Chemical formula: C₁₃H₁₃N₃O₃ Molecular mass: 259.261 g/mol PubChem compound: 216326
Lenalidomide interacts in the following cases:
Lenalidomide is primarily excreted by the kidney; patients with greater degrees of renal impairment can have impaired treatment tolerance. Care should be taken in dose selection and monitoring of renal function is advised.
No dose adjustments are required for patients with mild renal impairment and multiple myeloma, myelodysplastic syndromes, mantle cell lymphoma, or follicular lymphoma.
The following dose adjustments are recommended at the start of therapy and throughout treatment for patients with moderate or severe impaired renal function or end stage renal disease. There are no phase 3 trial experiences with End Stage Renal Disease (ESRD) (CLcr <30 mL/min, requiring dialysis).
Multiple myeloma:
| Renal function (CLcr) | Dose adjustment |
|---|---|
| Moderate renal impairment (30 ≤ CLcr < 50 mL/min) | 10 mg once daily1 |
| Severe renal impairment (CLcr < 30 mL/min, not requiring dialysis) | 7.5 mg once daily2 15 mg every other day |
| End Stage Renal Disease (ESRD) (CLcr < 30 mL/min, requiring dialysis) | 5 mg once daily. On dialysis days, the dose should be administered following dialysis |
1 The dose may be escalated to 15 mg once daily after 2 cycles if patient is not responding to treatment and is tolerating the treatment.
2 In countries where the 7.5 mg capsule is available.
Myelodysplastic syndromes:
| Renal function (CLcr) | Dose adjustment | |
|---|---|---|
| Moderate renal impairment (30 ≤ CLcr < 50 mL/min) | Starting dose | 5 mg once daily (days 1 to 21 of repeated 28-day cycles) |
| Dose level -1* | 2.5 mg once daily (days 1 to 28 of repeated 28-day cycles) | |
| Dose level -2* | 2.5 mg once every other day (days 1 to 28 of repeated 28-day cycles) | |
| Severe renal impairment (CLcr < 30 mL/min, not requiring dialysis) | Starting dose | 2.5 mg once daily (days 1 to 21 of repeated 28-day cycles) |
| Dose level -1* | 2.5 mg every other day (days 1 to 28 of repeated 28-day cycles) | |
| Dose level -2* | 2.5 mg twice a week (days 1 to 28 of repeated 28-day cycles) | |
| End Stage Renal Disease (ESRD) (CLcr < 30 mL/min, requiring dialysis) On dialysis days, the dose should be administered following dialysis. | Starting dose | 2.5 mg once daily (days 1 to 21 of repeated 28-day cycles) |
| Dose level -1* | 2.5 mg every other day (days 1 to 28 of repeated 28-day cycles) | |
| Dose level -2* | 2.5 mg twice a week (days 1 to 28 of repeated 28-day cycles) | |
* Recommended dose reduction steps during treatment and restart of treatment to manage grade 3 or 4 neutropenia or thrombocytopenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide, as described above.
Mantle cell lymphoma:
| Renal function (CLcr) | Dose adjustment (days 1 to 21 of repeated 28-day cycles) |
|---|---|
| Moderate renal impairment (30 ≤ CLcr < 50 mL/min) | 10 mg once daily1 |
| Severe renal impairment (CLcr < 30 mL/min, not requiring dialysis) | 7.5 mg once daily2 15 mg every other day |
| End Stage Renal Disease (ESRD) (CLcr < 30 mL/min, requiring dialysis) | 5 mg once daily. On dialysis days, the dose should be administered following dialysis. |
1 The dose may be escalated to 15 mg once daily after 2 cycles if patient is not responding to treatment and is tolerating the treatment.
2 In countries where the 7.5 mg capsule is available.
Follicular lymphoma:
| Renal function (CLcr) | Dose adjustment (days 1 to 21 of repeated 28-day cycles) |
|---|---|
| Moderate renal impairment (30 ≤ CLcr < 60 mL/min) | 10 mg once daily1,2 |
| Severe renal impairment (CLcr < 30 mL/min, not requiring dialysis) | 5 mg once daily |
| End Stage Renal Disease (ESRD) (CLcr < 30 mL/min, requiring dialysis) | 5 mg once daily. On dialysis days, the dose should be administered following dialysis. |
1 The dose may be escalated to 15 mg once daily after 2 cycles if the patient has tolerated therapy.
2 For patients on a starting dose of 10 mg, in case of dose reduction to manage Grade 3 or 4 neutropenia or thrombocytopenia, or other Grade 3 or 4. Toxicity judged to be related to lenalidomide do not dose below 5 mg every other day or 2.5 mg once daily.
After initiation of lenalidomide therapy, subsequent lenalidomide dose modification in renally impaired patients should be based on individual patient treatment tolerance, as described above.
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.
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.
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).
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.
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. Therefore, a teratogenic effect of lenalidomide is expected and lenalidomide is contraindicated during pregnancy.
It is not known whether lenalidomide is excreted in breast milk. Therefore, breast-feeding should be discontinued during therapy with lenalidomide.
Due to the teratogenic potential, lenalidomide must be prescribed under a Pregnancy Prevention Programme 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. 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.
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%), anaemia (70.7%), thrombocytopenia (70.0%), leucopenia (38.8%), constipation (34.0%), diarrhoea (33.3%), rash (28.9%), pyrexia (27.0%), peripheral oedema (25.0%), cough (24.0%), decreased appetite (23.7%), and asthenia (22.0%).
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%), anaemia (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. 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. 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%), anaemia (28.7%), diarrhoea (22.8%), fatigue (21.0%), constipation (17.4%), pyrexia (16.8%), and rash (including dermatitis allergic) (16.2%).
In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths. Patients with high tumour burden at baseline are at increased risk of early death, 16/81 (20%) early deaths in the lenalidomide arm and 2/28 (7%) early deaths in the control arm. Within 52 weeks corresponding figures were 32/81 (39.5%) and 6/28 (21%).
During treatment cycle 1, 11/81 (14%) patients with high tumour burden were withdrawn from therapy in the lenalidomide arm vs. 1/28 (4%) in the control group. The main reason for treatment withdrawal for patients with high tumour burden during treatment cycle 1 in the lenalidomide arm was adverse events, 7/11 (64%). High tumour burden was defined as at least one lesion ≥5 cm in diameter or 3 lesions ≥3 cm.
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 NHL007. Additionally, adverse drug reactions from supportive study NHL-008 have been included in Table 5.
The serious adverse reactions observed most frequently (with a difference of at least 1 percentage point) in study NHL-007 in the lenalidomide/rituximab arm compared with the placebo/rituximab arm were:
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%).
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.
Table 1. ADRs reported in clinical trials in patients with multiple myeloma treated with lenalidomide maintenance therapy:
| System Organ Class/Preferred Term | All ADRs/Frequency | Grade 3-4 ADRs/Frequency |
|---|---|---|
| Infections and Infestations | Very Common Pneumonia◊,a, Upper respiratory tract infection, Neutropenic infection, Bronchitis◊, Influenza◊, Gastroenteritis◊, Sinusitis, Nasopharyngitis, Rhinitis Common Infection◊, Urinary tract infection◊,*, Lower respiratory tract infection, Lung infection◊ | Very Common Pneumonia◊,a, Neutropenic infection Common Sepsis◊,b, Bacteraemia, Lung infection◊, Lower respiratory tract infection bacterial, Bronchitis◊, Influenza◊, Gastroenteritis◊, Herpes zoster◊, Infection◊ |
| Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps) | Common Myelodysplastic syndrome◊,* | |
| Blood and Lymphatic System Disorders | Very Common Neutropenia^,◊, Febrile neutropenia^,◊, Thrombocytopenia^,◊, Anaemia, Leucopenia◊, Lymphopenia | Very Common Neutropenia^,◊, Febrile neutropenia^,◊, Thrombocytopenia^,◊, Anaemia, Leucopenia◊, Lymphopenia Common Pancytopenia◊ |
| Metabolism and Nutrition Disorders | Very Common Hypokalaemia | Common Hypokalaemia, Dehydration |
| Nervous System Disorders | Very Common Paraesthesia Common Peripheral neuropathyc | Common Headache |
| Vascular Disorders | Common Pulmonary embolism◊,* | Common Deep vein thrombosis^,◊,d |
| Respiratory, Thoracic and Mediastinal Disorders | Very Common Cough Common Dyspnoea◊, Rhinorrhoea | Common Dyspnoea◊ |
| Gastrointestinal Disorders | Very Common Diarrhoea, Constipation, Abdominal pain, Nausea Common Vomiting, Abdominal pain upper | Common Diarrhoea, Vomiting, Nausea |
| Hepatobiliary Disorders | Very Common Abnormal liver function tests | Common Abnormal liver function tests |
| Skin and Subcutaneous Tissue Disorders | Very Common Rash, Dry skin | Common Rash, Pruritus |
| Musculoskeletal and Connective Tissue Disorders | Very Common Muscle spasms Common Myalgia, Musculoskeletal pain | |
| General Disorders and Administration Site Conditions | Very Common Fatigue, Asthenia, Pyrexia | Common Fatigue, Asthenia |
◊ Adverse reactions reported as serious in clinical trials in patients with NDMM who had undergone ASCT
* PApplies to serious adverse drug reactions only
^ see description of selected adverse reactions
a “Pneumonia” combined AE term includes the following PTs: Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis
b “Sepsis” combined AE term includes the following PTs: Bacterial sepsis, Pneumococcal sepsis, Septic shock, Staphylococcal sepsis
c “Peripheral neuropathy” combined AE term includes the following preferred terms (PTs): Neuropathy peripheral, Peripheral sensory neuropathy, Polyneuropathy
d “Deep vein thrombosis” combined AE term includes the following PTs: Deep vein thrombosis, Thrombosis, Venous thrombosis
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.
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:
| System Organ Class / Preferred Term | All ADRs/Frequency | Grade 3−4 ADRs/Frequency |
|---|---|---|
| Infections and Infestations | 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◊ | Common Pneumonia◊,◊◊, Bacterial, viral and fungal infections (including opportunistic infections)◊, Cellulitis◊, Sepsis◊,◊◊, Lung infection◊◊, Bronchitis◊, Respiratory tract infection◊◊, Urinary tract infection◊◊, Enterocolitis infectious |
| Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps) | Uncommon Basal cell carcinoma^,◊, Squamous skin cancer^,◊,* | Common Acute myeloid leukaemia◊, Myelodysplastic syndrome◊, Squamous cell carcinoma of skin^,◊,** Uncommon T-cell type acute leukaemia◊, Basal cell carcinoma^,◊, Tumour lysis syndrome |
| Blood and Lymphatic System Disorders | Very Common Neutropenia^,◊,◊◊, Thrombocytopenia^,◊,◊◊, Anaemia◊, Haemorrhagic disorder^, Leucopenia, Lymphopenia Common Febrile neutropenia^,◊, Pancytopenia◊ Uncommon Haemolysis, Autoimmune haemolytic anaemia, Haemolytic anaemia | Very Common Neutropenia^,◊,◊◊, Thrombocytopenia^,◊,◊◊, Anaemia◊, Leucopenia, Lymphopenia Common Febrile neutropenia^,◊, Pancytopenia◊, Haemolytic anaemia Uncommon Hypercoagulation, Coagulopathy |
| Immune System Disorders | Uncommon Hypersensitivity^ | |
| Endocrine Disorders | Common Hypothyroidism | |
| Metabolism and Nutrition Disorders | Very Common Hypokalaemia◊,◊◊, Hyperglycaemia, Hypoglycaemia, Hypocalcaemia◊, Hyponatraemia◊, Dehydration◊◊, Decreased appetite◊◊, Weight decreased Common Hypomagnesaemia, Hyperuricaemia, Hypercalcaemia+ | Common Hypokalaemia◊,◊◊, Hyperglycaemia, Hypocalcaemia◊, Diabetes mellitus◊, Hypophosphataemia, Hyponatraemia◊, Hyperuricaemia, Gout, Dehydration◊◊, Decreased appetite◊◊, Weight decreased |
| Psychiatric Disorders | Very Common Depression, Insomnia Uncommon Loss of libido | Common Depression, Insomnia |
| Nervous System Disorders | Very Common Peripheral neuropathies◊◊, Paraesthesia, Dizziness◊◊, Tremor, Dysgeusia, Headache Common Ataxia, Balance impaired, Syncope◊◊, Neuralgia, Dysaesthesia | Very Common Peripheral neuropathies◊◊ Common Cerebrovascular accident◊, Dizziness◊◊, Syncope◊◊, Neuralgia Uncommon Intracranial haemorrhage^, Transient ischaemic attack, Cerebral ischemia |
| Eye Disorders | Very Common Cataracts, Blurred vision Common Reduced visual acuity | Common Cataract Uncommon Blindness |
| Ear and Labyrinth Disorders | Common Deafness (Including Hypoacusis), Tinnitus | |
| Cardiac Disorders | Common Atrial fibrillation◊,◊◊, Bradycardia Uncommon Arrhythmia, QT prolongation, Atrial flutter, Ventricular extrasystoles | Common Myocardial infarction (including acute)^,◊, Atrial fibrillation◊,◊◊, Congestive cardiac failure◊, Tachycardia, Cardiac failure◊,◊◊, Myocardial ischemia◊ |
| Vascular Disorders | Very Common Venous thromboembolic events^, predominantly deep vein thrombosis and pulmonary embolism^,◊,◊◊, Hypotension◊◊ Common Hypertension, Ecchymosis^ | Very Common Venous thromboembolic events^, predominantly deep vein thrombosis and pulmonary embolism^,◊,◊◊ Common Vasculitis, Hypotension◊◊, Hypertension Uncommon Ischemia, Peripheral ischemia, Intracranial venous sinus thrombosis |
| Respiratory, Thoracic and Mediastinal Disorders | Very Common Dyspnoea◊,◊◊, Epistaxis^, Cough Common Dysphonia | Common Respiratory distress◊, Dyspnoea◊,◊◊, Pleuritic pain◊◊, Hypoxia◊◊ |
| Gastrointestinal Disorders | 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 | Common Gastrointestinal haemorrhage^,◊,◊◊, Small intestinal obstruction◊◊, Diarrhoea◊◊, Constipation◊, Abdominal pain◊◊, Nausea, Vomiting◊◊ |
| Hepatobiliary Disorders | Very Common Alanine aminotransferase increased, Aspartate aminotransferase increased Common Hepatocellular injury◊◊, Abnormal liver function tests◊, Hyperbilirubinaemia Uncommon Hepatic failure^ | Common Cholestasis◊, Hepatotoxicity, Hepatocellular injury◊◊, Alanine aminotransferase increased, Abnormal liver function tests◊ Uncommon Hepatic failure^ |
| Skin and Subcutaneous Tissue Disorders | 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 | Common Rashes◊◊ Uncommon Drug rash with eosinophilia and systemic symptoms◊◊ |
| Musculoskeletal and Connective Tissue Disorders | 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 | Common Muscular weakness◊◊, Bone pain◊, Musculoskeletal and connective tissue pain and discomfort (including back pain◊,◊◊) Uncommon Joint swelling |
| Renal and Urinary Disorders | Very Common Renal failure (including acute)◊,◊◊ Common Haematuria^, Urinary retention, Urinary incontinence Uncommon Acquired Fanconi syndrome | Uncommon Renal tubular necrosis |
| Reproductive System and Breast Disorders | Common Erectile dysfunction | |
| General Disorders and Administration Site Conditions | 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 | Very Common Fatigue◊,◊◊ Common Oedema peripheral, Pyrexia◊,◊◊, Asthenia |
| Investigations | Very Common Blood alkaline phosphatase increased Common C-reactive protein increased | |
| Injury, Poisoning and Procedural Complications | 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 description of selected adverse reactions
◊ PAdverse 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#:
| System Organ Class / Preferred Term | All ADRs/Frequency | Grade 3−4 ADRs/Frequency |
|---|---|---|
| Infections and Infestations | Very Common Bacterial, viral and fungal infections (including opportunistic infections)◊ | Very Common Pneumonia◊ Common Bacterial, viral and fungal infections (including opportunistic infections)◊, Bronchitis |
| Blood and Lymphatic System Disorders | Very Common Thrombocytopenia^,◊, Neutropenia^,◊, Anaemia◊, Leucopenia | Very Common Thrombocytopenia^,◊, Neutropenia^,◊, Anaemia◊, Leucopenia Common Febrile neutropenia^,◊ |
| Endocrine Disorders | Very Common Hypothyroidism | |
| Metabolism and Nutrition Disorders | Very Common Decreased appetite Common Iron overload, Weight decreased | Common Hyperglycaemia◊, Decreased appetite |
| Psychiatric Disorders | Common Altered mood◊,~ | |
| Nervous System Disorders | Very Common Dizziness, Headache Common Paraesthesia | |
| Cardiac Disorders | Common Acute myocardial infarction^,◊, Atrial fibrillation◊, Cardiac failure◊ | |
| Vascular Disorders | Common Hypertension, Haematoma | Common Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism^,◊ |
| Respiratory, Thoracic and Mediastinal Disorders | Very Common Epistaxis^ | |
| Gastrointestinal Disorders | Very Common Diarrhoea◊, Abdominal pain (including upper), Nausea, Vomiting, Constipation Common Dry mouth, Dyspepsia | Common Diarrhoea◊, Nausea, Toothache |
| Hepatobiliary Disorders | Common Abnormal liver function tests | Common Abnormal liver function tests |
| Skin and Subcutaneous Tissue Disorders | Very Common Rashes, Dry Skin, Pruritus | Common Rashes, Pruritus |
| Musculoskeletal and Connective Tissue Disorders | Very Common Muscle spasms, Musculoskeletal pain (including back pain◊ and pain in extremity), Arthralgia, Myalgia | Common Back pain◊ |
| Renal and Urinary Disorders | Common Renal failure◊ | |
| General Disorders and Administration Site Conditions | Very Common Fatigue, Peripheral oedema, Influenza like illness syndrome (including pyrexia, cough, pharyngitis, myalgia, musculoskeletal pain, headache) | Common Pyrexia |
| Injury, Poisoning and Procedural Complications | Common Fall |
^ see 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:
| System Organ Class / Preferred Term | All ADRs/Frequency | Grade 3−4 ADRs/Frequency |
|---|---|---|
| Infections and Infestations | Very Common Bacterial, viral and fungal infections (including opportunistic infections)◊, Nasopharyngitis, Pneumonia◊ Common Sinusitis | Common Bacterial, viral and fungal infections (including opportunistic infections)◊, Pneumonia◊ |
| Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps) | Common Tumour flare reaction | Common Tumour flare reaction, Squamous skin cancer^,◊, Basal cell carcinoma^,◊ |
| Blood and Lymphatic System Disorders | Very Common Thrombocytopenia^, Neutropenia^,◊, Leucopenia◊, Anaemia◊ Common Febrile neutropenia^,◊ | Very Common Thrombocytopenia^, Neutropenia^,◊, Anaemia◊ Common Febrile neutropenia^,◊, Leucopenia◊ |
| Metabolism and Nutrition Disorders | Very Common Decreased appetite, Weight decreased, Hypokalaemia Common Dehydration◊ | Common Dehydration◊, Hyponatraemia, Hypocalcaemia |
| Psychiatric Disorders | Common Insomnia | |
| Nervous System Disorders | Common Dysgeuesia, Headache, neuropathy peripheral | Common Peripheral sensory neuropathy, Lethargy |
| Ear and Labyrinth Disorders | Common Vertigo | |
| Cardiac Disorders | Common Myocardial infarction (including acute)^,◊, Cardiac failure | |
| Vascular Disorders | Common Hypotension◊ | Common Deep vein thrombosis◊, pulmonary embolism^,◊, Hypotension◊ |
| Respiratory, Thoracic and Mediastinal Disorders | Very Common Dyspnoea◊ | Common Dyspnoea◊ |
| Gastrointestinal Disorders | Very Common Diarrhoea◊, Nausea◊, Vomiting◊, Constipation Common Abdominal pain◊ | Common Diarrhoea◊, Abdominal pain◊, Constipation |
| Skin and Subcutaneous Tissue Disorders | Very Common Rashes (including dermatitis allergic), Pruritus Common Night sweats, Dry skin | Common Rashes |
| Musculoskeletal and Connective Tissue Disorders | Very Common Muscle spasms, Back pain Common Arthralgia, Pain in extremity, Muscular weakness◊ | Common Back pain, Muscular weakness◊, Arthralgia, Pain in extremity |
| Renal and Urinary Disorders | Common Renal failure◊ | |
| General Disorders and Administration Site Conditions | Very Common Fatigue, Asthenia◊, Peripheral oedema, Influenza like illness syndrome (including pyrexia◊, cough) Common Chills | Common Pyrexia◊, Asthenia◊, Fatigue |
^ see description of selected adverse reactions
◊ PAdverse events reported as serious in mantle cell lymphoma clinical trials. Algorithm applied for mantle cell lymphoma:
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.
Table 5. ADRs reported in clinical trials in patients with follicular lymphoma treated with lenalidomide in combination with rituximab:
| System Organ Class / Preferred Term | All ADRs/Frequency | Grade 3−4 ADRs/Frequency |
|---|---|---|
| Infections and Infestations | Very Common Upper respiratory tract infection Common Pneumonia◊, Influenza, Bronchitis, Sinusitis, Urinary tract infection | Common Pneumonia◊, Sepsis◊, Lung infection, Bronchitis, Gastroenteritis, Sinusitis, Urinary tract infection, Cellulitis◊ |
| Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps) | Very Common Tumour flare^ Common Squamous Cell Carcinoma of Skin◊,^,+ | Common Basal cell carcinoma^,◊ |
| Blood and Lymphatic System Disorders | Very Common Neutropenia^,◊, Anaemia◊, Thrombocytopenia^, Leucopenia** Lymphopenia*** | Very Common Neutropenia^,◊ Common Anaemia◊, Thrombocytopenia^, Febrile neutropenia◊, Pancytopenia, Leucopenia**, Lymphopenia*** |
| Metabolism and Nutrition Disorders | Very Common Decreased appetite, Hypokalaemia Common Hypophosphataemia, Dehydration | Common Dehydration, Hypercalcaemia◊, Hypokalaemia, Hypophosphataemia, Hyperuricaemia |
| Psychiatric Disorders | Common Depression, Insomnia | |
| Nervous System Disorders | Very Common Headache, Dizziness Common Peripheral sensory neuropathy, Dysgeusia | Common Syncope |
| Cardiac Disorders | Uncommon Arrhythmia◊ | |
| Vascular Disorders | Common Hypotension | Common Pulmonary embolism^,◊, Hypotension |
| Respiratory, Thoracic and Mediastinal Disorders | Very Common Dyspnoea◊, Cough, Common Oropharyngeal pain, Dysphonia | Common Dyspnoea◊ |
| Gastrointestinal Disorders | Very Common Abdominal pain◊, Diarrhoea, Constipation, Nausea, Vomiting, Dyspepsia Common Upper abdominal pain, Stomatitis, Dry mouth | Common Abdominal pain◊, Diarrhoea, Constipation, Stomatitis |
| Skin and Subcutaneous Tissue Disorders | Very Common Rash*, Pruritus Common Dry skin, Night sweats, Erythema | Common Rash*, Pruritus |
| Musculoskeletal and Connective Tissue Disorders | Very Common Muscle spasms, Back pain, Arthralgia Common Pain in extremity, Muscular weakness, Musculoskeletal pain, Myalgia, Neck pain | Common Muscular weakness, Neck pain |
| Renal and Urinary Disorders | Common Acute kidney injury◊ | |
| General Disorders and Administration Site Conditions | Very Common Pyrexia, Fatigue, Asthenia, Peripheral oedema Common Malaise, Chills | Common Fatigue, Asthenia |
| Investigations | Very Common Alanine aminotransferase increased Common Weight decreased, Blood Bilirubin increased |
^ see description of selected adverse reactions
Algorithm applied for follicular lymphoma:
◊ Adverse events reported as serious in follicular lymphoma clinical trials
+ Applies to serious adverse drug reactions only
* Rash includes PT of rash and rash maculo-papular
** PLeucopenia includes PT leucopenia and white blood cell count decreased
*** Lymphopenia includes PT lymphopenia and lymphocyte count decreased
In addition to the above adverse reactions identified from the pivotal clinical trials, the following table is derived from data gathered from post-marketing data.
Table 6. ADRs reported in post-marketing use in patients treated with lenalidomide:
| System Organ Class / Preferred Term | All ADRs/Frequency | Grade 3−4 ADRs/Frequency |
|---|---|---|
| Infections and Infestations | Not Known Viral infections, including herpes zoster and hepatitis B virus reactivation | Not Known Viral infections, including herpes zoster and hepatitis B virus reactivation |
| Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps) | Rare Tumour lysis syndrome | |
| Blood and Lymphatic System Disorders | Not Known Acquired haemophilia | |
| Immune System Disorders | Rare Anaphylactic reaction^ Not Known Solid organ transplant rejection | Rare Anaphylactic reaction^ |
| Endocrine Disorders | Common Hyperthyroidism | |
| Respiratory, Thoracic and Mediastinal Disorders | Uncommon Pulmonary hypertension | Rare Pulmonary hypertension Not Known Interstitial pneumonitis |
| Gastrointestinal Disorders | Not Known Pancreatitis, Gastrointestinal perforation (including diverticular, intestinal and large intestine perforations)^ | |
| Hepatobiliary Disorders | Not Known Acute hepatic failure^, Hepatitis toxic^, Cytolytic hepatitis^, Cholestatic hepatitis^, Mixed cytolytic/cholestatic hepatitis^ | Not Known Acute hepatic failure^, Hepatitis toxic^ |
| Skin and Subcutaneous Tissue Disorders | Uncommon Angioedema Rare Stevens-Johnson Syndrome^, Toxic epidermal necrolysis^ Not Known Leukocytoclastic vasculitis, Drug Reaction with Eosinophilia and Systemic Symptoms^ |
^ see 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. 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.
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.
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).
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 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 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.
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. 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. 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%).
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.
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 perforations have been reported during treatment with lenalidomide. Gastrointestinal perforations may lead to septic complications and may be associated with fatal outcome.
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