenia 59 (17.1) 34 (9.9)
Eye Disorders
Vision Blurred 51 (14.7) 36 (10.4)
Gastrointestinal Disorders
Constipation 134 (38.7) 64 (18.6)
Diarrhea NOS 101 (29.2) 85 (24.6)
Nausea 76 (22.0) 66 (19.1)
Dyspepsia 48 (13.9) 46 (13.3)
Vomiting NOS 35 (10.1) 28 (8.1)
General Disorders and Administration Site Conditions
Fatigue 133 (38.4) 129 (37.4)
Asthenia 81 (23.4) 86 (24.9)
Pyrexia 80 (23.1) 67 (19.4)
Edema Peripheral 73 (21.1) 65 (18.8)
Infections and Infestations
Upper Respiratory Tract Infection NOS 47 (13.6) 43 (12.5)
Pneumonia NOS 39 (11.3) 26 (7.5)
Investigations
Weight Decreased 63 (18.2) 48 (13.9)
Metabolism and Nutrition Disorders
Hyperglycemia NOS 52 (15.0) 49 (14.2)
Anorexia 47 (13.6) 30 (8.7)
Hypokalemia 39 (11.3) 18 (5.2)
Musculoskeletal and Connective Tissue Disorders
Muscle Cramp 104 (30.1) 71 (20.6)
Back Pain 53 (15.3) 49 (14.2)
Muscle Weakness NOS 52 (15.0) 53 (15.4)
Arthralgia 36 (10.4) 51 (14.8)
Nervous System Disorders
Headache 74 (21.4) 74 (21.4)
Dizziness 72 (20.8) 53 (15.4)
Tremor 68 (19.7) 24 (7.0)
Dysgeusia 46 (13.3) 32 (9.3)
Paresthesia 40 (11.6) 43 (12.5)
Psychiatric Disorders
Insomnia 111 (32.1) 128 (37.1)
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea NOS 70 (20.2) 53 (15.4)
Cough 50 (14.5) 71 (20.6)
Skin and Subcutaneous Tissue Disorders
Rash NOS 55 (15.9) 28 (8.1)
Vascular Disorders
Deep Vein Thrombosisa 27 (7.8) 11 (3.2)
Pulmonary Embolisma 11 (3.2) 3 (0.9)
a See WARNINGS
Table 7 summarizes the Grade 3/4 adverse events reported in ? 2% of patients in either treatment group in Studies 1 and 2.
Table 7: Adverse Events with NCI CTC Grades 3 and 4 Reported In At Least 2% of Patients by Preferred Term and Treatment Group - (Safety Population)System organ class/Preferred term Revlimid/Dex (N=346) Placebo/Dex (N=345)
Grade 3 Grade 4 Grade 3 Grade 4
n (%) n (%) n (%) n (%)
Patients with at least one Grade 3 or 4 AE 225 (65.0) 25 (7.2) 186 (53.9) 31 (9.0)
Blood and Lymphatic System Disorders
Neutropenia 60 (17.3) 13 (3.8) 8 (2.3) 2 (0.6)
Thrombocytopenia 31 (9.0) 4 (1.2) 16 (4.6) 3 (0.9)
Anemia NOS 25 (7.2) 4 (1.2) 10 (2.9) 2 (0.6)
Leukopenia NOS 12 (3.5) 0 (0.0) 1 (0.3) 0 (0.0)
Lymphopenia 8 (2.3) 0 (0.0) 4 (1.2) 0 (0.0)
Cardiac Disorders
Atrial Fibrillation 9 (2.6) 1 (0.3) 2 (0.6) 1 (0.3)
Gastrointestinal Disorders
Diarrhea NOS 8 (2.3) 0 (0.0) 2 (0.6) 0 (0.0)
Constipation 7 (2.0) 0 (0.0) 1 (0.3) 0 (0.0)
General Disorders and Administration Site Conditions
Fatigue 20 (5.8) 1 (0.3) 13 (3.8) 0 (0.0)
Asthenia 14 (4.0) 0 (0.0) 16 (4.6) 0 (0.0)
Pyrexia 4 (1.2) 0 (0.0) 8 (2.3) 0 (0.0)
Infections and Infestations
Pneumonia NOS 18 (5.2) 4 (1.2) 15 (4.3) 3 (0.9)
Metabolism and Nutrition Disorders
Hyperglycemia NOS 22 (6.4) 4 (1.2) 19 (5.5) 7 (2.0)
Hypocalcemia 8 (2.3) 5 (1.4) 4 (1.2) 1 (0.3)
Hypokalemia 9 (2.6) 1 (0.3) 5 (1.4) 0 (0.0)
Musculoskeletal and Connective Tissue Disorders
Muscle Weakness NOS 18 (5.2) 0 (0.0) 10 (2.9) 0 (0.0)
Nervous System Disorders
Syncope 7 (2.0) 0 (0.0) 3 (0.9) 0 (0.0)
Neuropathy NOS 7 (2.0) 0 (0.0) 2 (0.6) 0 (0.0)
Psychiatric Disorders
Depression 9 (2.6) 0 (0.0) 5 (1.4) 1 (0.3)
Confusional State 6 (1.7) 0 (0.0) 8 (2.3) 0 (0.0)
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea NOS 6 (1.7) 3 (0.9) 7 (2.0) 1 (0.3)
Vascular Disorders
Deep Vein Thrombosisa 23 (6.6) 1 (0.3) 9 (2.6) 1 (0.3)
Pulmonary Embolisma 2 (0.6) 9 (2.6) 1 (0.3) 2 (0.6)
a See WARNINGS
Thrombotic Events
(See WARNINGS)
In the pooled analysis, thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, thrombosis, and intracranial venous sinus thrombosis, were reported more frequently in patients treated with REVLIMID® (lenalidomide)/dexamethasone combination. The number of patients experiencing a thrombotic event in the combination arm were 43/346 (12%) compared with those in the placebo/dexamethasone arm 14/345 (4%).
In these and other clinical studies of REVLIMID® (lenalidomide) in patients with multiple myeloma, the following serious adverse events (considered related to study drug treatment) not described in Table 7 were reported:
Blood and lymphatic system disorders: pancytopenia, anemia NOS aggravated
Cardiac disorders: cardiac failure congestive, atrial flutter, pulmonary edema
Endocrine disorders: adrenal insufficiency NOS, acquired hypothyroidism
Eye disorders:blindness
Gastrointestinal disorders: abdominal pain NOS, colitis pseudomembranous, gastritis NOS, gastrointestinal hemorrhage NOS, peptic ulcer hemorrhage, upper gastrointestinal hemorrhage
General disorders and administration site conditions: performance status decreased
Hepatobiliary disorders: hepatic failure, hepatitis toxic
Infections and infestations: bronchopneumonia NOS, cellulitis, Pneumocystis carinii pneumonia, sepsis NOS, bursitis infective NOS, cellulitis staphylococcal, Enterobacter bacteremia, Escherichia sepsis, gastrointestinal infection NOS, herpes zoster, herpes zoster ophthalmic, infection NOS, lung infection NOS, neutropenic sepsis, pneumonia bacterial NOS, pneumonia cytomegaloviral, pneumonia pneumococcal, pneumonia primary atypical, pneumonia staphylococcal, septic shock, streptococcal sepsis, subacute endocarditis, urinary tract infection NOS
Investigations: International normalized ratio increased, weight decreased, blood creatinine increased, body temperature increased, c-reactive protein increased, hemoglobin decreased, white blood cell count decreased
Metabolism and nutrition disorders: dehydration, diabetes mellitus NOS, diabetes with hyperosmolarity, diabetic ketoacidosis
Musculoskeletal and connective tissue disorders: myopathy steroid, back pain, myopathy
Nervous system disorders: dizziness, memory impairment, brain edema, cerebral infarction, cerebral ischemia, cerebrovascular accident, encephalitis NOS, intracranial hemorrhage NOS, intracranial venous sinus thrombosis NOS, leukoencephalopathy, somnolence, tremor
Psychiatric disorders: mental status changes, delirium, delusion NOS, insomnia, psychotic disorder NOS
Renal and urinary disorders: Fanconi syndrome acquired, hematuria, renal failure acute, renal failure NOS, renal tubular necrosis, urinary retention
Respiratory, thoracic and mediastinal disorders: bronchopneumopathy, hypoxia
Skin and subcutaneous tissue disorders: rash NOS, skin desquamation NOS
Vascular system disorders:phlebitis NOS, venous thrombosis NOS limb, circulatory collapse, hypertension NOS, hypotension NOS, orthostatic hypotension, peripheral ischemia