Does Revlimid (lenalidomide) cause side effects?

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

Common side effects of Revlimid include

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.

What are the important side effects of lenalidomide?

Common side effects of lenalidomide are:

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.

Revlimid (lenalidomide) side effects list for healthcare professionals

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

The most frequently reported Grade 3 or 4 reactions included

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 ReactionsaGrade 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)
Asthenia150(28)123 (23)124 (23)41 (8)33 (6)32 (6)
Pyrexiac114 (21)102(19)76 (14)13 (2)7 (1)7 (1)
Non-cardiac chest pain f29 (5)31 (6)18 (3)<1%< 1%< 1%
Gastrointestinal disorders
Diarrhea242 (45)208 (39)89 (16)21 (4)18 (3)8 (1)
Abdominal pain%f109 (20)78 (14)60 (11)7 (1)9 (2)< 1%
Dyspepsia f57 (11)28 (5)36 (7)<1%< 1%0 (0)
Musculoskeletal and connective tissue disorders
Back painc170 (32)145 (27)116(21)37 (7)34 (6)28 (5)
Muscle spasms f109 (20)102(19)61 (11)< 1%< 1%< 1%
Arthralgia f101 (19)71(13)66 (12)9 (2)8 (1)8 (1)
Bone pain f87 (16)77 (14)62(11)16 (3)15 (3)14 (3)
Pain in extremity f79 (15)66 (12)61 (11)8 (2)8 (1)7 (1)
Musculoskeletal pain f67(13)59(11)36 (7)< 1%< 1%< 1%
Musculoskeletal chest pain f60 (11)51 (9)39 (7)6 (1)< 1%< 1%
Muscular weakness f43 (8)35 (6)29 (5)< 1%8 (1)< 1%
Neck pain f40 (8)19 (4)10 (2)< 1%< 1%< 1%
Infections and infestations
Bronchitisc90 (17)59(11)43 (8)9 (2)6 (1)< 1%
Nasopharyngitis f80 (15)54 (10)33 (6)0 (0)0 (0)0 (0)
Urinary tract infection f76 (14)63 (12)41 (8)8 (2)8 (1)< 1%
Upper respiratory tract infectionc% f69 (13)53 (10)31 (6)< 1%8 (1)< 1%
Pneumoniac@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 f33 (6)23 (4)15 (3)< 1%< 1%0 (0)
Gastroenteritis f32 (6)17 (3)13 (2)0 (0)< 1%< 1%
Lower respiratory tract infection29 (5)14 (3)16 (3)10 (2)< 1%< 1%
Rhinitis f29 (5)24 (4)14 (3)0 (0)0 (0)0 (0)
Cellulitisc< 5%< 5%< 5%8 (2)< 1%< 1%
Sepsisc@33 (6)26 (5)18 (3)26 (5)20 (4)13 (2)
Nervous system disorders
Headache f75 (14)52( 10)56 (10)< 1%< 1%< 1%
Dysgeusia f39 (7)45 (8)22 (4)< 1%0 (0.0)< 1%
Blood and lymphatic system disordersd
Anemia233 (44)193 (36)229(42)97(18)85 (16)102 (19)
Neutropenia186(35)178 (33)328 (61)148 (28)143 (26)243 (45)
Thrombocytopenia104(20)100(19)135 (25)44 (8)43 (8)60(11)
Febrile neutropenia7 (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
Coughf121(23)94 (17)68(13)< 1%< 1%< 1%
Dyspneac,e117 (22)89 (16)113 (21)30 (6)22 (4)18 (3)
Epistaxis f32 (6)31 (6)17 (3)< 1%< 1%0 (0)
Oropharyngeal pain f30 (6)22 (4)14 (3)0 (0)0 (0)0 (0)
Dyspnea exertional e27 (5)29 (5)< 5%6 (1)< 1%0 (0)
Metabolism and nutrition disorders
Decreased appetite123 (23)115 (21)72(13)14 (3)7 (1)< 1%
Hypokalemia%91 (17)62(11)38 (7)35 (7)20 (4)11 (2)
Hyperglycemia62 (12)52 (10)19 (4)28 (5)23 (4)9 (2)
Hypocalcemia57 (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
Rash139(26)151 (28)105 (19)39 (7)38 (7)33 (6)
Pruritus f47 (9)49 (9)24 (4)< 1%< 1%< 1%
Psychiatric disorders
Insomnia147 (28)127 (24)53( 10)< 1%6 (1)0 (0)
Depression58(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 f43 (8)25 (5)25 (5)< 1%6 (1)6 (1)
Contusion f33 (6)24 (4)15 (3)< 1%< 1%0 (0)
Eye disorders
Cataract73 (14)31 (6)< 1%31 (6)14 (3)< 1%
Cataract subcapsular e< 5%< 5%< 5%7 (1)0 (0)0 (0)
Investigations
Weight decreased72 (14)78 (14)48 (9)11 (2)< 1%< 1%
Cardiac disorders
Atrial fibrillationc37 (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)c@,f49 (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
  • 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 ReactionMaintenance Study 1Maintenance Study 2
All Adverse Reactions aGrade 3/4 Adverse Reactions bAll Adverse Reactions aGrade 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 c51 (23)25( 11)45 (20)22 (10)93 (32)21 (8)71 (24)5 (2)
Anemia47 (21)27 (12)23 (10)18 (8)26 (9)15 (5)11 (4)3 (1)
Lymphopenia40 (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 c39 (17)34 (15)39 (17)34 (15)7 (2)< 1%5 (2)< 1%
Infections and infestations#
Upper respiratory tract infection e60 (27)35 (16)7 (3)9 (4)32 (11)18 (6)< 1%0 (0)
Neutropenic infection40 (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 c10 (4)9 (4)< 1%5 (2)139 (47)104 (37)4 (1)< 1%
Nasopharyngitis e5 (2)< 1%0 (0)0 (0)102 (35)84 (30)< 1%0 (0)
Gastroenteritis c0 (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 e8 (4)3 (1)0 (0)0 (0)41 (14)26 (9)0 (0)< 1%
Influenza c8 (4)5 (2)< 1%< 1%39 (13)19 (7)3 (1)0 (0)
Lung infectionc21 (9)< 1%19 (8)< 1%9 (3)4 (1)< 1%0 (0)
Lower respiratory tract infection e13 (6)5 (2)6 (3)4 (2)4 (1)4 (1)0 (0)< 1%
Infection c12 (5)6 (3)9 (4)5 (2)17 (6)5 (2)0 (0)0 (0)
Urinary tract infection c d e9 (4)5 (2)4 (2)4 (2)22 (8)17 (6)< 1%0 (0)
Lower respiratory tract infection bacterial d6 (3)< 1%4 (2)0 (0)0 (0)0 (0)0 (0)0 (0)
Bacteremia d5 (2)0 (0)4 (2)0 (0)0 (0)0 (0)0 (0)0 (0)
Herpes zoster c d11 (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
Diarrhea122 (54)83 (38)22 (10)17 (8)114 (39)34 (12)7 (2)0 (0)
Nausea e33 (15)22 (10)16 (7)10 (5)31 (11)28( 10)0 (0)0 (0)
Vomiting17 (8)12 (5)8 (4)5 (2)16 (5)15 (5)< 1%0 (0)
Constipation e12 (5)8 (4)0 (0)0 (0)37 (13)25 (9)< 1%0 (0)
Abdominal pain e8 (4)7 (3)< 1%4 (2)31 (11)15 (5)< 1%< 1%
Abdominal pain upper e0 (0)0 (0)0 (0)0 (0)20 (7)12 (4)< 1%0 (0)
General disorders and administration site conditions
Asthenia0 (0)< 1%0 (0)0 (0)87 (30)53 (19)10 (3)< 1%
Fatigue51 (23)30 (14)21 (9)9 (4)31 (11)15 (5)3 (1)0 (0)
Pyrexia e17 (8)10 (5)< 1%< 1%60 (20)26 (9)< 1%0 (0)
Skin and subcutaneous tissue disorders
Dry skin e9 (4)4 (2)0 (0)0 (0)31 (11)21 (8)0 (0)0 (0)
Rash71 (32)48 (22)11 (5)5 (2)22 (8)17 (6)3 (1)0 (0)
Pruritus9 (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* e34 (15)30 (14)8 (4)8 (4)29 (10)15 (5)4 (1)< 1%
Headache d11 (5)8 (4)5 (2)< 1%25 (9)21 (8)0 (0)0 (0)
Investigations
Alanine aminotransferase increased16 (7)3 (1)8 (4)0 (0)5 (2)5 (2)0 (0)< 1%
Aspartate aminotransferase increased d13 (6)5 (2)6 (3)0 (0)< 1%5 (2)0 (0)0 (0)
Metabolism and nutrition disorders
Hypokalemia24 (11)13 (6)16 (7)12 (5)12 (4)< 1%< 1%0 (0)
Dehydration9 (4 )5 (2)7 (3)3 (1)0 (0)0 (0)0 (0)0 (0)
Hypophosphatemiad16 (7)15 (7)13 (6)14 (6)0 (0)< 1%0 (0)0 (0)
Musculoskeletal and connective tissue disorders
Muscle spasms e0 (0)< 1%0 (0)0 (0)98 (33)43 (15)< 1%0 (0)
Myalgia e7 (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 e34 (15)19 (9)4 (2)< 1%4 (1)< 1%< 1%0 (0)
Respiratory, thoracic and mediastinal disorders
Coughe23 (10)12 (5)3 (1)< 1%80 (27)56 (20)0 (0)0 (0)
Dyspnea c e15 (7)9 (4)8 (4)4 (2)17 (6)9 (3)< 1%0 (0)
Rhinorrhea e0 (0)3 (1)0 (0)0 (0)15 (5)6 (2)0 (0)0 (0)
Pulmonary embolism c d e0 (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 e5 (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)
[email protected]111 (31)83 (24)
[email protected]76 (22)37 (11)
Leukopenia28 (8)4 (1)
Lymphopenia19 (5)5 (1)
General disorders and administration site conditions
Fatigue155 (44)146 (42)
Pyrexia97 (27)82 (23)
Peripheral edema93 (26)74 (21)
Chest pain29 (8)20 (6)
Lethargy24 (7)8 (2)
Gastrointestinal disorders
Constipation143 (41)74 (21)
[email protected]136 (39)96 (27)
[email protected]92 (26)75(21)
[email protected]43 (12)33 (9)
Abdominal [email protected]35( 10)22 (6)
Dry mouth25 (7)13 (4)
Musculoskeletal and connective tissue disorders
Muscle cramp118 (33)74 (21)
Back pain91 (26)65(19)
Bone pain48(14)39 (11)
Pain in limb42 (12)32 (9)
Nervous system disorders
Dizziness82 (23)59 (17)
Tremor75(21)26 (7)
Dysgeusia54(15)34 (10)
Hypoesthesia36 (10)25 (7)
Neuropathya23 (7)13 (4)
Respiratory, thoracic and mediastinal disorders
Dyspnea83 (24)60 (17)
Nasopharyngitis62 (18)31 (9)
Pharyngitis48 (14)33 (9)
Bronchitis40 (11)30 (9)
Infectionsb and infestations
Upper respiratory tract infection87 (25)55 (16)
Pneumonia®48 (14)29 (8)
Urinary tract infection30 (8)19 (5)
Sinusitis26 (7)16 (5)
Skin and subcutaneous system disorders
Rashc75 (21)33 (9)
Sweating increased35 (10)25 (7)
Dry skin33 (9)14 (4)
Pruritus27 (8)18 (5)
Metabolism and nutrition disorders
Anorexia55 (16)34( 10)
Hypokalemia48 (14)21 (6)
Hypocalcemia31 (9)10 (3)
Appetite decreased24 (7)14 (4)
Dehydration23 (7)15 (4)
Hypomagnesemia24 (7)10 (3)
Investigations
Weight decreased69 (20)52 (15)
Eye disorders
Blurred vision61 (17)40(11)
Vascular disorders
Deep vein thrombosis%33 (9)15 (4)
Hypertension28 (8)20 (6)
Hypotension25 (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 Revlimid/dexamethasone and Placebo/dexamethasone groups

Body System
Adverse Reaction
Revlimid/Dex
(N=353)
n (%)
Placebo/Dex
(N=350)
n (%)
Blood and lymphatic system disorders
Neutropenia%118(33)12 (3)
[email protected]43 (12)22 (6)
[email protected]35 (10)20 (6)
Leukopenia14 (4)< 1%
Lymphopenia10 (3)4 (1)
Febrile neutropenia%8 (2)0 (0)
General disorders and administration site conditions
Fatigue23 (7)17 (5)
Vascular disorders
Deep vein thrombosis%29 (8)12 (3)
Infections and infestations
[email protected]30 (8)19 (5)
Urinary tract infection5 (1)< 1%
Metabolism and nutrition disorders
Hypokalemia17 (5)5 (1)
Hypocalcemia13 (4)6 (2)
Hypophosphatemia9 (3)0 (0)
Respiratory, thoracic and mediastinal disorders
Pulmonary [email protected]14 (4)< 1%
Respiratory distress®4 (1)0 (0)
Musculoskeletal and connective tissue disorders
Muscle weakness20 (6)10 (3)
Gastrointestinal disorders
[email protected]11 (3)4 (1)
Constipation7 (2)< 1%
[email protected]6 (2)< 1%
Cardiac disorders
Atrial [email protected]13 (4)4 (1)
Tachycardia6 (2)< 1%
Cardiac failure [email protected]5 (1)< 1%
Nervous system disorders
Syncope10 (3)< 1%
Dizziness7 (2)< 1%
Eye disorders
Cataract6 (2)< 1%
Cataract unilateral5 (1)0 (0)
Psychiatric disorder
Depression10 (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 Revlimid/dexamethasone and Placebo/dexamethasone Groups

Body System
Adverse Reaction
Revlimid/Dex
(N=353)
n (%)
Placebo/Dex
(N=350)
n (%)
Blood and lymphatic system disorders
Febrile neutropenia%6 (2)0 (0)
Vascular disorders
Deep vein thrombosis%26 (7)11 (3)
Infections and infestations
[email protected]33 (9)21 (6)
Respiratory, thoracic, and mediastinal disorders
Pulmonary [email protected]13 (4)< 1%
Cardiac disorders
Atrial [email protected]11 (3)< 1%
Cardiac failure [email protected]5 (1)0 (0)
Nervous system disorders
Cerebrovascular [email protected]7 (2)< 1%
Gastrointestinal disorders
Diarrhea @6 (2)< 1%
Musculoskeletal and connective tissue disorders
Bone pain4 (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

  • 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 reaction148 (100)
Blood and Lymphatic System Disorders
Thrombocytopenia91 (61)
Neutropenia87 (59)
Anemia17 (11)
Leukopenia12 (8)
Febrile Neutropenia8 (5)
Skin and Subcutaneous Tissue Disorders
Pruritus62 (42)
Rash53 (36)
Dry Skin21 (14)
Contusion12 (8)
Night Sweats12 (8)
Sweating Increased10 (7)
Ecchymosis8 (5)
Erythema8 (5)
Gastrointestinal Disorders
Diarrhea72 (49)
Constipation35 (24)
Nausea35 (24)
Abdominal Pain18 (12)
Vomiting15 (10)
Abdominal Pain Upper12 (8)
Dry Mouth10 (7)
Loose Stools9 (6)
Respiratory, Thoracic and Mediastinal Disorders
Nasopharyngitis34 (23)
Cough29 (20)
Dyspnea25 (17)
Pharyngitis23 (16)
Epistaxis22 (15)
Dyspnea Exertional10 (7)
Rhinitis10 (7)
Bronchitis9 (6)
General Disorders and Administration Site Conditions
Fatigue46 (31)
Pyrexia31 (21)
Edema Peripheral30 (20)
Asthenia22 (15)
Edema15 (10)
Pain10 (7)
Rigors9 (6)
Chest Pain8 (5)
Musculoskeletal and Connective Tissue Disorders
Arthralgia32 (22)
Back Pain31 (21)
Muscle Cramp27 (18)
Pain in Limb16 (11)
Myalgia13 (9)
Peripheral Swelling12 (8)
Nervous System Disorders
Dizziness29 (20)
Headache29 (20)
Hypoesthesia10 (7)
Dysgeusia9 (6)
Peripheral Neuropathy8 (5)
Infections and Infestations
Upper Respiratory Tract Infection22 (15)
Pneumonia17 (11)
Urinary Tract Infection16 (11)
Sinusitis12 (8)
Cellulitis8 (5)
Metabolism and Nutrition Disorders
Hypokalemia16 (11)
Anorexia15 (10)
Hypomagnesemia9 (6)
Investigations
Alanine Aminotransferase Increased12 (8)
Psychiatric Disorders
Insomnia15 (10)
Depression8 (5)
Renal and Urinary Disorders
Dysuria10 (7)
Vascular Disorders
Hypertension9 (6)
Endocrine Disorders
Acquired Hypothyroidism10 (7)
Cardiac Disorders
Palpitations8 (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 Reactions210 mg
(N=148)
Patients with at least one Grade 3/4 AE131 (89)
Neutropenia79 (53)
Thrombocytopenia74 (50)
Pneumonia11 (7)
Rash10 (7)
Anemia9 (6)
Leukopenia8 (5)
Fatigue7 (5)
Dyspnea7 (5)
Back Pain7 (5)
Febrile Neutropenia6 (4)
Nausea6 (4)
Diarrhea5 (3)
Pyrexia5 (3)
Sepsis4 (3)
Dizziness4 (3)
Granulocytopenia3 (2)
Chest Pain3 (2)
Pulmonary Embolism3 (2)
Respiratory Distress3 (2)
Pruritus3 (2)
Pancytopenia3 (2)
Muscle Cramp3 (2)
Respiratory Tract Infection2 (1)
Upper Respiratory Tract Infection2 (1)
Asthenia2 (1)
Multi-organ Failure2 (1)
Epistaxis2 (1)
Hypoxia2 (1)
Pleural Effusion2 (1)
Pneumonitis2 (1)
Pulmonary Hypertension2 (1)
Vomiting2 (1)
Sweating Increased2 (1)
Arthralgia2 (1)
Pain in Limb2 (1)
Headache2 (1)
Syncope2 (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
Fatigue45 (34)9 (7)
Pyrexia$31 (23)3 (2)
Edema peripheral21(16)0
Asthenia$19 (14)4 (3)
General physical health deterioration3 (2)2 (1)
Gastrointestinal disorders
Diarrhea$42 (31)8 (6)
Nausea$40 (30)1 (<1)
Constipation21 (16)1 (<1)
Vomiting$16 (12)1 (<1)
Abdominal pain$13 (10)5 (4)
Musculoskeletal and connective tissue disorders
Back pain18(13)2 (1)
Muscle spasms17(13)1 (<1)
Arthralgia11 (8)2 (1)
Muscular weakness$8 (6)2 (1)
Respiratory, thoracic and mediastinal disorders
Cough38 (28)1 (<1)
Dyspnea$24 (18)8 (6)
Pleural Effusion10 (7)2 (1)
Hypoxia3 (2)2 (1)
Pulmonary embolism3 (2)2 (1)
Respiratory distress$2 (1)2 (1)
Oropharyngeal pain13 (10)0
Infections and infestations
[email protected] $19 (14)12 (9)
Upper respiratory tract infection17 (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)
Pruritus23 (17)1 (<1)
Blood and lymphatic system disorders
Neutropenia65(49)58(43)
Thrombocytopenia%$48 (36)37 (28)
Anemia$41 (31)15 (11)
Leukopenia$20 (15)9 (7)
Lymphopenia10 (7)5 (4)
Febrile neutropenia$8 (6)8 (6)
Metabolism and nutrition disorders
Decreased appetite19 (14)1 (<1)
Hypokalemia17 (13)3 (2)
Dehydration$10 (7)4 (3)
Hypocalcemia4 (3)2 (1)
Hyponatremia3 (2)3 (2)
Renal and urinary disorders
Renal failure$5 (4)2 (1)
Vascular disorders
[email protected]$9 (7)4 (3)
Deep vein thrombosis$5 (4)5 (4)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Tumor flare13 (10)0
Squamous cell carcinoma of skin$4 (3)4 (3)
Investigations
Weight decreased17 (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.

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

Body System
Adverse Reaction*
All Adverse Reactions1Grade 3 / 4 Adverse Reactions2
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 infection32 (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)
Sinusitis13 (7)5 (2.8)0 (0)0 (0)
Urinary tract infection$13 (7)7(3.9)1 (< 1)1 (< 1)
Bronchitis8 (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)
Lymphopenia8 (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 Appetite23 (13)11 (6)2 (1.1)0 (0)
Hypokalemia %14 (8)5 (2.8)4(2.3)0 (0)
Hyperuricemia10 (6)8 (4.4)1 (< 1)1 (< 1)
Nervous system disorders
Headache26 (15)17 (9)1 (< 1)0 (0)
Dizziness15 (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 b43 (24)35(19)1 (< 1)0 (0)
Dyspnea $19 (11)8 (4.4)2 (1.1)1 (< 1)
Oropharyngeal pain10 (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)
Constipation46 (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)
Dyspepsia16 (9)5 (2.8)0 (0)0 (0)
Stomatitis9 (5)7 (3.9)0 (0)0 (0)
Skin and subcutaneous tissue disorders
Rash $d39 (22)14 (8)5 (2.8)2 (1.1)
Pruritus $,e36 (20)9 (5)2 (1.1)0 (0)
Dry skin9 (5)6 (3.3)0 (0)0 (0)
Dermatitis acneiform8 (4.5)0 (0)2 (1.1)0 (0)
Musculoskeletal and connective tissue disorders
Muscle Spasms23 (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[email protected]%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
Fatigue38 (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)
Chills14 (8)8 (4.4)0 (0)0 (0)
Malaise13 (7)10 (6)0 (0)0 (0)
Influenza like illness9 (5)7 (3.9)0 (0)0 (0)
Psychiatric disorders
Insomnia14 (8)11 (6)0 (0)0 (0)
Investigations
Alanine Aminotransferase Increased18 (10)15 (8)3 (1.7)1 (< 1)
WBC count decreased16 (9)13 (7)5 (2.8)2 (1.1)
Lymphocyte count decreased12 (7)12 (7)6 (3.4)2 (1.1)
Blood bilirubin increased10 (6)0 (0)0 (0)0 (0)
Weight Decreased12 (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: pruritius, pruritus generalized, rash pruritic, and pruritus allergic.

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)

What drugs interact with Revlimid (lenalidomide)?

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.

Summary

Revlimid (lenalidomide) is an oral anti-cancer medication used to treat several types of lymphoma. 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. 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. Revlimid should not be used by females who are breastfeeding.

Treatment & Diagnosis

Medications & Supplements

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Medically Reviewed on 10/2/2020
References
FDA Prescribing Information

Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.
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