Side Effects of Revlimid (lenalidomide)

Revlimid (lenalidomide) is an oral anti-cancer medication used to treat several types of lymphoma. Lenalidomide is similar to thalidomide, an older cancer medicine that, although effective, was associated with serious side effects. 

The exact mechanism through which Revlimid stops the growth of cancer cells is not understood. Revlimid stimulates or regulates the body's immune system to attack and kill cancer cells, reduces the formation of new blood vessels that supply nutrients to the cancer cells, and prevents or stops growth of the cancer. 

Laboratory studies have shown that Revlimid inhibits cancer growth and causes programmed cell death in certain types of cancers, including

• multiple myeloma,
• mantle cell lymphoma, and
• del (5q) myelodysplastic syndromes.

Common side effects of Revlimid include

• diarrhea,
• itching,
• rash,
• tiredness,
• fatigue,
• low white blood cell count (neutropenia),
• constipation,
• diarrhea,
• muscle cramps,
• anemia,
• fever,
• swelling in extremities nausea,
• back pain,
• upper respiratory tract infection,
• shortness of breath,
• dizziness,
• low blood platelets (thrombocytopenia),
• tremor, and
• rash.

Serious side effects of Revlimid are rare and may include

• increased risk of death in patients who have chronic lymphocytic leukemia (CLL);
• risk of new cancers;
• severe liver problems;
• serious skin reactions;
• tumor lysis syndrome, or
• TLS (caused by the fast breakdown of cancer cells);
• formation of blood clots in the arteries, veins, and lungs;
• serious birth defects or death of an unborn baby; and
• worsening of tumors.

Drug interactions of Revlimid include digoxin, because it increases the blood levels of digoxin which may lead to unwanted side effects. 

Due to the increased risk of forming blood clots in the arteries, veins, or lungs, Revlimid should be used cautiously in patients using erythropoietin-stimulating agents and estrogen-containing therapies. 

Revlimid is similar to thalidomide which is a known human teratogen that causes life-threatening birth defects or embryo-fetal death. It should not be used during pregnancy. 

A program called Revlimid REMS was developed to prevent fetal exposure to Revlimid. Patients, prescribers, and pharmacies must be registered in the Revlimid REMS programs to receive, prescribe, and dispense Revlimid. 

Females must not get pregnant for 4 weeks before starting Revlimid, while taking Revlimid, during any breaks in treatment, and for 4 weeks after stopping Revlimid. As Revlimid may pass into human semen, all males taking Revlimid must use a latex or synthetic condom during any sexual contact with a pregnant female or a female who can become pregnant. 

It is unknown if Revlimid is excreted in breast milk and its effect on the nursing infant. Revlimid should not be used by females who are breastfeeding.

Common side effects of lenalidomide are:

• diarrhea,
• itching,
• rash,
• tiredness,
• fatigue,
• neutropenia (a drop in white blood cell count),
• constipation,
• diarrhea,
• muscle cramp,
• anemia,
• fever,
• peripheral edema (swelling in the ankles, feet, or legs),
• nausea,
• back pain,
• upper respiratory tract infection,
• shortness of breath,
• dizziness,
• thrombocytopenia ( a drop in the platelet count),
• tremor, and
• rash.

Lenalidomide may cause some other rare but serious side effects. These include:

• increase risk of death in patients who have chronic lymphocytic leukemia (CLL);
• risk of new cancers;
• severe liver problems;
• serious skin reactions;
• tumor lysis syndrome, or TLS (caused by the fast breakdown of cancer cells);
• formation of blood clots in the arteries, veins, and lungs;
• serious birth defects or death of an unborn baby;
• and worsening of tumors.

The following clinically significant adverse reactions are described in detail in other sections of the prescribing information:

• Embryo-Fetal Toxicity
• Hematologic Toxicity
• Venous and Arterial Thromboembolism
• Increased Mortality in Patients with CLL
• Second Primary Malignancies
• Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone
• Hepatotoxicity
• Severe Cutaneous Reactions Including Hypersensitivity Reactions
• Tumor Lysis Syndrome
• Tumor Flare Reactions
• Impaired Stem Cell Mobilization
• Thyroid Disorders
• Early Mortality in Patients with MCL

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*

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*

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

Table 7: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and with a ≥1% Difference in Proportion of Patients with MM between the Revlimid/dexamethasone and Placebo/dexamethasone groups

Table 8: Serious Adverse Reactions Reported in ≥1% Patients and with a ≥1% Difference in Proportion of Patients with MM between the Revlimid/dexamethasone and Placebo/dexamethasone Groups

• Median duration of exposure among patients treated with Revlimid/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks.
• This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups Revlimid/dexamethasone vs. placebo/dexamethasone.

Venous And Arterial Thromboembolism

• VTE and ATE are increased in patients treated with Revlimid.
• Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the Revlimid/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups.
• In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively.
• Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%).
• Interruption of Revlimid treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms.
• Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the Revlimid/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups.
• In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).
• Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the Revlimid/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/dexamethasone group.
• Discontinuation due to MI (including acute) adverse reactions was 0.8% in Revlimid/dexamethasone group and none in the placebo/dexamethasone group.
• In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively.
• Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the Revlimid/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group.
• Discontinuation due to stroke (CVA) was 1.4% in Revlimid/ dexamethasone group and 0.3% in the placebo/dexamethasone group.
• In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively.

Other Adverse Reactions: After At Least One Prior Therapy For MM

In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported:

Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia

Cardiac disorders: bradycardia, myocardial infarction, angina pectoris

Endocrine disorders: hirsutism

Eye disorders: blindness, ocular hypertension

Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia

General disorders and administration site conditions: malaise

Investigations: liver function tests abnormal, alanine aminotransferase increased

Nervous system disorders: cerebral ischemia

Psychiatric disorders: mood swings, hallucination, loss of libido

Reproductive system and breast disorders: erectile dysfunction

Respiratory, thoracic and mediastinal disorders: cough, hoarseness

Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation

Myelodysplastic Syndromes

• A total of 148 patients received at least 1 dose of 10 mg Revlimid in the del 5q MDS clinical study.
• At least one adverse reaction was reported in all of the 148 patients who were treated with the 10 mg starting dose of Revlimid.
• The most frequently reported adverse reactions were related to
  • blood and lymphatic system disorders,
  • skin and subcutaneous tissue disorders,
  • gastrointestinal disorders, and
  • general disorders and administrative site conditions.
• Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse reactions.
• The next most common adverse reactions observed were
  • diarrhea (48.6%; 72/148),
  • pruritus (41.9%; 62/148),
  • rash (35.8%; 53/148) and
  • fatigue (31.1%; 46/148).
• Table 9 summarizes the adverse reactions that were reported in ≥ 5% of the Revlimid treated patients in the del 5q MDS clinical study.
• Table 10 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with Revlimid.
• In the single-arm studies conducted, it is often not possible to distinguish adverse reactions that are drug-related and those that reflect the patient's underlying disease.

Table 9: Summary of Adverse Reactions Reported in ≥5% of the Revlimid Treated Patients in del 5q MDS Clinical Study

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

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

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).
• 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, 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 on AUGMENT and 29% on 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

Postmarketing Experience

The following adverse drug reactions have been identified from the worldwide post-marketing experience with Revlimid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure

Endocrine disorders: Hypothyroidism, hyperthyroidism

Hepatobiliary disorders: Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient abnormal liver laboratory tests

Immune system disorders: Angioedema, 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)

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.

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.