Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile
Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with REVLIMID maintenance A conservative approach was applied to determine the adverse reactions from CALGB 100104. The adverse reactions described in Table 1 included events reported post-HDM/ASCT as well as events from the maintenance treatment period. A second analysis that identified events that occurred after the start of maintenance treatment suggests that the frequencies described in Table 1 may be higher than actually observed during the maintenance treatment period. In IFM 2005-02, the adverse reactions were from the maintenance treatment period only.

The serious adverse reactions observed more frequently (≥5%) with REVLIMID maintenance than placebo were:
• Pneumonia (10.6%; combined term) from IFM 2005-02
• Lung infection (9.4% [9.4% after the start of maintenance treatment]) from CALGB 100104 
In the IFM 2005-02 study, the adverse reactions observed more frequently with REVLIMID maintenance than placebo were neutropenia (60.8%), bronchitis (47.4%), diarrhoea (38.9%), nasopharyngitis (34.8%), muscle spasms (33.4%), leucopenia (31.7%), asthenia (29.7%), cough (27.3%), thrombocytopenia (23.5%), gastroenteritis (22.5%) and pyrexia (20.5%).

In the CALGB 100104 study, the adverse reactions observed more frequently with REVLIMID maintenance than placebo were neutropenia (79.0% [71.9% after the start of maintenance treatment]), thrombocytopenia (72.3% [61.6%]), diarrhoea (54.5% [46.4%]), rash (31.7% [25.0%]), upper respiratory tract infection (26.8% [26.8%]), fatigue (22.8% [17.9%]), leucopenia (22.8% [18.8%]) and anaemia (21.0% [13.8%]).

Newly diagnosed multiple myeloma patients receiving REVLIMID in combination with bortezomib and dexamethasone
In the SWOG S0777 study, the serious adverse reactions observed more frequently (≥ 5%) with REVLIMID in combination with intravenous bortezomib and dexamethasone than with REVLIMID in combination with dexamethasone were:
• Hypotension (6.5%), lung infection (5.7%), dehydration (5.0%)

The adverse reactions observed more frequently with REVLIMID in combination with bortezomib and dexamethasone than with REVLIMID in combination with dexamethasone were: Fatigue (73.7%), peripheral neuropathy (71.8%), thrombocytopenia (57.6%), constipation (56.1%), hypocalcaemia (50.0%).

The most frequent adverse events with the Revlimid, bortezomib and dexamethasone combination across the 3 studies were in the System Organ Classes of Nervous System Disorders, Blood and Lymphatic System Disorders and Gastrointestinal Disorders. Compared with Revlimid and dexamethasone, the combination of Revlimid, bortezomib and dexamethasone was associated with increased incidences of treatment-emergent serious adverse events (40.1% RVd vs.
28.5% Rd) and discontinuations due to treatment emergent AEs (22.9% RVd vs. 9.4% Rd). Increases in the incidence of


Grade 3/ 4 adverse events in the RVd arm versus the Rd arm were most notable for peripheral sensory and motor neuropathy, thrombocytopenia, hypotension, diarrhoea, syncope, hypokalaemia and dehydration.


Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with REVLIMID in combination with low dose dexamethasone
The serious adverse reactions observed more frequently (≥5%) with REVLIMID 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%).

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with REVLIMID in combination with melphalan and prednisone
The serious adverse reactions observed more frequently (≥5%) with melphalan, prednisone and REVLIMID followed by REVLIMID maintenance (MPR+R) or melphalan, prednisone and REVLIMID 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%), leucopenia (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%).

Multiple myeloma: patients with at least one prior therapy
In two phase 3 placebo-controlled studies, 353 patients with multiple myeloma were exposed to the REVLIMID/dexamethasone combination and 351 to the placebo/dexamethasone combination.

The most serious adverse reactions observed more frequently in REVLIMID/dexamethasone than placebo/dexamethasone combination were:
•     Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)
•     Grade 4 neutropenia (see section 4.4) 
The observed adverse reactions which occurred more frequently with REVLIMID 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%).

Myelodysplastic syndromes
The overall safety profile of REVLIMID in patients with myelodysplastic syndromes is based on data from a total of 286 patients from one phase 2 study and one phase 3 study (see section 5.1). In the phase 2, all 148 patients were on REVLIMID treatment. In the phase 3 study, 69 patients were on REVLIMID 5 mg, 69 patients on REVLIMID 10 mg and 67 patients were on placebo during the double-blind phase of the study.


Most adverse reactions tended to occur during the first 16 weeks of therapy with REVLIMID.
Serious adverse reactions include:
•     Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)
•    Grade 3 or 4 neutropenia, febrile neutropenia and Grade 3 or 4 thrombocytopenia (see section 4.4).

The most commonly observed adverse reactions which occurred more frequently in the REVLIMID groups compared to the control arm in the phase 3 study were neutropenia (76.8%), thrombocytopenia (46.4%), diarrhoea (34.8%), constipation (19.6%), nausea (19.6%), pruritus (25.4%), rash (18.1%), fatigue (18.1%) and muscle spasms (16.7%).

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 2 randomised, controlled study MCL-002 (see section 5.1).
Additionally, adverse drug reactions 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 REVLIMID 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 REVLIMID 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 REVLIMID 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%) (see section 5.1).
During treatment cycle 1, 11/81 (14%) patients with high tumour burden were withdrawn from therapy in the REVLIMID 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 REVLIMID 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.

Follicular lymphoma
The overall safety profile of REVLIMID in combination with rituximab in patients with previously treated follicular lymphoma is based on data from 294 patients from a Phase 3 randomised, controlled study NHL-007.
Additionally, adverse drug reactions from supportive study NHL-008 have been included in Table 5.

The serious adverse reactions observed most frequently (with a difference of at least 1 percentage point) in study NHL-007 in the REVLIMID/rituximab arm compared with the placebo/rituximab arm were: • Febrile neutropenia (2.7%)
• Pulmonary embolism (2.7%)
• Pneumonia (2.7%)

In the NHL-007 study the adverse reactions observed more frequently in the REVLIMID/rituximab arm compared with the placebo/rituximab arm (with at least 2% higher frequency between arms) were neutropenia (58.2%), diarrhoea (30.8%), leucopenia (28.8%), constipation (21.9%), cough (21.9%) and fatigue (21.9%).


Tabulated list of adverse reactions
The adverse reactions observed in patients treated with Revlimid 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).

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.

Tabulated summary for monotherapy in MM
The following table is derived from data gathered during NDMM studies in patients who have undergone ASCT treated with REVLIMID maintenance. The data were not adjusted according to the longer duration of treatment in the REVLIMID-containing arms continued until disease progression versus the placebo arms in the pivotal multiple myeloma studies (see section 5.1).

Table 1. ADRs reported in clinical trials in patients with multiple myeloma treated with REVLIMID maintenance therapy
System Organ Class/Preferred       All ADRs/Frequency                   Grade 3-4 ADRs/Frequency Term
Very Common                          Very Common
Pneumonia◊,a, Upper respiratory      Pneumonia◊,a, Neutropenic tract infection, Neutropenic         infection infection, Bronchitis◊, Influenza◊,
Gastroenteritis◊, Sinusitis,         Common
Infections and Infestations        Nasopharyngitis, Rhinitis            Sepsis◊,b, Bacteraemia, Lung infection◊, Lower respiratory tract
Common                               infection bacterial, Bronchitis◊, Infection◊, Urinary tract            Influenza◊, Gastroenteritis◊, ◊,
infection *, Lower respiratory       Herpes zoster◊, Infection◊
◊ tract infection, Lung infection
Neoplasms Benign, Malignant        Common and Unspecified (incl cysts and    Myelodysplastic syndrome◊,* polyps)
Very Common                          Very Common
Neutropenia^,◊, Febrile              Neutropenia^,◊, Febrile
^,◊ neutropenia ,                        neutropenia^,◊,
Blood and Lymphatic System         Thrombocytopenia^,◊, Anaemia,        Thrombocytopenia^,◊, Anaemia, ◊
Disorders                          Leucopenia , Lymphopenia             Leucopenia◊, Lymphopenia 
Common
Pancytopenia◊
Metabolism and Nutrition             Very Common                          Common Disorders                            Hypokalaemia                         Hypokalaemia, Dehydration Very Common                          Common
Paraesthesia                         Headache
Nervous System Disorders
Common
Peripheral neuropathyc
Vascular Disorders                   Common                               Common System Organ Class/Preferred                All ADRs/Frequency                              Grade 3-4 ADRs/Frequency Term
Pulmonary embolism◊,*                           Deep vein thrombosis^,◊,d Very Common                                     Common
Cough                                           Dyspnoea◊
Respiratory, Thoracic and
Mediastinal Disorders
Common
Dyspnoea◊, Rhinorrhoea
Very Common                                     Common
Diarrhoea, Constipation, Abdominal              Diarrhoea, Vomiting, Nausea pain, Nausea
Gastrointestinal Disorders
Common
Vomiting, Abdominal pain upper
Very Common                                     Common
Hepatobiliary Disorders
Abnormal liver function tests                   Abnormal liver function tests Skin and Subcutaneous Tissue                Very Common                                     Common Disorders                                   Rash, Dry skin                                  Rash, Pruritus Very Common
Muscle spasms
Musculoskeletal and Connective
Tissue Disorders
Common
Myalgia, Musculoskeletal pain
General Disorders and                       Very Common                                     Common Administration Site Conditions              Fatigue, Asthenia, Pyrexia                      Fatigue, Asthenia ◊ Adverse reactions reported as serious in clinical trials in patients with NDMM who had undergone ASCT * Applies to serious adverse drug reactions only
^ See section 4.8 description of selected adverse reactions a “Pneumonia” combined AE term includes the following PTs: Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia, 
Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis b “Sepsis” combined AE term includes the following PTs: Bacterial sepsis, Pneumococcal sepsis, Septic shock, Staphylococcal sepsis c “Peripheral neuropathy” combined AE term includes the following preferred terms (PTs): Neuropathy peripheral, Peripheral sensory neuropathy, 
Polyneuropathy d “Deep vein thrombosis” combined AE term includes the following PTs: Deep vein thrombosis, Thrombosis, Venous thrombosis 

Tabulated summary for combination therapy in MM
The following table is derived from data gathered during the multiple myeloma studies with combination therapy. The data were not adjusted according to the longer duration of treatment in the REVLIMID-containing arms continued until disease progression versus the comparator arms in the pivotal multiple myeloma studies (see section 5.1).



Table 2. ADRs reported in clinical studies in patients with multiple myeloma treated with REVLIMID in combination with bortezomib and dexamethasone, dexamethasone, or 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)◊, Cellulitis◊, Bronchitis◊, Rhinitis                          Sepsis◊,◊◊, Lung infection◊◊, Common                                         Bronchitis◊, Respiratory tract Sepsis◊,◊◊, Lung infection◊◊, Urinary tract    infection◊◊, Urinary tract ◊◊            ◊ infection , Sinusitis                          infection◊◊, Enterocolitis infectious
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        , Neutropenia^,◊,◊◊, ◊                         ^
System Disorders Anaemia , Haemorrhagic disorder ,                 Thrombocytopenia^,◊,◊◊, Leucopenia, Lymphopenia                        Anaemia◊, Leucopenia, Lymphopenia
Common
Febrile neutropenia^,◊, Pancytopenia◊          Common
Febrile neutropenia^,◊,
Uncommon                                       Pancytopenia◊, Haemolytic Haemolysis, Autoimmune haemolytic              anaemia anaemia, Haemolytic anaemia
Uncommon
Hypercoagulation,
Coagulopathy
Immune System       Uncommon
Disorders           Hypersensitivity^
Endocrine           Common
Disorders           Hypothyroidism



System Organ       All ADRs/Frequency                             Grade 3−4 ADRs/Frequency Class
/ Preferred Term
Metabolism and     Very Common                                    Common Nutrition          Hypokalaemia◊,◊◊, Hyperglycaemia,              Hypokalaemia◊,◊◊, Disorders          Hypoglycaemia, Hypocalcaemia◊,                 Hyperglycaemia, Hyponatraemia◊, Dehydration◊◊, Decreased       Hypocalcaemia◊, Diabetes appetite◊◊, Weight decreased                   mellitus◊,
Hypophosphataemia,
Common                                         Hyponatraemia◊,
Hypomagnesaemia, Hyperuricaemia,               Hyperuricaemia, Gout,
Hypercalcaemia+                                Dehydration◊◊, Decreased appetite◊◊, Weight decreased
Psychiatric        Very Common                                    Common Disorders          Depression, Insomnia                           Depression, Insomnia 
Uncommon
Loss of libido
Nervous System     Very Common                                    Very Common Disorders          Peripheral neuropathies◊◊, Paraesthesia,       Peripheral neuropathies◊◊ Dizziness◊◊, Tremor, Dysgeusia, Headache
Common
Common                                         Cerebrovascular accident◊, Ataxia, Balance impaired, Syncope◊◊,           Dizziness◊◊, Syncope◊◊, Neuralgia, Dysaesthesia                        Neuralgia

Uncommon
Intracranial haemorrhage^,,
Transient ischaemic attack,
Cerebral ischemia
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 Ventricular extrasystoles                      cardiac failure◊, Tachycardia, Cardiac failure◊,◊◊, Myocardial ischemia◊



System Organ       All ADRs/Frequency                           Grade 3−4 ADRs/Frequency Class
/ Preferred Term
Vascular           Very Common                                  Very Common Disorders          Venous thromboembolic events^,               Venous thromboembolic predominantly deep vein thrombosis and       events^, predominantly deep pulmonary embolism^,◊,◊◊, Hypotension◊◊      vein thrombosis and pulmonary embolism^,◊,◊◊
Common                                       Common
Hypertension, Ecchymosis^                    Vasculitis, Hypotension◊◊, Hypertension
Uncommon
Ischemia, Peripheral ischemia,
Intracranial venous sinus thrombosis
Respiratory,       Very Common                                  Common Thoracic           Dyspnoea◊,◊◊, Epistaxis^, Cough              Respiratory distress◊, and Mediastinal                                                 Dyspnoea◊,◊◊, Pleuritic pain◊◊, Disorders          Common                                       Hypoxia◊◊ Dysphonia
Gastrointestinal   Very Common                                  Common Disorders          Diarrhoea◊,◊◊, Constipation◊, Abdominal      Gastrointestinal pain◊◊, Nausea, Vomiting◊◊, Dyspepsia, Dry   haemorrhage^,◊,◊◊, Small mouth, Stomatitis                            intestinal obstruction◊◊, Diarrhoea◊◊, Constipation◊,
Common                                       Abdominal pain◊◊, Nausea, Gastrointestinal haemorrhage (including      Vomiting◊◊ rectal haemorrhage, haemorrhoidal haemorrhage, peptic ulcer haemorrhage and gingival bleeding)^,◊◊, Dysphagia

Uncommon
Colitis, Caecitis
Hepatobiliary      Very Common                                  Common Disorders          Alanine aminotransferase increased,          Cholestasis◊, Hepatotoxicity, Aspartate aminotransferase increased         Hepatocellular injury◊◊, Alanine aminotransferase
Common                                       increased, Abnormal liver Hepatocellular injury◊◊, Abnormal liver      function tests◊ function tests◊, Hyperbilirubinaemia
Uncommon
Uncommon                                     Hepatic failure^
Hepatic failure^



System Organ       All ADRs/Frequency                           Grade 3−4 ADRs/Frequency Class
/ Preferred Term
Skin and           Very Common                                  Common Subcutaneous       Rashes◊◊, Pruritus                           Rashes◊◊ Tissue Disorders
Common                                       Uncommon
Urticaria, Hyperhidrosis, Dry skin, Skin     Drug rash with eosinophilia hyperpigmentation, Eczema, Erythema          and systemic symptoms◊◊ 
Uncommon
Drug rash with eosinophilia and systemic symptoms◊◊, Skin discolouration,
Photosensitivity reaction
Musculoskeletal    Very Common                                  Common and Connective     Muscular weakness◊◊, Muscle spasms, Bone     Muscular weakness◊◊, Bone Tissue Disorders   pain◊,                                       pain◊, Musculoskeletal and Musculoskeletal and connective tissue pain   connective tissue pain and and discomfort (including back pain◊,◊◊),    discomfort (including back Pain in extremity, Myalgia, Arthralgia◊      pain◊,◊◊)

Common                                       Uncommon
Joint swelling                               Joint swelling
Renal and          Very Common                                  Uncommon Urinary                                                         Renal tubular necrosis Disorders          Renal failure (including acute)◊,◊◊

Common
Haematuria^, Urinary retention,
Urinary incontinence

Uncommon
Acquired Fanconi syndrome
Reproductive       Common
System and         Erectile dysfunction
Breast Disorders
General            Very Common                                  Very Common Disorders          Fatigue◊,◊◊, Oedema (including peripheral    Fatigue◊,◊◊ and                oedema), Pyrexia◊,◊◊, Asthenia, Influenza
Administration     like illness syndrome (including pyrexia,    Common Site Conditions    cough, myalgia, musculoskeletal pain,        Oedema peripheral, headache and rigors)                         Pyrexia◊,◊◊, Asthenia Common
Chest pain◊,◊◊, Lethargy
Investigations     Very Common
Blood alkaline phosphatase increased

Common
C-reactive protein increased

System Organ               All ADRs/Frequency                                          Grade 3−4 ADRs/Frequency Class
/ Preferred Term
Injury, Poisoning          Common and Procedural             Fall, Contusion^
Complications
◊◊Adverse  reactions reported as serious in clinical trials in patients with NDMM who had received REVLIMID in combination with bortezomib and dexamethasone
^See section 4.8 description of selected adverse reactions
◊ Adverse reactions reported as serious in clinical trials in patients with multiple myeloma treated with REVLIMID in combination with dexamethasone, or with melphalan and prednisone
+ Applies to serious adverse drug reactions only
* Squamous skin cancer was reported in clinical trials in previously treated myeloma patients with REVLIMID/dexamethasone compared to controls ** Squamous cell carcinoma of skin was reported in a clinical trial in newly diagnosed myeloma patients with REVLIMID/dexamethasone compared to controls

Tabulated summary from monotherapy
The following tables are derived from data gathered during the main studies in monotherapy for myelodysplastic syndromes and mantle cell lymphoma.

Table 3. ADRs reported in clinical trials in patients with myelodysplastic syndromes treated with REVLIMID#
System Organ Class /     All ADRs/Frequency                         Grade 3−4 ADRs/Frequency Preferred Term
Infections and           Very Common                                Very Common Infestations             Bacterial, viral and fungal infections     Pneumonia◊ ◊
(including opportunistic infections)
Common
Bacterial, viral and fungal infections
(including opportunistic infections)◊,
Bronchitis
Blood and Lymphatic      Very Common                                Very Common System Disorders         Thrombocytopenia^,◊, Neutropenia^,◊,       Thrombocytopenia^,◊, Neutropenia^,◊, Leucopenia                                 Leucopenia

Common
Febrile neutropenia^,◊
Endocrine Disorders                 Very Common
Hypothyroidism
Metabolism and                      Very Common                                           Common Nutrition Disorders                 Decreased appetite                                    Hyperglycaemia◊, Decreased appetite 
Common
Iron overload, Weight decreased
Psychiatric Disorders                                                                     Common Altered mood◊,~
Nervous System                      Very Common
Disorders                           Dizziness, Headache

Common
Paraesthesia

System Organ Class /                All ADRs/Frequency                                      Grade 3−4 ADRs/Frequency Preferred Term
Cardiac Disorders                                                                           Common Acute myocardial infarction^,◊, Atrial fibrillation◊, Cardiac failure◊
Vascular Disorders                  Common                                                  Common Hypertension, Haematoma                                 Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism^,◊
Respiratory, Thoracic               Very Common and Mediastinal                     Epistaxis^
Disorders
Gastrointestinal                    Very Common                                             Common Disorders                           Diarrhoea◊, Abdominal pain (including                   Diarrhoea◊, Nausea, Toothache upper), Nausea, Vomiting, Constipation

Common
Dry mouth, Dyspepsia
Hepatobiliary                       Common                                                  Common Disorders                           Abnormal liver function tests                           Abnormal liver function tests Skin and Subcutaneous               Very Common                                             Common Tissue Disorders                    Rashes, Dry Skin, Pruritus                              Rashes, Pruritus Musculoskeletal and                 Very Common                                             Common Connective Tissue                   Muscle spasms, Musculoskeletal pain                     Back pain◊ Disorders                           (including back pain◊ and pain in extremity), Arthralgia, Myalgia
Renal and Urinary                                                                           Common Disorders                                                                                   Renal failure◊ General Disorders and               Very Common                                             Common Administration Site                 Fatigue, Peripheral oedema, Influenza                   Pyrexia Conditions                          like illness syndrome (including pyrexia, cough, pharyngitis, myalgia,
musculoskeletal pain, headache)
Injury, Poisoning and                                                                       Common Procedural                                                                                  Fall Complications
^see section 4.8 description of selected adverse reactions
◊Adverse events reported as serious in myelodysplastic syndromes clinical trials 
~Altered mood was reported as a common serious adverse event in the myelodysplastic syndromes phase 3 study; it was not reported as a Grade 3 or 4 adverse event
Algorithm applied for inclusion in the SmPC: All ADRs captured by the phase 3 study algorithm are included in the EU SmPC. For these ADRs, an additional check of the frequency of the ADRs captured by the phase 2 study algorithm was undertaken and, if the frequency of the ADRs in the phase 2 study was higher than in the phase 3 study, the event was included in the EU SmPC at the frequency it occurred in the phase 2 study.
# Algorithm applied for myelodysplastic syndromes:
•    Myelodysplastic syndromes phase 3 study (double-blind safety population, difference between REVLIMID 5/10mg and placebo by initial dosing regimen occurring in at least 2 subjects) o All treatment-emergent adverse events with ≥ 5% of subjects in REVLIMID and at least 2% difference in proportion between REVLIMID and placebo o All treatment-emergent Grade 3 or 4 adverse events in 1% of subjects in REVLIMID and at least 1% difference in proportion between REVLIMID and placebo o All treatment-emergent serious adverse events in 1% of subjects in REVLIMID and at least 1% difference in proportion between REVLIMID and placebo
•    Myelodysplastic syndromes phase 2 study o All treatment-emergent adverse events with ≥ 5% of REVLIMID treated subjects o All treatment-emergent Grade 3 or 4 adverse\events in 1% of REVLIMID treated subjects o All treatment-emergent serious adverse events in 1% of REVLIMID treated subjects Table 4. ADRs reported in clinical trials in patients with mantle cell lymphoma treated with REVLIMID 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                                          cancer^,◊, Basal cell carcinoma^,◊ Unspecified
(incl cysts and polyps)
Blood and       Very Common                            Very Common
Lymphatic       Thrombocytopenia^, Neutropenia^,◊, Thrombocytopenia^, Neutropenia^,◊, System          Leucopenia◊, Anaemia◊                  Anaemia◊ Disorders       Common                                 Common
Febrile neutropenia^,◊                 Febrile neutropenia^,◊, Leucopenia◊ 

Metabolism       Very Common                        Common and Nutrition    Decreased appetite, Weight         Dehydration◊, Hyponatraemia, Disorders        decreased, Hypokalaemia            Hypocalcaemia
Common
Dehydration◊
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                                           Myocardial infarction (including acute)^,◊, Cardiac failure
Vascular         Common                             Common
Disorders        Hypotension◊                       Deep vein thrombosis◊, pulmonary embolism^,◊, Hypotension◊
Respiratory,     Very Common                        Common
Thoracic and     Dyspnoea◊                          Dyspnoea◊
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
^see section 4.8 description of selected adverse reactions
◊Adverse events reported as serious in mantle cell lymphoma clinical trials Algorithm applied for mantle cell lymphoma: 
•    Mantle cell lymphoma controlled phase 2 study o All treatment-emergent adverse events with ≥ 5% of subjects in REVLIMID arm and at least 2% difference in proportion between REVLIMID and control arm o All treatment-emergent Grade 3 or 4 adverse events in ≥1% of subjects in REVLIMID arm and at least 1.0% difference in proportion between REVLIMID and control arm o All Serious treatment-emergent adverse events in ≥1% of subjects in REVLIMID arm and at least 1.0% difference in proportion between REVLIMID and control arm
•    Mantle cell lymphoma single arm phase 2 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 for combination therapy in FL
The following table is derived from data gathered during the main studies (NHL-007 and NHL-008) using REVLIMID in combination with rituximab for patients with follicular lymphoma.

Table 5. ADRs reported in clinical trials in patients with follicular lymphoma treated with REVLIMID in combination with rituximab



System Organ Class /      All ADRs/Frequency                      Grade 3−4 ADRs/Frequency Preferred Term
Infections and            Very Common                             Common Infestations              Upper respiratory tract infection       Pneumonia◊, Sepsis◊, Lung infection, Common                                  Bronchitis, Gastroenteritis, Sinusitis, Pneumonia◊, Influenza, Bronchitis,      Urinary tract infection, Cellulitis◊ Sinusitis, Urinary tract infection
Neoplasms Benign,         Very Common                             Common Malignant and             Tumour flare^                           Basal cell carcinoma^,◊ Unspecified (incl cysts   Common and polyps)               Squamous Cell Carcinoma of Skin◊,^,+
Blood and Lymphatic       Very Common                             Very Common System Disorders          Neutropenia^,◊, Anaemia◊,               Neutropenia^,◊ Thrombocytopenia^, Leucopenia**         Common
Lymphopenia***                          Anaemia◊, Thrombocytopenia^, Febrile neutropenia◊, Pancytopenia,
Leucopenia**, Lymphopenia***
Metabolism and            Very Common                             Common Nutrition Disorders       Decreased appetite, Hypokalaemia        Dehydration, Hypercalcaemia◊, Common                                  Hypokalaemia, Hypophosphataemia, Hypophosphataemia, Dehydration          Hyperuricaemia

Psychiatric Disorders     Common
Depression, Insomnia
Nervous System            Very Common                             Common Disorders                 Headache, Dizziness                     Syncope Common
Peripheral sensory neuropathy,
Dysgeusia
Cardiac Disorders         Uncommon
Arrhythmia◊
Vascular Disorders        Common                                  Common Hypotension                             Pulmonary embolism^,◊, Hypotension Respiratory, Thoracic     Very Common                             Common and Mediastinal           Dyspnoea◊, Cough,                       Dyspnoea◊ Disorders                 Common
Oropharyngeal pain, Dysphonia
Gastrointestinal          Very Common                             Common Disorders                 Abdominal pain◊, Diarrhoea,             Abdominal pain◊, Diarrhoea, Constipation, Nausea, Vomiting,         Constipation, Stomatitis
Dyspepsia
Common
Upper abdominal pain, Stomatitis, Dry mouth
Skin and Subcutaneous     Very Common                             Common Tissue Disorders          Rash*, Pruritus                         Rash*, Pruritus Common
Dry skin, Night sweats, Erythema


System Organ Class /              All ADRs/Frequency                                   Grade 3−4 ADRs/Frequency Preferred Term
Musculoskeletal and               Very Common                                          Common Connective Tissue                 Muscle spasms, Back pain, Arthralgia                 Muscular weakness, Neck pain Disorders                         Common
Pain in extremity, Muscular weakness,
Musculoskeletal pain, Myalgia, Neck pain
Renal and Urinary                                                                      Common Disorders                                                                              Acute kidney injury◊ General Disorders and             Very Common                                          Common Administration Site               Pyrexia, Fatigue, Asthenia, Peripheral               Fatigue, Asthenia Conditions                        oedema
Common
Malaise, Chills
Investigations                    Very Common
Alanine aminotransferase increased
Common
Weight decreased, Blood Bilirubin increased
^see section 4.8 description of selected adverse reactions
Algorithm applied for follicular lymphoma:
Controlled– Phase 3 trial: o NHL-007 ADRs- All treatment-emergent AEs with ≥ 5.0% of subjects in REVLIMID/rituximab arm and at least 2.0% higher frequency (%) in Len arm compared to control arm - (Safety population) o NHL-007 Gr 3/4 ADRs- All Grades 3 or Grade 4 treatment-emergent AEs with at least 1.0% subjects in REVLIMID/rituximab arm and at least 1.0% higher frequency in REVLIMID arm compared to control arm - (safety population) o NHL-007 Serious ADRs- All serious treatment-emergent AEs with at least 1.0% subjects in REVLIMID/rituximab arm and at least 1.0% higher frequency in REVLIMID/rituximab arm compared to control arm - (safety population) FL single arm - phase 3 trial: o NHL-008 ADRs- All treatment-emergent adverse events with ≥ 5.0% of subjects o NHL-008 Gr 3/4 ADRs- All Grade 3/4 treatment-emergent adverse events reported in ≥ 1.0% of subjects o NHL-008 Serious ADRs- All serious treatment-emergent adverse events reported in ≥ 1.0% of subjects ◊Adverse events reported as serious in follicular lymphoma clinical trials + Applies to serious adverse drug reactions only
* Rash includes PT of rash and rash maculo-papular
**Leucopenia includes PT leucopenia and white blood cell count decreased 
***Lymphopenia includes PT lymphopenia and lymphocyte count decreased 
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 6. ADRs reported in post-marketing use in patients treated with REVLIMID System Organ Class /      All ADRs/Frequency                            Grade 3−4 ADRs/Frequency Preferred Term
Infections and            Not Known                                     Not Known Infestations              Viral infections, including herpes zoster and Viral infections, including herpes hepatitis B virus reactivation                zoster and hepatitis B virus reactivation
Neoplasms Benign,                                                       Rare Malignant and                                                           Tumour lysis syndrome Unspecified (incl cysts and polyps)


System Organ Class /                   All ADRs/Frequency                              Grade 3−4 ADRs/Frequency Preferred Term
Blood and Lymphatic                    Not Known
System Disorders                       Acquired haemophilia
Immune System                          Rare                                            Rare Disorders                              Anaphylactic reaction^                          Anaphylactic reaction^ 
Not Known
Solid organ transplant rejection
Endocrine Disorders                    Common
Hyperthyroidism
Respiratory, Thoracic                  Uncommon                                        Rare and Mediastinal                        Pulmonary hypertension                          Pulmonary hypertension Disorders
Not Known
Interstitial pneumonitis
Gastrointestinal                                                                       Not Known Disorders                                                                              Pancreatitis, Gastrointestinal perforation (including diverticular, intestinal and large intestine perforations)^
Hepatobiliary Disorders                Not Known                                       Not Known Acute hepatic failure^, Hepatitis toxic^,       Acute hepatic failure^, Hepatitis Cytolytic hepatitis^, Cholestatic hepatitis^,   toxic^
Mixed cytolytic/cholestatic hepatitis^
Skin and Subcutaneous                                                                  Uncommon Tissue Disorders                                                                       Angioedema Rare
Stevens-Johnson Syndrome^,
Toxic epidermal necrolysis^

Not Known
Leukocytoclastic vasculitis, Drug
Reaction with Eosinophilia and
Systemic Symptoms^
^see section 4.8 description of selected adverse reactions

Description of selected adverse reactions
Teratogenicity
REVLIMID is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. In monkeys, REVLIMID induced malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If REVLIMID is taken during pregnancy, a teratogenic effect of REVLIMID in humans is expected.

Neutropenia and thrombocytopenia
• Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with REVLIMID maintenance
REVLIMID maintenance after ASCT is associated with a higher frequency of Grade 4 neutropenia compared to placebo maintenance (32.1% vs 26.7% [16.1% vs 1.8% after the start of maintenance treatment] in CALGB 100104 and 16.4% vs 0.7% in IFM 2005-02, respectively). Treatment-emergent AEs of neutropenia leading to REVLIMID discontinuation were reported in 2.2% of patients in CALGB 100104 and 2.4% of patients in IFM 2005-02, respectively. Grade 4 febrile neutropenia was reported at similar frequencies in the REVLIMID maintenance arms compared to placebo maintenance arms in both studies (0.4% vs 0.5% [0.4% vs 0.5% after the start of maintenance treatment] in CALGB 100104 and 0.3% vs 0% in IFM 2005-02, respectively).

REVLIMID maintenance after ASCT is associated with a higher frequency of Grade 3 or 4 thrombocytopenia compared to placebo maintenance (37.5% vs 30.3% [17.9% vs 4.1% after the start of maintenance treatment] in CALGB 100104 and 13.0% vs 2.9% in IFM 2005-02, respectively).

•   Newly diagnosed multiple myeloma patients who are not eligible for transplant receiving REVLIMID in combination with bortezomib and dexamethasone
Grade 4 neutropenia was observed in the RVd arm to a lesser extent than in the Rd comparator arm (2.7% vs 5.9%) in the SWOG S0777 study. Grade 4 febrile neutropenia was reported at similar frequencies in the RVd arm compared to the Rd arm (0.0% vs 0.4%).

Grade 3 or 4 thrombocytopenia was observed in the RVd arm to a greater extent than in the Rd comparator arm (17.2 % vs 9.4%).

•   Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with REVLIMID in combination with dexamethasone
The combination of REVLIMID with dexamethasone in newly diagnosed multiple myeloma patients is associated with a lower frequency of Grade 4 neutropenia (8.5% in Rd and Rd18, compared with MPT (15%).
Grade 4 febrile neutropenia was observed infrequently (0.6% in Rd and Rd18 compared with 0.7% in MPT).

The combination of REVLIMID with dexamethasone in newly diagnosed multiple myeloma patients is associated with a lower frequency of Grade 3 and 4 thrombocytopenia (8.1% in Rd and Rd18) compared with MPT (11.1%).

•     Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with REVLIMID in combination with melphalan and prednisone
The combination of REVLIMID with melphalan and prednisone in newly diagnosed multiple myeloma patients is associated with a higher frequency of Grade 4 neutropenia (34.1% in MPR+R/MPR+p) compared with MPp+p (7.8%). There was a higher frequency of Grade 4 febrile neutropenia observed (1.7% in MPR+R/MPR+p compared to 0.0% in MPp+p).

The combination of REVLIMID with melphalan and prednisone in newly diagnosed multiple myeloma patients is associated with a higher frequency of Grade 3 and Grade 4 thrombocytopenia (40.4% in MPR+R/MPR+p) compared with MPp+p (13.7%).

• Multiple myeloma: patients with at least one prior therapy
The combination of REVLIMID with dexamethasone in multiple myeloma patients is associated with a higher incidence of Grade 4 neutropenia (5.1% in REVLIMID/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in REVLIMID/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients).

The combination of REVLIMID with dexamethasone in multiple myeloma patients is associated with a higher incidence of Grade 3 and Grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in REVLIMID/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients).


• Myelodysplastic syndromes patients
In myelodysplastic syndromes patients, REVLIMID is associated with a higher incidence of Grade 3 or 4 neutropenia (74.6% in REVLIMID-treated patients compared with 14.9% in patients on placebo in the phase 3 study). Grade 3 or 4 febrile neutropenia episodes were observed in 2.2% of REVLIMID-treated patients compared with 0.0% in patients on placebo). REVLIMID is associated with a higher incidence of Grade 3 or 4 thrombocytopenia (37% in REVLIMID-treated patients compared with 1.5% in patients on placebo in the phase 3 study).

• Mantle cell lymphoma patients
In mantle cell lymphoma patients, REVLIMID is associated with a higher incidence of Grade 3 or 4 neutropenia (43.7% in REVLIMID-treated patients compared with 33.7% in patients in the control arm in the phase 2 study). Grade 3 or 4 febrile neutropenia episodes were observed in 6.0% of REVLIMID-treated patients compared with 2.4% in patients on control arm.

• Follicular lymphoma patients
The combination of REVLIMID with rituximab in follicular lymphoma is associated with a higher rate of grade 3 or grade 4 neutropenia (50.7% in REVLIMID/rituximab treated patients compared with 12.2% in placebo/rituximab treated patients). All grade 3 or 4 neutropenia were reversible through dose interruption, reduction and/or supportive care with growth factors. Additionally, febrile neutropenia was observed infrequently (2.7% in REVLIMID/rituximab treated patients compared with 0.7% in placebo/rituximab treated patients).

REVLIMID in combination with rituximab is also associated with a higher incidence of grade 3 or 4 thrombocytopenia (1.4% in REVLIMID/rituximab treated patients compared to 0% in placebo/rituximab patients).

Venous thromboembolism
An increased risk of DVT and PE is associated with the use of the combination of REVLIMID with dexamethasone in patients with multiple myeloma, and to a lesser extent in patients treated with REVLIMID in combination with melphalan and prednisone or in patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma treated with REVLIMID monotherapy (see section 4.5).
Concomitant administration of erythropoietic agents or previous history of DVT may also increase thrombotic risk in these patients.

Myocardial infarction
Myocardial infarction has been reported in patients receiving REVLIMID, particularly in those with known risk factors.

Haemorrhagic disorders
Haemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system disorders; nervous system disorders (intracranial haemorrhage); respiratory, thoracic and mediastinal disorders (epistaxis); gastrointestinal disorders (gingival bleeding, haemorrhoidal haemorrhage, rectal haemorrhage); renal and urinary disorders (haematuria); injury, poisoning and procedural complications (contusion) and vascular disorders (ecchymosis).

Allergic reactions and severe skin reactions
Cases of allergic reactions including angioedema, anaphylactic reaction and severe cutaneous reactions including SJS, TEN and DRESS have been reported with the use of REVLIMID. A possible cross-reaction 

between REVLIMID and thalidomide has been reported in the literature. Patients with a history of severe rash associated with thalidomide treatment should not receive REVLIMID (see section 4.4).

Second primary malignancies
In clinical trials in previously treated myeloma patients with REVLIMID/dexamethasone compared to controls, mainly comprising of basal cell or squamous cell skin cancers.

Acute myeloid leukaemia
• Multiple myeloma
Cases of AML have been observed in clinical trials of newly diagnosed multiple myeloma in patients taking REVLIMID treatment in combination with melphalan or immediately following HDM/ASCT (see section 4.4).
This increase was not observed in clinical trials of newly diagnosed multiple myeloma in patients taking REVLIMID in combination with dexamethasone compared to thalidomide in combination with melphalan and prednisone.

• Myelodysplastic syndromes
Baseline variables including complex cytogenetics and TP53 mutation are associated with progression to AML in subjects who are transfusion dependent and have a Del (5q) abnormality (see section 4.4). The estimated 2- year cumulative risk of progression to AML were 13.8% in patients with an isolated Del (5q) abnormality compared to 17.3% for patients with Del (5q) and one additional cytogenetic abnormality and 38.6% in patients with a complex karyotype.
In a post-hoc analysis of a clinical trial of REVLIMID in myelodysplastic syndromes, the estimated 2-year rate of progression to AML was 27.5 % in patients with IHC-p53 positivity and 3.6% in patients with IHC-p53 negativity (p=0.0038). In the patients with IHC-p53 positivity, a lower rate of progression to AML was observed amongst patients who achieved a transfusion independence (TI) response (11.1%) compared to a non- responder (34.8%).

Hepatic disorders
The following post-marketing adverse reactions have been reported (frequency unknown): acute hepatic failure and cholestasis (both potentially fatal), toxic hepatitis, cytolytic hepatitis, mixed cytolytic/cholestatic hepatitis.

Rhabdomyolysis
Rare cases of rhabdomyolysis have been observed, some of them when REVLIMID is administered with a statin.

Thyroid disorders
Cases of hypothyroidism and cases of hyperthyroidism have been reported (see section 4.4 Thyroid disorders).
Tumour flare reaction and tumour lysis syndrome
In study MCL-002, approximately 10% of REVLIMID-treated patients experienced TFR compared to 0% in the control arm. The majority of the events occurred in cycle 1, all were assessed as treatment-related, and the majority of the reports were grade 1 or 2. Patients with high MIPI at diagnosis or bulky disease (at least one lesion that is ≥ 7 cm in the longest diameter) at baseline may be at risk of TFR. In study MCL-002, TLS was reported for one patient in each of the two treatment arms. In the supportive study MCL-001, approximately 10% of subjects experienced TFR; all report were grade 1 or 2 in severity and all were assessed as treatment- related. The majority of the events occurred in cycle 1. There were no reports of TLS in study MCL-001 (see section 4.4).

In study NHL-007, TFR was reported in 19/146 (13.0%) of patients in the REVLIMID/rituximab arm versus 1/148 (0.7%) patients in the placebo/rituximab arm. Most TFRs (18 out of 19) reported in the REVLIMID/rituximab arm occurred during first two cycles of treatment. One FL patient in the REVLIMID/rituximab arm experienced a Grade 3 TFR event versus no patients in the placebo/rituximab arm.
In study NHL-008, 7/177 (4.0%) of FL patients experienced TFR; (3 reports were Grade 1 and 4 reports were Grade 2 severity); while 1 report was considered serious. In study NHL-007, TLS occurred in 2 FL patients (1.4%) in the REVLIMID/rituximab arm and no FL patients in the placebo/rituximab arm; neither patient had a Grade 3 or 4 event. TLS occurred in 1 FL patient (0.6%) in study NHL-008. This single event was identified as a serious, Grade 3 adverse reaction. For study NHL-007 no patients had to discontinue REVLIMID/rituximab therapy due to TFR or TLS.

Gastrointestinal disorders
Gastrointestinal perforations have been reported during treatment with REVLIMID. Gastrointestinal perforations may lead to septic complications and may be associated with fatal outcome.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com