Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS

The following adverse reactions are described in detail in other sections of the prescribing information: o Embryo-Fetal Toxicity [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] o Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] o Venous and arterial thromboembolism [see Warnings and Precautions (5.4)] o Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] o Second Primary Malignancies [see Warnings and Precautions (5.6)] o Hepatotoxicity [see Warnings and Precautions (5.7)] o Allergic Reactions [see Warnings and Precautions (5.8)] o Tumor lysis syndrome [see Warnings and Precautions (5.9)] o Tumor flare reactions [see Warnings and Precautions (5.10)] o Cataract [see Warnings and Precautions (5.11)] o Peripheral Neuropathy [see Warnings and Precautions (5.12)]

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.

6.1 Clinical Trials Experience in Multiple Myeloma

Summary of the safety profile in newly diagnosed multiple myeloma in patients treated with lenalidomide in combination with low dose dexamethasone:

The serious adverse reactions observed more frequently (≥5%) with lenalidomide in combination with low dose dexamethasone (Rd and Rd18) than with melphalan, prednisone and thalidomide (MPT) were:
• Pneumonia (9.8%)
• Renal failure (including acute) (6.3%)

The adverse reactions observed more frequently with Rd or Rd18 than MPT were: diarrhoea (45.5%), fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), and muscle spasms (20.5%).

Summary of the safety profile in newly diagnosed multiple myeloma patients treated with lenalidomide in combination with melphalan and prednisone:

The serious adverse reactions observed more frequently (≥5%) with melphalan prednisone, and lenalidomide followed by lenalidomide maintenance (MPR+R) or melphalan prednisone, and lenalidomide followed by placebo (MPR+p) than melphalan, prednisone and placebo followed by placebo (MPp+p) were:
• Febrile neutropenia (6.0%)
• Anaemia (5.3%)

The adverse reactions observed more frequently with MPR+R or MPR+ p than MPp+p were: neutropenia (83.3%), anaemia (70.7%), thrombocytopenia (70.0%), leukopenia (38.8%), constipation (34.0%), diarrhoea (33.3%), rash (28.9%), pyrexia (27.0%), peripheral oedema (25.0%), cough (24.0%), decreased appetite (23.7%), and asthenia (22.0%).Summary of the safety profile in multiple myeloma patients with at least one prior therapy 
In two Phase III placebo-controlled studies, 353 patients with multiple myeloma were exposed to the lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination.
The most serious adverse reactions observed more frequently in lenalidomide/dexamethasone than placebo/dexamethasone combination were:
•     Venous thromboembolism (deep vein thrombosis, pulmonary embolism)
•     Grade 4 neutropenia.

The observed adverse reactions which occurred more frequently with lenalidomide and dexamethasone than placebo and dexamethasone in pooled multiple myeloma clinical trials (MM-009 and MM-010) were fatigue (43.9%), neutropenia (42.2%), constipation (40.5%), diarrhoea (38.5%), muscle cramp (33.4%), anaemia (31.4%), thrombocytopenia (21.5%), and rash (21.2%).


Mantle cell lymphoma
The overall safety profile of Revlimid in patients with mantle cell lymphoma is based on data from 254 patients from a Phase II randomized, controlled study MCL-002.
Additionally, ADRs from supportive study MCL-001 have been included in table 3.

The serious adverse reactions observed more frequently in Study MCL-002 (with a difference of at least 2 percentage points) in the lenalidomide arm compared with the control arm were: • Neutropenia (3.6%)
• Pulmonary embolism (3.6%)
• Diarrhoea (3.6%)

The most frequently observed adverse reactions which occurred more frequently in the lenalidomide arm compared with the control arm in Study MCL-002 were neutropenia (50.9%), anaemia (28.7%), diarrhoea (22.8%), fatigue (21.0%), constipation (17.4%), pyrexia (16.8%), and rash (including dermatitis allergic) (16.2%).

In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths.
Patients with high tumour burden at baseline are at increased risk of early death, 16/81 (20%) early deaths in the lenalidomide arm and 2/28 (7%) early deaths in the control arm. Within 52 weeks corresponding figures were 32/81 (39.5%) and 6/28 (21%).
During treatment cycle 1, 11/81 (14%) patients with high tumour burden were withdrawn from therapy in the lenalidomide arm vs. 1/28 (4%) in the control group. The main reason for treatment withdrawal for patients with high tumour burden during treatment cycle 1 in the lenalidomide arm was adverse events, 7/11 (64%). High tumour burden was defined as at least one lesion ≥5 cm in diameter or 3 lesions ≥3 cm.

Tabulated summary of adverse reactions for combination therapy

The adverse reactions observed in patients treated for multiple myeloma are listed below by system organ class and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

The following table is derived from data gathered during the multiple myeloma studies with combination therapy. The data were not adjusted according to the greater duration of treatment in the lenalidomide/dexamethasone versus the placebo/dexamethasone arms in the pivotal multiple myeloma studies.
Adverse reactions have been included under the appropriate category in the table below according to the highest frequency observed in any of the main clinical trials.

Table 1: ADRs reported in clinical studies in patients with multiple myeloma treated with lenalidomide in combination with dexamethasone, or with melphalan and prednisone
System Organ        All ADRs/Frequency                           Grade 3−4 ADRs/Frequency Class
/ Preferred Term
Infections          Very Common                                  Common and Infestations    Pneumonia, Upper respiratory tract           Pneumonia, Bacterial, viral infection, Bacterial, viral and fungal       and fungal infections infections (including opportunistic          (including opportunistic infections), Nasopharyngitis, Pharyngitis,   infections), Sepsis, Bronchitis Bronchitis
Common
Sepsis, Sinusitis
Neoplasms           Uncommon                                     Common Benign,             Basal cell carcinoma                         Acute myeloid leukaemia, Malignant and       Squamous skin cancer^*                       Myelodysplastic syndrome, Unspecified (incl                                                Squamous cell carcinoma of cysts and polyps)                                                skin** Uncommon
T-cell type acute leukaemia,
Basal cell carcinoma, Tumour lysis syndrome
Blood and           Very Common                                  Very Common Lymphatic           Neutropenia, Thrombocytopenia, Anaemia,      Neutropenia, System Disorders Haemorrhagic disorder, Leucopenias              Thrombocytopenia, Anaemia, Common                                       Leucopenias
Febrile neutropenia, Pancytopenia            Common
Uncommon                                     Febrile neutropenia,
Haemolysis, Autoimmune haemolytic            Pancytopenia, Haemolytic anaemia, Haemolytic anaemia                  anaemia
Uncommon
Hypercoagulation,
Coagulopathy
Immune System       Uncommon
Disorders           Hypersensitivity
Endocrine           Common
Disorders           Hypothyroidism
Metabolism and      Very Common                                  Common Nutrition           Hypokalaemia,    Hyperglycaemia,             Hypokalaemia, Disorders           Hypocalcaemia, Decreased appetite, Weight Hyperglycaemia, decreased                                    Hypocalcaemia, Diabetes
Common                                       mellitus, Hypophosphataemia, Hypomagnesaemia, Hyperuricaemia,             Hyponatraemia,
Dehydration                                  Hyperuricaemia, Gout,
Decreased appetite, Weight decreased
System Organ       All ADRs/Frequency                             Grade 3−4 ADRs/Frequency Class
/ Preferred Term
Psychiatric        Very Common                                    Common Disorders          Depression, Insomnia                           Depression, Insomnia Uncommon
Loss of libido
Nervous System     Very Common                                    Common Disorders          Peripheral neuropathies (excluding motor       Cerebrovascular accident, neuropathy), Dizziness, Tremor, Dysgeusia,     Dizziness, Syncope
Headache                                       Uncommon
Common                                         Intracranial haemorrhage, Ataxia, Balance impaired                       Transient ischaemic attack, Cerebral ischaemia
Eye Disorders      Very Common                                    Common Cataracts, Blurred vision                      Cataract
Common                                         Uncommon
Reduced visual acuity                          Blindness
Ear and            Common
Labyrinth          Deafness (Including Hypoacusis), Tinnitus
Disorders
Cardiac            Common                                         Common Disorders          Atrial fibrillation, Bradycardia               Myocardial infarction Uncommon                                       (including acute) , Atrial Arrhythmia, QT prolongation, Atrial flutter,   fibrillation, Congestive cardiac Ventricular extrasystoles                      failure, Tachycardia, Cardiac failure, Myocardial ischaemia
Vascular           Very Common                                    Very Common Disorders          Venous thromboembolic events,                  Venous thromboembolic predominantly deep vein thrombosis and         events, predominantly deep pulmonary embolism                             vein thrombosis and
Common                                         pulmonary embolism
Hypotension, Hypertension, Ecchymosis          Common
Vasculitis
Uncommon
Ischemia, Peripheral ischemia,
Intracranial venous sinus thrombosis
Respiratory,       Very Common                                    Common Thoracic           Dyspnoea, Epistaxis                            Respiratory distress, Dyspnoea and Mediastinal
Disorders
System Organ       All ADRs/Frequency                           Grade 3−4 ADRs/Frequency Class
/ Preferred Term
Gastrointestinal   Very Common                                  Common Disorders          Diarrhoea, Constipation, Abdominal pain,     Diarrhoea, Constipation, Nausea, Vomiting, Dyspepsia                  Abdominal pain, Nausea,
Common                                       Vomiting
Gastrointestinal haemorrhage (including rectal haemorrhage, haemorrhoidal haemorrhage, peptic ulcer haemorrhage and gingival bleeding), Dry mouth, Stomatitis,
Dysphagia
Uncommon
Colitis, Caecitis
Hepatobiliary      Common                                       Common Disorders          Abnormal liver function tests                Cholestasis, Abnormal liver Uncommon                                     function tests
Hepatic failure                              Uncommon
Hepatic failure
Skin and           Very Common                                  Common Subcutaneous       Rashes, Pruritus                             Rashes Tissue Disorders   Common
Urticaria, Hyperhidrosis, Dry skin, Skin hyperpigmentation, Eczema, Erythema
Uncommon
Skin discolouration, Photosensitivity reaction
Musculoskeletal    Very Common                                  Common and Connective     Muscle spasms, Bone pain,                    Muscular weakness, Bone Tissue Disorders   Musculoskeletal and connective tissue pain   pain and discomfort, Arthralgia                   Uncommon
Common                                       Joint swelling
Muscular weakness, Joint swelling, Myalgia
Renal and          Very Common                                  Uncommon Urinary            Renal failure (including acute)              Renal tubular necrosis Disorders          Common
Haematuria, Urinary retention,
Urinary incontinence
Uncommon
Acquired Fanconi syndrome
Reproductive       Common
System and         Erectile dysfunction
Breast Disorders
General            Very Common                                 Common Disorders          Fatigue, Oedema (including peripheral       Fatigue, Pyrexia, Asthenia and                oedema), Pyrexia, Asthenia, Influenza like
Administration     illness syndrome (including pyrexia, cough,
Site Conditions    myalgia, musculoskeletal pain, headache and rigors)
Common
Chest pain, Lethargy
System Organ                  All ADRs/Frequency                                                    Grade 3−4 ADRs/Frequency Class
/ Preferred Term
Investigations                Common
C-reactive protein increased
Injury, Poisoning             Common and Procedural                Fall, Contusion^
Complications
* Squamous skin cancer was reported in clinical trials in previously treated myeloma patients with lenalidomide/dexamethasone compared to controls
** Squamous cell carcinoma of skin was reported in a clinical trial in newly diagnosed myeloma patients with lenalidomide/dexamethasone compared to controls
Venous and Arterial Thromboembolism [see Warnings and Precautions (5.4)] 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 (0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade ¾) in the placebo/dexamethasone group in the 2 studies in patients with at least 1 prior therapy, with discontinuations due to PE adverse reactions were at comparable rates between groups. In the NDMM study (MM-020), 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 low, 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 Multiple Myeloma In these 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, reduced visual acuity
Ear and Labyrinth Disorders: deafness
Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia
General disorders and administration site conditions: influenza-like illness (includes pyrexia, myalgia, musculoskeletal pain, headache and rigors), malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Neoplasms benign, malignant and unspecified: basal cell carcinoma
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 In other clinical studies of REVLIMID in MM patients, the following serious or nonserious adverse events (regardless of relationship to study drug treatment) not described in Tables attached were reported:
Ear and Labyrinth Disorders: tinnitus, hypoacusis
Gastrointestinal disorders: colitis, caecitis
Renal & urinary disorders: Fanconi syndrome, renal tubular necrosis
Skin and subcutaneous tissue disorders: photosensitivity reaction

6.2 Clinical Trials Experience in 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 event was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID. 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.

Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events. 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 2 summarizes the adverse events that were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. Table 3 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 events that are drug-related and those that reflect the patient’s underlying disease.

Table 2: Summary of Adverse Events Reported in ≥5% of the
REVLIMID Treated Patients in del 5q MDS Clinical Study
10 mg Overall
System organ class/Preferred term     [a]            (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                                            17      (11.5)
Leukopenia                                        12       (8.1)
Febrile Neutropenia                                8       (5.4)
Skin and Subcutaneous Tissue Disorders
Pruritus                                          62      (41.9)
Rash                                              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                                          72      (48.6)
Constipation                                      35      (23.6)
Nausea                                            35      (23.6)
Abdominal Pain                                    18      (12.2)
Vomiting                                          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                                        25      (16.9)
Pharyngitis                                    23      (15.5)
Epistaxis                                      22      (14.9)
Dyspnea Exertional                             10       (6.8)
Rhinitis                                       10       (6.8)
Bronchitis                                      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                                          15      (10.1)
Pain                                           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                               8        (5.4)
Infections and Infestations
Upper Respiratory Tract Infection                  22      (14.9)
Pneumonia                                          17      (11.5)
Urinary Tract Infection                            16      (10.8)
Sinusitis                                          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) Renal and Urinary Disorders
Dysuria                                                       10         (6.8) Vascular Disorders
Hypertension                                                     9      ( 6.1) Endocrine Disorders
Acquired Hypothyroidism                                       10        (6.8) 
Cardiac Disorders
Palpitations                                                     8      (5.4) [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 3: Most Frequently Observed Grade 3 and 4 Adverse Events [1]
Regardless of Relationship to Study Drug Treatment
10 mg
Preferred term [2]                                        (N=148)

Patients with at least one Grade 3/4 AE                      131       (88.5) Neutropenia                                                  79       (53.4) Thrombocytopenia                                             74       (50.0) Pneumonia                                                    11        (7.4) Rash                                                         10        (6.8) Anemia                                                        9        (6.1) Leukopenia                                                    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                                                                                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                                                                             2        (1.4) Pulmonary Hypertension                                                                  2        (1.4) Vomiting                                                                                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 in MDS patients, the following serious adverse events (regardless of relationship to study drug treatment) not described in Table 5 or 6 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

6.3 Clinical Trials Experience in 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 4 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 events, and 51 patients (38%) underwent at least one dose reduction due to adverse events.
Twenty-six patients (19%) discontinued treatment due to adverse events.
Table 4: ADRs reported in clinical trials in patients with mantle cell lymphoma treated with lenalidomide
System Organ All ADRs/Frequency                        Grade 3−4 ADRs/Frequency Class
/ Preferred
Term
Infections and Very Common                             Common
Infestations       Bacterial, viral and fungal         Bacterial, viral and fungal infections infections (including opportunistic (including opportunistic infections) ◊, infections), Nasopharyngitis,       Pneumonia◊
Pneumonia
Common
Sinusitis
Neoplasms          Common                              Common
Benign,            Tumour flare reaction               Tumour flare reaction, Squamous skin Malignant and                                          cancerˆ◊, Basal cell Carcinoma◊ Unspecified
(incl cysts and polyps)
Blood and          Very Common                         Very Common
Lymphatic          Thrombocytopenia, Neutropenia,      Thrombocytopenia, Neutropenia◊, System             Leucopenias, Anaemia                Anaemia◊
Disorders          Common                              Common
Febrile neutropenia                 Febrile neutropenia^◊, Leucopenias◊ 

Metabolism        Very Common                           Common and Nutrition     Decreased appetite, Weight            Dehydration◊, Hyponatraemia, Disorders         decreased, Hypokalaemia               Hypocalcaemia Common
Dehydratation,
Psychiatric       Common
Disorders         Insomnia
Nervous           Common                                Common
System            Dysgeuesia, Headache, neuropathy      Peripheral sensory neuropathy, Disorders         peripheral                            Lethargy
Ear and           Common
Labyrinth         Vertigo
Disorders
Cardiac                                                 Common
Disorders                                               Acute myocardial infarction (including acute) ◊, Cardiac failure
Vascular          Common                                Common
Disorders         Hypotension                           Deep vein thrombosis◊, pulmonary embolism^◊, Hypotension◊
Respiratory,      Very Common                           Common
Thoracic and      Dyspnoeia                             Dyspnoeia◊
Mediastinal
Disorders
System Organ All ADRs/Frequency                            Grade 3−4 ADRs/Frequency Class
/ Preferred
Term
Gastrointestina Very Common                                Common l Disorders     Diarrhoea, Nausea◊, Vomiting◊,             Diarrhoea◊, Abdominal pain◊, Constipation                               Constipation
Common
Abdominal pain
Skin and        Very Common                                Common
Subcutaneous    Rashes (including dermatitis               Rashes
Tissue          allergic), Pruritus
Disorders       Common
Night sweats, Dry skin

Musculoskeleta    Very Common                              Common l and             Muscle spasms, Back pain                 Back pain, Muscular weakness◊, Connective        Common                                   Arthralgia, Pain in extremity Tissue            Arthralgia, Pain in extremity,
Disorders         Muscular weakness
Renal and                                                  Common
Urinary                                                    Renal failure◊ Disorders
General           Very Common                              Common
Disorders and     Fatigue, Asthenia, Peripheral            Pyrexia◊, Asthenia◊, Fatigue Administration    oedema, Influenza like illness
Site Conditions   syndrome (including pyrexia,
cough)
Common
Chills
◊
Adverse events reported as serious in mantle cell lymphoma clinical trials Algorithm applied for mantle cell lymphoma:
• Mantle cell lymphoma controlled Phase II study o All treatment-emergent adverse events with ≥ 5% of subjects in lenalidomide arm and at least 2% difference in proportion between lenalidomide and control arm o All treatment-emergent grade 3 or 4 adverse events in ≥1% of subjects in lenalidomide arm and at least 1.0% difference in proportion between lenalidomide and control arm o All Serious treatment-emergent adverse events in ≥1% of subjects in lenalidomide arm and at least 1.0% difference in proportion between lenalidomide and control arm •   Mantle cell lymphoma single arm Phase II study o   All treatment-emergent adverse events with ≥ 5% of subjects o All grade 3 or 4 treatment-emergent adverse events reported in 2 or more subjects o   All Serious treatment-emergent adverse events reported in 2 or more subjects 
Tabulated summary of post-marketing adverse reactions
In addition to the above adverse reactions identified from the pivotal clinical trials, the following table is derived from data gathered from post-marketing data.

Table 5: ADRs reported in post-marketing use in patients treated with lenalidomide System Organ         All ADRs/Frequency                              Grade 3−4 Class                                                                ADRs/Frequency / Preferred Term
Infections and       Not known                                       Not known Infestations         Viral infections, including herpes zoster and   Viral infections, including hepatitis B virus reactivation                  herpes zoster and hepatitis B virus reactivation
Neoplasms Benign,                                                    Rare Malignant and                                                        Tumour lysis syndrome Unspecified (incl cysts and polyps)
Blood and            Not known
Lymphatic System     Acquired haemophilia
Disorders
Endocrine            Common
Disorders            Hyperthyroidism
Respiratory,                                                         Not Known Thoracic and                                                         Interstitial pneumonitis Mediastinal
Disorders
Gastrointestinal                                                     Not Known Disorders                                                            Pancreatitis, Gastrointestinal perforation (including diverticular, intestinal and large intestine perforations)

Hepatobiliary        Not Known                                       Not Known Disorders            Acute hepatic failure, Hepatitis toxic,         Acute hepatic failure, Hepatitis Cytolytic hepatitis, Cholestatic hepatitis,     toxic^
Mixed cytolytic/cholestatic hepatitis
Skin and                                                             Uncommon Subcutaneous                                                         Angioedema Tissue Disorders                                                     Rare Stevens-Johnson Syndrome,
Toxic epidermal necrolysis
Not Known
Leukocytoclastic vasculitis