Lenalidomide Accord

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



 2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

Lenalidomide Accord  2.5 mg hard capsules 

Lenalidomide Accord 5 mg hard capsules 

Lenalidomide Accord 7.5 mg hard capsules 

Lenalidomide Accord 10 mg hard capsules 

Lenalidomide Accord 15 mg hard capsules 

Lenalidomide Accord 20 mg hard capsules 

Lenalidomide Accord 25 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Lenalidomide Accord  2.5 mg hard capsules 

Each  hard  capsule contains 2.5 mg of lenalidomide. 

 

Excipient with known effect 

Each hard capsule contains 36 mg of lactose. 

 

Lenalidomide Accord  5 mg hard capsules 

Each  hard  capsule contains 5 mg of lenalidomide. 

 

Excipient  with known effect 

Each  hard capsule contains 33 mg of lactose. 

 

Lenalidomide Accord 7.5 mg hard capsules 

Each  hard  capsule contains 7.5 mg of lenalidomide. 

 

Excipient with known effect 

Each  hard capsule contains50 mg of lactose. 

 

Lenalidomide Accord  10 mg hard capsules 

Each hard capsule contains 10 mg of lenalidomide. 

 

Excipientwith known effect 

Each hard capsule contains 67mg of lactose. 

 

Lenalidomide Accord 15 mg hard capsules  

Each hard capsule contains 15 mg of lenalidomide. 

Excipient with known effect 

Each hard capsule contains100 mg of lactose. 

 

Lenalidomide Accord 20 mg hard capsules  

Each hard capsule contains 20 mg of lenalidomide. 

 

Excipient with known effect 

Each hard capsule contains134  mg of lactose. 

 

Lenalidomide Accord  25 mg hard capsules 

Each hard capsule contains 25 mg of lenalidomide. 

 

Excipient with known effect 



 3 

Each hard capsule contains167  mg of lactose. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Hard capsule (capsule) 

 

Lenalidomide Accord 2.5 mg hard capsules  

Gelatin hard capsules size “5” approximately 11.0 mm to 11.8 mm in length, grey cap and opaque 

white body with “LENALIDOMIDE” printed on cap in black and “2.5 mg” printed on body in green, 

containing white to off white coloured powder. 

 

Lenalidomide Accord 5 mg hard capsules  

Gelatin hard capsules size “5” approximately 11.0 mm to 11.8 mm in length, opaque white cap and 

body with “LENALIDOMIDE” printed on cap in black and “5 mg” printed on body in green, 

containing white to off white coloured powder. 

 

Lenalidomide Accord 7.5 mg hard capsules  

Gelatin hard capsules size “4” approximately 14.0 mm to 14.8 mm in length, opaque lavender cap and 

opaque white body with “LENALIDOMIDE” printed on cap in black and “7.5 mg” printed on body in 

green, containing white to off white coloured powder. 

 

Lenalidomide Accord 10 mg hard capsules  

Gelatin hard capsules size “3” approximately 15.4 mm to 16.2 mm in length, leaf green cap and 

opaque white body with “LENALIDOMIDE” printed on cap in black and “10 mg” printed on body in 

green, containing white to off white coloured powder. 

 

Lenalidomide Accord 15 mg hard capsules  

Gelatin hard capsules size “2” approximately 17.4 mm to 18.2 mm in length, opaque orange cap and 

opaque white body with “LENALIDOMIDE” printed on cap in black and “15 mg” printed on body in 

green, containing white to off white coloured powder. 

 

Lenalidomide Accord 20 mg hard capsules  

Gelatin hard capsules size “1” approximately 19.0 mm to 19.8 mm in length, opaque green cap and 

opaque white body with “LENALIDOMIDE” printed on cap in black and “20 mg” printed on body in 

green, containing white to off white coloured powder. 

 

Lenalidomide Accord 25 mg hard capsules  

Gelatin hard capsules size “0” approximately 21.0 mm to 21.8 mm in length, white opaque cap and 

body with “LENALIDOMIDE” printed on cap in black and “25 mg” printed on body in green, 

containing white to off white coloured powder. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Multiple myeloma 

Lenalidomide Accord as monotherapy is indicated for the maintenance treatment of adult patients with 

newly diagnosed multiple myeloma who have undergone autologous stem cell transplantation. 

 

Lenalidomide Accord as combination therapy with dexamethasone, or bortezomib and 

dexamethasone, or melphalan and prednisone (see section 4.2) is indicated for the treatment of adult 

patients with previously untreated multiple myeloma who are not eligible for transplant. 

 



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Lenalidomide Accord in combination with dexamethasone is indicated for the treatment of multiple 

myeloma in adult patients who have received at least one prior therapy. 

 

Follicular lymphoma 

Lenalidomide Accord in combination with rituximab (anti-CD20 antibody) is indicated for the 

treatment of adult patients with previously treated follicular lymphoma (Grade 1 – 3a). 

 

4.2 Posology and method of administration 
 

Lenalidomide treatment should be supervised by a physician experienced in the use of anti-cancer 

therapies. 

 

For all indications described below: 

 Dose is modified based upon clinical and laboratory findings (see section 4.4). 

 Dose adjustments, during treatment and restart of treatment, are recommended to manage 
Grade 3 or 4 thrombocytopenia, neutropenia, or other Grade 3 or 4 toxicity judged to be 

related to lenalidomide. 

 In case of neutropenia, the use of growth factors in patient management should be considered. 

 If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more 
than 12 hours has elapsed since missing a dose at the normal time, the patient should not take 

the dose, but take the next dose at the normal time on the following day.  
 

Posology 

Newly diagnosed multiple myeloma (NDMM) 

 

Lenalidomide maintenance in patients who have undergone autologous stem cell transplantation 

(ASCT) 

Lenalidomide maintenance should be initiated after adequate haematologic recovery following ASCT 

in patients without evidence of progression. Lenalidomide must not be started if the Absolute 

Neutrophil Count (ANC) is < 1.0 x 109/L, and/or platelet counts are < 75 x 109/L. 

 

Recommended dose 

The recommended starting dose is lenalidomide 10 mg orally once daily continuously (on days 1 to 28 

of repeated 28-day cycles) given until disease progression or intolerance. After 3 cycles of 

lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated.  

 

Dose reduction steps 

 Starting dose (10 mg) If dose increased (15 mg) a 

Dose level -1 5 mg 10 mg 

Dose level -2 5 mg (days 1-21 every 28 days) 5 mg 

Dose level -3 Not applicable 5 mg (days 1-21 every 28 days) 

 Do not dose below 5 mg (days 1-21 every 28 days) 
a After 3 cycles of lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated. 

 

Thrombocytopenia 

When platelets Recommended course 

Falls to < 30 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 30 x 109/L Resume lenalidomide at dose level -1 once 

daily 

For each subsequent drop below 30 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 30 x 109/L Resume lenalidomide at next lower dose level 

once daily 

 

Absolute neutrophil count (ANC)-neutropenia 

When ANC Recommended coursea 

Falls to < 0.5 x 109/L Interrupt lenalidomide treatment  

Returns to ≥ 0.5 x 109/L Resume lenalidomide at dose level -1 once 



 5 

When ANC Recommended coursea 

daily 

For each subsequent drop below < 0.5 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 0.5 x 109/L Resume lenalidomide at next lower dose level 

once daily 
a At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and 

maintain the dose level of lenalidomide. 

 

Lenalidomide in combination with dexamethasone until disease progression in patients who are not 

eligible for transplant 

Lenalidomide treatment must not be started if the ANC is < 1.0 x 109/L, and/or platelet counts are 

< 50 x 109/L. 

 

Recommended dose 

The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 

28-day cycles.  

The recommended dose of dexamethasone is 40 mg orally once daily on days 1, 8, 15 and 22 of 

repeated 28-day cycles. Patients may continue lenalidomide and dexamethasone therapy until disease 

progression or intolerance.  

 

Dose reduction steps 

 Lenalidomidea Dexamethasonea 

Starting dose 25 mg 40 mg 

Dose level -1 20 mg 20 mg 

Dose level -2 15 mg 12 mg 

Dose level -3 10 mg 8 mg 

Dose level- 4 5 mg 4 mg 

Dose level -5 2.5 mg Not applicable 
ª Dose reduction for both medicinal  products can be managed independently 

 

Thrombocytopenia 

When platelets Recommended course 

Falls to < 25 x 109/L Stop lenalidomide dosing for remainder of 

cycleª 

Returns to ≥ 50 x 109/L Decrease by one dose level when dosing 

resumed at next cycle 

ª If Dose limiting toxicity (DLT) occurs on > day15 of a cycle, lenalidomide dosing will be interrupted for at least the remainder of the 
current 28-day cycle. 
 

Absolute neutrophil count (ANC) - neutropenia 

When ANC Recommended course 

First falls to < 0.5 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 1 x 109/L when neutropenia is the only 

observed toxicity 

Resume lenalidomide at starting dose once 

daily 

Returns to ≥ 0.5 x 109/L when dose-dependent 

haematological toxicities other than neutropenia are 

observed 

Resume lenalidomide at dose level -1 once 

daily 

For each subsequent drop below < 0.5 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 0.5 x 109/L Resume lenalidomide at next lower dose level 

once daily.  
a At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and 

maintain the dose level of lenalidomide. 

 

For hematologic toxicity the dose of lenalidomide may be re-introduced to the next higher dose level 

(up to the starting dose) upon improvement in bone marrow function (no hematologic toxicity for at 

least 2 consecutive cycles: ANC ≥1,5 x 109/L with a platelet count ≥ 100 x 109/L at the beginning of a 

new cycle). 

 



 6 

 

 Lenalidomide in combination with bortezomib and dexamethasone followed by lenalidomide 
and dexamethasone until disease progression in patients who are not eligible for transplant 

Initial treatment: Lenalidomide in combination with bortezomib and dexamethasone 

Lenalidomide in combination with bortezomib and dexamethasone must not be started if the ANC is 

< 1.0 x 109/L, and/or platelet counts are < 50 x 109/L.  

 

The recommended starting dose is lenalidomide 25 mg orally once daily days 1-14 of each 21-day 

cycle in combination with bortezomib and dexamethasone. Bortezomib should be administered via 

subcutaneous injection (1.3 mg/m2 body surface area) twice weekly on days 1, 4, 8 and 11 of each 21-

day. For additional information on the dose, schedule and dose adjustments of medicinal products 

administered with lenalidomide, see Section 5.1 and the corresponding Summary of Product 

Characteristics.  

 

Up to eight 21-day treatment cycles (24 weeks of initial treatment) are recommended.  

 

Continued treatment: Lenalidomide in combination with dexamethasone until progression 

Continue lenalidomide 25 mg orally once daily on days 1-21 of repeated 28-day cycles in combination 

with dexamethasone. Treatment should be continued until disease progression or unaccepToxicity.  

 

 Dose reduction steps 

 Lenalidomidea 

Starting dose 25 mg 

Dose level -1 20 mg 

Dose level -2 15 mg 

Dose level -3 10 mg 

Dose level- 4 5 mg 

Dose level -5 2.5 mg 
ª Dose reduction for all products can be managed independently 

 

 Thrombocytopenia 

When platelets Recommended course 

Falls to < 30 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 50 x 109/L Resume lenalidomide at dose level -1 once 

daily 

For each subsequent drop below 30 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 50 x 109/L Resume lenalidomide at next lower dose level 

once daily 

 

 Absolute neutrophil count (ANC) - neutropenia 

When ANC Recommended coursea 

First falls to < 0.5 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 1 x 109/L when neutropenia is the only 

observed toxicity 

Resume lenalidomide at starting dose once 

daily 

Returns to ≥ 0.5 x 109/L when dose-dependent 

haematological toxicities other than neutropenia are 

observed 

Resume lenalidomide at dose level -1 once 

daily 

For each subsequent drop below < 0.5 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 0.5 x 109/L Resume lenalidomide at next lower dose level 

once daily.  
a At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and 

maintain the dose level of lenalidomide. 

 

 

Lenalidomide in combination with melphalan and prednisone followed by lenalidomide maintenance 

in patients who are not eligible for transplant 



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Lenalidomide treatment must not be started if the ANC is < 1.5 x 109/L, and/or platelet counts are 

< 75 x 109/L. 

 

Recommended dose 

The recommended starting dose is lenalidomide 10 mg orally once daily on days 1 to 21 of 

repeated 28-day cycles for up to 9 cycles, melphalan 0.18 mg/kg orally on days 1 to 4 of repeated 

28-day cycles, prednisone 2 mg/kg orally on days 1 to 4 of repeated 28-day cycles. Patients who 

complete 9 cycles or who are unable to complete the combination therapy due to intolerance are 

treated with lenalidomide monotherapy as follows: 10 mg orally once daily on days 1 to 21 of 

repeated 28-day cycles given until disease progression.  

 

 Dose reduction steps 

 Lenalidomide Melphalan Prednisone 

Starting dose 10 mgª 0.18 mg/kg 2 mg/kg 

Dose level -1 7.5 mg 0.14 mg/kg 1 mg/kg 

Dose level -2 5 mg 0.10 mg/kg 0.5 mg/kg 

Dose level -3 2.5 mg Not applicable 0.25 mg/kg 
ª If neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of 

lenalidomide 

 

 Thrombocytopenia 

When platelets Recommended course 

First falls to < 25 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 25 x 109/L Resume lenalidomide and melphalan at dose 

level -1  

For each subsequent drop below 30 x 109/L Interrupt lenalidomide treatment 

Return to ≥ 30 x 109/L Resume lenalidomide at next lower dose level 

(dose level -2 or -3) once daily.  

 

 Absolute neutrophil count (ANC) - neutropenia 

When ANC Recommended course 

First falls to < 0.5 x 109/Lª Interrupt lenalidomide treatment 

Returns to ≥ 0.5 x 109/L when neutropenia is the 

only observed toxicity 

Resume lenalidomide at starting dose once 

daily 

Returns to ≥ 0.5 x 109/L when dose-dependent 

haematological toxicities other than neutropenia are 

observed 

Resume lenalidomide at dose level -1 once 

daily 

For each subsequent drop below < 0.5 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 0.5 x 109/L Resume lenalidomide at next lower dose level 

once daily.  
a At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and 
maintain the dose level of lenalidomide. 
Multiple myeloma with at least one prior therapy 

Lenalidomide treatment must not be started if the ANC < 1.0 x 109/L, and/or platelet counts 

< 75 x 109/L or, dependent on bone marrow infiltration by plasma cells, platelet counts < 30 x 109/L. 

 

Recommended dose 

The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 

28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1 to 4, 9 

to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily on 

days 1 to 4 every 28 days. 

Prescribing physicians should carefully evaluate which dose of dexamethasone to use, taking into 

account the condition and disease status of the patient. 

Dose reduction steps 

Starting dose 25 mg 

Dose level -1 15 mg 

Dose level -2 10 mg 



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Dose level -3 5 mg 

 

Thrombocytopenia 

When platelets Recommended course 

First fall to < 30 x 109/L Interrupt lenalidomide treatment 

Return to ≥ 30 x 109/L Resume lenalidomide at dose level -1  

For each subsequent drop below 30 x 109/L Interrupt lenalidomide treatment 

Return to ≥ 30 x 109/L Resume lenalidomide at next lower dose level 

(dose level -2 or -3) once daily. Do not dose 

below 5 mg once daily. 

 

• Absolute neutrophil count (ANC) - neutropenia 

When ANC Recommended course 

First falls to < 0.5 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 0.5 x 109/L when neutropenia is the 

only observed toxicity 

Resume lenalidomide at starting dose once 

daily 

Returns to ≥ 0.5 x 109/L when dose-dependent 

haematological toxicities other than neutropenia are 

observed 

Resume lenalidomide at dose level -1 once 

daily 

For each subsequent drop below < 0.5 x 109/L Interrupt lenalidomide treatment 

Returns to ≥ 0.5 x 109/L Resume lenalidomide at next lower dose level 

(dose level -1, -2 or -3) once daily. Do not dose 

below 5 mg once daily. 
a At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and 
maintain the dose level of lenalidomide. 

 

Follicular lymphoma (FL) 

Lenalidomide treatment must not be started if the ANC is < 1 x 109/L, and/or platelet count < 50 x 

109/L, unless secondary to lymphoma infiltration of bone marrow.  

 

Recommended dose 

The recommended starting dose of lenalidomide is 20 mg, orally once daily on days 1 to 21 of 

repeated 28-day cycles for up to 12 cycles of treatment. The recommended starting dose of rituximab 

is 375 mg/m2 intravenously (IV) every week in Cycle 1 (days 1, 8, 15, and 22) and day 1 of every 28-

day cycle for cycles 2 through 5. 

 

 Dose reduction steps 

Starting dose  20 mg once daily on days 1-21, every 28 days 

Dose Level -1 15 mg once daily on days 1-21, every 28 days 

Dose Level -2  10 mg once daily on days 1-21, every 28 days 

Dose Level -3 5 mg once daily on days 1-21, every 28 days 

 

For dose adjustments due to toxicity with rituximab, refer to the corresponding summary of product 

characteristics. 

 

 Thrombocytopenia 

When platelets Recommended course 

Falls to < 50 x 109/L Interrupt lenalidomide treatment and conduct 

CBC at least every 7 days 

Returns to ≥ 50 x 109/L Resume at next lower dose level (dose level -1) 

For each subsequent drop below 50 x 109/L 

 

 

Returns to ≥ 50 x 109/L 

Interrupt lenalidomide treatment and conduct 

CBC at least every 7 days 

 

Resume lenalidomide at next lower dose level 

(dose level -2, -3). Do not dose below dose 



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level -3.  

 

 Absolute neutrophil count (ANC) - neutropenia 

When ANC  Recommended course ª 

Falls < 1.0 x 109/L for at least 7 days or 

Falls to < 1.0 x 109/L with associated fever (body 

temperature ≥ 38.5°C) or  

Falls to < 0.5 x 109/L 

Interrupt lenalidomide treatment and conduct 

CBC at least every 7 days  

Returns to ≥ 1.0 x 109/L Resume lenalidomide at next lower dose level 

(dose level -1) 

For each subsequent drop below 1.0 x 109/L for at 

least 7 days or drop to < 1.0 x 109/L with associated 

fever (body temperature ≥ 38.5°C) or drop to < 0.5 x 

109/L 

 

Returns to ≥1.0 x 109/L 

Interrupt lenalidomide treatment and conduct 

CBC at least every 7 days  

 

 

Resume lenalidomide at next lower dose level 

(dose level -2, -3). Do not dose below dose 

level-3 
ª At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add G-CSF 

 

Follicular lymphoma (FL)  

Tumour lysis syndrome (TLS)  

All patients should receive TLS prophylaxis (allopurinol, rasburicase or equivalent as per institutional 

guidelines) and be well hydrated (orally) during the first week of the first cycle or for a longer period 

if clinically indicated.  To monitor for TLS, patients should have a chemistry panel drawn weekly 

during the first cycle and as clinically indicated. 

Lenalidomide may be continued (maintain dose) in patients with laboratory TLS or Grade 1 clinical 

TLS, or at the physician’s discretion, reduce dose by one level and continue lenalidomide. Vigorous 

intravenous hydration should be provided and appropriate medical management according to the local 

standard of care, until correction of electrolyte abnormalities. Rasburicase therapy may be needed to 

reduce hyperuricaemia. Hospitalisation of the patient will be at physician’s discretion. 

In patients with Grade 2 to 4 clinical TLS, interrupt lenalidomide and obtain a chemistry panel weekly 

or as clinically indicated. Vigorous intravenous hydration should be provided and appropriate medical 

management according to the local standard of care, until correction of electrolyte abnormalities. 

Rasburicase therapy and hospitalisation will be at physician’s discretion. When the TLS resolves to 

Grade 0, restart lenalidomide at next lower dose per physician’s discretion (see section 4.4). 

 

Tumour flare reaction 

At the physician’s discretion, lenalidomide may be continued in patients with Grade 1 or 2 tumour 

flare reaction (TFR) without interruption or modification. At the physician’s discretion, , therapy with 

non-steroidal anti-inflammatory drugs (NSAIDs), limited duration corticosteroids, and/or narcotic 

analgesics may be administered. In patients with Grade 3 or 4 TFR, withhold treatment with 

lenalidomide and initiate therapy with NSAIDs, corticosteroids and/or narcotic analgesics. WhenTFR 

resolves to ≤ Grade 1 , restart lenalidomide treatment at the same dose level for the rest of the cycle. 

Patients may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 

TFR (see section 4.4).  

 

All indications 

For other Grade 3 or 4 toxicities judged to be related to lenalidomide, treatment should be stopped and 

only restarted at next lower dose level when toxicity has resolved to ≤ Grade 2 depending on the 

physician’s discretion. 

 

Lenalidomide interruption or discontinuation should be considered for Grade 2 or 3 skin rash. 

Lenalidomide must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if 

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or Drug Reaction with 

Eosinophilia and Systemic Symptoms (DRESS) is suspectedand should not be resumed following 

discontinuation from these reactions. 

 



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Special populations 

Elderly 

Currently available pharmacokinetic data are described in section 5.2. Lenalidomide has been used in 

clinical trials in multiple myeloma patients up to 91 years of age (see section 5.1).  

 

Because elderly patients are more likely to have decreased renal function, care should be taken in dose 

selection and it would be prudent to monitor renal function. 

 

Newly diagnosed multiple myeloma: patients who are not eligible for transplant 

Patients with newly diagnosed multiple myeloma aged 75 years and older should be carefully assessed 

before treatment is considered (see section 4.4). 

 

For patients older than 75 years of age treated with lenalidomide in combination with dexamethasone, 

the starting dose of dexamethasone is 20 mg once daily on days 1, 8, 15 and 22 of each 28-day 

treatment cycle. 

 

No dose adjustment is proposed for patients older than 75 years who are treated with lenalidomide in 

combination with melphalan and prednisone. 

 

In patients with newly diagnosed multiple myeloma aged 75 years and older who received 

lenalidomide, there was a higher incidence of serious adverse reactions and adverse reactions that led 

to treatment discontinuation. 

 

Lenalidomide combined therapy was less tolerated in newly diagnosed multiple myeloma patients 

older than 75 years of age compared to the younger population. These patients discontinued at a higher 

rate due to intolerance (Grade 3 or 4 adverse events and serious adverse events), when compared to 

patients < 75 years. 

 

Multiple myeloma: patients with at least one prior therapy  

The percentage of multiple myeloma patients aged 65 or over was not significantly different between 

the lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in safety 

or efficacy was observed between these patients and younger patients, but greater pre-disposition of 

older individuals cannot be ruled out.  

 

Follicular lymphoma 

For follicular lymphoma patients treated with lenalidomide in combination with rituximab, the overall 

rate of adverse events is similar for patients aged 65 years or over compared with patients under 65 

years of age. No overall difference in efficacy was observed between the two age groups. 

 

Patients with renal impairment 

Lenalidomide is primarily excreted by the kidney; patients with greater degrees of renal impairment 

can have impaired treatment tolerance (see section 4.4). 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 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 III 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 7.5 mg once daily2 



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(CLcr < 30 mL/min, not requiring dialysis) 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) 

No data available3 

 

End Stage Renal Disease (ESRD) 

(CLcr < 30 mL/min, requiring dialysis) 

No data available3 

 
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. 
 3 Patients with severe renal impairment or ESRD were excluded from study. 

 

After initiation of lenalidomide therapy, subsequent lenalidomide dose modification in renally 

impaired patients should be based on individual patient treatment tolerance, as described above. 

 

 Patients with hepatic impairment 
Lenalidomide has not formally been studied in patients with impaired hepatic function and there are 

no specific dose recommendations. 

 

•       Paediatric population 

Lenalidomide should not be used in children and adolescents from birth to less than 18 years because 

of safety concerns (see section 5.1). 

 

Method of administration  

Oral use.  

Lenalidomide Accord hard  capsules should be taken orally at about the same time on the scheduled 

days. The capsules should not be opened, broken or chewed. The capsules should be swallowed 

whole, preferably with water, either with or without food. 

 

It is recommended to press only on one end of the capsule to remove it from the blister thereby 

reducing the risk of capsule deformation or breakage. 

 

4.3 Contraindications 

 

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 Women who are pregnant.  

 Women of childbearing potential unless all of the conditions of the Pregnancy Prevention 
Programme are met (see sections 4.4 and 4.6). 

 

4.4 Special warnings and precautions for use 
 

When lenalidomide is given in combination with other medicinal products, the corresponding 

Summary of Product Characteristics must be consulted prior to initiation of treatment.  

 

Pregnancy warning 

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’  



 12 

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. 

 

Criteria for women of non-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: 

 Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancer therapy 
or during breast-feeding does not rule out childbearing potential). 

 Premature ovarian failure confirmed by a specialist gynaecologist 

 Previous bilateral salpingo-oophorectomy, or hysterectomy 

 XY genotype, Turner syndrome, uterine agenesis. 
 

Counselling 

For women of childbearing potential, lenalidomide is contraindicated unless all of the following are 

met: 

 She understands the expected teratogenic risk to the unborn child 

 She understands the need for effective contraception, without interruption, at least 4 weeks 
before starting treatment, throughout the entire duration of treatment, and at least 4 weeks after 

the end of treatment 

 Even if a woman of childbearing potential has amenorrhea she must follow all the advice on 
effective contraception 

 She should be capable of complying with effective contraceptive measures 

 She is informed and understands the potential consequences of pregnancy and the need to 
rapidly consult if there is a risk of pregnancy 

 She understands the need to commence the treatment as soon as lenalidomide is dispensed 
following a negative pregnancy test 

 She understands the need and accepts to undergo pregnancy testing at least every 4 weeks 
except in case of confirmed tubal sterilisation 

 She acknowledges that she understands the hazards and necessary precautions associated with 
the use of lenalidomide. 

 

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: 

 Understand the expected teratogenic risk if engaged in sexual activity with a pregnant woman or 
a woman of childbearing potential 

 Understand the need for the use of a condom if engaged in sexual activity with a pregnant 
woman or a woman of childbearing potential not using effective contraception (even if the man 

has had a vasectomy), during treatment and for at least 7 days after dose interruptions and/or 

cessation of treatment. 

 Understand that if his female partner becomes pregnant whilst he is taking lenalidomide  or 
shortly after he has stopped taking lenalidomide , he should inform his treating physician 

immediately and that it is recommended to refer the female partner to a physician specialised or 

experienced in teratology for evaluation and advice. 

 

The prescriber must ensure that for women of childbearing potential: 

 The patient complies with the conditions of the Pregnancy Prevention Programme, including 
confirmation that she has an adequate level of understanding 

 The patient has acknowledged the aforementioned conditions. 
 

Contraception 



 13 

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: 

 Implant 

 Levonorgestrel-releasing intrauterine system (IUS) 

 Medroxyprogesterone acetate depot 

 Tubal sterilisation 

 Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two 
negative semen analyses 

 Ovulation inhibitory progesterone-only pills (i.e. desogestrel) 
 

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, 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. 

 

Pregnancy testing 

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. 

 

Prior to starting treatment 

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. 

 

Follow-up and end of treatment 

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. 

 

Additional precautions 

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. 

 



 14 

Patients should not donate blood during therapy or for at least 7 daysfollowing discontinuation of 

lenalidomide. 

 

Educational materials, prescribing and dispensing restrictions 

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. 

 

Other special warnings and precautions for use 

Myocardial infarction 

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). 

 

Venous and arterial thromboembolic events 

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, , 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 thromboembolismis 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. 

 



 15 

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. 

 

Neutropenia and thrombocytopenia 

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 follicular lymphoma, the monitoring scheme should be weekly for the first 3 weeks of cycle 1 (28 

days), every 2 weeks during cycles 2 through 4, and then at the start of each cycle thereafter. A dose 

interruption and/or 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 epistaxis, 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 reductions 

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). 

 



 16 

 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). 

 

 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).  



 17 

 

Thyroid disorders 

Cases of hypothyroidism and cases of hyperthyroidism have been reported. Optimal control of 

co-morbid 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. 

 

 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). 

 

Allergic reactions 

Cases of allergic reaction/hypersensitivity reactions have been reported in patients treated with 

lenalidomide (see section 4.8). 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.  

 

Severe skin reactions 

Severe cutaneous reactions including SJS, and TEN and DRESS have been reported with the use of 

lenalidomide. 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 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 with a history of severe rash associated with thalidomide treatment 

should not receive lenalidomide. 

 



 18 

Second primary malignancies 

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 acute myeloid leukaemia [AML], 

myelodysplastic syndrome [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  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. 

 

Second primary malignancies in follicular lymphoma 

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).  

 



 19 

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 disorders 

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. 

 

Infection with or without neutropenia 

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. 

 

Viral reactivation 

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. 

 

 Newly diagnosed multiple myeloma patients 
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 



 20 

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 

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. 

 

Progressive multifocal leukoencephalopathy (PML) 

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. 

 

Lactose intolerance 

Lenalidomide Accord hard capsules contain lactose. Patients with rare hereditary problems of 

galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this 

medicinal product.  

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

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). 

 

Oral contraceptives 

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). 

 

Warfarin 

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. 

 

Digoxin 



 21 

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. 

 

Statins 

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. 

 

Dexamethasone 

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). 

 

Interactions with P-glycoprotein (P-gp) inhibitors 

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. 

 

4.6 Fertility, pregnancy and lactation 
 

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 / Contraception in males and females 

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. 

 

Pregnancy 

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). 

 

Breast-feeding 

It is not known whether lenalidomide is excreted in breast milk. Therefore breast-feeding should be 

discontinued during therapy with lenalidomide. 

 

Fertility 

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 



 22 

effects on fertility and no parental toxicity. 

 

4.7 Effects on ability to drive and use machines 
 

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. 

 

4.8 Undesirable effects 

 

Summary of the safety profile  

Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with lenalidomide 

maintenance 

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: 

 Pneumonia (10.6%; combined term) from IFM 2005-02 

 Lung infection (9.4% [9.4% after the start of maintenance treatment]) from CALGB 100104 
 

In the IFM 2005-02 study, the adverse reactions observed more frequently with lenalidomide 

maintenance than placebo were neutropenia (60.8%), bronchitis (47.4%), diarrhoea (38.9%), 

nasopharyngitis (34.8%), muscle spasms (33.4%), leucopenia (31.7%), asthenia (29.7%), cough 

(27.3%), thrombocytopenia (23.5%), gastroenteritis (22.5%) and pyrexia (20.5%). 

 

In the CALGB 100104 study, the adverse reactions observed more frequently with lenalidomide 

maintenance than placebo were neutropenia (79.0% [71.9% after the start of maintenance treatment]), 

thrombocytopenia (72.3% [61.6%]), diarrhoea (54.5% [46.4%]), rash (31.7% [25.0%]), upper 

respiratory tract infection (26.8% [26.8%]), fatigue (22.8% [17.9%]), leucopenia (22.8% [18.8%]) and 

anaemia (21.0% [13.8%]). 

 

Newly diagnosed multiple myeloma patients who are not eligible for transplant receiving lenalidomide 

in combination with bortezomib and dexamethasone 

In the SWOG S0777 study, the serious adverse reactions observed more frequently (≥ 5%) with 

lenalidomide in combination with intravenous bortezomib and dexamethasone than with lenalidomide 

in combination with dexamethasone were:  

 Hypotension (6.5%), lung infection (5.7%), dehydration (5.0%) 
 

The adverse reactions observed more frequently with lenalidomide in combination with bortezomib 

and dexamethasone than with lenalidomide in combination with dexamethasone were: Fatigue 

(73.7%), peripheral neuropathy (71.8%), thrombocytopenia (57.6%), constipation (56.1%), 

hypocalcaemia (50.0%).  

 

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with 

lenalidomide in combination with low dose dexamethasone 

The serious adverse reactions observed more frequently (≥5%) with lenalidomide in combination with 

low dose dexamethasone (Rd and Rd18) than with melphalan, prednisone and thalidomide (MPT) 

were: 

 Pneumonia (9.8%) 

 Renal failure (including acute) (6.3%) 
 



 23 

The adverse reactions observed more frequently with Rd or Rd18 than MPT were: diarrhoea (45.5%), 

fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%), decreased 

appetite (23.1%), cough (22.7%), pyrexia (21.4%), and muscle spasms (20.5%). 

 

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with 

lenalidomide in combination with melphalan and prednisone 

The serious adverse reactions observed more frequently (≥5%) with melphalan, prednisone and 

lenalidomide followed by lenalidomide maintenance (MPR+R) or melphalan, prednisone and 

lenalidomide followed by placebo (MPR+p) than melphalan, prednisone and placebo followed by 

placebo (MPp+p) were: 

 Febrile neutropenia (6.0%) 

 Anaemia  (5.3%) 
 

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%). 

 

Multiple myeloma: patients with at least one prior therapy 

In two phase III placebo-controlled studies, 353 patients with multiple myeloma were exposed to the 

lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination.  

 

The most serious adverse reactions observed more frequently in lenalidomide/dexamethasone than 

placebo/dexamethasone combination were: 

 Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4) 

 Grade 4 neutropenia (see section 4.4). 
 

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%). 

 

Tabulated list of adverse reactions 

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. 

 

Follicular lymphoma  

The overall safety profile of lenalidomide in combination with rituximab in patients with previously 

treated follicular lymphoma is based on data from 294 patients from a Phase 3 randomised, controlled 

study NHL-007. Additionally, adverse drug reactions from supportive study NHL-008 have been 

included 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: 

 Febrile neutropenia (2.7%) 

 Pulmonary embolism (2.7%) 

 Pneumonia (2.7%) 
 

In the NHL-007 study the adverse reactions observed more frequently in the lenalidomide/rituximab 

arm compared with the placebo/rituximab arm (with at least 2% higher frequency between arms) were 



 24 

neutropenia (58.2%), diarrhoea (30.8%), leucopenia (28.8%), constipation (21.9%), cough (21.9%)  

and fatigue (21.9%). 

 

Tabulated summary for monotherapy in MM 

The following table is derived from data gathered during NDMM studies in patients who have 

undergone ASCT treated with lenalidomide maintenance. The data were not adjusted according to the 

longer duration of treatment in the lenalidomide-containing arms continued until disease progression 

versus the placebo arms in the pivotal multiple myeloma studies (see section 5.1). 

 

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 



 25 

System Organ 

Class/Preferred Term 

All ADRs/Frequency Grade 3-4 ADRs/Frequency 

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 
* Applies to serious adverse drug reactions only 
^ See section 4.8 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 
 

Tabulated summary for combination therapy in MM 

The following table is derived from data gathered during the multiple myeloma studies with 

combination therapy. The data were not adjusted according to the longer duration of treatment in the 

lenalidomide-containing arms continued until disease progression versus the comparator arms in the 

pivotal multiple myeloma studies (see 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 

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 



 26 

System Organ 

Class / Preferred 

Term 

All ADRs/Frequency Grade 3−4 ADRs/Frequency 

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, Insomnias 

Nervous System 

Disorders 

Very Common 

Peripheral neuropathies ◊◊, Paraesthesia,, 

Dizziness◊◊, Tremor, Dysgeusia, Headache 

 

Common 

Ataxia, Balance impaired , Syncope◊◊, 

Neuralgia, Dysaesthesias 

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 
 



 27 

System Organ 

Class / Preferred 

Term 

All ADRs/Frequency Grade 3−4 ADRs/Frequency 

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 event^,, 

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 

Common 

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^ 



 28 

System Organ 

Class / Preferred 

Term 

All ADRs/Frequency Grade 3−4 ADRs/Frequency 

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, Confusion^ 
 

◊◊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 



 29 

* 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 
 

Tabulated summary for combination therapy in FL 

The following table is derived from data gathered during the main studies (NHL-007 and NHL-008) 

using lenalidomide in combination with rituximab for patients with follicular lymphoma. 

 

Table 3: 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 



 30 

System Organ Class / 

Preferred Term 

All ADRs/Frequency Grade 3−4 ADRs/Frequency 

 

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 section 4.8 description of selected adverse reactions 

Algorithm applied for follicular lymphoma: 

Controlled– Phase 3 trial:  
o NHL-007 ADRs- All treatment-emergent AEs with ≥ 5.0% of subjects in lenalidomide/rituximab arm and at least 

2.0% higher frequency (%) in Len arm compared to control arm - (Safety population) 

o NHL-007 Gr 3/4 ADRs- All Grades 3 or Grade 4 treatment-emergent AEs with at least 1.0% subjects in 
lenalidomide/rituximab arm and at least 1.0% higher frequency in lenalidomide arm compared to control arm - (safety 

population) 

o NHL-007 Serious ADRs- All serious treatment-emergent AEs with at least 1.0% subjects in lenalidomide/rituximab 
arm and at least 1.0% higher frequency in lenalidomide/rituximab arm compared to control arm - (safety population) 

FL single arm - phase 3 trial: 

o NHL-008 ADRs- All treatment-emergent adverse events with ≥ 5.0% of subjects  
o NHL-008 Gr 3/4 ADRs- All Grade 3/4 treatment-emergent adverse events reported in ≥ 1.0% of subjects  
o NHL-008 Serious ADRs- All serious treatment-emergent adverse events reported in ≥ 1.0% of subjects  

◊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 
**Leucopenia includes PT leucopenia and white blood cell count decreased 
***Lymphopenia includes PT lymphopenia and lymphocyte count decreased 

 

Tabulated summary of post-marketing adverse reactions 

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 4. 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 

 



 31 

System Organ 

Class / Preferred 

Term 

All ADRs/Frequency Grade 3−4 ADRs/Frequency 

 

Blood and 

Lymphatic 

System Disorders 

Not Known 

Acquired haemophilia 
 

Immune System 

Disorders 

Not Known 

Solid organ transplant rejection 
 

Endocrine 

Disorders 

Common 

Hyperthyroidism 
 

Respiratory, 

Thoracic and 

Mediastinal 

Disorders 

 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 section 4.8 description of selected adverse reactions 
 

Description of selected adverse reactions 

Teratogenicity 

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active 

substance that causes severe life-threatening birth defects. In monkeys , lenalidomide induced 

malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide 

is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected. 

 

Neutropenia and thrombocytopenia 

 

Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with lenalidomide 

maintenance 

Lenalidomide maintenance after ASCT is associated with a higher frequency of Grade 4 neutropenia 

compared to placebo maintenance (32.1% vs 26.7% [16.1% vs 1.8% after the start of maintenance 

treatment] in CALGB 100104 and 16.4% vs 0.7% in IFM 2005-02, respectively). Treatment-emergent 

AEs of neutropenia leading to lenalidomide discontinuation were reported in 2.2% of patients in 

CALGB 100104 and 2.4% of patients in IFM 2005-02, respectively.  Grade 4 febrile neutropenia was 

reported at similar frequencies in the lenalidomide maintenance arms compared to placebo 

maintenance arms in both studies (0.4% vs 0.5% [0.4% vs 0.5% after the start of maintenance 

treatment] in CALGB 100104 and 0.3% vs 0% in IFM 2005-02, respectively). 

 



 32 

Lenalidomide maintenance after ASCT is associated with a higher frequency of Grade 3 or 4 

thrombocytopenia compared to placebo maintenance (37.5% vs 30.3% [17.9% vs 4.1% after the start 

of maintenance treatment] in CALGB 100104 and 13.0% vs 2.9% in IFM 2005-02, respectively). 

 

 Newly diagnosed multiple myeloma patients who are not eligible for transplant receiving 
lenalidomide in combination with bortezomib and dexamethasone 

Grade 4 neutropenia was observed in the RVd arm to a lesser extent than in the Rd comparator arm 

(2.7% vs 5.9%) in the SWOG S0777 study. Grade 4 febrile neutropenia was reported at similar 

frequencies in the RVd arm compared to the Rd arm (0.0% vs 0.4%).  

 

Grade 3 or 4 thrombocytopenia was observed in the RVd arm to a greater extent than in the Rd 

comparator arm (17.2 % vs 9.4%). 

 

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with 

lenalidomide in combination with dexamethasone 

The combination of lenalidomide with dexamethasone in newly diagnosed multiple myeloma patients 

is associated with a lower frequency of Grade 4 neutropenia (8.5% in Rd and Rd18, compared with 

MPT (15%). Grade 4 febrile neutropenia was observed infrequently (0.6% in Rd and Rd18 compared 

with 0.7% in MPT). 

 

The combination of lenalidomide withdexamethasone 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%). 

 

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with 

lenalidomide in combination with melphalan and prednisone 

 

The combination of lenalidomide with melphalan and prednisone in newly diagnosed multiple 

myeloma patients is associated with a higher frequency of Grade 4 neutropenia (34.1% in 

MPR+R/MPR+p) compared with MPp+p (7.8%). There was a higher frequency of grade 4 febrile 

neutropenia observed (1.7% in MPR+R/MPR+p compared to 0.0% in MPp+p).  

 

The combination of lenalidomide with melphalan and prednisone in newly diagnosed multiple 

myeloma patients is associated with a higher frequency of Grade 3 and Grade 4 thrombocytopenia 

(40.4% in MPR+R/MPR+p) compared with MPp+p (13.7%).  

Multiple myeloma: patients with at least one prior therapy 

The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with 

a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients 

compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes 

were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% 

in placebo/dexamethasone treated patients). 

 

The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with 

a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in 

lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in 

placebo/dexamethasone-treated patients). 

 

 Follicular lymphoma patients 
The combination of lenalidomide with rituximab in follicular lymphoma is associated with a higher 

rate of grade 3 or grade 4 neutropenia (50.7% in lenalidomide/rituximab treated patients compared 

with 12.2% in placebo/rituximab treated patients). All grade 3 or 4 neutropenia were reversible 

through dose interruption, reduction and/or supportive care with growth factors. Additionally, febrile 

neutropenia was observed infrequently (2.7% in lenalidomide/rituximab treated patients compared 

with 0.7% in placebo/rituximab treated patients).   

 



 33 

Lenalidomide in combination with rituximab is also associated with a higher incidence of grade 3 or 

4 thrombocytopenia (1.4% in lenalidomide/rituximab treated patients compared to 0% in 

placebo/rituximab patients).  

 

Venous thromboembolism 

An increased risk of DVT and PE is associated with the use of the combination of lenalidomide with 

dexamethasone in patients with multiple myeloma, and to a lesser extent in patients treated with 

lenalidomide in combination with melphalan and prednisone or in patients with multiple myeloma, 

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 

Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with 

known risk factors. 

 

Haemorrhagic disorders 

Haemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system 

disorders; nervous system disorders (intracranial haemorrhage); respiratory, thoracic and mediastinal 

disorders (epistaxis); gastrointestinal disorders (gingival bleeding, haemorrhoidal haemorrhage, rectal 

haemorrhage); renal and urinary disorders (haematuria); injury, poisoning and procedural 

complications (contusion) and vascular disorders (ecchymosis). 

 

Allergic reactions 

Cases of allergic reaction/hypersensitivity reactions have been reported. A possible cross-reaction 

between lenalidomide and thalidomide has been reported in the literature. 

 

Severe skin reactions 

Severe cutaneous reactions including SJS, TEN and DRESS have been reported with the use of 

lenalidomide. Patients with a history of severe rash associated with thalidomide treatment should not 

receive lenalidomide (see section 4.4). 

 

Second primary malignancies 

In clinical trials in previously treated myeloma patients with lenalidomide/dexamethasone compared 

to controls, mainly comprising of basal cell or squamous cell skin cancers. 

 

 

 

Acute myeloid leukaemia  

Multiple myeloma 

Cases of AML have been observed in clinical trials of newly diagnosed multiple myeloma in patients 

taking lenalidomide treatment in combination with melphalan or immediately following HDM/ASCT 

(see section 4.4). This increase was not observed in clinical trials of newly diagnosed multiple 

myeloma in patients taking lenalidomide in combination with low dose dexamethasone compared to 

thalidomide in combination with melphalan and prednisone. 

 

Hepatic disorders 

The following post-marketing adverse reactions have been reported (frequency unknown): acute 

hepatic failure and cholestasis (both potentially fatal), toxic hepatitis, cytolytic hepatitis, mixed 

cytolytic/cholestatic hepatitis. 

 
Rhabdomyolysis 

Rare cases of rhabdomyolysis have been observed, some of them when lenalidomide is administered 

with a statin. 

 
Thyroid disorders  



 34 

Cases of hypothyroidism and cases of hyperthyroidism have been reported (see section 4.4 Thyroid 

disorders). 

 

Tumour flare reaction and tumour lysis syndrome 

 

In study NHL-007, TFR was reported in 19/146 (13.0%) of patients in the lenalidomide/rituximab arm 

versus 1/148 (0.7%) patients in the placebo/rituximab arm. Most TFRs (18 out of 19) reported in the 

lenalidomide/rituximab arm occurred during first two cycles of treatment. One FL patient in the 

lenalidomide/rituximab arm experienced a Grade 3 TFR event versus no patients in the 

placebo/rituximab arm. In study NHL-008, 7/177 (4.0%) of FL patients experienced TFR; (3 reports 

were Grade 1 and 4 reports were Grade 2 severity); while 1 report was considered serious. In study 

NHL-007, TLS occurred in 2 FL patients (1.4%) in the lenalidomide/rituximab arm and no FL patients 

in the placebo/rituximab arm; neither patient had a Grade 3 or 4 event. TLS occurred in 1 FL patient 

(0.6%) in study NHL-008. This single event was identified as a serious, Grade 3 adverse reaction. For 

study NHL-007 no patients had to discontinue lenalidomide/rituximab therapy due to TFR or TLS. 

 

Gastrointestinal disorders 

Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinal 

perforations may lead to septic complications and may be associated with fatal outcome. 

 
Reporting of suspected adverse reactions 

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. 

 
4.9 Overdose 
 

There is no specific experience in the management of lenalidomide overdose in patients, although in 

dose-ranging studies some patients were exposed to up to 150 mg, and in single-dose studies, some 

patients were exposed to up to 400 mg. The DLT in these studies was essentially haematological. In 

the event of overdose, supportive care is advised.  

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Immunosuppressants, Other immunosuppressants. ATC code: L04AX04. 

 

Mechanism of action 

 

Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme 

complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 

(CUL4), and regulator of cullins 1 (Roc1). In haematopoietic cells, lenalidomide binding to cereblon 

recruits substrate proteins Aiolos and Ikaros lymphoid transcriptional factors, leading to their 

ubiquitination and subsequent degradation resulting in direct cytotoxic and immunomodulatory 

effects. 

 

Specifically, lenalidomide inhibits proliferation and enhances apoptosis of certain haematopoietic 

tumour cells (including MM plasma tumour cells and follicular lymphoma tumour cells), enhances T 

cell- and Natural Killer (NK) cell-mediated immunity and increases the number of NK, T and NK T 

cells. The combination of lenalidomide and rituximab increases ADCC and direct tumor apoptosis in 

follicular lymphoma cells. 

 

The lenalidomide mechanism of action also includes additional activities such as anti-angiogenic and 

pro-erythropoietic properties. Lenalidomide inhibits angiogenesis by blocking the migration and 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 35 

adhesion of endothelial cells and the formation of microvessels, augments foetal haemoglobin 

production by CD34+ haematopoietic stem cells, and inhibits production of pro-inflammatory 

cytokines (e.g., TNF-α and IL-6) by monocytes. 

 

Clinical efficacy and safety 

Lenalidomide efficacy and safety have been evaluated in five phase III studies in newly diagnosed 

multiple myeloma, two phase III studies in relapsed refractory multiple myelomaas and one phase 3 

and one phase 3b study in iNHL described below. 

 

Newly diagnosed multiple myelomaLenalidomide maintenance in patients who have undergone ASCT 

The efficacy and safety of lenalidomide maintenance was assessed in two phase 3 multicentre, 

randomised, double-blind 2-arm, parallel group, placebo-controlled studies: CALGB 100104 and IFM 

2005-02 

 

CALGB 100104 

Patients between 18 and 70 years of age with active MM requiring treatment and without prior 

progression after initial therapy were eligible. 

 

Patients were randomised 1:1 within 90-100 days after ASCT to receive either lenalidomide or placebo 

maintenance. The maintenance dose was 10 mg once daily on days 1-28 of repeated 28-day cycles 

(increased up to 15 mg once daily after 3 months in the absence of dose-limiting toxicity), and 

treatment was continued until disease progression. 

 

The primary efficacy endpoint in the study was progression free survival (PFS) from randomisation to 

the date of progression or death, whichever occurred first; the study was not powered for the overall 

survival endpoint. In total 460 patients were randomised: 231 patients to lenalidomide and 229 patients 

to placebo. The demographic and disease-related characteristics were balanced across both arms. 

 

The study was unblinded upon the recommendations of the data monitoring committee after 

surpassing the threshold for a preplanned interim analysis of PFS. After unblinding, patients in the 

placebo arm were allowed to cross over to receive lenalidomide before disease progression. 

 

The results of PFS at unblinding, following a preplanned interim analysis, using a cut-off of 17 

December 2009 (15.5 months follow up) showed a 62% reduction in risk of disease progression or 

death favouring lenalidomide (HR = 0.38; 95% CI 0.27, 0.54; p <0.001). The median overall PFS was 

33.9 months (95% CI NE, NE) in the lenalidomide arm versus 19.0 months (95% CI 16.2, 25.6) in the 

placebo arm.  

 

The PFS benefit was observed both in the subgroup of patients with CR and in the subgroup of 

patients who had not achieved a CR. 

 

The results for the study, using a cut-off of 1 February 2016, are presented in Table 4 

 



 36 

Table 5: Summary of overall efficacy data 

 Lenalidomide 

(N = 231) 

Placebo 

(N = 229) 

Investigator-assessed PFS   

Mediana PFS time, months (95% CI)b 56.9 (41.9, 71.7) 29,4 (20.7, 35.5) 

HR [95% CI]c; p-valued 0.61 (0.48, 0.76); <0.001 

PFS2e   

Mediana PFS2 time, months (95% CI) b 80.2 (63.3, 101.8) 52.8 (41.3, 64.0) 

HR [95% CI]c ; p-valued 0.61 (0.48, 0.78); <0.001 

Overall survival   

Mediana OS time, months (95% CI)b 111.0 (101.8, NE) 84.2 (71.0, 102.7) 

8-year survival rate, % (SE) 60.9 (3.78) 44.6 (3.98) 

HR [95% CI]c ; p-valued 0.61 (0.46, 0.81); <0.001 

Follow-up   

Medianf (min, max), months: all surviving patients 81.9 (0.0, 119.8) 81.0 (4.1, 119.5) 
CI = confidence interval; HR = hazard ratio; max = maximum; min = minimum; NE = not estimable; OS = overall survival; 

PFS = progression-free survival;  
a The median is based on the Kaplan-Meier estimate. 
b The 95% CI about the median. 
c Based on Cox proportional hazards model comparing the hazard functions associated with the indicated treatment arms. 
d The p-value is based on the unstratified log-rank test of Kaplan-Meier curve differences between the indicated treatment arms. 
e Exploratory endpoint (PFS2). Lenalidomide received by subjects in the placebo arm who crossed over prior to PD upon study unblinding 

was not considered as a second-line therapy. 
f Median follow-up post-ASCT for all surviving subjects. 

Data cut-off dates: 17 Dec 2009 and 01 Feb 2016  

 

IFM 2005-02 

Patients aged < 65 years at diagnosis who had undergone ASCT and had achieved at least a stable 

disease response at the time of hematologic recovery were eligible. Patients were randomised 1:1 to 

receive either lenalidomide or placebo maintenance (10 mg once daily on days 1-28 of repeated 28-

day cycles increased up to 15 mg once daily after 3 months in the absence of dose-limiting toxicity) 

following 2 courses of lenalidomide consolidation (25 mg/day, days 1-21 of a 28-day cycle). 

Treatment was to be continued until disease progression. 

 

The primary endpoint was PFS defined from randomisation to the date of progression or death, 

whichever occurred first; the study was not powered for the overall survival endpoint. In total 614 

patients were randomised: 307 patients to lenalidomide and 307 patients to placebo. 

 

The study was unblinded upon the recommendations of the data monitoring committee after 

surpassing the threshold for a preplanned interim analysis of PFS. After unblinding, patients receiving 

placebo were not crossed over to lenalidomide therapy prior to progressive disease. The lenalidomide 

arm was discontinued, as a proactive safety measure, after observing an imbalance of SPMs (see 

section 4.4). 

 

The results of PFS at unblinding, following a preplanned interim analysis, using a cut-off of 7 July 

2010 (31.4 months follow up) showed a 48% reduction in risk of disease progression or death favoring 

lenalidomide (HR = 0.52; 95% CI 0.41, 0.66; p <0.001). The median overall PFS was 40.1 months 

(95% CI 35.7, 42.4) in the lenalidomide arm versus 22.8 months (95% CI 20.7, 27.4) in the placebo 

arm. 

 

The PFS benefit was less in the subgroup of patients with CR than in the subgroup of patients who had 

not achieved a CR. 

 

The updated PFS, using a cut-off of 1 February 2016 (96.7 months follow up) continues to show a PFS 

advantage: HR = 0.57 (95% CI 0.47, 0.68; p < 0.001). The median overall PFS was 44.4 months (39.6, 

52.0) in the lenalidomide arm versus 23.8 months (95% CI 21.2, 27.3) in the placebo arm. For PFS2, 

the observed HR was 0.80 (95% CI 0.66, 0.98; p = 0.026) for lenalidomide versus placebo. The 

median overall PFS2 was 69.9 months (95% CI 58.1, 80.0) in the lenalidomide arm versus 58.4 

months (95% CI 51.1, 65.0) in the placebo arm. For OS, the observed HR was 0.90: (95% CI 0.72, 

1.13; p = 0.355) for lenalidomide versus placebo. The median overall survival time was 105.9 months 



 37 

(95% CI 88.8, NE) in the lenalidomide arm versus 88.1 months (95% CI 80.7, 108.4) in the placebo 

arm. 

 

Lenalidomide in combination with bortezomib and dexamethasone in patients who are not eligible 

for stem cell transplantation 

The SWOG S0777 study evaluated the addition of bortezomib to a foundation of lenalidomide and 

dexamethasone, as initial treatment, followed by continued Rd until disease progression, in patients 

with previously untreated multiple myeloma who are either ineligible for transplant or eligible for 

transplant with no plan to undertake immediate transplant.  
 
Patients in the lenalidomide, bortezomib and dexamethasone (RVd) arm received lenalidomide 

25 mg/day orally on days 1-14, intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, and 

dexamethasone 20 mg/day orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of repeated 21-day cycles for up to 

eight 21-day cycles (24 weeks). Patients in the lenalidomide and dexamethasone (Rd) arm received 

lenalidomide 25 mg/day orally on days 1-21, and dexamethasone 40 mg/day orally on days 1, 8, 15, 

and 22 of repeated 28-day cycles for up to six 21-day cycles (24 weeks). Patients in both arms took 

continued Rd: lenalidomide 25 mg/day orally on days 1-21 and dexamethasone 40 mg/day orally on 

days 1, 8, 15, and 22 of repeated 28-day cycles. Treatment was to be continued until disease 

progression. 

 

The primary efficacy endpoint in the study was progression free survival (PFS). In total 523 patients 

were enrolled into the study, with 263 patients randomised to RVd and 260 patients randomised to Rd. 

The demographics and disease-related baseline characteristics of the patients were well balanced 

between arms.  

 

The results of PFS, as assessed by IRAC, at the time of the primary analysis, using a cut-off of 05 

November 2015 (50.6 months follow up) showed a 24% reduction in risk of disease progression or 

death favouring RVd (HR = 0.76; 95% CI 0.61, 0.94; p = 0.010). The median overall PFS was 42.5 

months (95% CI 34.0, 54.8) in the RVd arm versus 29.9 months (95% CI 25.6, 38.2) in the Rd arm. 

The benefit was observed regardless of eligibility for stem cell transplant. 

 

The results for the study, using a cut-off of 01 December 2016, where the median follow-up time for 

all surviving subjects was 69.0 months, are presented in Table 8. The benefit favouring RVd was 

observed regardless of eligibility for stem cell transplant. 

 

Table 6. Summary of overall efficacy data 

 Initial treatment 

RVd 

(3-week cycles  8) 

(N = 263) 

Rd 

(4-week cycles  6) 

(N = 260) 

IRAC-assessed PFS (months) 

Mediana PFS time, months (95% CI)b 41.7 (33.1, 51.5) 29.7 (24.2, 37.8) 

HR [95% CI]c; p-valued 0.76 (0.62, 0.94); 0.010 

Overall survival (months) 

Mediana OS time, months (95% CI)b 89.1 (76.1, NE) 67.2 (58.4, 90.8) 

HR [95% CI]c; p-valuee 0.72 (0.56, 0.94); 0.013 

Responsef – n (%) 

Overall response: CR, VGPR, or PR 199 (75.7) 170 (65.4) 

≥ VGPR 153 (58.2) 83 (31.9) 

Follow-up (months) 

Medianf (min, max): all patients 61.6 (0.2, 99.4) 59.4 (0.4, 99.1) 
a CI = confidence interval; HR = hazard ratio; max = maximum; min = minimum; NE = not estimable; OS = overall survival; 
PFS = progression-free survival; Median follow-up was calculated from the date of randomization. 
b The median is based on Kaplan-Meier estimate. 
c Two-sided 95% CI about the median time. 
d Based on unstratified Cox proportional hazards model comparing hazard functions associated with treatment arms (RVd:Rd). 
e The p-value is based on unstratified log-rank test. 
Data cutoff date = 01 Dec 2016. 



 38 

 

Updated OS results, using a cut-off of 01 May 2018 (84.2 months median follow-up for surviving 

subjects) continue to show an OS advantage favouring RVd: HR = 0.73 (95% CI 0.57, 0.94; p=0.014). 

The proportion of subjects alive after 7 years was 54.7% in the RVd arm versus 44.7% in the Rd arm. 

 

 Lenalidomide in combination with dexamethasone in patients who are not eligible for stem 
cell transplantation 

The safety and efficacy of lenalidomide was assessed in a phase III, multicentre, randomised, open-

label, 3-arm study (MM-020) of patients who were at least 65 years of age or older or, if younger than 

65 years of age, were not candidates for stem cell transplantation because they declined to undergo 

stem cell transplantation or stem cell transplantation is not available to the patient due to cost or other 

reason.The study (MM-020) compared lenalidomide and dexamethasone (Rd) given for 2 different 

durations of time (i.e., until progressive disease [Arm Rd] or for up to eighteen 28-day cycles [72 

weeks, Arm Rd18]) to melphalan, prednisone and thalidomide (MPT) for a maximum of twelve 

42-day cycles (72 weeks). Patients were randomised (1:1:1) to 1 of 3 treatment arms. Patients were 

stratified at randomisation by age (≤75 versus >75 years), stage (ISS Stages I and II versus Stage III), 

and country. 

 

Patients in the Rd and Rd18 arms took lenalidomide 25 mg once daily on days 1 to 21 of 28-day cycles 

according to protocol arm. Dexamethasone 40 mg was dosed once daily on days 1, 8, 15, and 22 of 

each 28-day cycle. Initial dose and regimen for Rd and Rd18 were adjusted according to age and renal 

function (see section 4.2). Patients >75 years received a dexamethasone dose of 20 mg once daily on 

days 1, 8, 15, and 22 of each 28-day cycle. All patients received prophylactic anticoagulation (low 

molecular weight heparin, warfarin, heparin, low-dose acetylsalicylic acid  during the study. 

 

The primary efficacy endpoint in the study was progression free survival (PFS). In total 1623 patients 

were enrolled into the study, with 535 patients randomised to Rd, 541 patients randomised to Rd18 

and 547 patients randomised to MPT. The demographics and disease-related baseline characteristics of 

the patients were well balanced in all 3 arms. In general, study subjects had advanced-stage disease: of 

the total study population, 41% had ISS stage III, 9% had severe renal insufficiency (creatinine 

clearance [CLcr] < 30 mL/min). The median age was 73 in the 3 arms. 

 

In an updated analysis of PFS, PFS2 and OS using a cut off of 3 March 2014 where the median 

follow-up time for all surviving subjects was 45.5 months, the results of the study are presented in 

Table 5: 

 

Table 7. Summary of overall efficacy data 

 Rd 

(N = 535) 

Rd18 

(N = 541) 

MPT 

(N = 547) 

Investigator-assessed PFS  (months)    

Mediana PFS time, months (95% CI)b 26.0 (20.7, 29.7) 21.0 (19.7, 22.4) 21.9 (19.8, 23.9) 

HR [95% CI]c; p-valued    

Rd vs MPT 0.69 (0.59, 0.80); <0.001 

Rd vs Rd18 0.71 (0.61, 0.83); <0.001 

Rd18 vs MPT 0.99 (0.86, 1.14); 0.866 

PFS2e  (months)    

Mediana PFS2 time, months (95% CI)b 42.9 (38.1, 47.4) 40.0 (36.2, 44.2) 35.0 (30.4, 37.8) 

HR [95% CI]c; p-valued    

Rd vs MPT 0.74 (0.63, 0.86); <0.001 

Rd vs Rd18 0.92 (0.78, 1.08); 0.316 

Rd18 vs MPT 0.80 (0.69, 0.93); 0.004 

Overall survival (months)    

Mediana OS time, months (95% CI)b 58.9 (56.0, NE) 56.7 (50.1, NE) 48.5 (44.2, 52.0) 

HR [95% CI]c; p-valued    

Rd vs MPT 0.75 (0.62, 0.90); 0.002 



 39 

 Rd 

(N = 535) 

Rd18 

(N = 541) 

MPT 

(N = 547) 

Rd vs Rd18 0.91 (0.75, 1.09); 0.305 

Rd18 vs MPT 0.83 (0.69, 0.99); 0.034 

Follow-up (months)    

Medianf (min, max): all patients 40.8 (0.0, 65.9) 40.1 (0.4, 65.7) 38.7 (0.0, 64.2) 

Myeloma responseg n (%)    

CR 81 (15.1) 77 (14.2) 51 (9.3) 

VGPR 152 (28.4) 154 (28.5) 103 (18.8) 

PR 169 (31.6) 166 (30.7) 187 (34.2) 

Overall response: CR, VGPR, or PR 402 (75.1) 397 (73.4) 341 (62.3) 

Duration of response  (months) h    

Mediana (95% CI)b 35.0 (27.9, 43.4) 22.1 (20.3, 24.0) 22.3 (20.2, 24.9) 
AMT = antimyeloma therapy; CI = confidence interval; CR = complete response; d = low-dose dexamethasone; HR = hazard ratio; 

IMWG = International Myeloma Working Group; IRAC = Independent Response Adjudication Committee; M = melphalan; 

max = maximum; min = minimum; NE = not estimable; OS = overall survival; P = prednisone; PFS = progression-free survival; 
PR = partial response; R = lenalidomide; Rd = Rd given until documentation of progressive disease; Rd18 = Rd given for  18 cycles; 

SE = standard error; T = thalidomide; VGPR = very good partial response; vs = versus. 
a   The median is based on the Kaplan-Meier estimate. 
b   The 95% CI about the median. 
c  Based on Cox proportional hazards model comparing the hazard functions associated with the indicated treatment arms. 
d  The p-value is based on the unstratified log-rank test of Kaplan-Meier curve differences between the indicated treatment arms. 
e   Exploratory endpoint (PFS2) 
f   The median is the univariate statistic without adjusting for censoring. 
g    Best assessment of adjudicated response during the treatment phase of the study (for definitions of each response category, Data cut-off 

date = 24 May 2013). 
h data cut 24 May 2013  

 

 

Lenalidomide in combination with melphalan and prednisone followed by maintenance therapy in 

patients who are not eligible for transplant 

The safety and efficacy of lenalidomide was assessed in a phase III multicentre, randomised double 

blind 3 arm study (MM-015) of patients who were 65 years or older and had a serum creatinine < 

2.5 mg/dL. The study compared lenalidomide in combination with melphalan and prednisone (MPR) 

with or without lenalidomide maintenance therapy until disease progression, to that of melphalan and 

prednisone for a maximum of 9 cycles. Patients were randomised in a 1:1:1 ratio to one of 3 treatment 

arms. Patients were stratified at randomisation by age ( 75 vs. > 75 years) and stage (ISS; Stages I 

and II vs. stage III). 

 

This study investigated the use of combination therapy of MPR (melphalan 0.18 mg/kg orally on days 

1 to 4 of repeated 28-day cycles; prednisone 2 mg/kg orally on days 1 to 4 of repeated 28-day cycles; 

and lenalidomide 10 mg/day orally on days 1 to 21 of repeated 28-day cycles) for induction therapy, 

up to 9 cycles. Patients who completed 9 cycles or who were unable to complete 9 cycles due to 

intolerance proceeded to maintenance therapy starting with lenalidomide 10 mg orally on days 1 to 21 

of repeated 28-day cycles until disease progression. 

 

The primary efficacy endpoint in the study was progression free survival (PFS). In total 459 patients 

were enrolled into the study, with 152 patients randomised to MPR+R, 153 patients randomised to 

MPR+p and 154 patients randomised to MPp+p. The demographics and disease-related baseline 

characteristics of the patients were well balanced in all 3 arms; notably, approximately 50% of the 

patients enrolled in each arm had the following characteristics; ISS Stage III, and creatinine clearance 

< 60 mL/min. The median age was 71 in the MPR+R and MPR+p arms and 72 in the MPp+p arm. 

 

In an analysis of PFS, PFS2, OS using a cut-off of April 2013 where the median follow up time for all 

surviving subjects was 62.4 months, the results of the study are presented in Table 6: 

 

Table8. Summary of overall efficacy data 

 MPR+R  

(N = 152) 

MPR+p 

(N = 153) 

MPp +p 

(N = 154) 



 40 

 MPR+R  

(N = 152) 

MPR+p 

(N = 153) 

MPp +p 

(N = 154) 

Investigator-assessed PFS  (months)   

Mediana PFS time, months (95% CI) 27.4 (21.3, 35.0) 14.3 (13.2, 15.7) 13.1 (12.0, 14.8) 

HR [95% CI]; p-value  

MPR+R vs MPp+p 0.37 (0.27, 0.50); <0.001 

MPR+R vs MPR+p 0.47 (0.35, 0.65); <0.001 

MPR+p vs MPp +p 0.78 (0.60, 1.01); 0.059 

PFS2  (months) ¤  

Mediana PFS2 time, months (95% CI) 39.7 (29.2, 48.4) 27.8 (23.1, 33.1) 28.8 (24.3, 33.8) 

HR [95% CI]; p-value  

MPR+R vs MPp+p 0.70 (0.54, 0.92); 0.009 

MPR+R vs MPR+p 0.77 (0.59, 1.02); 0.065 

MPR+p vs MPp +p 0.92 (0.71, 1.19); 0.051 

Overall survival (months)  

Mediana OS time, months (95% CI) 55.9 (49.1, 67.5) 51.9 (43.1, 60.6) 53.9 (47.3, 64.2) 

HR [95% CI]; p-value  

MPR+R vs MPp+p 0.95 (0.70, 1.29); 0.736 

MPR+R vs MPR+p 0.88 (0.65, 1.20); 0.43 

MPR+p vs MPp +p 1.07 (0.79, 1.45); 0.67 

Follow-up (months)  

Median (min, max): all patients 48.4 (0.8, 73.8) 46.3 (0.5, 71.9) 50.4 (0.5, 73.3) 

Investigator-assessed Myeloma response 

n (%) 

 

CR 30 (19.7) 17 (11.1) 9 (5.8) 

PR 90 (59.2) 99 ( 64.7) 75 (48.7) 

Stable Disease (SD) 24 (15.8) 31 (20.3) 63 (40.9) 

Response Not Evaluable (NE) 8 (5.3) 4 (2.6) 7 (4.5) 

Investigator-assessed Duration of 

response (CR+PR)  (months)     

Mediana (95% CI) 26.5 (19.4, 35.8) 12.4 (11.2, 13.9) 12.0 (9.4, 14.5) 
CI = confidence interval; CR = complete response; HR = Hazard Rate; M = melphalan; NE = not estimable; OS = overall survival; p = 
placebo; P = prednisone;  

PD = progressive disease; PR = partial response; R = lenalidomide; SD = stable disease; VGPR = very good partial response. 

ª The median is based on the Kaplan-Meier estimate 
¤PFS2 (an exploratory endpoint) was defined for all patients (ITT) as time from randomisation to start of 3rd line antimyeloma therapy 

(AMT) or death for all randomised patients 

 

Supportive newly diagnosed multiple myeloma studies 

An open-label, randomised, multicentre, phase III study (ECOG E4A03) was conducted in 445 

patients with newly diagnosed multiple myeloma; 222 patients were randomised to the 

lenalidomide/low dose dexamethasone arm, and 223 were randomised to the lenalidomide/standard 

dose dexamethasone arm. Patients randomised to the lenalidomide/standard dose dexamethasone arm 

received lenalidomide 25 mg/day, days 1 to 21 every 28 days plus dexamethasone 40 mg/day on days 

1 to 4, 9 to 12, and 17 to 20 every 28 days for the first four cycles. Patients randomised to the 

lenalidomide/low dose dexamethasone arm received lenalidomide 25 mg/day, days 1 to 21 every 28 

days plus low dose dexamethasone – 40 mg/day on days 1, 8, 15, and 22 every 28 days. In the 

lenalidomide/low dose dexamethasone group, 20 patients (9.1%) underwent at least one dose 

interruption compared to 65 patients (29.3%) in the lenalidomide/standard dose dexamethasone arm. 

 

In a post-hoc analysis, lower mortality was observed in the lenalidomide/low dose dexamethasone arm 

6.8% (15/220) compared to the lenalidomide/standard dose dexamethasone arm 19.3% (43/223), in the 

newly diagnosed multiple myeloma patient population, with a median follow up of 72.3 weeks. 

 

However with a longer follow-up, the difference in overall survival in favour of lenalidomide/ low 

dose dexamethasone tends to decrease. 



 41 

 

Multiple myeloma with at least one prior therapy 

The efficacy and safety of lenalidomide were evaluated in two phase III multi-centre, randomised, 

double-blind, placebo-controlled, parallel-group controlled studies (MM-009 and MM-010) of 

lenalidomide plus dexamethasone therapy versus dexamethasone alone in previously treated patients 

with multiple myeloma. Out of 353 patients in the MM-009 and MM-010 studies who received 

lenalidomide/dexamethasone, 45.6% were aged 65 or over. Of the 704 patients evaluated in the 

MM-009 and MM-010 studies, 44.6% were aged 65 or over. 

 

In both studies, patients in the lenalidomide/dexamethasone (len/dex) group took 25 mg of 

lenalidomide orally once daily on days 1 to 21 and a matching placebo capsule once daily on days 22 

to 28 of each 28-day cycle. Patients in the placebo/dexamethasone (placebo/dex) group took 1 placebo 

capsule on days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of 

dexamethasone orally once daily on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 

4 cycles of therapy. The dose of dexamethasone was reduced to 40 mg orally once daily on days 1 to 4 

of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue until 

disease progression. In both studies, dose adjustments were allowed based on clinical and laboratory 

finding. 

 

The primary efficacy endpoint in both studies was time to progression (TTP). In total, 353 patients 

were evaluated in the MM-009 study; 177 in the len/dex group and 176 in the placebo/dex group and, 

in total, 351 patients were evaluated in the MM-010 study; 176 in the len/dex group and 175 in the 

placebo/dex group. 

 

In both studies, the baseline demographic and disease-related characteristics were comparable between 

the len/dex and placebo/dex groups. Both patient populations presented a median age of 63 years, with 

a comparable male to female ratio. The ECOG performance status was comparable between both 

groups, as was the number and type of prior therapies. 

 

Pre-planned interim analyses of both studies showed that len/dex was statistically significantly 

superior (p < 0.00001) to dexamethasone alone for the primary efficacy endpoint, TTP (median 

follow-up duration of 98.0 weeks). Complete response and overall response rates in the len/dex arm 

were also significantly higher than the placebo/dex arm in both studies. Results of these analyses 

subsequently led to an unblinding in both studies, in order to allow patients in the placebo/dex group 

to receive treatment with the len/dex combination. 

 

An extended follow-up efficacy analysis was conducted with a median follow-up of 130.7 weeks. 

Table 7 summarises the results of the follow-up efficacy analyses – pooled studies MM-009 and 

MM-010. 
 

In this pooled extended follow-up analysis, the median TTP was 60.1 weeks (95% CI: 44.3, 73.1) in 

patients treated with len/dex (N = 353) versus 20.1 weeks (95% CI: 17.7, 20.3) in patients treated with 

placebo/dex (N = 351). The median progression free survival was 48.1 weeks (95% CI: 36.4, 62.1) in 

patients treated with len/dex versus 20.0 weeks (95% CI: 16.1, 20.1) in patients treated with 

placebo/dex. The median duration of treatment was 44.0 weeks (min: 0.1, max: 254.9) for len/dex and 

23.1 weeks (min: 0.3, max: 238.1) for placebo/dex. Complete response (CR), partial response (PR) 

and overall response (CR+PR) rates in the len/dex arm remain significantly higher than in the 

placebo/dex arm in both studies. The median overall survival in the extended follow-up analysis of the 

pooled studies is 164.3 weeks (95% CI: 145.1, 192.6) in patients treated with len/dex versus 136.4 

weeks (95% CI: 113.1, 161.7) in patients treated with placebo/dex. Despite the fact that 170 out of the 

351 patients randomised to placebo/dex received lenalidomide after disease progression or after the 

studies were unblinded, the pooled analysis of overall survival demonstrated a statistically significant 

survival advantage for len/dex relative to placebo/dex (HR = 0.833, 95% CI = [0.687, 1.009], 

p=0.045). 

 



 42 

Table 9. Summary of results of efficacy analyses as of cut-off date for extended follow-up — 

pooled studies MM-009 and MM-010 (cut-offs 23 July 2008 and 2 March 2008, respectively) 

Endpoint len/dex 

(N=353) 

placebo/dex(N=351)  

Time to event    HR [95% CI], p-value a 

Time to progression  

Median [95% CI], weeks 

60.1 [44.3, 

73.1] 

20.1 [17.7, 20.3] 0.350 [0.287, 0.426], p < 0.001  

Progression free survival  

Median [95% CI], weeks 

48.1  

[36.4, 62.1] 

20.0 [16.1, 20.1] 0.393 [0.326, 0.473], p < 0.001  

Overall survival 

Median [95% CI], weeks 

1-year Overall survival rate 

164.3 

[145.1, 

192.6] 

82% 

136.4 [113.1, 161.7] 

75% 

0.833 [0.687, 1.009], p = 0.045  

Response rate   Odds ratio [95% CI], p-value 
b 

Overall response [n, %] 

Complete response [n, %] 

212 (60.1) 

58 (16.4) 

75 (21.4) 

11 (3.1) 

5.53 [3.97, 7.71], p < 0.001 

6.08 [3.13, 11.80], p < 0.001  
a: Two-tailed log rank test comparing survival curves between treatment groups. 

b: Two-tailed continuity-corrected chi-square test. 

 

Follicular lymphoma 

AUGMENT - CC-5013-NHL-007  

The efficacy and safety of lenalidomide in combination with rituximab versus rituximab plus placebo 

was evaluated in patients with relapsed/refractory iNHL including FL in a phase 3, multicentre, 

randomised, double- blind controlled study (CC-5013-NHL-007 [AUGMENT]). 

 

A total of 358 patients who were at least 18 years of age with histologically confirmed MZL or Grade 

1, 2 or 3a FL (CD20+ by flow cytometry or histochemistry) as assessed by the investigator or local 

pathologist were randomised in a 1:1 ratio. Subjects had been previously treated with at least one prior 

systemic chemotherapy, immunotherapy or chemoimmunotherapy. 

 

Lenalidomide was administered orally 20 mg once daily for the first 21 days of repeating 28-day 

cycles for 12 cycles or until unacceptable toxicity. The dose of rituximab was 375 mg/m2 every week 

in Cycle 1 (days 1, 8, 15, and 22) and on day 1 of every 28-day cycle from cycles 2 through 5. All 

dosage calculations for rituximab were based on the patient’s body surface area (BSA), using actual 

patient weight. 

 

The demographic and disease-related baseline characteristics were similar across the 2 treatment 

groups. 

 

The primary objective of the study was to compare the efficacy of lenalidomide in combination with 

rituximab to rituximab plus placebo in subjects with relapsed/refractory FL Grade 1, 2 or 3a or MZL. 

Efficacy determination was based upon PFS as the primary endpoint, as assessed by the IRC using the 

2007 International Working Group (IWG) criteria but without positron emission tomography (PET).  

 

The secondary objectives of the study were to compare the safety of lenalidomide in combination with 

rituximab versus rituximab plus placebo. Further secondary objectives were to compare the efficacy of 

rituximab plus lenalidomide versus rituximab plus placebo using the following other parameters of 

efficacy: 

Overall response rate (ORR), CR rate, and duration of response (DoR) by IWG 2007 without PET and 

OS. 

 

Results from the overall population including FL and MZL showed that at a median follow up of 

28.3°months, the study met its primary endpoint of PFS with a hazard ratio (HR) (95% confidence 

interval [CI]) of 0.45 (0.33,0.61) p-value < 0.0001. The efficacy results from the follicular lymphoma 

population are presented in Table 14. 

 



 43 

Table 10: Summary of follicular lymphoma efficacy data- Study CC-5013-NHL-007 

 FL 

(N = 295) 

 Lenalidomide and Rituximab  

(N = 147) 

Placebo and Rituximab  

(N = 148) 

Progression-free survival (PFS) (EMA Censoring Rules) 

Median PFS a (95% CI) (months) 39.4 

 (25.1, NE) 

13.8  

(11.2, 16.0) 

HR [95% CI] 0.40 (0.29, 0.55)b 

p-value < 0.0001c 

Objective responsed (CR +PR), n 

(%)  (IRC, 2007  IWGRC) 

 95 % CIf 

118 (80.3) 

(72.9, 86.4) 

82 (55.4) 

(47.0, 63.6) 

Complete responsed, n (%)  

(IRC, 2007  

IWGRC) 

95 % CIf 

51 (34.7) 

(27.0, 43.0) 

29 (19.6) 

(13.5, 26.9) 

Duration of responsed (median) 

(months) 

 95% CI a 

36.6  

(24.9, NE) 

15.5 

(11.2, 25.0) 

Overall Survivald,e (OS) 

OS rate at 2 years 

% 

139 (94.8) 

(89.5, 97.5) 

127 (85.8) 

(78.5, 90.7) 

HR [95% CI]  0.45 (0.22, 0.92)b 

Follow-up   

Median duration of follow-up 

(min, max) (months) 
29.2 

(0.5, 50.9) 

27.9 

(0.6, 50.9) 
ª Median estimate from Kaplan-Meier analysis 
b Hazard ratio and its confidence interval were estimated from unstratified Cox proportional hazard model. 
c P-value from log-rank test  
d Secondary and exploratory endpoints are not α-controlled 
e With a median follow up of 28.6 months, there were 11 deaths in the R2 arm and 24 deaths in the Control Arm. 
f Exact confidence interval for binomial distribution. 

 

Follicular lymphoma for patients refractory to Rituximab 

MAGNIFY - CC-5013-NHL-008   

A total of 232 subjects who were at least 18 years of age with histologically confirmed FL (Grade 1, 2, 

3a or MZL), as assessed by the investigator or local pathologist, were enrolled into the initial treatment 

period with 12 cycles of lenalidomide plus rituximab. Subjects who achieved CR/CRu, PR, or SD by 

the end of the induction treatment period were randomised to enter the maintenance treatment period. 

All enrolled subjects must have previously been treated with at least one prior systemic antilymphoma 

therapy. In contrast to study NHL-007, the NHL-008 study included patients who were refractory to 

rituximab (no response or relapsed within 6 months of rituximab treatment or who were double-

refractory to rituximab and chemotherapy). 

 

During the induction treatment period, lenalidomide 20 mg was given on Days 1-21 of repeated 28-

day cycles for up to 12 cycles or until unacceptable toxicity, or withdrawal of consent or disease 

progression. The dose of rituximab was 375 mg/m2 every week in Cycle 1 (Days 1, 8, 15, and 22) and 

on Day 1 of every other 28-day cycle (cycles 3, 5, 7, 9, and 11) up to 12 cycles therapy. All dosage 

calculations for rituximab were based on the patient body surface area (BSA) and actual weight. 

 

The data presented are based on an interim analysis focusing on the single-arm induction treatment 

period.. Efficacy determinations are based on ORR by best response as the primary endpoint, using a 



 44 

modification of the 1999 International Working Group Response Criteria (IWGRC). The secondary 

objective was to evaluate other parameters of efficacy, such as DoR. 

 

Table 11: Summary of overall efficacy data (InductionTreatment Period) - Study CC-5013-

NHL-008 

 All Subjects FL Subjects 

 

Total 

N=187 a 

Rituximab 

Refractory: 

Yes 

N=77 

Rituximab 

Refractory: 

No 

N=110 

Total 

N=148 

Rituximab 

Refractory: 

Yes 

N=60 

Rituximab 

Refractory: 

No 

N=88 

ORR, n (%)  

(CR+CRu+PR) 

127 (67.9) 45 (58.4) 82 (75.2) 104 (70.3) 35 (58.3) 69 (79.3) 

CRR, n (%)  

(CR+Cru) 

79 (42.2) 27 (35.1) 52 (47.7) 62 (41.9) 20 (33.3) 42 (48.3) 

Number of Responders N=127 N=45 N=82 N=104 N=35 N=69 

% of Subjects with DoR 
b 

≥ 6 months (95% CI) c 

93.0 

(85.1, 

96.8) 

90.4 

(73.0, 96.8) 

94.5 

(83.9, 98.2) 

94.3 

(85.5, 97.9) 

96.0 

(74.8, 99.4) 

93.5 

(81.0, 97.9) 

% of Subjects with DoR 
b 

≥ 12 months (95% CI) c 

79.1 

(67.4, 

87.0) 

73.3 

(51.2, 86.6) 

82.4 

(67.5, 90.9) 

79.5 

(65.5, 88.3) 

73.9 

(43.0, 89.8) 

81.7 

(64.8, 91.0) 

CI = confidence interval; DOR = duration of response; FL = follicular lymphoma 
a Primary Analysis Population for this study is induction efficacy evaluable (IEE) population. 
b Duration of response is defined as the time (months) from the initial response (at least PR) to documented disease progression or death, 

whichever occurs first. 
c Statistics obtained from Kaplan-Meier method. 95% CI is based on Greenwood formula. 

Notes: The analysis is only performed for subjects who have achieved PR or better after the first dose date of induction therapy and prior to 

any Maintenance Period treatment and any subsequent anti-lymphoma therapy in Induction Period. Percentage is based on the total number 
of responders. 

 

Paediatric population 

The European Medicines Agency (EMA) has granted a product-specific waiver for Lenalidomide 

Accord that applies to all subsets of the paediatric population for mature B-cell neoplasm conditions., 

(see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 
 

Lenalidomide has an asymmetric carbon atom and can therefore exist as the optically active forms S(-) 

and R(+). Lenalidomide is produced as a racemic mixture. Lenalidomide is generally more soluble in 

organic solvents but exhibits the greatest solubility in 0.1N HCl buffer. 

 

Absorption 

Lenalidomide is rapidly absorbed following oral administration in healthy volunteers, under fasting 

conditions, with maximum plasma concentrations occurring between 0.5 and 2 hours post-dose. In 

patients, as well as in healthy volunteers, the maximum concentration (Cmax) and area-under-the-

concentration time curve (AUC) increase proportionally with increases in dose. Multiple dosing does 

not cause marked medicinal product accumulation. In plasma, the relative exposures of the S- and R- 

enantiomers of lenalidomide are approximately 56% and 44%, respectively. 

 

Co-administration with a high-fat and high-calorie meal in healthy volunteers reduces the extent of 

absorption, resulting in an approximately 20% decrease in area under the concentration versus time 

curve (AUC) and 50% decrease in Cmax in plasma. However, in the main multiple myeloma 



 45 

registration trials where the efficacy and safety were established for lenalidomide, the medicinal 

product was administered without regard to food intake. Thus, lenalidomide can be administered with 

or without food. 

 

Distribution 

In vitro (14C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at 

23% and 29% in multiple myeloma patients and healthy volunteers, respectively. 

 

Lenalidomide is present in human semen (< 0.01% of the dose) after administration of 25 mg/day and 

the medicinal product is undetectable in semen of a healthy subject 3 days after stopping the substance 

(see section 4.4). 

 

Biotransformation and elimination 

Results from human in vitro metabolism studies indicate that lenalidomide is not metabolised by 

cytochrome P450 enzymes suggesting that administration of lenalidomide with medicinal products 

that inhibit cytochrome P450 enzymes is not likely to result in metabolic medicinal product 

interactions in humans. In vitro studies indicate that lenalidomide has no inhibitory effect on CYP1A2, 

CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, or UGT1A1. Therefore, lenalidomide is unlikely to 

cause any clinically relevant medicinal product interactions when co-administered with substrates of 

these enzymes. 

 

In vitro studies indicate that lenalidomide is not a substrate of human breast cancer resistance protein 

(BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion 

transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), 

organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) 

MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. 

 

In vitro studies indicate that lenalidomide has no inhibitory effect on human bile salt export pump 

(BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, and OCT2. 

 

A majority of lenalidomide is eliminated through urinary excretion. The contribution of renal 

excretion to total clearance in subjects with normal renal function was 90%, with 4% of lenalidomide 

eliminated in faeces. 

 

Lenalidomide is poorly metabolized as 82% of the dose is excreted unchanged in urine. Hydroxy-

lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, 

respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is 

at least actively secreted to some extent. 

 

At doses of 5 to 25 mg/day, half-life in plasma is approximately 3 hours in healthy volunteers and 

ranges from 3 to 5 hours in patients with multiple myeloma. 

 

Elderly  

No dedicated clinical studies have been conducted to evaluate pharmacokinetics of lenalidomide in the 

elderly. Population pharmacokinetic analyses included patients with ages ranging from 39 to 85 years 

old and indicate that age does not influence lenalidomide clearance (exposure in plasma). Because 

elderly patients are more likely to have decreased renal function, care should be taken in dose 

selection and it would be prudent to monitor renal function. 

 

Renal impairment 

The pharmacokinetics of lenalidomide was studied in subjects with renal impairment due to 

nonmalignant conditions. In this study, two methods were used to classify renal function: the urinary 

creatinine clearance measured over 24 hours and the creatinine clearance estimated by Cockcroft-

Gault formula. The results indicate that as renal function decreases (< 50 mL/min), the total 

lenalidomide clearance decreases proportionally resulting in an increase in AUC. The AUC was 

increased by approximately 2.5, 4 and 5-fold in subjects with moderate renal impairment, severe renal 

impairment, and end-stage renal disease, respectively, compared to the group combining subjects with 



 46 

normal renal function and subjects with mild renal impairment. The half-life of lenalidomide increased 

from approximately 3.5 hours in subjects with creatinine clearance > 50 mL/min to more than 9 hours 

in subjects with reduced renal function < 50 mL/min. However, renal impairment did not alter the oral 

absorption of lenalidomide. The Cmax was similar between healthy subjects and patients with renal 

impairment. Approximately 30% of the medicinal product in the body was removed during a single 4-

hour dialysis session. Recommended dose adjustments in patients with impaired renal function are 

described in section 4.2. 

 

Hepatic impairment  

Population pharmacokinetic analyses included patients with mild hepatic impairment (N=16, total 

bilirubin >1 to ≤1.5 x ULN or AST > ULN) and indicate that mild hepatic impairment does not 

influence lenalidomide clearance (exposure in plasma). There are no data available for patients with 

moderate to severe hepatic impairment.  

 

Other intrinsic factors  

Population pharmacokinetic analyses indicate that body weight (33- 135 kg), gender, race and type of 

haematological malignancy  do not have a clinically relevant effect on lenalidomide clearance in adult 

patients.  

 

5.3 Preclinical safety data 
 

An embryofoetal development study has been conducted in monkeys administered lenalidomide at 

doses from 0.5 and up to 4 mg/kg/day. Findings from this study indicate that lenalidomide produced 

external malformations including non-patent anus and malformations of upper and lower extremities 

(bent, shortened, malformed, malrotated and/or absent part of the extremities, oligo and/or 

polydactyly) in the offspring of female monkeys who received the active substance during pregnancy.  

 

Various visceral effects (discoloration, red foci at different organs, small colourless mass above atrio-

ventricular valve, small gall bladder, malformed diaphragm) were also observed in single foetuses. 

 

Lenalidomide has a potential for acute toxicity; minimum lethal doses after oral administration were 

> 2000 mg/kg/day in rodents. Repeated oral administration of 75, 150 and 300 mg/kg/day to rats for 

up to 26 weeks produced a reversible treatment-related increase in kidney pelvis mineralisation in all 

3 doses, most notably in females. The no observed adverse effect level (NOAEL) was considered to be 

less than 75 mg/kg/day, and is approximately 25-fold greater than the human daily exposure based on 

AUC exposure. Repeated oral administration of 4 and 6 mg/kg/day to monkeys for up to 20 weeks 

produced mortality and significant toxicity (marked weight loss, reduced red and white blood cell and 

platelet counts, multiple organ haemorrhage, gastrointestinal tract inflammation, lymphoid, and bone 

marrow atrophy). Repeated oral administration of 1 and 2 mg/kg/day to monkeys for up to 1 year 

produced reversible changes in bone marrow cellularity, a slight decrease in myeloid/erythroid cell 

ratio and thymic atrophy. Mild suppression of white blood cell count was observed at 1 mg/kg/day 

corresponding to approximately the same human dose based on AUC comparisons. 

 

In vitro (bacterial mutation, human lymphocytes, mouse lymphoma, Syrian Hamster Embryo cell 

transformation) and in vivo (rat micronucleus) mutagenicity studies revealed no drug related effects at 

either the gene or chromosomal level. Carcinogenicity studies with lenalidomide have not been 

conducted. 

 

Developmental toxicity studies were previously conducted in rabbits. In these studies, rabbits were 

administered 3, 10 and 20 mg/kg/day orally. An absence of the intermediate lobe of the lung was 

observed at 10 and 20 mg/kg/day with dose dependence and displaced kidneys were observed at 

20 mg/kg/day. Although it was observed at maternotoxic levels they may be attributable to a direct 

effect. Soft tissue and skeletal variations in the foetuses were also observed at 10 and 20 mg/kg/day.  

 

 

6. PHARMACEUTICAL PARTICULARS 

 



 47 

6.1 List of excipients 
 

Capsule contents 

 

Lactose  

Microcrystalline cellulose 

Croscarmellose sodium 

Colloidal anhydrous silica 

Magnesium stearate 

 

Capsule shell 

 

Lenalidomide Accord 2.5 mg hard capsules 

Gelatin 

Iron oxide black (E172) 

Titanium dioxide (E171) 

 

Lenalidomide Accord 5 mg and Lenalidomide Accord 25 mg hard capsules 

Gelatin 

Titanium dioxide (E171) 

 

Lenalidomide Accord 7.5 mg hard capsules 

Gelatin 

Iron oxide red (E172) 

Titanium dioxide (E171) 

Indigo carmine (E132) 

 

Lenalidomide Accord 10 mg and Lenalidomide Accord 20 mg hard capsules 

Gelatin  

Indigo carmine (E132) 

Iron oxide yellow (E172) 

Titanium dioxide (E171) 

 

Lenalidomide Accord 15 mg hard capsules 

Gelatin  

Iron oxide red (E172) 

Iron oxide yellow (E172) 

Titanium dioxide (E171) 

 

Printing ink 

 

Shellac  

Propylene glycol  

Iron oxide black (E172) 

Iron oxide yellow (E172) 

Potassium hydroxide  

Titanium dioxide (E171) 

Indigo carmine (E132) 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 

 

3 years 

 



 48 

6.4 Special precautions for storage 
 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 
 

Lenalidomide Accord hard capsules are available in OPA AL PVC/Aluminium foil perforated unit 

dose blister. 

 

Lenalidomide Accord 2.5 mg, Lenalidomide Accord 5 mg, Lenalidomide Accord 10 mg and 

Lenalidomide Accord 15 mg hard capsules 

 

Pack size of 7x1 or 21x1 capsules. 

 

Not all pack sizes may be marketed. 

 

Lenalidomide Accord 7.5 mg, Lenalidomide Accord 20 mg and Lenalidomide Accord 25 mg hard 

capsules 

 

Pack size of 21x1 capsules. 

 

6.6 Special precautions for disposal  
 

Capsules should not be opened or crushed. If powder from lenalidomide makes contact with the skin, 

the skin should be washed immediately and thoroughly with soap and water. If lenalidomide makes 

contact with the mucous membranes, they should be thoroughly flushed with water. 

 

Any unused product or waste material should be returned to the pharmacist for safe disposal in 

accordance with local requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona,  

s/n, Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

Lenalidomide Accord 2.5 mg hard capsules 

EU/1/18/1316/001 

EU/1/18/1316/002 

 

Lenalidomide Accord 5 mg hard capsules 

EU/1/18/1316/003 

EU/1/18/1316/004 

 

Lenalidomide Accord 7.5 mg hard capsules 

EU/1/18/1316/005 

 

Lenalidomide Accord 10 mg hard capsules 

EU/1/18/1316/006 

EU/1/18/1316/007 



 49 

 

Lenalidomide Accord 15 mg hard capsules 

EU/1/18/1316/008 

EU/1/18/1316/009 

 

Lenalidomide Accord 20 mg hard capsules  

EU/1/18/1316/010 

 

Lenalidomide Accord 25 mg hard capsules 

EU/1/18/1316/011  

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 20th September 2018 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency: http://www.ema.europa.eu/. 



 50 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

A. MANUFACTURER (S) RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 



 51 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

Accord Healthcare Limited 

Sage House 

319 Pinner Road 

North Harrow 

Middlesex  

HA1 4HF 

United Kingdom 

Pharmadox Healthcare Limited  

KW20A Kordin Industrial Park,  

Paola  

PLA 3000,  

Malta 

 

Accord Healthcare Polska Sp.z o.o., 

ul. Lutomierska 50,95-200 Pabianice, Poland 

 

Accord Healthcare B.V.,  

Winthontlaan 200,  

3526 KV Utrecht,  

The Netherlands 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 Periodic safety update reports  

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 Risk Management Plan (RMP) 

The MAH shall perform the required  pharmacovigilance activities and interventions detailed in the  

agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreeed  subsequent 



 52 

updates of the RMP. 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached.  

 Additional risk minimisation measures  

1. The MAH shall agree the details of a controlled distribution system with the National Competent 
Authorities and must implement such programme nationally to ensure that:  

 

Prior to prescribing (and where appropriate, and in agreement with the National Competent Authority, 

prior to dispensing) all healthcare professionals who intend to prescribe (and dispense) Lenalidomide 

Accord are provided with a physician information pack containing the following:  

 Educational Health Care Professional’s kit  

 Educational brochures for Patients  

 Patient cards  

 Summary of Product Characteristics (SmPC) and Package Leaflet and Labelling.  

2. The MAH shall implement a pregnancy prevention programme (PPP) in each Member State. Details 

of the PPP including the set-up of national measures to assess the effectiveness of and compliance 

with the PPP should be agreed with the National Competent Authorities in each Member State and put 

in place prior to the marketing of the product.  

3. The MAH should agree the final text of the healthcare profesional’s information pack contents with 

the National Competent Authority in each Member State and ensure that the materials contain the key 

elements as described below.  

4. The MAH should agree on the implementation of the patient card system in each Member State.  

Key elements to be included  

The Educational Healthcare Professional’s Kit  

The Educational Health Care Professional’s Kit shall contain the following elements:  

 Brief background on lenalidomide and its licensed indication  

 Posology  

 The need to avoid foetal exposure due to teratogenicity of lenalidomide in animals and the 

expected teratogenic effect of lenalidomide in humans 

Obligations of the health care professional in relation to the prescribing of Lenalidomide Accord  

 Need to provide comprehensive advice and counselling to patients  

 That patients should be capable of complying with the requirements for the safe use of 

Lenalidomide Accord  

 Need to provide patients with appropriate patient educational brochure and patient card  

Safety advice relevant to all patients  



 53 

 Description and management of neutropenia and thrombocytopenia including incidence rates 

from clinical trials  

 Description and management of cutaneous reactions 

 Description and management of hypersensitivity and angioedema 

 Description and management of thromboembolic risk including incidence rates from clinical 

trials and post-marketing experience  

 Use in patients with hepatic and/or renal impairment  

 Disposal of unwanted medicine  

 Local country specific arrangements for a prescription for Lenalidomide Accord to be 

dispensed  

 Explanation of the risk of neuropathy with long term use  

 Description of risk of SPM 

 

Description of the PPP and categorisation of patients based on sex and childbearing potential  

 Algorithm for implementation of PPP  

 Definition of women of childbearing potential (WCBP) and actions the physician should take 

if unsure  

Safety advice for women of childbearing potential  

 The need to avoid foetal exposure  

 Description of the PPP  

 Need for adequate contraception (even if woman has amenorrhoea) and definition of adequate 

contraception  

 Pregnancy test regime  

o Advice on suitable tests  

o Before commencing treatment  

o During treatment based on method of contraception  

o After finishing treatment  

 Need to stop Lenalidomide Accord immediately upon suspicion of pregnancy  

 Need to tell treating doctor immediately upon suspicion of pregnancy  

Safety advice for men  

 The need to avoid foetal exposure  

 The need to use condoms if sexual partner is pregnant or a WCBP not using effective 

contraceptions (even if man has had a vasectomy)  

o During Lenalidomide Accord treatment  

o For one week following final dose  

 That if his partner becomes pregnant whilst he is taking Lenalidomide Accord or shortly after 

he has stopped taking Lenalidomide Accord he should inform his treating doctor immediately  

Requirements in the event of pregnancy  

 Instructions to stop Lenalidomide Accord immediately upon suspicion of pregnancy  

 Need to refer to physician specialised or experienced in dealing with teratology and its 

diagnosis for evaluation and advice  



 54 

 Local contact details for reporting of any suspected pregnancy  

 Pregnancy reporting form  

Check list for physicians ensuring that patients receive the appropriate counselling concerning the 

treatment, contraceptive methods and pregnancy prevention appropriate for their sex and childbearing 

status  

Adverse event reporting forms  

Educational Brochures for patients  

The Educational brochures for patients should be of 3 types:  

 Brochure for women patients of childbearing potential and their partners  

 Brochure for women patients who are not of childbearing potential  

 Brochure for male patients  

All patient brochures should contain the following elements:  

 That lenalidomide is teratogenic in animals and is expected to be teratogenic in humans  

 That Lenalidomide Accord may cause neutropenia and thrombocytopenia and the need for 

regular blood tests  

 That Lenalidomide Accord may cause venous and arterial thromboembolism  

 Description of the patient card and its necessity  

 Disposal of unwanted medicine  

 Guidance on handling lenalidomide for patients, caregivers and family members 

 National or other applicable specific arrangements for a prescription for Lenalidomide Accord 

to be dispensed  

 That the patient should not give Lenalidomide Accord to any other person  

 That the patient should not donate blood  

 That the patient should tell their doctor about any adverse events  

The following information should also be provided in the appropriate brochure:  

Brochure for women patients with childbearing potential  

 The need to avoid foetal exposure  

 Description of the PPP  

 Need for adequate contraception and definition of adequate contraception  

 Pregnancy test regime  

o Before commencing treatment  

o During treatment, every 4 weeks except in case of confirmed tubal sterilisation  

o After finishing treatment  

 The need to stop Lenalidomide Accord immediately upon suspicion of pregnancy  

 The need to contact their doctor immediately upon suspicion of pregnancy  

Brochure for male patients  

 The need to avoid foetal exposure  



 55 

 The need to use condoms if sexual partner is pregnant or a WCBP not using effective 

contraceptions (even if man has had vasectomy)  

o During Lenalidomide Accord treatment  

o For one week following final dose  

 That if his partner becomes pregnant he should inform his treating doctor immediately  

Patient Card  

The patient card shall contain the following elements:  

 Verification that appropriate counselling has taken place  

 Documentation of childbearing status potential  

 Pregnancy test dates and results  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 56 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

 



 57 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 



 58 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER  CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord  2.5 mg hard capsules 

lenalidomide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 2.5 mg of  lenalidomide. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

 

7x1 hard capsules 

21x1 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

  

WARNING: Risk of severe birth defects. Do not use while pregnant or breastfeeding. 

You must follow the Lenalidomide Pregnancy Prevention Programme 

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 



 59 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona,  

s/n, Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

 

EU/1/18/1316/001  7x1 hard capsules 

EU/1/18/1316/002  21x1 hard capsules 

 

 

13. BATCH NUMBER 

 

Lot :  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lenalidomide Accord 2.5 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2 D bar code carrying the unique identifier 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 



 60 

 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 2.5 mg hard capsules 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Accord 

 

 

3. EXPIRY DATE 

 

EXP: 

 

 

4. BATCH NUMBER 

 

Lot: 

 

 

5. OTHER 

 

 



 61 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER  CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 5 mg hard capsules 

lenalidomide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 5 mg of  lenalidomide. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

 

Hard capsule 

7x1 hard capsules 

21x1 hard capsules  

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

WARNING: Risk of severe birth defects. Do not use while pregnant or breastfeeding. 

You must follow the Lenalidomide Pregnancy Prevention Programme  

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 62 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona,  

s/n, Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/18/1316/003  7x1 hard capsules 

EU/1/18/1316/004  21x1 hard capsules 

 

 

13. BATCH NUMBER 

 

Lot: 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lenalidomide Accord  5 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2 D bar code carrying the unique identifier 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 



 63 

 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 5 mg hard capsules 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Accord 

 

 

3. EXPIRY DATE 

 

EXP: 

 

 

4. BATCH NUMBER 

 

Lot: 

 

 

5. OTHER 

 

 



 64 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER  CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 7.5 mg hard capsules 

lenalidomide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 7.5 mg of lenalidomide 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

21x1 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

WARNING: Risk of severe birth defects. Do not use while pregnant or breastfeeding. 

You must follow the Lenalidomide Pregnancy Prevention Programme  

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 65 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona,  

s/n, Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/18/1316/005  21x1 hard capsules 

 

 

13. BATCH NUMBER 

 

Lot: 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lenalidomide Accord 7.5 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2 D bar code carrying the unique identifier 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 



 66 

 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 7.5 mg hard capsules 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Accord 

 

 

3. EXPIRY DATE 

 

EXP: 

 

 

4. BATCH NUMBER 

 

Lot: 

 

 

5. OTHER 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 67 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER  CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 10 mg hard capsules 

lenalidomide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 10 mg  of  lenalidomide. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

7x1 hard capsules 

21x1 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

WARNING: Risk of severe birth defects. Do not use while pregnant or breastfeeding. 

You must follow the Lenalidomide Pregnancy Prevention Programme 

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 68 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona,  

s/n, Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/18/1316/006  7x1 hard capsules 

EU/1/18/1316/007  21x1 hard capsules 

 

 

13. BATCH NUMBER 

 

Lot: 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lenalidomide Accord 10 mg  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2 D bar code carrying the unique identifier 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 



 69 

 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 10 mg hard capsules 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Accord 

 

 

3. EXPIRY DATE 

 

EXP: 

 

 

4. BATCH NUMBER 

 

Lot: 

 

 

5. OTHER 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 70 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER  CARTON  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 15 mg hard capsules 

lenalidomide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 15 mg of lenalidomide. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

 

Hard capsule 

7x1 hard capsules 

21x1 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

WARNING: Risk of severe birth defects. Do not use while pregnant or breastfeeding. 

You must follow the Lenalidomide Pregnancy Prevention Programme 

 

 

8. EXPIRY DATE 

 

EXP:  

 

 

9. SPECIAL STORAGE CONDITIONS 

 



 71 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona,  

s/n, Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/18/1316/008   7x1 hard capsules 

EU/1/18/1316/009  21x1 hard capsules 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lenalidomide Accord 15 mg  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2 D bar code carrying the unique identifier 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 



 72 

 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

 Lenalidomide Accord 15 mg hard capsules 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Accord 

 

 

3. EXPIRY DATE 

 

EXP: 

 

 

4. BATCH NUMBER 

 

Lot: 

 

 

5. OTHER 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 73 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER  CARTON  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

 Lenalidomide Accord 20 mg hard capsuleslenalidomide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 20 mg of lenalidomide. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

21x1 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

WARNING: Risk of severe birth defects. Do not use while pregnant or breastfeeding. 

You must follow the Lenalidomide Pregnancy Prevention Programme 

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 74 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona,  

s/n, Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/18/1316/010   21x1 hard capsules 

 

 

13. BATCH NUMBER 

 

Lot: 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lenalidomide Accord 20 mg  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2 D bar code carrying the unique identifier 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 



 75 

 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 20 mg hard capsules 

 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Accord 

 

 

3. EXPIRY DATE 

 

EXP: 

 

 

4. BATCH NUMBER 

 

Lot: 

 

 

5. OTHER 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 76 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

OUTER  CARTON  

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 25 mg hard capsules 

lenalidomide 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 25 mg of lenalidomide. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule 

21x1 hard capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

WARNING: Risk of severe birth defects. Do not use while pregnant or breastfeeding. 

You must follow the Lenalidomide Pregnancy Prevention Programme 

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 



 77 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona,  

s/n, Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/18/1316/011   21x1 hard capsules 

 

 

13. BATCH NUMBER 

 

Lot: 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lenalidomide Accord 25 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2 D bar code carrying the unique identifier 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

 

 



 78 

 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lenalidomide Accord 25 mg hard capsules 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Accord 

 

 

3. EXPIRY DATE 

 

EXP: 

 

 

4. BATCH NUMBER 

 

Lot: 

 

 

5. OTHER 

 

 

 



 79 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 80 

Package leaflet: Information for the patient 

 

Lenalidomide Accord 2.5 mg hard capsules 

                                            Lenalidomide Accord 5 mg hard capsules 

Lenalidomide Accord 7.5 mg hard capsules 

Lenalidomide Accord 10 mg hard capsules 

Lenalidomide Accord 15 mg hard capsules 

Lenalidomide Accord 20 mg hard capsules 

Lenalidomide Accord 25 mg hard capsules 
 

lenalidomide 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm 

them, even if their signs of illness are the same as yours. 

- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 
1. What Lenalidomide Accord is and what it is used for  

2. What you need to know before you take  Lenalidomide Accord 

3. How to take Lenalidomide Accord 

4. Possible side effects 

5. How to store Lenalidomide Accord 

6. Contents of the pack and other information 

 

 

1. What Lenalidomide Accord is and what it is used for 
 

What Lenalidomide Accord is  

Lenalidomide Accord  contains the active substance ‘lenalidomide’. This medicine belongs to a group 

of medicines which affect how your immune system works. 

 

What Lenalidomide Accord is used for 
Lenalidomide Accord is used in adults for multiple myeloma and follicular lymphoma. 

 

Multiple myeloma 

Multiple myeloma is a type of cancer which affects a certain kind of white blood cell, called the 

plasma cell. These cells collect in the bone marrow and divide, becoming out of control. This can 

damage the bones and kidneys.  

 

Multiple myeloma generally cannot be cured. However, the signs and symptoms can be greatly 

reduced or disappear for a period of time. This is called a ‘response’. 

 

Newly diagnosed multiple myeloma – in patients who have had a bone marrow transplant 

Lenalidomide Accord is used on its own as maintenance therapy after patients have recovered enough 

following a bone marrow transplant. 

 

Newly diagnosed multiple myeloma – in patients who cannot have a bone marrow transplant 

Lenalidomide Accord is taken with other medicines: These may include: 



 81 

 a chemotherapy medicine called ‘bortezomib’ 
 an anti-inflammatory medicine called ‘dexamethasone’ 

 a chemotherapy medicine called ‘melphalan’ and 

 an immunosuppressant medicine called ‘prednisone’.  
You will take these other medicines at the start of treatment and then continue to take lenalidomide  on 

its own. 

 

If you are aged 75 years or older or have moderate to severe kidney problems - your doctor will check 

you carefully before starting treatment. 

 

Multiple myeloma – in patients who have had treatment before 

Lenalidomide Accord is taken together with an anti-inflammatory medicine called ‘dexamethasone’.  

 

Lenalidomide can stop the signs and symptoms of multiple myeloma getting worse. It has also been 

shown to delay multiple myeloma from coming back following treatment.  

 

Follicular lymphoma (FL) 

FL is a slow growing cancer that affects the B-lymphocytes. These are a type of white blood cells that 

help your body fight infection. When you have FL, too many of these B-lymphocytes may collect in 

your blood, bone marrow, lymph nodes and spleen. 

 

Lenalidomide is taken together with another medicine called ‘rituximab’ for the treatment of adult 

patients with previously treated follicular lymphoma. 

 

How Lenalidomide Accord works 

Lenalidomide works by affecting the body’s immune system and directly attacking the cancer. It 

works in a number of different ways: 

 by stopping the cancer cells developing 

 by stopping blood vessels growing in the cancer 

 by stimulating part of the immune system to attack the cancer cells. 
 

 

2. What you need to know before you take Lenalidomide Accord  

You must read the package leaflet of all medicinal products to be taken in combination with 

Lenalidomide Accord before starting treament with Lenalidomide Accord. 

 

Do not take Lenalidomide Accord : 

 if you are pregnant, think you may be pregnant or are planning to become pregnant, as 
lenalidomide  is expected to be harmful to an unborn child (see section 2, ‘Pregnancy, breast-

feeding and contraception – information for women and men’). 

 if you are able to become pregnant, unless you follow all the necessary measures to prevent you 
from becoming pregnant (see section 2, ‘Pregnancy, breast-feeding and contraception – 

information for women and men’). If you are able to become pregnant, your doctor will record 

with each prescription that the necessary measures have been taken and provide you with this 

confirmation. 

 if you are allergic to lenalidomide or any of the other ingredients of this medicine listed in 
section 6. If you think you may be allergic, ask your doctor for advice. 

 

If any of these apply to you, do not take lenalidomide. Talk to your doctor if you are not sure. 

 

Warnings and precautions 

Talk to your doctor, pharmacist or nurse before taking lenalidomide   

 if you have had blood clots in the past - you have an increased risk of developing blood clots in 
the veins and arteries during treatment 

 if you have any signs of an infection, such as a cough or fever  



 82 

 if you have or have ever had previous viral infection, particularly hepatitis B infection, varicella 
zona, HIV. If you are in doubt, talk to your doctor. Treatment with lenalidomide may cause virus 

to become active again, in patients who carry the virus, resulting in a recurrence of the infection. 
Your doctor should check whether you have ever had hepatitis B infection 

 if you have kidney problems - your doctor may adjust your dose of lenalidomide if you have had a 
heart attack, have ever had a blood clot, or if you smoke, have high blood pressure or raised 

cholesterol levels 

 if you have had an allergic reaction whilst taking thalidomide (another medicine used to treat 
multiple myeloma) such as rash, itching, swelling, dizziness or difficulty breathing 

 you have experienced in the past a combination of any of the following symptoms: widespread 
rash, red skin, high body temperature, flu-like symptoms, liver enzyme elevations, blood 

abnormalities (eosinophilia), enlarged lymph nodes – these are signs of a severe skin reaction 

called Drug Reaction with Eosinophilia and Systemic Symptoms which is also known as DRESS 

or drug hypersensitivity syndrome. (see also section 4 “Possible side effects”). 

 

If any of the above applies to you, tell your doctor, pharmacist or nurse before starting treatment. 

 

At any time during or after your treatment, tell your doctor or nurse immediately if you:  
experience blurred, loss of or double vision, difficulty speaking, weakness in an arm or a leg, a change 

in the way you walk or problems with your balance, persistent numbness, decreased sensation or loss 

of sensation, memory loss or confusion. These may all be symptoms of a serious and potentially fatal 

brain condition known as progressive multifocal leukoencephalopathy (PML). If you had these 

symptoms prior to treatment with lenalidomide, tell your doctor about any change in these symptoms. 

 

Tests and checks 
Before and during the treatment with lenalidomide you will have regular blood tests as it may cause a 

fall in the blood cells that help fight infection (white blood cells) and help the blood to clot (platelets).  

Your doctor will ask you to have a blood test: 

 before treatment  

 every week for the first 8 weeks of treatment 

 then at least every month after that. 
 

For patients with FL taking lenalidomide 

Your doctor will ask you to have a blood test: 

 before treatment  

 every week for the first 3 weeks (1 cycle) of treatment 

 then every 2 weeks in cycles 2 to 4 (see Section 3 ‘Treatment cycle’ for more information) 

 After this it will happen at the start of each cycle and 

 at least every month. 
 

Your doctor may check if you have a high total amount of tumour throughout the body, including your 

bone marrow. This could lead to a condition where the tumours break down and cause unusual levels 

of chemicals in the blood which can lead to kidney failure (this condition is called ‘Tumour Lysis 

Syndrome’).  

 

Your doctor may check you for changes to your skin such as red spots or rashes. 

 

Your doctor may adjust your dose of lenalidomide or stop your treatment based on the results of your 

blood tests and on your general condition. If you are newly diagnosed, your doctor may also assess 

your treatment based on your age and other conditions you already have. 

 

Blood donation 

You should not donate blood during treatment and for at least 7 days after the end of treatment. 

 

Children and adolescents 

Lenalidomide is not recommended for use in children and adolescents under 18 years.  



 83 

 

Elderly and people with kidney problems 

If you are aged 75 years or older or have moderate to severe kidney problems - your doctor will check 

you carefully before starting treatment. 

 

Other medicines and Lenalidomide Accord 

Tell your doctor or nurse if you are taking ,have recently taken or might take  any other medicines. 

This is because lenalidomide  can affect the way some other medicines work. Also, some other 

medicines can affect the way lenalidomide works.  

 

In particular, tell your doctor or nurse if you are taking any of the following medicines: 

 some medicines used to prevent pregnancy such as oral contraceptives, as they may stop working 

 some medicines used for heart problems – such as digoxin 

 some medicines used to thin the blood – such as warfarin 

 some medicines used to treat raised cholesterol - such as statins 
 

Pregnancy, breast-feeding and contraception - information for women and men 

 

Pregnancy  

For women taking  lenalidomide  

 You must not take lenalidomide  if you are pregnant, as it is expected to be harmful to an unborn 
baby.  

 You must not become pregnant while taking lenalidomide. Therefore you must use effective 
methods of contraception if you are a woman of childbearing potential (see ‘Contraception’). 

 If you do become pregnant during your treatment with lenalidomide , you must stop the treatment 
and inform your doctor immediately. 

 

For men taking lenalidomide  

 If your partner becomes pregnant whilst you are taking lenalidomide , you should inform your 
doctor immediately. It is recommended that your partner seeks medical advice. 

 You must also use effective methods of contraception (see ‘Contraception’). 
 

Breast-feeding 

You must not breast-feed when taking lenalidomide , as it is not known if lenalidomide passes into 

breast milk. 

 

Contraception 

For women taking lenalidomide   

Before starting the treatment, ask your doctor if you are able to become pregnant, even if you think 

this is unlikely. 

 

If you are able to become pregnant  

 you will have pregnancy tests under the supervision of your doctor (before every treatment, at 
least  every 4 weeks during treatment, and at least 4 weeks after the treatment has finished) except 

where it has been confirmed that the fallopian tubes have been severed and sealed, to stop eggs 

from reaching the uterus (tubal sterilisation) 

AND 

 you must use effective methods of contraception for at least 4 weeks before starting treatment, 
during treatment, and until  at least 4 weeks after stopping treatment. Your doctor will advise you 

on appropriate methods of contraception. 

 

For men taking lenalidomide  

Lenalidomide passes into human semen. If your female partner is pregnant or able to become 

pregnant, and she does not use effective methods of contraception, you must use condoms during 

treatment and for at  least 7 daysafter the end of treatment, even if you have had a vasectomy.  

 



 84 

Driving and using machines 
Do not drive or operate machines if you feel dizzy, tired, sleepy, have vertigo or blurred vision after 

taking lenalidomide . 

 

Lenalidomide Accord  contains lactose 

Lenalidomide Accord  contains lactose. If you have been told by your doctor that you have an 

intolerance to some sugars, contact your doctor before taking this  medicinal product. 

 

 

3. How to take Lenalidomide Accord  
 

Lenalidomide Accord must be given to you by healthcare professionals with experience in treating 

multiple myeloma or FL. 

 

 When lenalidomide is used to treat multiple myeloma in patients who cannot have a bone marrow 
transplant or have had other treatments before, it is taken with other medicines (see section 1 

‘What lenalidomide is used for’).  

 When lenalidomide is used to treat multiple myeloma in patients who have had a bone marrow 
transplant, it is taken alone.  

 When lenalidomide is used to treat follicular lymphoma, it is taken with another medicine called 

‘rituximab’. 

 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 

if you are not sure. 

 

If you are taking lenalidomide   in combination with other medicines, you should refer to the package 

leaflets for these medicines for further information on their use and effects. 

 

Treatment cycle 

Lenalidomide is taken on certain days over 3 weeks (21 days).  

 Every 21 days is called a ‘treatment cycle’. 

 Depending on the day of the cycle, you will take one or more of the medicines. However, on some 
days you do not take any of the medicines. 

 After completing every 21-day cycle, you should start a new ‘cycle’ over the next 21 days.  
OR 

Lenalidomide is taken on certain days over 4 weeks (28 days).  

 Each 28 day is called a ‘treatment cycle’. 

 Depending on the day of the cycle, you will take one or more of the medicines. However, on 
some days you do not take any of the medicines. 

 After completing each 28-day cycle, you should start a new ‘cycle’ over the next 28 days.  
 

How much Lenalidomide to take 

Before you start treatment, your doctor will tell you: 

 how much lenalidomide you should take 
 how much of the other medicines you should take in combination with lenalidomide, if any 
 on what days of your treatment cycle to take each medicine. 

 
How and when to take lenalidomide  

 swallow the capsules whole, preferably with water.  
 do not break, open or chew the capsules. If powder from a broken lenalidomide capsule makes 

contact with the skin, wash the skin immediately and thoroughly with soap and water. 

 the capsules can be taken either with or without food. 

 you should take lenalidomide at about the same time on the scheduled days. 
 

Taking this medicine 

To remove the capsule from the blister: 



 85 

 press only one end of the capsule out to push it through the foil 

 do not put pressure on the center of the capsule, as this can cause it to break. 
 

 
 

Duration of the treatment with  lenalidomide  

Lenalidomide  is taken in treatment cycles, each cycle lasting 21 or 28 days (see above ‘Treatment 

cycle’). You should continue the cycles of treatment until your doctor tells you to stop. 

 

If you take more lenalidomide  than you should 

If you take more lenalidomide  than was prescribed, tell your doctor immediately. 

 

If you forget to take  lenalidomideIf you forget to take lenalidomide at your regular time and  

 less than 12 hours have passed - take your capsule immediately. 

 more than 12 hours have passed - do not take your capsule. Take your next capsule at the usual 
time the next day. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine  can cause side effects, although not everybody gets them.  

 

Serious side effects which may affect more than 1 in 10 people (very common) 
Lenalidomide  may reduce the number of white blood cells that fight infection, red blood cells which 

carry oxygen and also the blood cells which help the blood to clot (platelets) Lenalidomide  may also 

cause blood clots in the veins (thrombosis). 

 

Therefore you must tell your doctor immediately if you experience: 

 Fever, chills, sore throat, cough, mouth ulcers or any other symptoms of infection including 
within the bloodstream (sepsis) 

 Bleeding or bruising in the absence of injury 

 Chest pain or leg pain 

 Shortness of breath 

 Bone pain, muscle weakness, confusion or tiredness that might be due to high level of calcium in 
the blood.  

 

Other side effects 

It is important to note that a small number of patients may develop additional types of cancer, and it is 

possible that this risk may be increased with lenalidomide treatment, therefore your doctor should 

carefully evaluate the benefit and risk when you are prescribed lenalidomide . 

 

Very common side effects (may affect more than 1 in 10 people): 

 A fall in the number of red blood cells which may cause anaemia leading to tiredness and 
weakness 



 86 

 Rashes, itching  

 Muscle cramps muscle weakness, muscle pain, muscle aches, bone pain, joint pain, back pain, 
pain in the extremities 

 Generalised swelling including swelling of your arms and legs 

 Weakness, tiredness 

 Fever and flu like symptoms including fever, muscle ache, headache, ear ache, cough  and chills 

 Numbness, tingling or burning sensation to the skin, pains in hands or feet, dizziness, tremor 

 Decreased appetite, change in the way things taste 

 Increase in pain, tumour size or redness around the tumour 

 Weight loss 

 Constipation, diarrhoea, nausea, vomiting, stomach pain, heartburn  

 Low levels of potassium or calcium and/or sodium in the blood 

 Thyroid functioning less than it should be 

 Leg pain (which could be a symptom of thrombosis), chest pain or shortness of breath (which 
may be a symptom of blood clots in the lungs, called pulmonary embolism) 

 Infections of all types, including infection of the sinuses that surround the nose, infection of the 
lung and the upper respiratory tract 

 Shortness of breath 

 Blurred vision 

 Clouding of your eye (cataract) 

 Kidney problems which include kidneys not working properly or not being able to maintain 
normal function 

 Abnormal liver test results 

 Increase in liver test results 

 Changes to a protein in the blood that can cause swelling of the arteries (vasculitis) 

 Increases in your blood sugar levels (diabetes) 

 Decreases in your blood sugar levels 

 Headache 

 Nosebleed 

 Dry skin 

 Depression, mood change, difficulty sleeping 

 Cough 

 A fall in blood pressure 

 A vague feeling of bodily discomfort, feeling bad 

 Sore inflamed mouth, dry mouth 

 Dehydration 
 

Common side effects (may affect up to 1 in 10 people): 

 Destruction of red blood cells (haemolytic anaemia)  

 Certain types of skin tumour 

 Bleeding of the gums, stomach, or bowels 

 Increased blood pressure, slow, fast or irregular heart beat 

 Increase in the amount of a substance which results from normal and abnormal breakdown of red 
blood cells 

 Increase in a type of protein that indicates inflammation in body 

 Darkening of your skin, discoloration of your skin resulting from bleeding underneath, typically 
caused by bruising, swelling of skin filled with blood, bruise 

 Increase in uric acid in the blood 

 Skin eruptions, redness of skin, cracking, flaking or peeling skin, hives 

 Increased sweating, night sweats 

 Difficulty swallowing, sore throat, difficulty with voice quality or voice changes 

 Runny nose 

 Production of much more or much less urine than usual or the inability to control when to urinate  

 Passing blood in the urine 



 87 

 Shortness of breath especially when lying down (which may be a symptom of heart failure) 

 Difficulty getting an erection 

 Stroke, fainting, vertigo (problem with inner ear which leads to feeling that everything is 
spinning), temporary loss of consciousness 

 Chest pain spreading to the arms, neck, jaw, back or stomach, feeling sweaty and breathless, 
feeling sick or vomiting, which may be symptoms of a heart attack (myocardial infarction) 

 Muscle weakness, lack of energy 

 Neck pain, chest pain 

 Chills 

 Joint swelling 

 Bile flow from liver slowed or blocked 

 Low levels of phosphate or magnesium in the blood 

 Difficulty speaking 

 Liver injury 

 Impaired balance, difficulty moving  

 Deafness, ringing in the ears (tinnitus) 

 Nerve pain, unpleasant abnormal sensation especially to touch 

 An excess of iron in the body 

 Thirst 

 Confusion 

 Toothache 

 Fall which may result in injury 
 

Uncommon side effects (may affect up to 1 in 100 people): 

 Bleeding within the skull  

 Circulatory problems 

 Loss of vision 

 Loss of sex drive (libido) 

 Passing large amount of urine with bone pain and weakness, which may be symptoms of a kidney 
disorder (Fanconi syndrome) 

 Yellow pigmentation to the skin, mucus membrane or eyes (jaundice), pale coloured stools, dark 
coloured urine, skin itch, rash, pain or swelling of the stomach – these may be symptoms of 

injury to the liver (hepatic failure) 

 Stomach pain, bloating, or diarrhoea, which may be symptoms of inflammation in the large 
intestine (called colitis or caecitis) 

 Damage to the cells of the kidney (called renal tubular necrosis) 

 Changes to the colour of your skin, sensitivity to sunlight 

 Hives, rashes, swelling of eyes, mouth or face, difficulty breathing, or itching, which may be 
symptoms of an allergic reaction 

 Tumour lysis syndrome - metabolic complications that can occur during treatment of cancer and 
sometimes even without treatment. These complications are caused by the break-down products 

of dying cancer cells and may include the following: changes to blood chemistry; high potassium, 

phosphorus, uric acid, and low calcium consequently leading to changes in kidney function, heart 

beat, seizures, and sometimes death. 

 Widespread rash, high body temperature, liver enzyme elevations, blood abnormalities 
(eosinophilia), enlarged lymph nodes and other body organs involvement (Drug Reaction with 

Eosinophilia and Systemic Symptoms which is also known as DRESS or drug hypersensitivity 

syndrome). Stop using Lenalidomide Accord if you develop these symptoms and contact your 

doctor or seek medical attention immediately. See also section 2. 

 

Rare side effects (may affect up to 1 in 1,000 people): 

 Serious allergic reaction that may begin as rash in one area but spread with extensive loss of skin 
over the whole body (Stevens-Johnson syndrome and/or toxic epidermal necrolysis). 

 

Not known side effects (frequency cannot be estimated from the available data): 



 88 

 Sudden, or mild but worsening pain in the upper stomach and/or back, which remains for a few 
days, possibly accompanied by nausea, vomiting, fever and a rapid pulse. These symptoms may 

be due to inflammation of the pancreas. 

 Wheezing, breathlessness  or a dry cough, which may be symptoms caused by inflammation of 
the tissue in the lungs. 

 Rare cases of muscle breakdown (muscle pain, weakness or swelling) which can lead to kidney 
problems (rhabdomyolysis) have been observed, some of them when lenalidomide is 

administered with a statin (a type of cholesterol lowering medicines). 

 A condition affecting the skin caused by inflammation of small blood vessels, along with pain in 
the joints and fever (leukocytoclastic vasculitis). 

 Breakdown of the wall of the stomach or gut. This may lead to very serious infection. Tell your 
doctor if you have severe stomach pain, fever, nausea, vomiting, blood in your stool, or changes 

in bowel habits. 

 Viral infections, including herpes zoster (also known as ‘shingles’, a viral disease that causes a 
painful skin rash with blisters) and recurrence of hepatitis B infection (which can cause yellowing 

of the skin and eyes, dark brown-colored urine, right-sided stomach pain, fever and feeling 

nauseous or being sick). 

 Rejection of solid organ transplant (such as kidney, heart). 
 

Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

5. How to store Lenalidomide Accord 

 

 Keep this medicine out of the sight and reach of children.  

 Do not use this medicine after the expiry date, which is stated on the carton and blister after 

‘EXP’. The expiry date refers to the last day of that month. 

 This medicinal product  does not require any special storage conditions. 

 Do not use this medicine if you notice any damage or signs of tampering to the pack. 

 Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how 
to throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Lenalidomide Accord contains 
 

 Lenalidomide Accord 2.5 mg hard capsules: 

• The active substance is lenalidomide. Each capsule contains 2.5 mg of lenalidomide. 

• The other ingredients are:  

- capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, colloidal 

anhydrous silica, magnesium stearate.  

- capsule shell: gelatin, iron oxide black (E172), titanium dioxide (E171) 

- printing ink: black and green ink (which contains shellac, propylene glycol, iron oxide black 

(E172), iron oxide yellow (E172), titanium dioxide (E171), indigo carmine (E132) and potassium 

hydroxide) 

 

 Lenalidomide Accord 5 mg hard capsules: 

• The active substance is lenalidomide. Each capsule contains 5 mg of lenalidomide. 

• The other ingredients are:  

- capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, colloidal 

anhydrous silica, magnesium stearate.  

- capsule shell: gelatin, titanium dioxide (E171) 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 89 

- printing ink: black and green ink (which contains shellac, propylene glycol, iron oxide black 

(E172), iron oxide yellow (E172), titanium dioxide (E171), indigo carmine (E132) and potassium 

hydroxide) 

 

 Lenalidomide Accord 7.5 mg hard capsules: 

• The active substance is lenalidomide. Each capsule contains 7.5 mg of lenalidomide. 

• The other ingredients are:  

- capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, colloidal 

anhydrous silica, magnesium stearate.  

- capsule shell: gelatin, iron oxide red (E172), titanium dioxide (E171), indigo carmine (E132) 

- printing ink: black and green ink (which contains shellac, propylene glycol, iron oxide black 

(E172), iron oxide yellow (E172), titanium dioxide (E171), indigo carmine (E132) and potassium 

hydroxide) 

 

Lenalidomide Accord 10 mg hard capsules: 

 The active substance is lenalidomide. Each capsule contains 10 mg of lenalidomide. 

 The other ingredients are:  

- capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, colloidal 

anhydrous silica, magnesium stearate.  

- capsule shell: gelatin, indigo carmine (E132), iron oxide yellow (E172) and titanium 

dioxide (E171) 

- printing ink: black and green ink (which contains shellac, propylene glycol, iron oxide 

black (E172), iron oxide yellow (E172), titanium dioxide (E171), indigo carmine (E132) 

and potassium hydroxide) 

 

Lenalidomide Accord 15 mg hard capsules: 

 The active substance is lenalidomide. Each capsule contains 15 mg of lenalidomide. 

 The other ingredients are:  

- capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, colloidal 

anhydrous silica, magnesium stearate.  

- capsule shell: gelatin, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide 

(E171) 

- printing ink: black and green ink (which contains shellac, propylene glycol, iron oxide black 

(E172), iron oxide yellow (E172), titanium dioxide (E171), indigo carmine (E132) and 

potassium hydroxide) 

Lenalidomide Accord 20 mg hard capsules: 

 The active substance is lenalidomide. Each capsule contains 20 mg of lenalidomide. 

 The other ingredients are:  

- capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, colloidal 

anhydrous silica, magnesium stearate.  

- capsule shell: gelatin, indigo carmine (E132), iron oxide yellow (E172) and titanium dioxide 

(E171) 

- printing ink: black and green ink (which contains shellac, propylene glycol, iron oxide black 

(E172), iron oxide yellow (E172), titanium dioxide (E171), indigo carmine (E132) and 

potassium hydroxide) 

 

Lenalidomide Accord 25 mg hard capsules: 

 The active substance is lenalidomide. Each capsule contains 25 mg of lenalidomide. 

 The other ingredients are:  

- capsule contents: lactose, microcrystalline cellulose, croscarmellose sodium, colloidal 

anhydrous silica, magnesium stearate.  

- capsule shell: gelatin, titanium dioxide (E171) 



 90 

- printing ink: black and green ink (which contains shellac, propylene glycol, iron oxide black 

(E172), iron oxide yellow (E172), titanium dioxide (E171), indigo carmine (E132) and 

potassium hydroxide) 

 

What Lenalidomide Accord looks like and contents of the pack 
 

Lenalidomide Accord 2.5 mg are gelatin hard capsules size “5” approximately 11.0 mm to 11.8 mm in 

length, grey cap and opaque white body with “LENALIDOMIDE” printed on cap in black and 

“2.5 mg” printed on body in green, containing white to off white coloured powder. 

 

Lenalidomide Accord 5 mg are gelatin hard capsules size “5” approximately 11.0 mm to 11.8 mm in 

length, opaque white cap and body with “LENALIDOMIDE” printed on cap in black and “5 mg” 

printed on body in green, containing white to off white coloured powder. 

 

Lenalidomide Accord 7.5 mg are gelatin hard capsules size “4” approximately 14.0 mm to 14.8 mm in 

length, opaque lavender cap and opaque white body with “LENALIDOMIDE” printed on cap in black 

and “7.5 mg” printed on body in green, containing white to off white coloured powder. 

 

Lenalidomide Accord 10 mg are gelatin hard capsules size “3” approximately 15.4 mm to 16.2 mm in 

length, leaf green cap and opaque white body with “LENALIDOMIDE” printed on cap in black and 

“10 mg” printed on body in green, containing white to off white coloured powder. 

 

Lenalidomide Accord 15 mg are gelatin hard capsules size “2” approximately 17.4 mm to 18.2 mm in 

length, opaque orange cap and opaque white body with “LENALIDOMIDE” printed on cap in black and 

“15 mg” printed on body in green, containing white to off white coloured powder. 

 

Lenalidomide Accord 20 mg are gelatin hard capsules size “1” approximately 19.0 mm to 19.8 mm in 

length, opaque green cap and opaque white body with “LENALIDOMIDE” printed on cap in black 

and “20 mg” printed on body in green, containing white to off white coloured powder. 

 

Lenalidomide Accord 25 mg are gelatin hard capsules size “0” approximately 21.0 mm to 21.8 mm in 

length, white opaque cap and body with “LENALIDOMIDE” printed on cap in black and “25 mg” 

printed on body in green, containing white to off white coloured powder. 

 

Lenalidomide Accord hard capsules are available in OPA-AL-PVC/Aluminium foil perforated unit 

dose blister. 

 

Lenalidomide Accord 2.5 mg, Lenalidomide Accord 5 mg, Lenalidomide Accord 10 mg and 

Lenalidomide Accord 15 mg hard capsules 

Pack size of 7x1 or 21x1 capsules.  

 

Not all pack sizes may be marketed. 

 

Lenalidomide Accord 7.5 mg, Lenalidomide Accord 20 mg and Lenalidomide Accord 25 mg hard 

capsules 

Pack size of 21x1 capsules. 
 

Marketing Authorisation Holder  

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona,  

s/n, Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

Manufacturer 



 91 

Accord Healthcare Limited 

Sage House, 319 Pinner Road, North Harrow, Middlesex, HA1 4HF 

United Kingdom 

 

Pharmadox Healthcare Limited  

KW20A Kordin Industrial Park,  

Paola PLA 3000, Malta 

 

Accord Healthcare Polska Sp.z o.o., 

ul. Lutomierska 50,95-200 Pabianice, Poland 

 

Accord Healthcare B.V.,  

Winthontlaan 200,  

3526 KV Utrecht,  

The Netherlands 

 

 

This leaflet was last revised in 
 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu/. 

 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	LABELLING AND PACKAGE LEAFLET
	A. LABELLING
	B. PACKAGE LEAFLET