Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Mylan Ireland Limited, Unit 35/36 Grange Parade, Baldoyle Industrial Estate, Dublin 13, Ireland
When lenalidomide is given in combination with other medicinal products, the corresponding Summary of Product Characteristics must be consulted prior to initiation of treatment.
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential.
A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria:
For women of childbearing potential, lenalidomide is contraindicated unless all of the following are met:
For male patients taking lenalidomide, pharmacokinetic data has demonstrated that lenalidomide is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after stopping the substance in the healthy subject (see section 5.2). As a precaution and taking into account special populations with prolonged elimination time such as renal impairment, all male patients taking lenalidomide must meet the following conditions:
The prescriber must ensure that for women of childbearing potential:
Women of childbearing potential must use at least one effective method of contraception for at least 4 weeks before therapy, during therapy, and until at least 4 weeks after lenalidomide therapy and even in case of dose interruption unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated.
The following can be considered to be examples of suitable methods of contraception:
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide in combination therapy, and to a lesser extent in patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma taking lenalidomide monotherapy, combined oral contraceptive pills are not recommended (see also section 4.5). If a patient is currently using combined oral contraception the patient should switch to one of the effective methods listed above. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone (see section 4.5).
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia.
Copper-releasing intrauterine devices are generally not recommended due to the potential risks of infection at the time of insertion and menstrual blood loss which may compromise patients with neutropenia or thrombocytopenia.
According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for women of childbearing potential as outlined below. This requirement includes women of childbearing potential who practice absolute and continuous abstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the prescription.
A medically supervised pregnancy test should be performed during the consultation, when lenalidomide is prescribed, or in the 3 days prior to the visit to the prescriber once the patient had been using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant when she starts treatment with lenalidomide.
A medically supervised pregnancy test should be repeated at least every 4 weeks, including at least 4 weeks after the end of treatment, except in the case of confirmed tubal sterilisation. These pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.
Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment for safe disposal.
Patients should not donate blood during therapy or for at least 7 days following discontinuation of lenalidomide.
Healthcare professionals and caregivers should wear disposable gloves when handling the blister or capsule. Women who are pregnant or suspect they may be pregnant should not handle the blister or capsule (see section 6.6).
In order to assist patients in avoiding foetal exposure to lenalidomide, the marketing authorisation holder will provide educational material to health care professionals to reinforce the warnings about the expected teratogenicity of lenalidomide, to provide advice on contraception before therapy is started, and to provide guidance on the need for pregnancy testing. The prescriber must inform male and female patients about the expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme and provide patients with appropriate patient educational brochure, patient card and/or equivalent tool in accordance to the national implemented patient card system. A national controlled distribution system has been implemented in collaboration with each National Competent Authority. The controlled distribution system includes the use of a patient card and/or equivalent tool for prescribing and/or dispensing controls, and the collecting of detailed data relating to the indication in order to monitor closely the off-label use within the national territory. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the prescription and following a medically supervised negative pregnancy test result. Prescriptions for women of childbearing potential can be for a maximum duration of treatment of 4 weeks, and prescriptions for all other patients can be for a maximum duration of treatment of 12 weeks.
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors and within the first 12 months when used in combination with dexamethasone. Patients with known risk factors – including prior thrombosis – should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (eg. smoking, hypertension, and hyperlipidaemia).
In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism). The risk of venous thromboembolism was seen to a lesser extent with lenalidomide in combination with melphalan and prednisone.
In patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma, treatment with lenalidomide monotherapy was associated with a lower risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) than in patients with multiple myeloma treated with lenalidomide in combination therapy (see sections 4.5 and 4.8).
In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an increased risk of arterial thromboembolism (predominantly myocardial infarction and cerebrovascular event) and was seen to a lesser extent with lenalidomide in combination with melphalan and prednisone. The risk of arterial thromboembolism is lower in patients with multiple myeloma treated with lenalidomide monotherapy than in patients with multiple myeloma treated with lenalidomide in combination therapy.
Consequently, patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Concomitant administration of erythropoietic agents or previous history of thromboembolic events may also increase thrombotic risk in these patients. Therefore, erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone. A haemoglobin concentration above 12 g/dl should lead to discontinuation of erythropoietic agents.
Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Prophylactic antithrombotic medicines should be recommended, especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient’s underlying risk factors.
If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, the lenalidomide treatment may be restarted at the original dose dependent upon a benefit risk assessment. The patient should continue anticoagulation therapy during the course of lenalidomide treatment.
Cases of pulmonary hypertension, some fatal, have been reported in patients treated with lenalidomide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during lenalidomide therapy.
The major dose limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. A complete blood cell count, including white blood cell count with differential count, platelet count, haemoglobin, and haematocrit should be performed at baseline, every week for the first 8 weeks of lenalidomide treatment and monthly thereafter to monitor for cytopenias. In mantle cell lymphoma patients, the monitoring scheme should be every 2 weeks in Cycles 3 and 4, and then at the start of each cycle. A dose reduction may be required (see section 4.2).
In case of neutropenia, the physician should consider the use of growth factors in patient management.
Patients should be advised to promptly report febrile episodes.
Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in patients receiving concomitant medicinal products susceptible to induce bleeding (see section 4.8, Haemorrhagic disorders).
Co-administration of lenalidomide with other myelosuppressive agents should be undertaken with caution.
Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with lenalidomide maintenance:
The adverse reactions from CALGB 100104 included events reported post-high dose melphalan and ASCT (HDM/ASCT) as well as events from the maintenance treatment period. A second analysis identified events that occurred after the start of maintenance treatment. In IFM 2005-02, the adverse reactions were from the maintenance treatment period only.
Overall, grade 4 neutropenia was observed at a higher frequency in the lenalidomide maintenance arms compared to the placebo maintenance arms in the 2 studies evaluating lenalidomide maintenance in NDMM patients who have undergone ASCT (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). Patients should be advised to promptly report febrile episodes, a treatment interruption and/or dose reduction may be required (see section 4.2).
Grade 3 or 4 thrombocytopenia was observed at a higher frequency in the lenalidomide maintenance arms compared to the placebo maintenance arms in studies evaluating lenalidomide maintenance in NDMM patients who have undergone ASCT (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). Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in patients receiving concomitant medicinal products susceptible to induce bleeding (see section 4.8, Haemorrhagic disorders).
Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with bortezomib and dexamethasone:
Grade 4 neutropenia was observed at a lower frequency in the lenalidomide in combination with bortezomib and dexamethasone (RVd) arm compared to 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 and Rd arm (0.0% vs 0.4%). Patients should be advised to promptly report febrile episodes; a treatment interruption and/or dose reduction may be required (see section 4.2).
Grade 3 or 4 thrombocytopenia was observed at a higher frequency in the RVd arm compared to 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 low dose dexamethasone:
Grade 4 neutropenia was observed in the lenalidomide arms in combination with dexamethasone to a lesser extent than in the comparator arm (8.5% in the Rd [continuous treatment] and Rd18 [treatment for 18 four- week cycles] compared with 15% in the melphalan/prednisone/thalidomide arm, see section 4.8). Grade 4 febrile neutropenia episodes were consistent with the comparator arm (0.6 % in the Rd and Rd18 lenalidomide/dexamethasone-treated patients compared with 0.7% in the melphalan/prednisone/thalidomide arm, see section 4.8).
Grade 3 or 4 thrombocytopenia was observed to a lesser extent in the Rd and Rd18 arms than in the comparator arm (8.1% vs 11.1%, respectively).
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 clinical trials of newly diagnosed multiple myeloma patients is associated with a higher incidence of grade 4 neutropenia (34.1% in melphalan, prednisone and lenalidomide arm followed by lenalidomide [MPR+R] and melphalan, prednisone and lenalidomide followed by placebo [MPR+p] treated patients compared with 7.8% in MPp+p-treated patients; see section 4.8). Grade 4 febrile neutropenia episodes were observed infrequently (1.7% in MPR+R/MPR+p treated patients compared to 0.0% in MPp+p treated patients; see section 4.8).
The combination of lenalidomide with melphalan and prednisone in multiple myeloma patients is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (40.4% in MPR+R/MPR+p treated patients, compared with 13.7% in MPp+p-treated patients; see section 4.8).
Multiple myeloma: patients with at least one prior therapy:
The combination of lenalidomide with dexamethasone in multiple myeloma patients with at least one prior therapy 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; see section 4.8). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients; see section 4.8).
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; see section 4.8).
Myelodysplastic syndromes:
Lenalidomide treatment in myelodysplastic syndromes patients is associated with a higher incidence of grade 3 and 4 neutropenia and thrombocytopenia compared to patients on placebo (see section 4.8).
Mantle cell lymphoma:
Lenalidomide treatment in mantle cell lymphoma patients is associated with a higher incidence of Grade 3 and 4 neutropenia compared with patients on the control arm (see section 4.8).
Follicular lymphoma:
The combination of lenalidomide with rituximab in follicular lymphoma patients is associated with a higher incidence of Grade 3 or 4 neutropenia compared with patients on the placebo/rituximab arm. Febrile neutropenia and Grade 3 or 4 thrombocytopenia were more commonly observed in the lenalidomide/ rituximab arm (see section 4.8).
Thyroid disorders:
Cases of hypothyroidism and cases of hyperthyroidism have been reported. Optimal control of comorbid conditions influencing thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.
Peripheral neuropathy:
Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral neuropathy. There was no increase in peripheral neuropathy observed with lenalidomide in combination with dexamethasone or melphalan and prednisone or lenalidomide monotherapy or with long term use of lenalidomide for the treatment of newly diagnosed multiple myeloma.
The combination of lenalidomide with intravenous bortezomib and dexamethasone in multiple myeloma patients is associated with a higher frequency of peripheral neuropathy. The frequency was lower when bortezomib was administered subcutaneously. For additional information, see Section 4.8 and the SmPC for bortezomib.
Tumour flare reaction and tumour lysis syndrome:
Because lenalidomide has anti-neoplastic activity the complications of tumour lysis syndrome (TLS) may occur. TLS and tumour flare reaction (TFR) have commonly been observed in patients with chronic lymphocytic leukemia (CLL), and uncommonly in patients with lymphomas, who were treated with lenalidomide. Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS and TFR are those with high tumour burden prior to treatment. Caution should be practiced when introducing these patients to lenalidomide. These patients should be monitored closely, especially during the first cycle or dose-escalation, and appropriate precautions taken. There have been rare reports of TLS in patients with MM treated with lenalidomide and no reports in patients with MDS treated with lenalidomide.
Mantle cell lymphoma:
Careful monitoring and evaluation for TFR is recommended. Patients with high mantle cell lymphoma International Prognostic Index (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. Tumour flare reaction may mimic progression of disease (PD). Patients in studies MCL-002 and MCL-001 that experienced Grade 1 and 2 TFR were treated with corticosteroids, NSAIDs and/or narcotic analgesics for management of TFR symptoms. The decision to take therapeutic measures for TFR should be made after careful clinical assessment of the individual patient (see sections 4.2 and 4.8).
Follicular lymphoma:
Careful monitoring and evaluation for TFR is recommended. Tumour flare may mimic PD. Patients who experienced Grade 1 and 2 TFR were treated with corticosteroids, NSAIDs and/or narcotic analgesics for management of TFR symptoms. The decision to take therapeutic measures for TFR should be made after careful clinical assessment of the individual patient (see sections 4.2 and 4.8).
Careful monitoring and evaluation for TLS is recommended. Patients should be well hydrated and receive TLS prophylaxis, in addition to weekly chemistry panels during the first cycle or longer, as clinically indicated (see sections 4.2 and 4.8).
Mantle cell lymphoma:
Lenalidomide is not recommended for the treatment of patients with high tumour burden if alternative treatment options are available.
Early death: 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, there were 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 (40%) and 6/28 (21%) (See section 5.1).
Adverse events: In study MCL-002, 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%). Patients with high tumour burden should therefore be closely monitored for adverse reactions (see Section 4.8) including signs of tumour flare reaction (TFR). Please refer to section 4.2 for dose adjustments for TFR. High tumour burden was defined as at least one lesion ≥5 cm in diameter or 3 lesions ≥3 cm.
Cases of allergic reactions including angioedema, anaphylactic reaction and severe cutaneous reactions including SJS, TEN and DRESS have been reported in patients treated with lenalidomide (see section 4.8). Patients should be advised of the signs and symptoms of these reactions by their prescribers and should be told to seek medical attention immediately if they develop these symptoms. Lenalidomide must be discontinued for angioedema, anaphylactic reaction, exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed following discontinuation for these reactions. Interruption or discontinuation of lenalidomide should be considered for other forms of skin reaction depending on severity. Patients who had previous allergic reactions while treated with thalidomide should be monitored closely, as 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
An increase of second primary malignancies (SPM) has been observed in clinical trials in previously treated myeloma patients receiving lenalidomide/dexamethasone (3.98 per 100 person-years) compared to controls (1.38 per 100 person-years). Non-invasive SPM comprise basal cell or squamous cell skin cancers. Most of the invasive SPMs were solid tumour malignancies.
In clinical trials of newly diagnosed multiple myeloma patients not eligible for transplant, a 4.9-fold increase in incidence rate of hematologic SPM (cases of AML, MDS) has been observed in patients receiving lenalidomide in combination with melphalan and prednisone until progression (1.75 per 100 person-years) compared with melphalan in combination with prednisone (0.36 per 100 person-years).
A 2.12-fold increase in incidence rate of solid tumour SPM has been observed in patients receiving lenalidomide (9 cycles) in combination with melphalan and prednisone (1.57 per 100 person-years) compared with melphalan in combination with prednisone (0.74 per 100 person-years).
In patients receiving lenalidomide in combination with dexamethasone until progression or for 18 months, the hematologic SPM incidence rate (0.16 per 100 person-years) was not increased as compared to thalidomide in combination with melphalan and prednisone (0.79 per 100 person-years).
A 1.3-fold increase in incidence rate of solid tumour SPM has been observed in patients receiving lenalidomide in combination with dexamethasone until progression or for 18 months (1.58 per 100 person- years) compared to thalidomide in combination with melphalan and prednisone (1.19 per 100 person-years).
In newly diagnosed multiple myeloma patients receiving lenalidomide in combination with bortezomib and dexamethasone, the hematologic SPM incidence rate was 0.00 – 0.16 per 100 person-years and the incidence rate of solid tumour SPM 0.21 – 1.04 per 100 person-years.
The increased risk of secondary primary malignancies associated with lenalidomide is relevant also in the context of NDMM after stem cell transplantation. Though this risk is not yet fully characterized, it should be kept in mind when considering and using Lenalidomide Mylan in this setting.
The incidence rate of hematologic malignancies, most notably AML, MDS and B-cell malignancies (including Hodgkin’s lymphoma), was 1.31 per 100 person-years for the lenalidomide arms and 0.58 per 100 person-years for the placebo arms (1.02 per 100 person-years for patients exposed to lenalidomide after ASCT and 0.60 per 100 person-years for patients not-exposed to lenalidomide after ASCT). The incidence rate of solid tumour SPMs was 1.36 per 100 person-years for the lenalidomide arms and 1.05 per 100 person- years for the placebo arms (1.26 per 100 person-years for patients exposed to lenalidomide after ASCT and 0.60 per 100 person-years for patients not-exposed to lenalidomide after ASCT).
The risk of occurrence of hematologic SPM must be taken into account before initiating treatment with lenalidomide either in combination with melphalan or immediately following high-dose melphalan and ASCT. Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of SPM and institute treatment as indicated.
Karyotype:
Baseline variables including complex cytogenetics are associated with progression to AML in subjects who are transfusion dependent and have a Del (5q) abnormality. In a combined analysis of two clinical trials of lenalidomide in low- or intermediate-1-risk myelodysplastic syndromes, subjects who had a complex cytogenetics had the highest estimated 2-year cumulative risk of progression to AML (38.6%). The estimated 2-year rate of progression to AML in patients with an isolated Del (5q) abnormality was 13.8%, compared to 17.3% for patients with Del (5q) and one additional cytogenetic abnormality.
As a consequence, the benefit/risk ratio of lenalidomide when MDS is associated with Del (5q) and complex cytogenetics is unknown.
TP53 status:
A TP53 mutation is present in 20 to 25% of lower-risk MDS Del 5q patients and is associated with a higher risk of progression to acute myeloid leukaemia (AML). In a post-hoc analysis of a clinical trial of lenalidomide in low- or intermediate-1-risk myelodysplastic syndromes (MDS-004), the estimated 2-year rate of progression to AML was 27.5 % in patients with IHC-p53 positivity (1% cut-off level of strong nuclear staining, using immunohistochemical assessment of p53 protein as a surrogate for TP53 mutation status) and 3.6% in patients with IHC-p53 negativity (p=0.0038) (see section 4.8)
In mantle cell lymphoma, AML, B-cell malignancies and non-melanoma skin cancer (NMSC) are potential risks.
In a relapsed/refractory iNHL study which included follicular lymphoma patients, no increased risk of SPMs in the lenalidomide/rituximab arm, compared to the placebo/rituximab arm, was observed. Hematologic SPM of AML occurred in 0.29 per 100 person-years in the lenalidomide/rituximab arm compared with 0.29 per 100 person-years in patients receiving placebo/rituximab. The incidence rate of hematologic plus solid tumour SPMs (excluding non-melanoma skin cancers) was 0.87 per 100 person-years in the lenalidomide/rituximab arm, compared to 1.17 per 100 person-years in patients receiving placebo/rituximab with a median follow-up of 30.59 months (range 0.6 to 50.9 months).
Non-melanoma skin cancers are identified risks and comprise squamous cell carcinomas of skin or basal cell carcinomas.
Physicians should monitor patients for the development of SPMs. Both the potential benefit of lenalidomide and the risk of SPMs should be considered when considering treatment with lenalidomide.
Hepatic failure, including fatal cases, has been reported in patients treated with lenalidomide in combination therapy: acute hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis have been reported. The mechanisms of severe drug-induced hepatotoxicity remain unknown although, in some cases, pre-existing viral liver disease, elevated baseline liver enzymes, and possibly treatment with antibiotics might be risk factors.
Abnormal liver function tests were commonly reported and were generally asymptomatic and reversible upon dosing interruption. Once parameters have returned to baseline, treatment at a lower dose may be considered.
Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal impairment in order to avoid plasma levels which may increase the risk for higher haematological adverse reactions or hepatotoxicity. Monitoring of liver function is recommended, particularly when there is a history of or concurrent viral liver infection or when lenalidomide is combined with medicinal products known to be associated with liver dysfunction.
Patients with multiple myeloma are prone to develop infections including pneumonia. A higher rate of infections was observed with lenalidomide in combination with dexamethasone than with MPT in patients with NDMM who are not eligible for transplant, and with lenalidomide maintenance compared to placebo in patients with NDMM who had undergone ASCT. Grade ≥3 infections occurred within the context of neutropenia in less than one-third of the patients. Patients with known risk factors for infections should be closely monitored. All patients should be advised to seek medical attention promptly at the first sign of infection (eg, cough, fever, etc) thereby allowing for early management to reduce severity.
Cases of viral reactivation have been reported in patients receiving lenalidomide, including serious cases of herpes zoster or hepatitis B virus (HBV) reactivation.
Some of the cases of viral reactivation had a fatal outcome.
Some of the cases of herpes zoster reactivation resulted in disseminated herpes zoster, meningitis herpes zoster or ophthalmic herpes zoster requiring a temporary hold or permanent discontinuation of the treatment with lenalidomide and adequate antiviral treatment.
Reactivation of hepatitis B has been reported rarely in patients receiving lenalidomide who have previously been infected with the hepatitis B virus (HBV). Some of these cases have progressed to acute hepatic failure resulting in discontinuation of lenalidomide and adequate antiviral treatment. Hepatitis B virus status should be established before initiating treatment with lenalidomide. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.
Caution should be exercised when lenalidomide is used in patients previously infected with HBV, including patients who are anti-HBc positive but HBsAg negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy.
Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported with lenalidomide. PML was reported several months to several years after starting the treatment with lenalidomide. Cases have generally been reported in patients taking concomitant dexamethasone or prior treatment with other immunosuppressive chemotherapy. Physicians should monitor patients at regular intervals and should consider PML in the differential diagnosis in patients with new or worsening neurological symptoms, cognitive or behavioural signs or symptoms. Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.
The evaluation for PML should be based on neurological examination, magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR) or a brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additional follow-up and evaluation may be warranted if no alternative diagnosis can be established.
If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed, lenalidomide must be permanently discontinued.
There was a higher rate of intolerance (grade 3 or 4 adverse events, serious adverse events, discontinuation) in patients with age >75 years, ISS stage III, ECOG PS≥2 or CLcr<60 mL/min when lenalidomide is given in combination. Patients should be carefully assessed for their ability to tolerate lenalidomide in combination, with consideration to age, ISS stage III, ECOG PS≥2 or CLcr<60 mL/min (see sections 4.2 and 4.8).
Cataract has been reported with a higher frequency in patients receiving lenalidomide in combination with dexamethasone particularly when used for a prolonged time. Regular monitoring of visual ability is recommended.
Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone (see sections 4.4 and 4.8).
No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme inducer. In an in vitro study with human hepatocytes, lenalidomide, at various concentrations tested did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. Therefore, induction leading to reduced efficacy of medicinal products, including hormonal contraceptives, is not expected if lenalidomide is administered alone. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4 and is likely to also affect other enzymes as well as transporters. It may not be excluded that the efficacy of oral contraceptives may be reduced during treatment. Effective measures to avoid pregnancy must be taken (see sections 4.4 and 4.6).
Co-administration of multiple 10 mg doses of lenalidomide had no effect on the single dose pharmacokinetics of R- and S- warfarin. Co-administration of a single 25 mg dose of warfarin had no effect on the pharmacokinetics of lenalidomide. However, it is not known whether there is an interaction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is a weak to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin concentration is advised during the treatment.
Concomitant administration with lenalidomide 10 mg once daily increased the plasma exposure of digoxin (0.5 mg, single dose) by 14% with a 90% CI (confidence interval) [0.52%-28.2%]. It is not known whether the effect will be different in the clinical use (higher lenalidomide doses and concomitant treatment with dexamethasone). Therefore, monitoring of the digoxin concentration is advised during lenalidomide treatment.
There is an increased risk of rhabdomyolysis when statins are administered with lenalidomide, which may be simply additive. Enhanced clinical and laboratory monitoring is warranted notably during the first weeks of treatment.
Co-administration of single or multiple doses of dexamethasone (40 mg once daily) has no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg once daily).
In vitro, lenalidomide is a substrate of P-gp, but is not a P-gp inhibitor. Co-administration of multiple doses of the strong P-gp inhibitor quinidine (600 mg, twice daily) or the moderate P-gp inhibitor/substrate temsirolimus (25 mg) has no clinically relevant effect on the pharmacokinetics of lenalidomide (25 mg). Co-administration of lenalidomide does not alter the pharmacokinetics of temsirolimus.
Due to the teratogenic potential, lenalidomide must be prescribed under a Pregnancy Prevention Programme (see section 4.4) unless there is reliable evidence that the patient does not have childbearing potential.
Women of childbearing potential should use effective method of contraception. If pregnancy occurs in a woman treated with lenalidomide, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking lenalidomide, it is recommended to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice.
Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after stopping the substance in the healthy subject (see section 5.2). As a precaution and taking into account special populations with prolonged elimination time such as renal impairment, all male patients taking lenalidomide should use condoms throughout treatment duration, during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception.
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects.
Lenalidomide induced malformation in monkeys similar to those described with thalidomide (see section 5.3). Therefore, a teratogenic effect of lenalidomide is expected and lenalidomide is contraindicated during pregnancy (see section 4.3).
It is not known whether lenalidomide is excreted in breast milk. Therefore, breast-feeding should be discontinued during therapy with lenalidomide.
A fertility study in rats with lenalidomide doses up to 500 mg/kg (approximately 200 to 500 times the human doses of 25 mg and 10 mg, respectively, based on body surface area) produced no adverse effects on fertility and no parental toxicity.
Lenalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have been reported with the use of lenalidomide. Therefore, caution is recommended when driving or operating machines.
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 lenalidomide maintenance than placebo were:
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%]).
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:
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%).
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:
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%).
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:
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%).
In two phase 3 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:
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%).
The overall safety profile of lenalidomide 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 lenalidomide treatment. In the phase 3 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:
The most commonly observed adverse reactions which occurred more frequently in the lenalidomide 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%).
The overall safety profile of lenalidomide 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 lenalidomide arm compared with the control arm were:
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%) (see section 5.1).
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.
The adverse reactions observed in patients treated with lenalidomide 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.
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 section 5.1).
Table 1. ADRs reported in clinical trials in patients with multiple myeloma treated with lenalidomide maintenance therapy:
All ADRs:
Very common: Pneumonias◊,a, Upper respiratory tract infection, Neutropenic infection, Bronchitis◊, Influenza◊, Gastroenteritis◊, Sinusitis, Nasopharyngitis, Rhinitis
Common: Infection◊, Urinary tract infection◊,*, Lower respiratory tract infection, Lung infection◊
Grade 3-4 ADRs:
Very common: Pneumonias◊,a, Neutropenic infection
Common: Sepsis◊,b, Bacteraemia, Lung infection◊, Lower respiratory tract infection bacterial, Bronchitis◊, Influenza◊, Gastroenteritis◊, Herpes zoster◊, Infection◊
All ADRs:
Common: Myelodysplastic syndrome◊,*
All ADRs:
Very common: Neutropenia^,◊, Febrile neutropenia^,◊, Thrombocytopenia^,◊, Anemia, Leucopenia◊, Lymphopenia
Grade 3-4 ADRs:
Very common: Neutropenia^,◊, Febrile neutropenia^,◊, Thrombocytopenia^,◊, Anemia, Leucopenia◊, Lymphopenia
Common: Pancytopenia◊
All ADRs:
Very common: Hypokalaemia
Grade 3-4 ADRs:
Common: Hypokalaemia, Dehydration
All ADRs:
Very common: Paraesthesia
Common: Peripheral neuropathyc
Grade 3-4 ADRs:
Common: Headache
All ADRs:
Common: Pulmonary embolism◊,*
Grade 3-4 ADRs:
Common: Deep vein thrombosis^,◊,d
All ADRs:
Very common: Cough
Common: Dyspnoea◊, Rhinorrhoea
Grade 3-4 ADRs:
Common: Dyspnoea◊
All ADRs:
Very common: Diarrhoea, Constipation, Abdominal pain, Nausea
Common: Vomiting, Abdominal pain upper
Grade 3-4 ADRs:
Common: Diarrhoea, Vomiting, Nausea
All ADRs:
Very common: Abnormal liver function tests
Grade 3-4 ADRs:
Common: Abnormal liver function tests
All ADRs:
Very common: Rash, Dry skin
Grade 3-4 ADRs:
Common: Rash, Pruritus
All ADRs:
Very common: Muscle spasms
Common: Myalgia, Musculoskeletal pain
All ADRs:
Very common: Fatigue, Asthenia, Pyrexia
Grade 3-4 ADRs:
Common: 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 “Pneumonias” 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
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 section 5.1).
Table 2. ADRs reported in clinical studies in patients with multiple myeloma treated with lenalidomide in combination with bortezomib and dexamethasone, dexamethasone, or melphalan and prednisone:
All ADRs:
Very common: Pneumonia◊,◊◊, Upper respiratory tract infection◊, Bacterial, viral and fungal infections (including opportunistic infections)◊, Nasopharyngitis, Pharyngitis, Bronchitis◊, Rhinitis
Common: Sepsis◊,◊◊, Lung infection◊◊, Urinary tract infection◊◊, Sinusitis◊
Grade 3-4 ADRs:
Common: Pneumonia◊,◊◊, Bacterial, viral and fungal infections (including opportunistic infections)◊, Cellulitis◊, Sepsis◊,◊◊, Lung infection◊◊, Bronchitis◊, Respiratory tract infection◊◊, Urinary tract infection◊◊, Enterocolitis infectious
All ADRs:
Uncommon: Basal cell carcinoma^,◊, Squamous skin cancer^,◊,*
Grade 3-4 ADRs:
Common: Acute myeloid leukaemia◊, Myelodysplastic syndrome◊, Squamous cell carcinoma of skin^,◊,**
Uncommon: T-cell type acute leukaemia◊, Basal cell carcinoma^,◊, Tumour lysis syndrome
All ADRs:
Very common: Neutropenia^,◊,◊◊, Thrombocytopenia^,◊,◊◊, Anemia◊, Haemorrhagic disorder^, Leucopenias, Lymphopenia
Common: Febrile neutropenia^,◊, Pancytopenia◊
Uncommon: Haemolysis, Autoimmune haemolytic anemia, Haemolytic anemia
Grade 3-4 ADRs:
Very common: Neutropenia^,◊,◊◊, Thrombocytopenia^,◊,◊◊, Anemia◊, Leucopenias, Lymphopenia
Common: Febrile neutropenia^,◊, Pancytopenia◊, Haemolytic anemia
Uncommon: Hypercoagulation, Coagulopathy
All ADRs:
Uncommon: Hypersensitivity^
All ADRs:
Common: Hypothyroidism
All ADRs:
Very common: Hypokalaemia◊,◊◊, Hyperglycaemia, Hypoglycaemia, Hypocalcaemia◊, Hyponatraemia◊, Dehydration◊◊, Decreased appetite◊◊, Weight decreased
Common: Hypomagnesaemia, Hyperuricaemia, Hypercalcaemia+
Grade 3-4 ADRs:
Common: Hypokalaemia◊,◊◊, Hyperglycaemia, Hypocalcaemia◊, Diabetes mellitus◊, Hypophosphataemia, Hyponatraemia◊, Hyperuricaemia, Gout, Dehydration◊◊, Decreased appetite◊◊, Weight decreased
All ADRs:
Very common: Depression, Insomnia
Uncommon: Loss of libido
Grade 3-4 ADRs:
Common: Depression, Insomnia
All ADRs:
Very common: Peripheral neuropathies◊◊, Paraesthesia, Dizziness◊◊, Tremor, Dysgeusia, Headache
Common: Ataxia, Balance impaired, Syncope◊◊, Neuralgia, Dysaesthesia
Grade 3-4 ADRs:
Very common: Peripheral neuropathies◊◊
Common: Cerebrovascular accident◊, Dizziness◊◊, Syncope◊◊, Neuralgia
Uncommon: Intracranial haemorrhage^, Transient ischaemic attack, Cerebral ischemia
All ADRs:
Very common: Cataracts, Blurred vision
Common: Reduced visual acuity
Grade 3-4 ADRs:
Common: Cataract
Uncommon: Blindness
All ADRs:
Common: Deafness (Including Hypoacusis), Tinnitus
All ADRs:
Common: Atrial fibrillation◊,◊◊, Bradycardia
Uncommon: Arrhythmia, QT prolongation, Atrial flutter, Ventricular extrasystoles
Grade 3-4 ADRs:
Common: Myocardial infarction (including acute)^,◊, Atrial fibrillation◊,◊◊, Congestive cardiac failure◊, Tachycardia, Cardiac failure◊,◊◊, Myocardial ischemia◊
All ADRs:
Very common: Venous thromboembolic events^, predominantly deep vein thrombosis and pulmonary embolism^,◊,◊◊, Hypotension◊◊
Common: Hypertension, Ecchymosis^
Grade 3-4 ADRs:
Very common: Venous thromboembolic events^, predominantly deep vein thrombosis and pulmonary embolism^,◊,◊◊
Common: Vasculitis, Hypotension◊◊, Hypertension
Uncommon: Ischemia, Peripheral ischemia, Intracranial venous sinus thrombosis
All ADRs:
Very common: Dyspnoea◊,◊◊, Epistaxis^, Cough
Common: Dysphonia
Grade 3-4 ADRs:
Common: Respiratory distress◊, Dyspnoea◊,◊◊, Pleuritic pain◊◊, Hypoxia◊◊
All ADRs:
Very common: Diarrhoea◊,◊◊, Constipation◊, Abdominal pain◊◊, Nausea, Vomiting,◊◊, Dyspepsia, Dry mouth, Stomatitis
Common: Gastrointestinal haemorrhage (including rectal haemorrhage, haemorrhoidal haemorrhage, peptic ulcer haemorrhage and gingival bleeding)^ ,◊◊, Dysphagia
Uncommon: Colitis, Caecitis
Grade 3-4 ADRs:
Common: Gastrointestinal haemorrhage^,◊,◊◊, Small intestinal obstruction◊◊, Diarrhoea◊◊, Constipation◊, Abdominal pain◊◊, Nausea, Vomiting◊◊
All ADRs:
Very common: Alanine aminotransferase increased, Aspartate aminotransferase increased
Common: Hepatocellular injury◊◊, Abnormal liver function tests◊, Hyperbilirubinaemia
Uncommon: Hepatic failure^
Grade 3-4 ADRs:
Common: Cholestasis◊, Hepatotoxicity, Hepatocellular injury◊◊, Alanine aminotransferase increased, Abnormal liver function tests◊
Uncommon: Hepatic failure^
All ADRs:
Very common: Rashes◊◊, Pruritus
Common: Urticaria, Hyperhidrosis, Dry skin, Skin hyperpigmentation, Eczema, Erythema
Uncommon: Drug rash with eosinophilia and systemic symptoms◊◊, Skin discolouration, Photosensitivity reaction
Grade 3-4 ADRs:
Common: Rashes◊◊
Uncommon: Drug rash with eosinophilia and systemic symptoms◊◊
All ADRs:
Very common: Muscular weakness◊◊, Muscle spasms, Bone pain◊, Musculoskeletal and connective tissue pain and discomfort (including back pain◊,◊◊), Pain in extremity, Myalgia, Arthralgia◊
Common: Joint swelling
Grade 3-4 ADRs:
Common: Muscular weakness◊◊, Bone pain◊, Musculoskeletal and connective tissue pain and discomfort (including back pain◊,◊◊)
Uncommon: Joint swelling
All ADRs:
Very common: Renal failure (including acute)◊,◊◊
Common: Haematuria^, Urinary retention, Urinary incontinence
Uncommon: Acquired Fanconi syndrome
Grade 3-4 ADRs:
Uncommon: Renal tubular necrosis
All ADRs:
Common: Erectile dysfunction
All ADRs:
Very common: Fatigue◊,◊◊, Oedema (including peripheral oedema), Pyrexia◊,◊◊, Asthenia, Influenza like illness syndrome (including pyrexia, cough, myalgia, musculoskeletal pain, headache and rigors)
Common: Chest pain◊,◊◊, Lethargy
Grade 3-4 ADRs:
Very common: Fatigue◊,◊◊
Common: Oedema peripheral, Pyrexia◊,◊◊, Asthenia
All ADRs:
Very common: Blood alkaline phosphatase increased
Common: C-reactive protein increased
Common: Fall, Contusion^
◊◊ Adverse reactions reported as serious in clinical trials in patients with NDMM who had received lenalidomide 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 lenalidomide 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 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
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 lenalidomide#:
All ADRs:
Very common: Bacterial, viral and fungal infections (including opportunistic infections)◊
Grade 3-4 ADRs:
Very common: Pneumonia◊
Common: Bacterial, viral and fungal infections (including opportunistic infections)◊, Bronchitis
All ADRs:
Very common: Thrombocytopenia^,◊, Neutropenia^,◊, Leucopenias
Grade 3-4 ADRs:
Very common: Thrombocytopenia^,◊, Neutropenia^,◊, Leucopenias
Common: Febrile neutropenia^,◊
All ADRs:
Very common: Hypothyroidism
All ADRs:
Very common: Decreased appetite
Common: Iron overload, Weight decreased
Grade 3-4 ADRs:
Common: Hyperglycaemia◊, Decreased appetite
Grade 3-4 ADRs:
Common: Altered mood◊,~
All ADRs:
Very common: Dizziness, Headache
Common: Paraesthesia
Grade 3-4 ADRs:
Common: Acute myocardial infarction^,◊, Atrial fibrillation◊, Cardiac failure◊
All ADRs:
Common: Hypertension, Haematoma
Grade 3-4 ADRs:
Common: Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism^,◊
All ADRs:
Very common: Epistaxis^
All ADRs:
Very common: Diarrhoea◊, Abdominal pain (including upper), Nausea, Vomiting, Constipation
Common: Dry mouth, Dyspepsia
Grade 3-4 ADRs:
Common: Diarrhoea◊, Nausea, Toothache
All ADRs:
Common: Abnormal liver function tests
Grade 3-4 ADRs:
Common: Abnormal liver function tests
All ADRs:
Very common: Rashes, Dry Skin, Pruritus
Grade 3-4 ADRs:
Common: Rashes, Pruritus
All ADRs:
Very common: Muscle spasms, Musculoskeletal pain (including back pain◊ and pain in extremity), Arthralgia, Myalgia
Grade 3-4 ADRs:
Common: Back pain◊
Grade 3-4 ADRs:
Common: Renal failure◊
All ADRs:
Very common: Fatigue, Peripheral oedema, Influenza like illness syndrome (including pyrexia, cough, pharyngitis, myalgia, musculoskeletal pain, headache)
Grade 3-4 ADRs:
Common: Pyrexia
Grade 3-4 ADRs:
Common: Fall
^ 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:
Table 4. ADRs reported in clinical trials in patients with mantle cell lymphoma treated with lenalidomide:
All ADRs:
Very common: Bacterial, viral and fungal infections (including opportunistic infections)◊, Nasopharyngitis, Pneumonia◊
Common: Sinusitis
Grade 3-4 ADRs:
Common: Bacterial, viral and fungal infections (including opportunistic infections)◊, Pneumonia◊
All ADRs:
Common: Tumour flare reaction
Grade 3-4 ADRs:
Common: Tumour flare reaction, Squamous skin cancer^,◊, Basal cell carcinoma^,◊
All ADRs:
Very common: Thrombocytopenia^, Neutropenia^,◊, Leucopenias◊, Anemia◊
Common: Febrile neutropenia^,◊
Grade 3-4 ADRs:
Very common: Thrombocytopenia^, Neutropenia^,◊, Anemia◊
Common: Febrile neutropenia^,◊, Leucopenias◊
All ADRs:
Very common: Decreased appetite, Weight decreased, Hypokalaemia
Common: Dehydration◊◊
Grade 3-4 ADRs:
Common: Dehydration◊, Hyponatraemia, Hypocalcaemia
All ADRs:
Common: Insomnia
All ADRs:
Common: Dysgeuesia, Headache, neuropathy peripheral
Grade 3-4 ADRs:
Common: Peripheral sensory neuropathy, Lethargy
All ADRs:
Common: Vertigo
Grade 3-4 ADRs:
Common: Myocardial infarction (including acute)^,◊, Cardiac failure
All ADRs:
Common: Hypotension◊
Grade 3-4 ADRs:
Common: Deep vein thrombosis◊, pulmonary embolism^,◊, Hypotension◊
All ADRs:
Very common: Dyspnoea◊
Grade 3-4 ADRs:
Common: Dyspnoea◊
All ADRs:
Very common: Diarrhoea◊, Nausea◊, Vomiting◊, Constipation
Common: Abdominal pain◊
Grade 3-4 ADRs:
Common: Diarrhoea◊, Abdominal pain◊, Constipation
All ADRs:
Very common: Rashes (including dermatitis allergic), Pruritus
Common: Night sweats, Dry skin
Grade 3-4 ADRs:
Common: Rashes
All ADRs:
Very common: Muscle spasms, Back pain
Common: Arthralgia, Pain in extremity, Muscular weakness◊
Grade 3-4 ADRs:
Common: Back pain, Muscular weakness◊, Arthralgia, Pain in extremity
Grade 3-4 ADRs:
Common: Renal failure◊
All ADRs:
Very common: Fatigue, Asthenia◊, Peripheral oedema, Influenza like illness syndrome (including pyrexia◊, cough)
Common: Chills
Grade 3-4 ADRs:
Common: Pyrexia◊, Asthenia◊, Fatigue
^ see section 4.8 description of selected adverse reactions
◊ Adverse events reported as serious in mantle cell lymphoma clinical trialsAlgorithm applied for mantle cell lymphoma:
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:
All ADRs:
Not Known: Viral infections, including herpes zoster and hepatitis B virus reactivation
Grade 3-4 ADRs:
Not Known: Viral infections, including herpes zoster and hepatitis B virus reactivation
Grade 3-4 ADRs:
Rare: Tumour lysis syndrome
All ADRs:
Not Known: Acquired haemophilia
All ADRs:
Not Known: Solid organ transplant rejection
All ADRs:
Common: Hyperthyroidism
Grade 3-4 ADRs:
Not Known: Interstitial pneumonitis
Grade 3-4 ADRs:
Not Known: Pancreatitis, Gastrointestinal perforation (including diverticular, intestinal and large intestine perforations)^
All ADRs:
Not Known: Acute hepatic failure^, Hepatitis toxic^, Cytolytic hepatitis^, Cholestatic hepatitis^, Mixed cytolytic/cholestatic hepatitis^
Grade 3-4 ADRs:
Not Known: Acute hepatic failure^, Hepatitis toxic^
Grade 3-4 ADRs:
Uncommon: 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
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
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).
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%).
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%).
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%).
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).
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).
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.
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 (see section 4.5).
Concomitant administration of erythropoietic agents or previous history of DVT may also increase thrombotic risk in these patients.
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors.
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).
Cases of allergic reaction/hypersensitivity reactions have been reported. A possible cross-reaction between lenalidomide and thalidomide has been reported in the literature.
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 section 4.4).
In clinical trials in previously treated myeloma patients with lenalidomide/dexamethasone compared to controls, mainly comprising of basal cell or squamous cell skin cancers.
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 (see section 4.4). 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.
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 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 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%).
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.
Rare cases of rhabdomyolysis have been observed, some of them when lenalidomide is administered with a statin.
Cases of hypothyroidism and cases of hyperthyroidism have been reported (see section 4.4 Thyroid disorders).
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 (see section 4.4).
Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinal perforations may lead to septic complications and may be associated with fatal outcome.
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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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