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 or mantle cell lymphoma. he 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.
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.
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.
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.
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.
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. 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%), 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. 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%), anemia (28.7%), diarrhoea (22.8%), fatigue (21.0%), constipation (17.4%), pyrexia (16.8%), and rash (including dermatitis allergic) (16.2%).
In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths. Patients with high tumour burden at baseline are at increased risk of early death, 16/81 (20%) early deaths in the lenalidomide arm and 2/28 (7%) early deaths in the control arm. Within 52 weeks corresponding figures were 32/81 (39.5%) and 6/28 (21%).
During treatment cycle 1, 11/81 (14%) patients with high tumour burden were withdrawn from therapy in the lenalidomide arm vs. 1/28 (4%) in the control group. The main reason for treatment withdrawal for patients with high tumour burden during treatment cycle 1 in the lenalidomide arm was adverse events, 7/11 (64%). High tumour burden was defined as at least one lesion ≥5 cm in diameter or 3 lesions ≥3 cm.
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:
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 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.
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 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 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 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. 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.
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.
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 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.
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.
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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