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The adverse reactions observed more frequently with Rd or Rd18 than MPT were: Diarrhoea, fatigue, back pain, asthenia, insomnia, rash, decreased appetite, cough, pyrexia, and muscle spasms.
Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with Lenalidomide in combination with Melphalan and Prednisone: The serious adverse reactions observed more frequently 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, Anemia.
The adverse reactions observed more frequently with MPR+R or MPR+p than MPp+p were: neutropenia, anemia, thrombocytopenia, leukopenia, constipation, diarrhea, rash, pyrexia, peripheral oedema, cough, decreased appetite, and asthenia.
Multiple myeloma: patients with at least one prior therapy: 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 occured more frequently with lenalidomide and dexamethasone than placebo and dexamethasone in pooled multiple myeloma (MM-009 and MM-010) were fatigue, neutropenia, constipation, diarrhoea, muscle cramp, anemia, thrombocytopenia and rash.
Myelodysplastic syndromes: Most adverse reactions tended to occur during the first 16 weeks of therapy with lenalidomide.
Serious adverse reactions include: Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see PRECAUTIONS); Grade 3 or 4 neutropenia, febrile neutropenia and grade 3 or 4 thrombocytopenia (see PRECAUTIONS).
The most commonly observed adverse reactions which occurred more frequently in the lenalidomide groups compared to the control arm in the phase III study were neutropenia, thrombocytopenia, diarrhea, constipation, nausea, pruritus, rash, fatigue and muscle spasms.
Mantle cell lymphoma: The serious adverse reactions observed more frequently (with a difference of at least 2 percentage points) in the Lenalidomide arm compared with the control arm were: Neutropenia, Pulmonary embolism, Diarrhea.
The most frequently observed adverse reactions which occurred more frequently in the Lenalidomide arm compared with the control arm were neutropenia, anemia, diarrhea, fatigue, constipation, pyrexia, and rash (including dermatitis allergic).
There was overall an apparent increase in early (within 20 weeks) deaths. Patients with high tumor burden at baseline are at increased risk of early death, early death in the Lenalidomide arm and early death in the control arm. Within 52 weeks corresponding figures.
During treatment cycle 1, patients with high tumor 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 tumor burden during treatment cycle 1 in the lenalidomide arm was adverse events. High tumor burden was defined as at least one lesion ≥ 5 cm in diameter or 3 lesions ≥ 3 cm.
Tabulated list of adverse reactions: The adverse reactions observed in patients treated with Lenalidomide are listed as follows 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, common, uncommon, rare, very rare, not known (be estimated from the available data).
Adverse reactions have been included under the appropriate category in the table according to the highest frequency observed.
Tabulated summary for combination therapy in MM: See Tables 19 A and B.
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Click on icon to see table/diagram/imageTabulated summary from monotherapy: The following tables are derived from data gathered during the main studies in monotherapy for myelodysplastic syndromes and mantle cell lymphoma. (See Tables 20 and 21.)
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Click on icon to see table/diagram/imageTabulated summary of post-marketing adverse reactions: In addition to the previously mentioned adverse reactions identified, the following table is derived from data gathered from post-marketing data. (See Table 22.)
Click on icon to see table/diagram/imageDescription of selected adverse reactions: Teratogenicity: Lenalidomide is structurally related to Thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. If Lenalidomide is taken during pregnancy, a teratogenic effect of Lenalidomide in humans is expected.
Neutropenia and thrombocytopenia: a. Newly diagnosed multiple myeloma: Patients who are not eligible for transplant treated with Lenalidomide in combination with low dose Dexamethasone: The combination of Lenalidomide with low dose Dexamethasone in newly diagnosed multiple myeloma patients is associated with a lower frequency of grade 3 and 4 thrombocytopenia.
b. Newly diagnosed multiple myeloma: Patients who are not eligible for transplant treated with Lenalidomide in combination with Melphalan and Prednisone: The combination of Lenalidomide with Melphalan and Prednisone in newly diagnosed multiple myeloma patients is associated with a higher frequency of grade 4 neutropenia.
The combination of Lenalidomide with melphalan and prednisone in newly diagnosed multiple myeloma patients is associated with a higher frequency of grade 3 and grade 4 thrombocytopenia.
c. Multiple myeloma: Patients with at least one prior therapy: The combination of Lenalidomide with Dexamethasone in multiple myeloma patients is associated with a higher incidence of grade 4 neutropenia. Grade 4 febrile neutropenia episodes were observed infrequently.
The combination of Lenalidomide with Dexamethasone in multiple myeloma patients is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia.
d. Myelodysplastic syndromes patients: In myelodysplastic syndromes patients, Lenalidomide is associated with a higher incidence of grade 3 or 4 neutropenia. Grade 3 or 4 febrile neutropenia episodes were observed in lenalidomide-treated patients compared with in patients on placebo). Lenalidomide is associated with a higher incidence of grade 3 or 4 thrombocytopenia.
e. Mantle cell lymphoma patients: In mantle cell lymphoma patients, Lenalidomide is associated with a higher incidence of grade 3 or 4 neutropenia. Grade 3 or 4 febrile neutropenia episodes were observed in lenalidomide-treated patients compared with in patients on control arm.
Venous thromboembolism: An increased risk of DVT and PE is associated with the use of the combination of lenalidomide with dexamethasone in patients with multiple myeloma, and to a lesser extent in patients treated with melphalan and prednisone or as monotherapy in patients with myelodysplastic syndromes and mantle cell lymphoma treated with lenalidomide monotherapy (see INTERACTIONS). 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 lenalidomide, particularly in those with known risk factors.
Hemorrhagic disorders: Hemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system disorders; nervous system disorders (intracranial hemorrhage); respiratory, thoracic and mediastinal disorders (epistaxis); gastrointestinal disorders (gingival bleeding, hemorrhoidal hemorrhage, rectal hemorrhage); renal and urinary disorders (hematuria); injury, poisoning and procedural complications (contusion) and vascular disorders (ecchymosis).
Allergic reactions: Cases of allergic reaction/hypersensitivity reactions have been reported. A possible cross-reaction between Lenalidomide and Thalidomide has been reported in the literature.
Severe skin reactions: Severe cutaneous reactions including SJS, TEN and DRESS have been reported with the use of Lenalidomide. Patients with a history of severe rash associated with Thalidomide treatment should not receive Lenalidomide (see PRECAUTIONS).
Second primary malignancies: In previously treated myeloma patients with lenalidomide/dexamethasone compared to controls, mainly comprising of basal cell or squamous cell skin cancers.
Acute myeloid leukemia: a. Multiple myeloma: Cases of AML have been observed in newly diagnosed multiple myeloma in patients taking lenalidomide treatment in combination with Melphalan or immediately following HDM/ASCT (see PRECAUTIONS). This increase was not observed in newly diagnosed multiple myeloma in patients taking Lenalidomide in combination with low dose Dexamethasone compared to Thalidomide in combination with Melphalan and Prednisone.
b. 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 PRECAUTIONS). The estimated 2- year cumulative risk of progression to AML were in patients with an isolated Del (5q) abnormality compared to patients with Del (5q) and one additional cytogenetic abnormality and in patients with a complex karyotype.
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 lenalidomide is administered with a statin.
Thyroid disorders: Cases of hypothyroidism and cases of hyperthyroidism have been reported.
Tumour flare reaction and tumour lysis syndrome: In Lenalidomide-treated patients experienced TFR, 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 baseline may be at risk of TFR. TLS was reported for one patient in each of the two treatment arms.
Gastrointestinal disorders: Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinal perforations may lead to septic complications and may be associated with fatal outcome.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
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