Lenangio 10/Lenangio 15 Adverse Reactions

Summary of the safety profile: Newly diagnosed multiple myeloma in patients treated with lenalidomide in combination with low dose dexamethasone.
A conservative approach was applied to determine the adverse reactions from CALGB 100104. The adverse reactions described in Table 22 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 22 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 lenalidomide 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 lenalidomide 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 lenalidomide 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 anemia (21.0% [13.8%]).
Newly diagnosed multiple myeloma patients who are not eligible for transplant receiving lenalidomide in combination with bortezomib and dexamethasone: In the SWOG S0777 study, the serious adverse reactions observed more frequently (≥ 5%) with lenalidomide in combination with intravenous bortezomib and dexamethasone than with lenalidomide in combination with dexamethasone were: Hypotension (6.5%), lung infection (5.7%), dehydration (5.0%).
The adverse reactions observed more frequently with lenalidomide in combination with bortezomib and dexamethasone than with lenalidomide in combination with dexamethasone were: Fatigue (73.7%), peripheral neuropathy (71.8%), thrombocytopenia (57.6%), constipation (56.1%), hypocalcaemia (50.0%).
Newly diagnosed multiple myeloma: patients who are not eligible for transplant 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%).
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 (≥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%); Anemia (5.3%).
The adverse reactions observed more frequently with MPR+R or MPR+p than MPp+p were: neutropenia (83.3%), anemia (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%).
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%), anemia (31.4%), thrombocytopenia (21.5%), and rash (21.2%).
Myelodysplastic syndromes: The overall safety profile of lenalidomide in patients with myelodysplastic syndromes is based on data from a total of 286 patients from one phase II study and one phase III study. In the phase II, all 148 patients were on lenalidomide treatment. In the phase III study, 69 patients were on lenalidomide 5 mg, 69 patients on lenalidomide 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 lenalidomide.
Serious adverse reactions include: Venous thromboembolism (deep vein thrombosis, pulmonary embolism); Grade 3 or 4 neutropenia, febrile neutropenia and grade 3 or 4 thrombocytopenia.
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 (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 lenalidomide in patients with mantle cell lymphoma is based on data from 254 patients from a phase II randomised, controlled study MCL-002.
Additionally, adverse drug reactions from supportive study MCL-001 have been included in table 24.
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%), anemia (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.
Follicular lymphoma: The overall safety profile of lenalidomide 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.
The serious adverse reactions observed most frequently (with a difference of at least 1 percentage point) in study NHL-007 in the lenalidomide/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 lenalidomide/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 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 (≥ 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 as follows 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 lenalidomide maintenance.
The data were not adjusted according to the longer duration of treatment in the lenalidomide-containing arms continued until disease progression versus the placebo arms in the pivotal multiple myeloma studies. (See Table 22.)

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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 lenalidomide-containing arms continued until disease progression versus the comparator arms in the pivotal multiple myeloma studies. (See Table 23 a and b.)

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Tabulated summary from monotherapy: The following table are derived from data gathered during the main studies in monotherapy for myelodysplastic syndromes and mantle cell lymphoma. (See Table 24.)

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Algorithm applied for inclusion in the SmPC: All ADRs captured by the phase III study algorithm are included in the EU SmPC. For these ADRs, an additional check of the frequency of the ADRs captured by the phase II study algorithm was undertaken and, if the frequency of the ADRs in the phase II study was higher than in the phase III study, the event was included in the EU SmPC at the frequency it occurred in the phase II study.
# Algorithm applied for myelodysplastic syndromes: Myelodysplastic syndromes phase III study (double-blind safety population, difference between lenalidomide 5/10mg and placebo by initial dosing regimen occurring in at least 2 subjects); All treatment-emergent adverse events with ≥ 5% of subjects in lenalidomide and at least 2% difference in proportion between lenalidomide and placebo; All treatment-emergent grade 3 or 4 adverse events in 1% of subjects in lenalidomide and at least 1% difference in proportion between lenalidomide and placebo; All treatment-emergent serious adverse events in 1% of subjects in lenalidomide and at least 1% difference in proportion between lenalidomide and placebo.
Myelodysplastic syndromes phase II study: All treatment-emergent adverse events with ≥ 5% of lenalidomide treated subjects; All treatment-emergent grade 3 or 4 adverse\events in 1% of lenalidomide treated subjects; All treatment-emergent serious adverse events in 1% of lenalidomide treated subjects. (See Table 25.)

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Algorithm applied for mantle cell lymphoma: Mantle cell lymphoma controlled Phase II study; All treatment-emergent adverse events with ≥ 5% of subjects in lenalidomide arm and at least 2% difference in proportion between lenalidomide and control arm; 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; 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: All treatment-emergent adverse events with ≥ 5% of subjects; All grade 3 or 4 treatment-emergent adverse events reported in 2 or more subjects; 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 lenalidomide in combination with rituximab for patients with follicular lymphoma. (See Table 26.)

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Algorithm applied for follicular lymphoma: Controlled-Phase 3 trial: NHL-007 ADRs- All treatment-emergent AEs with ≥ 5.0% of subjects in lenalidomide/rituximab arm and at least 2.0% higher frequency (%) in Len arm compared to control arm - (Safety population); NHL-007 Gr 3/4 ADRs- All Grades 3 or Grade 4 treatment-emergent AEs with at least 1.0% subjects in lenalidomide/rituximab arm and at least 1.0% higher frequency in lenalidomide arm compared to control arm - (safety population); NHL-007 Serious ADRs- All serious treatment-emergent AEs with at least 1.0% subjects in lenalidomide/rituximab arm and at least 1.0% higher frequency in lenalidomide/rituximab arm compared to control arm - (safety population) FL single arm - phase 3 trial: NHL-008 ADRs - All treatment-emergent adverse events with ≥ 5.0% of subjects; NHL-008 Gr 3/4 ADRs - All Grade 3/4 treatment-emergent adverse events reported in ≥ 1.0% of subjects; NHL-008 Serious ADRs- All serious treatment-emergent adverse events reported in ≥ 1.0% of subjects.
Tabulated summary of post-marketing adverse reactions: In addition to the previously mentioned adverse reactions identified from the pivotal clinical trials, the following table is derived from data gathered from post-marketing data. (See Table 27.)

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Description 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. In monkeys, Lenalidomide induced malformations similar to those described with thalidomide. If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
Neutropenia and thrombocytopenia: Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with lenalidomide maintenance: Lenalidomide 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 lenalidomide 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 lenalidomide 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).
Lenalidomide 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 lenalidomide 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 lenalidomide in combination with dexamethasone: The combination of lenalidomide 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 lenalidomide 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 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 (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 lenalidomide 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 lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of Grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients).
The combination of lenalidomide 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 lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients).
Myelodysplastic syndromes patients: In myelodysplastic syndromes patients, lenalidomide is associated with a higher incidence of Grade 3 or 4 neutropenia (74.6% in lenalidomide-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 lenalidomide-treated patients compared with 0.0% in patients on placebo). Lenalidomide is associated with a higher incidence of Grade 3 or 4 thrombocytopenia (37% in lenalidomide-treated patients compared with 1.5% in patients on placebo in the phase 3 study).
Mantle cell lymphoma patients: In mantle cell lymphoma patients, lenalidomide is associated with a higher incidence of Grade 3 or 4 neutropenia (43.7% in lenalidomide-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 lenalidomide-treated patients compared with 2.4% in patients on control arm.
Follicular lymphoma patients: The combination of lenalidomide with rituximab in follicular lymphoma is associated with a higher rate of Grade 3 or Grade 4 neutropenia (50.7% in lenalidomide/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 lenalidomide/rituximab treated patients compared with 0.7% in placebo/rituximab treated patients).
Lenalidomide in combination with rituximab is also associated with a higher incidence of Grade 3 or 4 thrombocytopenia (1.4% in lenalidomide/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 lenalidomide with dexamethasone in patients with multiple myeloma, and to a lesser extent in patients treated with lenalidomide in combination with melphalan and prednisone or in patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma treated with lenalidomide monotherapy.
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.
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 lenalidomide. A possible cross-reaction between lenalidomide and thalidomide has been reported in the literature.
Patients with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.
Second primary malignancies: In clinical trials in previously treated myeloma patients with lenalidomide/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 lenalidomide treatment in combination with melphalan or immediately following HDM/ASCT. This increase was not observed in clinical trials of newly diagnosed multiple myeloma in patients taking lenalidomide 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. 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 lenalidomide 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 IHCp53 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 lenalidomide is administered with a statin.
Thyroid disorders: Cases of hypothyroidism and cases of hyperthyroidism have been reported (see Thyroid disorders under Precautions).
Tumour flare reaction and tumour lysis syndrome: In study MCL-002, approximately 10% of lenalidomide-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.
In study NHL-007, TFR was reported in 19/146 (13.0%) of patients in the lenalidomide/rituximab arm versus 1/148 (0.7%) patients in the placebo/rituximab arm. Most TFRs (18 out of 19) reported in the lenalidomide/rituximab arm occurred during first two cycles of treatment. One FL patient in the lenalidomide/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 lenalidomide/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 lenalidomide/rituximab therapy due to TFR or TLS.
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.