LENALIDOMIDE KRKA 2.5mg capsules medication leaflet

Lenalidomide Krka 2.5 mg hard capsules

Lenalidomide Krka 5 mg hard capsules

Lenalidomide Krka 7.5 mg hard capsules

Lenalidomide Krka 10 mg hard capsules

Lenalidomide Krka 15 mg hard capsules

Lenalidomide Krka 20 mg hard capsules

Lenalidomide Krka 25 mg hard capsules

Each hard capsule contains lenalidomide hydrochloride monohydrate equivalent to 2.5 mg, 5 mg,7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg lenalidomide.

For the full list of excipients, see section 6.1.

Hard capsule (capsule)

Lenalidomide Krka 2.5 mg hard capsules

Capsule cap is green, capsule body is green with imprinted black mark 2.5. Capsule content is white toyellow white or to brown white powder. Hard capsule size: 4, length 14 ± 1 mm.

Lenalidomide Krka 5 mg hard capsules

Capsule cap is blue, capsule body is blue with imprinted black mark 5. Capsule content is white toyellow white or to brown white powder. Hard capsule size: 2, length 18 ± 1 mm.

Lenalidomide Krka 7.5 mg hard capsules

Capsule cap is brown, capsule body is brown with imprinted white mark 7.5. Capsule content is whiteto yellow white or to brown white powder. Hard capsule size: 1, length 19 ± 1 mm.

Lenalidomide Krka 10 mg hard capsules

Capsule cap is green, capsule body is brown with imprinted white mark 10. Capsule content is white toyellow white or to brown white powder. Hard capsule size: 0, length 21 ± 1 mm.

Lenalidomide Krka 15 mg hard capsules

Capsule cap is brown, capsule body is blue with imprinted black mark 15. Capsule content is white toyellow white or to brown white powder. Hard capsule size: 2, length 18 ± 1 mm.

Lenalidomide Krka 20 mg hard capsules

Capsule cap is green, capsule body is blue with imprinted black mark 20. Capsule content is white toyellow white or to brown white powder. Hard capsule size: 1, length 19 ± 1 mm.

Lenalidomide Krka 25 mg hard capsules

Capsule cap is brown, capsule body is brown with imprinted white mark 25. Capsule content is whiteto yellow white or to brown white powder. Hard capsule size: 0, length 21 ± 1 mm.

Lenalidomide Krka as monotherapy is indicated for the maintenance treatment of adult patients withnewly diagnosed multiple myeloma who have undergone autologous stem cell transplantation.

Lenalidomide Krka as combination therapy with dexamethasone, or bortezomib and dexamethasone, ormelphalan and prednisone (see section 4.2) is indicated for the treatment of adult patients withpreviously untreated multiple myeloma who are not eligible for transplant.

Lenalidomide Krka in combination with dexamethasone is indicated for the treatment of multiplemyeloma in adult patients who have received at least one prior therapy.

Myelodysplastic syndromes

Lenalidomide Krka as monotherapy is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with anisolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient orinadequate.

Lenalidomide Krka as monotherapy is indicated for the treatment of adult patients with relapsed orrefractory mantle cell lymphoma (see sections 4.4 and 5.1).

Lenalidomide Krka in combination with rituximab (anti-CD20 antibody) is indicated for the treatmentof adult patients with previously treated follicular lymphoma (Grade 1 - 3a).

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

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 Grade3 or 4 thrombocytopenia, neutropenia, or other Grade 3 or 4 toxicity judged to be related tolenalidomide.

- 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 than12 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.

Newly diagnosed multiple myeloma (NDMM)

Lenalidomide in combination with dexamethasone until disease progression in patients who are noteligible for transplant

Lenalidomide treatment must not be started if the Absolute Neutrophil Count (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 repeated28-day cycles.

The recommended dose of dexamethasone is 40 mg orally once daily on days 1, 8, 15 and 22 ofrepeated 28-day cycles. Patients may continue lenalidomide and dexamethasone therapy until diseaseprogression 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 applicableª Dose reduction for both products can be managed independently

When platelets Recommended course

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

Return to ≥ 50 x 109/L Decrease by one dose level when dosing resumed at next cycleª If Dose limiting toxicity (DLT) occurs on > day15 of a cycle, lenalidomide dosing will be interrupted for at least the remainder of the current28-day cycle.

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 Resume lenalidomide at startingtoxicity dose once daily

Returns to ≥ 0.5 x 109/L when dose-dependent Resume lenalidomide at dose level -haematological toxicities other than neutropenia are observed 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 lowerdose 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) andmaintain 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 atleast 2 consecutive cycles: ANC ≥1.5 x 109/L with a platelet count ≥ 100 x 109/L at the beginning of anew cycle).

Lenalidomide in combination with bortezomib and dexamethasone followed by lenalidomide anddexamethasone 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-daycycle in combination with bortezomib and dexamethasone. Bortezomib should be administered viasubcutaneous 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 productsadministered 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 combinationwith dexamethasone. Treatment should be continued until disease progression or unacceptabletoxicity.

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 mgª Dose reduction for all products can be managed independently

When platelets Recommended course

Fall to < 30 x 10 /L Interrupt lenalidomide treatment

Return 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

Return to ≥ 50 x 109/L Resume lenalidomide at next lower dose levelonce 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 Resume lenalidomide at startingtoxicity dose once daily

Returns to ≥ 0.5 x 109/L when dose-dependent haematological Resume lenalidomide at dose leveltoxicities other than neutropenia are observed -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 lowerdose 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) andmaintain the dose level of lenalidomide.

Lenalidomide in combination with melphalan and prednisone followed by lenalidomide maintenance inpatients who are not eligible for transplant

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 repeated28-day cycles for up to 9 cycles, melphalan 0.18 mg/kg orally on days 1 to 4 of repeated 28-daycycles, prednisone 2 mg/kg orally on days 1 to 4 of repeated 28-day cycles. Patients who complete 9cycles or who are unable to complete the combination therapy due to intolerance are treated withlenalidomide monotherapy as follows: 10 mg orally once daily on days 1 to 21 of repeated 28-daycycles 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/kgª If neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level oflenalidomide

When platelets Recommended course

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

Return 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 (doselevel -2 or -3) once daily.

Absolute neutrophil count (ANC) - neutropenia

When ANC Recommended coursea

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

Returns to ≥ 0.5 x 109/L when neutropenia is the only Resume lenalidomide at startingobserved toxicity dose once daily

Returns to ≥ 0.5 x 109/L when dose-dependent haematological Resume lenalidomide at dose level -toxicities other than neutropenia are observed 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 lowerdose 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) andmaintain the dose level of lenalidomide.

Lenalidomide maintenance in patients who have undergone autologous stem cell transplantation(ASCT)

Lenalidomide maintenance should be initiated after adequate haematologic recovery following ASCT inpatients without evidence of progression. Lenalidomide must not be started if the 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 28of repeated 28-day cycles) given until disease progression or intolerance. After 3 cycles oflenalidomide 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.

When platelets Recommended course

Fall to < 30 x 109/L Interrupt lenalidomide treatment

Return 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

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

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 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 oncedailya At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) andmaintain 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 x109/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 repeated28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1 to 4, 9to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily ondays 1 to 4 every 28 days.

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

Dose level -3 5 mg

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 below5 mg once daily.

Absolute neutrophil count (ANC) - neutropenia

When ANC Recommended coursea

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

Returns to ≥ 0.5 x 109/L when neutropenia is Resume lenalidomide at starting dose once dailythe only observed toxicity

Returns to ≥ 0.5 x 109/L when dose-dependent Resume lenalidomide at dose level -1 once dailyhaematological toxicities other thanneutropenia are observed

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 dosebelow 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) andmaintain the dose level of lenalidomide.

Myelodysplastic syndromes (MDS)

Lenalidomide treatment must not be started if the ANC < 0.5 x 109/L and/or platelet counts < 25 x109/L.

Recommended dose

The recommended starting dose of lenalidomide is 10 mg orally once daily on days 1 to 21of repeated 28-day cycles.

Dose reduction steps

Starting dose 10 mg once daily on days 1 to 21 every 28 days

Dose level -1 5 mg once daily on days 1 to 28 every 28 days

Dose level -2 2.5 mg once daily on days 1 to 28 every 28 days

Dose level -3 2.5 mg every other day 1 to 28 every 28 days

Thrombocytopenia

When platelets Recommended course

Fall to < 25 x 109/L Interrupt lenalidomide treatment

Return to ≥ 25 x 109/L - < 50 x 109/L on at Resume lenalidomide at next lower dose level (doseleast 2 occasions for ≥ 7 days or when the level -1, -2 or -3)platelet count recovers to ≥ 50 x 109/L at anytime

Absolute neutrophil count (ANC) - neutropenia

When ANC Recommended course

Falls to < 0.5 x 109/L Interrupt lenalidomide treatment

Returns to ≥ 0.5 x 109/L Resume lenalidomide at next lower dose level (doselevel -1, -2 or -3)

Discontinuation of lenalidomide

Patients without at least a minor erythroid response within 4 months of therapy initiation,demonstrated by at least a 50% reduction in transfusion requirements or, if not transfused, a 1g/dlrise in haemoglobin, should discontinue lenalidomide treatment.

Mantle cell lymphoma (MCL)

Recommended dose

The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1 to 21of repeated 28-day cycles.

Dose reduction steps

Starting dose 25 mg once daily on days 1 to 21, every 28 days

Dose Level -1 20 mg once daily on days 1 to 21, every 28 days

Dose Level -2 15 mg once daily on days 1 to 21, every 28 days

Dose Level -3 10 mg once daily on days 1 to 21, every 28 days

Dose Level -4 5 mg once daily on days 1 to 21, every 28 days

Dose Level -5 2.5 mg once daily on days 1 to 21, every 28 days15 mg every other day on days 1 to 21, every 28 days1 - In countries where the 2.5 mg capsule is available.

Thrombocytopenia

When platelets Recommended course

Fall to < 50 x 109/L Interrupt lenalidomide treatment and conduct Complete Blood

Count (CBC) at least every 7 days

Return to ≥ 60 x 109/L Resume lenalidomide at next lower level (dose level -1)

For each subsequent drop Interrupt lenalidomide treatment and conduct the CBC at leastbelow 50 x 109/L every 7 days

Return to ≥60 x 109/L Resume lenalidomide at next lower level (dose level -2, -3, -4 or -5). Do not dose below dose level -5

Absolute neutrophil count (ANC) - neutropenia

When ANC Recommended course

Falls to < 1 x 109/L for at least 7 days or Interrupt lenalidomide treatment and

Falls to < 1 x 109/L with associated fever (body conduct the CBC at least every 7 daystemperature ≥ 38.5°C) or

Falls to < 0.5 x 109/L

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

For each subsequent drop below 1 x 109/L for at least Interrupt lenalidomide treatment7 days or drop to < 1 x 109/L with associated fever(body temperature ≥ 38.5°C) or drop to < 0.5 x 109/L

Returns to ≥1 x 109/L Resume Lenalidomide at next lower doselevel (dose level -2, -3, -4, -5). Do notdose below dose level -5

Follicular lymphoma (FL)

Lenalidomide treatment must not be started if the ANC is < 1 x 109 /L, and/or platelet count < 50 x109/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 ofrepeated 28- day cycles for up to 12 cycles of treatment. The recommended starting dose of rituximabis 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 productcharacteristics.

Thrombocytopenia

When platelets Recommended course

Fall to < 50 x 109/L Interrupt lenalidomide treatment and conduct CBC at least every 7days

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

For each subsequent drop Interrupt lenalidomide treatment and conduct CBC at least every 7below 50 x 109/L days

Return to ≥50 x 109/L Resume lenalidomide at next lower dose level (dose level -2, -3).

Do not dose below dose level -3.

Absolute neutrophil count (ANC) - neutropenia

When ANC Recommended coursea

Falls to < 1.0 x 109/L for at least 7 days or Interrupt lenalidomide treatment and conduct

Falls to < 1.0 x 109/L with associated fever CBC at least every 7 days(body temperature ≥ 38.5°C) or

Falls to < 0.5 x 109/L

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 Interrupt lenalidomide treatment and conduct CBCfor at least 7 days or drop to < 1.0 x 109/L at least every 7 dayswith associated fever (body temperature ≥38.5°C) or drop to < 0.5 x 109/L

Returns to ≥1.0 x 109/L Resume lenalidomide at next lower dose level (doselevel -2, -3). Do not dose below dose level -3ª At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add G-CSF

Mantle cell lymphoma (MCL) or follicular lymphoma (FL)

All patients should receive TLS prophylaxis (allopurinol, rasburicase or equivalent as perinstitutional guidelines) and be well hydrated (orally) during the first week of the first cycle or fora longer period if clinically indicated. To monitor for TLS, patients should have a chemistry paneldrawn weekly during the first cycle and as clinically indicated.

Lenalidomide may be continued (maintain dose) in patients with laboratory TLS or Grade 1clinical TLS, or at the physician’s discretion, reduce dose by one level and continue lenalidomide.

Vigorous intravenous hydration should be provided and appropriate medical managementaccording to the local standard of care, until correction of electrolyte abnormalities. Rasburicasetherapy may be needed to reduce hyperuricaemia. Hospitalisation of the patient will be atphysician’s discretion.

In patients with Grade 2 to 4 clinical TLS, interrupt lenalidomide and obtain a chemistry panelweekly or as clinically indicated. Vigorous intravenous hydration should be provided andappropriate medical management according to the local standard of care, until correction ofelectrolyte abnormalities.

Rasburicase therapy and hospitalisation will be at physician’s discretion. When the TLS resolvesto 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 tumourflare reaction (TFR) without interruption or modification. At the physician’s discretion, therapywith non-steroidal anti-inflammatory drugs (NSAIDs), limited duration corticosteroids, and/ornarcotic analgesics may be administered. In patients with Grade 3 or 4 TFR, withhold treatmentwith lenalidomide and initiate therapy with NSAIDs, corticosteroids and/or narcotic analgesics.

When TFR resolves to ≤ Grade 1, restart lenalidomide treatment at the same dose level for the restof the cycle. Patients may be treated for management of symptoms per the guidance for treatmentof Grade 1 and 2 TFR (see section 4.4).

For other Grade 3 or 4 toxicities judged to be related to lenalidomide, treatment should be stopped andonly restarted at next lower dose level when toxicity has resolved to ≤ Grade 2 depending on thephysician’s discretion.

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

Lenalidomide must be discontinued for angioedema, anaphylactic reaction, Grade 4 rash, exfoliative orbullous rash, or if Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or Drug Reactionwith Eosinophilia and Systemic Symptoms (DRESS) is suspected and should not be resumed followingdiscontinuation from these reactions.

Lenalidomide should not be used in children and adolescents from birth to less than 18 years becauseof safety concerns (see section 5.1).

Currently available pharmacokinetic data are described in section 5.2. Lenalidomide has been used inclinical trials in multiple myeloma patients up to 91 years of age, in myelodysplastic syndromes patientsup to 95 years of age and in mantle cell lymphoma patients up to 88 years of age (see section 5.1).

Because elderly patients are more likely to have decreased renal function, care should be taken in doseselection 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 assessedbefore 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-daytreatment cycle.

No dose adjustment is proposed for patients older than 75 years who are treated with lenalidomide incombination with melphalan and prednisone.

In patients with newly diagnosed multiple myeloma aged 75 years and older who receivedlenalidomide, there was a higher incidence of serious adverse reactions and adverse reactions that led totreatment discontinuation.

Lenalidomide combined therapy was less tolerated in newly diagnosed multiple myeloma patients olderthan 75 years of age compared to the younger population. These patients discontinued at a higher ratedue 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 betweenthe lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in safetyor efficacy was observed between these patients and younger patients, but greater pre-disposition ofolder individuals cannot be ruled out.

Myelodysplastic syndromes

For myelodysplastic syndromes patients treated with lenalidomide, no overall difference in safety andefficacy was observed between patients aged over 65 and younger patients.

For mantle cell lymphoma patients treated with lenalidomide, no overall difference in safety andefficacy was observed between patients aged 65 years or over compared with patients aged under 65years of age.

For follicular lymphoma patients treated with lenalidomide in combination with rituximab, the overallrate of adverse events is similar for patients aged 65 years or over compared with patients under 65years of age. No overall difference in efficacy was observed between the two age groups.

Lenalidomide is primarily excreted by the kidney; patients with greater degrees of renal impairmentcan have impaired treatment tolerance (see section 4.4). Care should be taken in dose selection andmonitoring of renal function is advised.

No dose adjustments are required for patients with mild renal impairment and multiple myeloma,myelodysplastic syndromes, mantle cell lymphoma, or follicular lymphoma.

The following dose adjustments are recommended at the start of therapy and throughout treatment forpatients with moderate or severe impaired renal function or end stage renal disease.

There are no phase 3 trial experiences with End Stage Renal Disease (ESRD) (CLcr < 30 mL/min,requiring dialysis).

Renal function (CLcr) Dose adjustment

Moderate renal impairment 10 mg once daily1(30 CLcr < 50 mL/min)

Severe renal impairment 7.5 mg once daily2(CLcr < 30 mL/min, not requiring 15 mg every other daydialysis)

End Stage Renal Disease (ESRD) 5 mg once daily. On dialysis days, the dose should be(CLcr < 30 mL/min, requiring dialysis) administered following dialysis.

1 The dose may be escalated to 15 mg once daily after 2 cycles if patient is not responding to treatment and is tolerating the treatment.2 In countries where the 7.5 mg capsule is available.

Myelodysplastic syndromes

Renal function (CLcr) Dose adjustment

Moderate renal impairment Starting dose 5 mg once daily(30  CLcr < 50 mL/min) (days 1 to 21 of repeated 28-daycycles)

Dose level -1* 2.5 mg once daily(days 1 to 28 of repeated 28-daycycles)

Dose level -2* 2.5 mg once every other day(days 1 to 28 of repeated 28-daycycles)

Severe renal impairment Starting dose 2.5 mg once daily(CLcr < 30 mL/min, not requiring (days 1 to 21 of repeated 28-daydialysis) cycles)

Dose level -1* 2.5 mg every other day(days 1 to 28 of repeated 28-daycycles)

Dose level -2* 2.5 mg twice a week(days 1 to 28 of repeated 28-daycycles)

End Stage Renal Disease (ESRD) Starting dose 2.5 mg once daily(CLcr < 30 mL/min, requiring dialysis) (days 1 to 21 of repeated 28-daycycles)

On dialysis days, the dose should be Dose level -1* 2.5 mg every other dayadministered following dialysis. (days 1 to 28 of repeated 28-daycycles)

Dose level -2* 2.5 mg twice a week(days 1 to 28 of repeated 28-daycycles)

* Recommended dose reduction steps during treatment and restart of treatment to manage Grade 3 or 4 neutropenia orthrombocytopenia, or other Grade 3 or 4 toxicity judged to be related to lenalidomide, as described above.

Renal function (CLcr) Dose adjustment(days 1 to 21 of repeated 28-daycycles)

Moderate renal impairment 10 mg once daily1(30  CLcr < 50 mL/min)

Severe renal impairment 7.5 mg once daily2(CLcr < 30 mL/min, not requiring dialysis) 15 mg every other day

End Stage Renal Disease (ESRD) 5 mg once daily. On dialysis days, the dose(CLcr < 30 mL/min, requiring dialysis) 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.

Renal function (CLcr) Dose adjustment(days 1 to 21 of repeated 28-daycycles)

Moderate renal impairment 10 mg once daily1,2(30  CLcr < 60 mL/min)

Severe renal impairment 5 mg once daily(CLcr < 30 mL/min, not requiring dialysis)

End Stage Renal Disease (ESRD) 5 mg once daily. On dialysis days, the dose(CLcr < 30 mL/min, requiring dialysis) should be administered following dialysis.

¹ The dose may be escalated to 15 mg once daily after 2 cycles if the patient has tolerated therapy.2 For patients on a starting dose of 10 mg, in case of dose reduction to manage Grade 3 or 4 neutropenia or thrombocytopenia,or other Grade 3 or 4. Toxicity judged to be related to lenalidomide do not dose below 5 mg every other day or 2.5 mg oncedaily.

After initiation of lenalidomide therapy, subsequent lenalidomide dose modification in renallyimpaired patients should be based on individual patient treatment tolerance, as described above.

Lenalidomide has not formally been studied in patients with impaired hepatic function and there are nospecific dose recommendations.

Oral use.

Lenalidomide Krka capsules should be taken orally at about the same time on the scheduled days. Thecapsules should not be opened, broken or chewed (see section 6.6). The capsules should be swallowedwhole, preferably with water, either with or without food.

Lenalidomide capsules should not be pushed through the foil in the blister pack as this could causedamage to the capsule. The capsule should be removed from the package by peeling off the foil fromone separated blister cell.

- 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).

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 activesubstance that causes severe life-threatening birth defects. In monkeys, lenalidomide inducedmalformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide istaken 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 isreliable 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 potentialunless she meets at least one of the following criteria:

- Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (Amenorrhoea following cancer therapyor 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.

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

- She understands the expected teratogenic risk to the unborn child

- She understands the need for effective contraception, without interruption, at least 4 weeksbefore starting treatment, throughout the entire duration of treatment, and at least 4 weeks afterthe end of treatment

- Even if a woman of childbearing potential has amenorrhea she must follow all the advice oneffective contraception

- She should be capable of complying with effective contraceptive measures

- She is informed and understands the potential consequences of pregnancy and the need torapidly consult if there is a risk of pregnancy

- She understands the need to commence the treatment as soon as lenalidomide is dispensedfollowing a negative pregnancy test

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

- She acknowledges that she understands the hazards and necessary precautions associated withthe use of lenalidomide.

For male patients taking lenalidomide, pharmacokinetic data has demonstrated that lenalidomide ispresent in human semen at extremely low levels during treatment and is undetectable in human semen3 days after stopping the substance in the healthy subject (see section 5.2). As a precaution and takinginto account special populations with prolonged elimination time such as renal impairment, all malepatients taking lenalidomide must meet the following conditions:

- Understand the expected teratogenic risk if engaged in sexual activity with a pregnant woman ora woman of childbearing potential.

- Understand the need for the use of a condom if engaged in sexual activity with a pregnant womanor a woman of childbearing potential not using effective contraception (even if the man has had avasectomy), during treatment and for at least 7 days after dose interruptions and/or cessation oftreatment.

- Understand that if his female partner becomes pregnant whilst he is taking lenalidomide orshortly after he has stopped taking lenalidomide, he should inform his treating physicianimmediately and that it is recommended to refer the female partner to a physician specialised orexperienced 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, includingconfirmation that she has an adequate level of understanding.

- The patient has acknowledged the aforementioned conditions.

Women of childbearing potential must use at least one effective method of contraception for at least 4weeks before therapy, during therapy, and until at least 4 weeks after lenalidomide therapy and even incase of dose interruption unless the patient commits to absolute and continuous abstinence confirmedon a monthly basis. If not established on effective contraception, the patient must be referred to anappropriately trained health care professional for contraceptive advice in order that contraception can beinitiated.

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 twonegative semen analyses

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

Because of the increased risk of venous thromboembolism in patients with multiple myeloma takinglenalidomide in combination therapy, and to a lesser extent in patients with multiple myeloma,myelodysplastic syndromes and mantle cell lymphoma taking lenalidomide monotherapy, combinedoral contraceptive pills are not recommended (see also section 4.5). If a patient is currently usingcombined 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 oralcontraception. The efficacy of contraceptive steroids may be reduced during co-treatment withdexamethasone (see section 4.5).

Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk ofinfection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should beconsidered particularly in patients with neutropenia.

Copper-releasing intrauterine devices are generally not recommended due to the potential risks ofinfection at the time of insertion and menstrual blood loss which may compromise patients withneutropenia or thrombocytopenia.

According to local practice, medically supervised pregnancy tests with a minimum sensitivity of25 mIU/mL must be performed for women of childbearing potential as outlined below. Thisrequirement 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 theprescription.

Prior to starting treatment

A medically supervised pregnancy test should be performed during the consultation, whenlenalidomide is prescribed, or in the 3 days prior to the visit to the prescriber once the patient had beenusing effective contraception for at least 4 weeks. The test should ensure the patient is not pregnantwhen 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 4weeks after the end of treatment, except in the case of confirmed tubal sterilisation. These pregnancytests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to theprescriber.

Additional precautions

Patients should be instructed never to give this medicinal product to another person and to return anyunused capsules to their pharmacist at the end of treatment for safe disposal.

Patients should not donate blood, semen or sperm during treatment (including during doseinterruptions) and for at least 7 days following discontinuation of lenalidomide.

Healthcare professionals and caregivers should wear disposable gloves when handling the blister orcapsule. Women who are pregnant or suspect they may be pregnant should not handle the blister orcapsule (see section 6.6).

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 healthcare professionals to reinforce the warnings about theexpected teratogenicity of lenalidomide, to provide advice on contraception before treatment is started,and to provide guidance on the need for pregnancy testing. The prescriber must inform the patient aboutthe 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 cardand/or equivalent tool as agreed with each National Competent Authority. In collaboration with each

National Competent Authority, a controlled access programme has been implemented which includes theuse of a patient card and/or equivalent tool for prescribing and/or dispensing controls, and the collectionof information relating to the indication in order to monitor 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 theprescription and following a medically supervised negative pregnancy test result. Prescriptions forwomen of childbearing potential can be for a maximum duration of treatment of 4 weeks according tothe approved indications dosing regimens (see section 4.2), and prescriptions for all other patients can befor a maximum duration of treatment of 12 weeks.

Other special warnings and precautions for use

Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those withknown 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, andaction should be taken to try to minimize all modifiable risk factors (eg. smoking, hypertension, andhyperlipidaemia).

Venous and arterial thromboembolic events

In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associatedwith an increased risk of venous thromboembolism (predominantly deep vein thrombosis andpulmonary embolism). The risk of venous thromboembolism was seen to a lesser extent withlenalidomide in combination with melphalan and prednisone.

In patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma, treatmentwith lenalidomide monotherapy was associated with a lower risk of venous thromboembolism(predominantly deep vein thrombosis and pulmonary embolism) than in patients with multiplemyeloma 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 associatedwith an increased risk of arterial thromboembolism (predominantly myocardial infarction andcerebrovascular event) and was seen to a lesser extent with lenalidomide in combination withmelphalan and prednisone. The risk of arterial thromboembolism is lower in patients with multiplemyeloma treated with lenalidomide monotherapy than in patients with multiple myeloma treated withlenalidomide 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 orprevious 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 ashormone replacement therapy, should be used with caution in multiple myeloma patients receivinglenalidomide with dexamethasone. A haemoglobin concentration above 12 g/dl should lead todiscontinuation of erythropoietic agents.

Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism.

Patients should be instructed to seek medical care if they develop symptoms such as shortness ofbreath, chest pain, arm or leg swelling. Prophylactic antithrombotic medicinal products should berecommended, especially in patients with additional thrombotic risk factors. The decision to takeantithrombotic prophylactic measures should be made after careful assessment of an individualpatient’s underlying risk factors.

If the patient experiences any thromboembolic events, treatment must be discontinued and standardanticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatmentand any complications of the thromboembolic event have been managed, the lenalidomide treatmentmay be restarted at the original dose dependent upon a benefit risk assessment. The patient shouldcontinue anticoagulation therapy during the course of lenalidomide treatment.

Cases of pulmonary hypertension, some fatal, have been reported in patients treated with lenalidomide.

Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior toinitiating and during lenalidomide therapy.

Neutropenia and thrombocytopenia

The major dose limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. Acomplete 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 oflenalidomide treatment and monthly thereafter to monitor for cytopenias. In mantle cell lymphomapatients, the monitoring scheme should be every 2 weeks in cycles 3 and 4, and then at the start of eachcycle. 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 doseinterruption 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, includingpetechiae and epistaxis, especially in patients receiving concomitant medicinal products susceptible toinduce bleeding (see section 4.8, Haemorrhagic disorders).

Co-administration of lenalidomide with other myelosuppressive agents should be undertaken withcaution.

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

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 analysisidentified events that occurred after the start of maintenance treatment. In IFM 2005-02, the adversereactions were from the maintenance treatment period only.

Overall, Grade 4 neutropenia was observed at a higher frequency in the lenalidomide maintenancearms compared to the placebo maintenance arms in the 2 studies evaluating lenalidomide maintenancein NDMM patients who have undergone ASCT (32.1% vs 26.7% [16.1% vs 1.8% after the start ofmaintenance 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 in2.2% of patients in CALGB 100104 and 2.4% of patients in IFM 2005-02, respectively. Grade 4febrile neutropenia was reported at similar frequencies in the lenalidomide maintenance armscompared to placebo maintenance arms in both studies (0.4% vs 0.5% [0.4% vs 0.5% after the start ofmaintenance treatment] in CALGB 100104 and 0.3% vs 0% in IFM 2005-02, respectively). Patientsshould be advised to promptly report febrile episodes, a treatment interruption and/or dose reductionmay be required (see section 4.2).

Grade 3 or 4 thrombocytopenia was observed at a higher frequency in the lenalidomide maintenancearms 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 ofmaintenance treatment] in CALGB 100104 and 13.0% vs 2.9% in IFM 2005-02, respectively). Patientsand physicians are advised to be observant for signs and symptoms of bleeding, including petechiaeand epistaxes, especially in patients receiving concomitant medicinal products susceptible to inducebleeding (see section 4.8, Haemorrhagic disorders).

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated withlenalidomide in combination with bortezomib and dexamethasone

Grade 4 neutropenia was observed at a lower frequency in the lenalidomide in combination withbortezomib 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 armand Rd arm (0.0% vs 0.4%). Patients should be advised to promptly report febrile episodes; atreatment 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 withlenalidomide in combination with low dose dexamethasone

Grade 4 neutropenia was observed in the lenalidomide arms in combination with dexamethasone to alesser extent than in the comparator arm (8.5% in the Rd [continuous treatment] and Rd18 [treatmentfor 18 four-week cycles] compared with 15% in the melphalan/prednisone/thalidomide arm, see section4.8). Grade 4 febrile neutropenia episodes were consistent with the comparator arm (0.6% in the Rdand Rd18 lenalidomide/dexamethasone-treated patients compared with 0.7% in themelphalan/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 thecomparator arm (8.1% vs 11.1%, respectively).

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated withlenalidomide in combination with melphalan and prednisone

The combination of lenalidomide with melphalan and prednisone in clinical trials of newly diagnosedmultiple myeloma patients is associated with a higher incidence of Grade 4 neutropenia (34.1% inmelphalan, 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 observedinfrequently (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 isassociated 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 oneprior therapy is associated with a higher incidence of Grade 4 neutropenia (5.1% inlenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treatedpatients; see section 4.8). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% inlenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treatedpatients; see section 4.8).

The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated witha higher incidence of Grade 3 and Grade 4 thrombocytopenia (9.9% and 1.4%, respectively, inlenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients; see section 4.8).

Myelodysplastic syndromes

Lenalidomide treatment in myelodysplastic syndromes patients is associated with a higher incidence of

Grade 3 and 4 neutropenia and thrombocytopenia compared to patients on placebo (see section 4.8).

Lenalidomide treatment in mantle cell lymphoma patients is associated with a higher incidence of

Grade 3 and 4 neutropenia compared with patients on the control arm (see section 4.8).

The combination of lenalidomide with rituximab in follicular lymphoma patients is associated with ahigher 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 thelenalidomide/rituximab arm (see section 4.8).

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 andongoing monitoring of thyroid function is recommended.

Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheralneuropathy. There was no increase in peripheral neuropathy observed with lenalidomide in combinationwith dexamethasone or melphalan and prednisone or lenalidomide monotherapy or with long term useof lenalidomide for the treatment of newly diagnosed multiple myeloma.

The combination of lenalidomide with intravenous bortezomib and dexamethasone in multiplemyeloma patients is associated with a higher frequency of peripheral neuropathy. The frequency waslower when bortezomib was administered subcutaneously. For additional information, see Section 4.8and 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. Cases of TLS and tumour flare reaction (TFR), including fatal cases, have been reported(see section 4.8). The patients at risk of TLS and TFR are those with high tumour burden prior totreatment. Caution should be practiced when introducing these patients to lenalidomide. These patientsshould be monitored closely, especially during the first cycle or dose-escalation, and appropriateprecautions taken.

Careful monitoring and evaluation for TFR is recommended. Patients with high mantle cell lymphoma

International Prognostic Index (MIPI) at diagnosis or bulky disease (at least one lesion that is ≥ 7 cm inthe longest diameter) at baseline may be at risk of TFR. Tumour flare reaction may mimic progressionof disease (PD). Patients in studies MCL-002 and MCL-001 that experienced Grade 1 and 2 TFR weretreated 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 ofthe individual patient (see sections 4.2 and 4.8).

Careful monitoring and evaluation for TFR is recommended. Tumour flare may mimic PD. Patientswho experienced Grade 1 and 2 TFR were treated with corticosteroids, NSAIDs and/or narcoticanalgesics for management of TFR symptoms. The decision to take therapeutic measures for TFRshould 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 andreceive TLS prophylaxis, in addition to weekly chemistry panels during the first cycle or longer, asclinically indicated (see sections 4.2 and 4.8).

Tumour burden

Lenalidomide is not recommended for the treatment of patients with high tumour burden if alternativetreatment options are available.

Early death

In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths. Patientswith high tumour burden at baseline are at increased risk of early death, there were 16/81 (20%) earlydeaths in the lenalidomide arm and 2/28 (7%) early deaths in the control arm. Within 52 weekscorresponding figures were 32/81 (40%) and 6/28 (21%) (See section 5.1).

Adverse events

In study MCL-002, during treatment cycle 1, 11/81 (14%) patients with high tumour burden werewithdrawn from therapy in the lenalidomide arm vs. 1/28 (4%) in the control group. The main reasonfor treatment withdrawal for patients with high tumour burden during treatment cycle 1 in thelenalidomide arm was adverse events, 7/11 (64%).

Patients with high tumour burden should therefore be closely monitored for adverse reactions (see

Section 4.8) including signs of tumour flare reaction (TFR). Please refer to section 4.2 for doseadjustments for TFR. High tumour burden was defined as at least one lesion ≥5 cm in diameter or 3lesions ≥3 cm.

Allergic reactions and severe skin reactions

Cases of allergic reactions including angioedema, anaphylactic reaction and severe cutaneous reactionsincluding SJS, TEN and DRESS have been reported in patients treated with lenalidomide (see section4.8). Patients should be advised of the signs and symptoms of these reactions by their prescribers andshould be told to seek medical attention immediately if they develop these symptoms. Lenalidomidemust be discontinued for angioedema, anaphylactic reaction, exfoliative or bullous rash, or if SJS, TENor 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 reactiondepending on severity. Patients who had previous allergic reactions while treated with thalidomideshould be monitored closely, as a possible cross-reaction between lenalidomide and thalidomide hasbeen reported in the literature. Patients with a history of severe rash associated with thalidomidetreatment should not receive lenalidomide.

Second primary malignancies

An increase of second primary malignancies (SPM) has been observed in clinical trials in previouslytreated 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 squamouscell 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-foldincrease in incidence rate of hematologic SPM (cases of AML, MDS) has been observed in patientsreceiving lenalidomide in combination with melphalan and prednisone until progression (1.75 per 100person-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 receivinglenalidomide (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 18months, the hematologic SPM incidence rate (0.16 per 100 person-years) was not increased ascompared 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 receivinglenalidomide in combination with dexamethasone until progression or for 18 months (1.58 per 100person-years) compared to thalidomide in combination with melphalan and prednisone (1.19 per 100person-years).

In newly diagnosed multiple myeloma patients receiving lenalidomide in combination withbortezomib and dexamethasone, the hematologic SPM incidence rate was 0.00 - 0.16 per 100 person-years and the incidence rate of solid tumour SPM was 0.21 - 1.04 per 100 person-years.

The increased risk of secondary primary malignancies associated with lenalidomide is relevant also inthe context of NDMM after stem cell transplantation. Though this risk is not yet fully characterized, itshould 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 0.58per 100 person-years for the placebo arms (1.02 per 100 person-years for patients exposed tolenalidomide 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 lenalidomidearms and 1.05 per 100 person-years for the placebo arms (1.26 per 100 person-years for patientsexposed to lenalidomide after ASCT and 0.60 per 100 person-years for patients not-exposed tolenalidomide after ASCT).

The risk of occurrence of hematologic SPM must be taken into account before initiating treatment withlenalidomide either in combination with melphalan or immediately following high-dose melphalan and

ASCT. Physicians should carefully evaluate patients before and during treatment using standard cancerscreening for occurrence of SPM and institute treatment as indicated.

Progression to acute myeloid leukaemia in low- and intermediate-1-risk MDS

Karyotype

Baseline variables including complex cytogenetics are associated with progression to AML in subjectswho are transfusion dependent and have a Del (5q) abnormality. In a combined analysis of two clinicaltrials of lenalidomide in low- or intermediate-1-risk myelodysplastic syndromes, subjects who had acomplex cytogenetics had the highest estimated 2-year cumulative risk of progression to AML (38.6%).

The estimated 2-year rate of progression to AML in patients with an isolated Del (5q) abnormality was13.8%, compared to 17.3% for patients with Del (5q) and one additional cytogenetic abnormality.

As a consequence, the benefit/risk ratio of lenalidomide when MDS is associated with Del (5q) andcomplex cytogenetics is unknown.

TP53 status

A TP53 mutation is present in 20 to 25% of lower-risk MDS Del 5q patients and is associated with ahigher risk of progression to acute myeloid leukaemia (AML). In a post-hoc analysis of a clinical trialof lenalidomide in low- or intermediate-1-risk myelodysplastic syndromes (MDS-004), the estimated 2-year rate of progression to AML was 27.5 % in patients with IHC-p53 positivity (1% cut-off level ofstrong nuclear staining, using immunohistochemical assessment of p53 protein as a surrogate for TP53mutation status) and 3.6% in patients with IHC-p53 negativity (p=0.0038) (see section 4.8).

Progression to other malignancies in mantle cell lymphoma

In mantle cell lymphoma, AML, B-cell malignancies and non-melanoma skin cancer (NMSC) areidentified risks.

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 armcompared with 0.29 per 100 person-years in patients receiving placebo/rituximab. The incidence rate ofhematologic 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 receivingplacebo/rituximab with a median follow-up of 30.59 months (range 0.6 to 50.9 months).

Non-melanoma skin cancers are identified risks and comprise squamous cell carcinomas of skin orbasal cell carcinomas.

Physicians should monitor patients for the development of SPMs. Both the potential benefit oflenalidomide 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 incombination therapy: acute hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, andmixed cytolytic/cholestatic hepatitis have been reported. The mechanisms of severe drug-inducedhepatotoxicity remain unknown although, in some cases, pre-existing viral liver disease, elevatedbaseline liver enzymes, and possibly treatment with antibiotics might be risk factors.

Abnormal liver function tests were commonly reported and were generally asymptomatic andreversible upon dosing interruption. Once parameters have returned to baseline, treatment at a lowerdose may be considered.

Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal impairmentin order to avoid plasma levels which may increase the risk for higher haematological adversereactions or hepatotoxicity. Monitoring of liver function is recommended, particularly when there is ahistory of or concurrent viral liver infection or when lenalidomide is combined with medicinalproducts 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 ofinfections was observed with lenalidomide in combination with dexamethasone than with MPT inpatients with NDMM who are not eligible for transplant, and with lenalidomide maintenance comparedto placebo in patients with NDMM who had undergone ASCT. Grade ≥ 3 infections occurred withinthe context of neutropenia in less than one-third of the patients. Patients with known risk factors forinfections should be closely monitored. All patients should be advised to seek medical attentionpromptly at the first sign of infection (eg, cough, fever, etc) thereby allowing for early management toreduce severity.

Cases of viral reactivation have been reported in patients receiving lenalidomide, including seriouscases 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, meningitisherpes zoster or ophthalmic herpes zoster requiring a temporary hold or permanent discontinuation ofthe treatment with lenalidomide and adequate antiviral treatment.

Reactivation of hepatitis B has been reported rarely in patients receiving lenalidomide who havepreviously been infected with the hepatitis B virus (HBV). Some of these cases have progressed toacute hepatic failure resulting in discontinuation of lenalidomide and adequate antiviral treatment.

Hepatitis B virus status should be established before initiating treatment with lenalidomide. Forpatients who test positive for HBV infection, consultation with a physician with expertise in thetreatment of hepatitis B is recommended. Caution should be exercised when lenalidomide is used inpatients previously infected with HBV, including patients who are anti-HBc positive but HBsAgnegative. These patients should be closely monitored for signs and symptoms of active HBV infectionthroughout therapy.

Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reportedwith lenalidomide. PML was reported several months to several years after starting the treatment withlenalidomide. Cases have generally been reported in patients taking concomitant dexamethasone orprior treatment with other immunosuppressive chemotherapy. Physicians should monitor patients atregular intervals and should consider PML in the differential diagnosis in patients with new orworsening neurological symptoms, cognitive or behavioural signs or symptoms. Patients should alsobe advised to inform their partner or caregivers about their treatment, since they may notice symptomsthat the patient is not aware of.

The evaluation for PML should be based on neurological examination, magnetic resonance imaging ofthe 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. Additionalfollow-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 isconfirmed, lenalidomide must be permanently discontinued.

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 whenlenalidomide is given in combination. Patients should be carefully assessed for their ability to toleratelenalidomide 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 combinationwith dexamethasone particularly when used for a prolonged time. Regular monitoring of visual abilityis recommended.

Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormonereplacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomidewith dexamethasone (see sections 4.4 and 4.8).

No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzymeinducer. In an in vitro study with human hepatocytes, lenalidomide, at various concentrations testeddid not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. Therefore, induction leadingto reduced efficacy of medicinal products, including hormonal contraceptives, is not expected iflenalidomide is administered alone. However, dexamethasone is known to be a weak to moderateinducer of CYP3A4 and is likely to also affect other enzymes as well as transporters. It may not beexcluded that the efficacy of oral contraceptives may be reduced during treatment. Effective measuresto avoid pregnancy must be taken (see sections 4.4 and 4.6).

Co-administration of multiple 10 mg doses of lenalidomide had no effect on the single dosepharmacokinetics of R- and S- warfarin. Co-administration of a single 25 mg dose of warfarin had noeffect on the pharmacokinetics of lenalidomide. However, it is not known whether there is aninteraction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is a weakto moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarinconcentration is advised during the treatment.

Concomitant administration with lenalidomide 10 mg once daily increased the plasma exposure ofdigoxin (0.5 mg, single dose) by 14% with a 90% CI (confidence interval) [0.52%-28.2%]. It is notknown whether the effect will be different in the clinical use (higher lenalidomide doses andconcomitant treatment with dexamethasone). Therefore, monitoring of the digoxin concentration isadvised during lenalidomide treatment.

Statins

There is an increased risk of rhabdomyolysis when statins are administered with lenalidomide, whichmay be simply additive. Enhanced clinical and laboratory monitoring is warranted notably during thefirst weeks of treatment.

Dexamethasone

Co-administration of single or multiple doses of dexamethasone (40 mg once daily) has no clinicallyrelevant 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 multipledoses of the strong P-gp inhibitor quinidine (600 mg, twice daily) or the moderate P-gpinhibitor/substrate temsirolimus (25 mg) has no clinically relevant effect on the pharmacokinetics oflenalidomide (25 mg). Co-administration of lenalidomide does not alter the pharmacokinetics oftemsirolimus.

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 childbearingpotential.

Women of childbearing potential should use effective method of contraception. If pregnancy occurs ina woman treated with lenalidomide, treatment must be stopped and the patient should be referred to aphysician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in apartner of a male patient taking lenalidomide, it is recommended to refer the female partner to aphysician specialised or experienced in teratology for evaluation and advice.

Lenalidomide is present in human semen at extremely low levels during treatment and is undetectablein human semen 3 days after stopping the substance in the healthy subject (see section 5.2). As aprecaution and taking into account special populations with prolonged elimination time such as renalimpairment, 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 ofchildbearing potential and has no contraception.

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic activesubstance that causes severe life-threatening birth defects.

In monkeys, lenalidomide induced malformations similar to those described with thalidomide (seesection 5.3). Therefore, a teratogenic effect of lenalidomide is expected and lenalidomide iscontraindicated during pregnancy (see section 4.3).

It is not known whether lenalidomide is excreted in breast milk. Therefore, breast-feeding should bediscontinued during therapy with lenalidomide.

A fertility study in rats with lenalidomide doses up to 500 mg/kg (approximately 200 to 500 times thehuman doses of 25 mg and 10 mg, respectively, based on body surface area) produced no adverseeffects on fertility and no parental toxicity.

Lenalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue,dizziness, somnolence, vertigo and blurred vision have been reported with the use of lenalidomide.

Therefore, caution is recommended when driving or operating machines.

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

A conservative approach was applied to determine the adverse reactions from CALGB 100104. Theadverse reactions described in Table 1 included events reported post-HDM/ASCT as well as eventsfrom the maintenance treatment period. A second analysis that identified events that occurred after thestart of maintenance treatment suggests that the frequencies described in Table 1 may be higher thanactually observed during the maintenance treatment period. In IFM 2005-02, the adverse reactionswere from the maintenance treatment period only.

The serious adverse reactions observed more frequently (≥5%) with lenalidomide maintenance thanplacebo 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 lenalidomidemaintenance 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 lenalidomidemaintenance 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%]), upperrespiratory tract infection (26.8% [26.8%]), fatigue (22.8% [17.9%]), leucopenia (22.8% [18.8%]) andanaemia (21.0% [13.8%]).

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

In the SWOG S0777 study, the serious adverse reactions observed more frequently (≥ 5%) withlenalidomide in combination with intravenous bortezomib and dexamethasone than with lenalidomidein 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 anddexamethasone 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 withlenalidomide in combination with low dose dexamethasone

The serious adverse reactions observed more frequently (≥5%) with lenalidomide in combination withlow dose dexamethasone (Rd and Rd18) than with melphalan, prednisone and thalidomide (MPT)were:

- Pneumonia (9.8%)

- Renal failure (including acute) (6.3%)

The adverse reactions observed more frequently with Rd or Rd18 than MPT were: diarrhoea (45.5%),fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%), decreasedappetite (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 withlenalidomide in combination with melphalan and prednisone

The serious adverse reactions observed more frequently (≥5%) with melphalan, prednisone andlenalidomide followed by lenalidomide maintenance (MPR+R) or melphalan, prednisone andlenalidomide followed by placebo (MPR+p) than melphalan, prednisone and placebo followed byplacebo (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 3 placebo-controlled studies, 353 patients with multiple myeloma were exposed to thelenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination.

The most serious adverse reactions observed more frequently in lenalidomide/dexamethasone thanplacebo/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 dexamethasonethan 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%).

Myelodysplastic syndromes

The overall safety profile of lenalidomide in patients with myelodysplastic syndromes is based on datafrom a total of 286 patients from one phase 2 study and one phase 3 study (see section 5.1). In thephase 2, all 148 patients were on lenalidomide treatment. In the phase 3 study, 69 patients were onlenalidomide 5 mg, 69 patients on lenalidomide 10 mg and 67 patients were on placebo during thedouble-blind phase of the study.

Most adverse reactions tended to occur during the first 16 weeks of therapy with lenalidomide. Seriousadverse reactions include:

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

- Grade 3 or 4 neutropenia, febrile neutropenia and Grade 3 or 4 thrombocytopenia (see section4.4).

The most commonly observed adverse reactions which occurred more frequently in the lenalidomidegroups compared to the control arm in the phase 3 study were neutropenia (76.8%), thrombocytopenia(46.4%), diarrhoea (34.8%), constipation (19.6%), nausea (19.6%), pruritus (25.4%), rash (18.1%),fatigue (18.1%) and muscle spasms (16.7%).

The overall safety profile of lenalidomide in patients with mantle cell lymphoma is based on data from254 patients from a phase 2 randomised, controlled study MCL-002 (see section 5.1).

Additionally, adverse drug reactions from supportive study MCL-001 have been included in table 3.

The serious adverse reactions observed more frequently in study MCL-002 (with a difference of atleast 2 percentage points) in the lenalidomide arm compared with the control arm were:

- Neutropenia (3.6%)

- Pulmonary embolism (3.6%)

- Diarrhoea (3.6%)

The most frequently observed adverse reactions which occurred more frequently in the lenalidomidearm compared with the control arm in study MCL-002 were neutropenia (50.9%), anaemia (28.7%),diarrhoea (22.8%), fatigue (21.0%), constipation (17.4%), pyrexia (16.8%), and rash (includingdermatitis allergic) (16.2%).

In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths. Patientswith high tumour burden at baseline are at increased risk of early death, 16/81 (20%) early deaths inthe lenalidomide arm and 2/28 (7%) early deaths in the control arm. Within 52 weeks correspondingfigures were 32/81 (39.5%) and 6/28 (21%) (see section 5.1).

During treatment cycle 1, 11/81 (14%) patients with high tumour burden were withdrawn from therapyin the lenalidomide arm vs. 1/28 (4%) in the control group. The main reason for treatment withdrawalfor patients with high tumour burden during treatment cycle 1 in the lenalidomide arm was adverseevents, 7/11 (64%). High tumour burden was defined as at least one lesion ≥5 cm in diameter or 3lesions ≥3 cm.

The overall safety profile of lenalidomide in combination with rituximab in patients with previouslytreated follicular lymphoma is based on data from 294 patients from a Phase 3 randomised, controlledstudy NHL-007. Additionally, adverse drug reactions from supportive study NHL-008 have beenincluded in Table 5.

The serious adverse reactions observed most frequently (with a difference of at least 1 percentagepoint) in study NHL-007 in the lenalidomide/rituximab arm compared with the placebo/rituximab armwere:

- 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/rituximabarm compared with the placebo/rituximab arm (with at least 2% higher frequency between arms) wereneutropenia (58.2%), diarrhoea (30.8%), leucopenia (28.8%), constipation (21.9%), cough (21.9%)and fatigue (21.9%).

The adverse reactions observed in patients treated with lenalidomide are listed below by system organclass and frequency. Within each frequency grouping, adverse reactions are presented in order ofdecreasing 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), notknown (cannot be estimated from the available data).

Adverse reactions have been included under the appropriate category in the table below according tothe highest frequency observed in any of the main clinical trials.

Tabulated summary for monotherapy in MM

The following table is derived from data gathered during NDMM studies in patients who haveundergone ASCT treated with lenalidomide maintenance. The data were not adjusted according to thelonger duration of treatment in the lenalidomide-containing arms continued until disease progressionversus 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 withlenalidomide maintenance therapy

System Organ Class/Preferred All ADRs/Frequency Grade 3-4 ADRs/Frequency

Term

Infections and Infestations Very common Very common

Pneumonia◊,a, Upper respiratory Pneumonia◊,a, Neutropenictract infection, Neutropenic infectioninfection, Bronchitis◊, Influenza◊,

Gastroenteritis◊, Sinusitis, Common

Nasopharyngitis, Rhinitis Sepsis◊,b, Bacteraemia, Lunginfection◊, Lower respiratory tract

Common infection bacterial, Bronchitis◊,

Infection◊, Urinary tract Influenza◊, Gastroenteritis◊,infection◊,*, Lower respiratory tract Herpes zoster◊, Infection◊infection, Lung infection◊

Neoplasms Benign, Malignant Commonand Unspecified (incl cysts and Myelodysplastic syndrome◊,*polyps)

Blood and Lymphatic System Very common Very common

Disorders Neutropenia^,◊, Neutropenia^,◊, Febrile

Febrile neutropenia^,◊, neutropenia^,◊,

Thrombocytopenia^,◊, Anaemia, Thrombocytopenia^,◊, Anaemia,

Leucopenia◊, Lymphopenia Leucopenia◊, Lymphopenia

Common

Pancytopenia◊

Metabolism and Nutrition Very common Common

Disorders Hypokalaemia Hypokalaemia, Dehydration

Nervous System Disorders Very common Common

Paraesthesia Headache

Common

Peripheral neuropathyc

Vascular Disorders Common Common

Pulmonary embolism◊,* Deep vein thrombosis^,◊,d

Respiratory, Thoracic and Very common Common

Mediastinal Disorders Cough Dyspnoea◊

Common

Dyspnoea◊, Rhinorrhoea

Gastrointestinal Disorders Very common Common

Diarrhoea, Constipation, Diarrhoea, Vomiting, Nausea

Abdominal pain, Nausea

Common

Vomiting, Abdominal pain upper

Hepatobiliary Disorders Very common Common

Abnormal liver function tests Abnormal liver function tests

Skin and Subcutaneous Tissue Very common Common

Disorders Rash, Dry skin Rash, Pruritus

Musculoskeletal and Connective Very common

Tissue Disorders Muscle spasms

Common

Myalgia, Musculoskeletal pain

General Disorders and Very common Common

Administration Site Conditions Fatigue, Asthenia, Pyrexia 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 reactionsa “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, Pneumonitisb “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,

Polyneuropathyd “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 withcombination therapy. The data were not adjusted according to the longer duration of treatment in thelenalidomide-containing arms continued until disease progression versus the comparator arms in thepivotal multiple myeloma studies (see section 5.1).

Table 2. ADRs reported in clinical studies in patients with multiple myeloma treated withlenalidomide in combination with bortezomib and dexamethasone, dexamethasone, ormelphalan and prednisone

System Organ Class All ADRs/Frequency Grade 3−4 ADRs/Frequency/ Preferred Term

Infections and Very common Common

Infestations Pneumonia◊,◊◊, Upper respiratory tract Pneumonia◊,◊◊, Bacterial, viral andinfection◊, Bacterial, viral and fungal fungal infections (includinginfections (including opportunistic opportunistic infections)◊,infections)◊, Nasopharyngitis, Pharyngitis, Cellulitis◊, Sepsis◊,◊◊, Lung

Bronchitis◊, Rhinitis infection◊◊, Bronchitis◊, Respiratorytract infection◊◊, Urinary tract

Common infection◊◊, Enterocolitis infectious

Sepsis◊,◊◊, Lung infection◊◊, Urinary tractinfection◊◊, Sinusitis◊

Neoplasms Benign, Uncommon Common

Malignant and Basal cell carcinoma^,◊, Squamous skin Acute myeloid leukaemia◊,

Unspecified (incl cancer^,◊,* Myelodysplastic syndrome◊,cysts and polyps) Squamous cell carcinoma ofskin^,◊,**

Uncommon

T-cell type acute leukaemia◊, Basalcell carcinoma^,◊, Tumour lysissyndrome

Blood and Very common Very common

Lymphatic System Neutropenia^,◊,◊◊, Thrombocytopenia^,◊,◊◊, Neutropenia^,◊,◊◊,

Disorders Anaemia◊, Haemorrhagic disorder^, Thrombocytopenia^,◊,◊◊, Anemia◊,

Leucopenia, Lymphopenia Leucopenia, Lymphopenia

Common Common

Febrile neutropenia^,◊, Pancytopenia◊ Febrile neutropenia^,◊,

Pancytopenia◊, Haemolytic anemia

Uncommon

Haemolysis, Autoimmune haemolytic Uncommonanaemia, Haemolytic anaemia Hypercoagulation, Coagulopathy

Immune System Uncommon

Disorders Hypersensitivity^

Endocrine Disorders Common

Metabolism and Very common Common

Nutrition Disorders Hypokalaemia◊,◊◊, Hyperglycaemia, Hypokalaemia◊,◊◊, Hyperglycaemia,

Hypoglycaemia, Hypocalcaemia◊, Hypocalcaemia◊, Diabetes mellitus◊,

Hyponatraemia◊, Dehydration◊◊, Decreased Hypophosphataemia,appetite◊◊, Weight decreased Hyponatraemia◊, Hyperuricaemia,

Gout, Dehydration◊◊, Decreased

Common appetite◊◊, Weight decreased

Hypomagnesaemia, Hyperuricaemia,

Hypercalcaemia+

Psychiatric Very common Common

Disorders Depression, Insomnia Depression, Insomnia

Uncommon

Loss of libido

Nervous System Very common Very common

Disorders Peripheral neuropathies◊◊, Paraesthesia, Peripheralneuropathies◊◊

Dizziness◊◊, Tremor, Dysgeusia, Headache

Common

Common Cerebrovascular accident◊,

Ataxia, Balance impaired, Syncope◊◊, Dizziness◊◊, Syncope◊◊, Neuralgia

Neuralgia, Dysaesthesia

Uncommon

Intracranial haemorrhage^,

Transient ischaemic attack,

Cerebral ischemia

Eye Disorders Very common Common

Cataracts, Blurred vision Cataract

Common Uncommon

Reduced visual acuity Blindness

Ear and Labyrinth Common

Disorders Deafness (Including Hypoacusis), Tinnitus

Cardiac Disorders Common Common

Atrial fibrillation◊,◊◊, Bradycardia Myocardial infarction (includingacute)^,◊, Atrial fibrillation◊,◊◊,

Uncommon Congestive cardiac failure◊,

Arrhythmia, QT prolongation, Atrial flutter, Tachycardia, Cardiac failure◊,◊◊,

Ventricular extrasystoles Myocardial ischemia◊

Vascular Disorders Very common Very common

Venous thromboembolic events^, Venous thromboembolic events^,predominantly deep vein thrombosis and predominantly deep veinpulmonary embolism^,◊,◊◊, Hypotension◊◊ thrombosis and pulmonaryembolism^,◊,◊◊

Common

Hypertension, Ecchymosis^ Common

Vasculitis, Hypotension◊◊,

Uncommon

Ischemia, Peripheral ischemia,

Intracranial venous sinusthrombosis

Respiratory, Very common Common

Thoracic and Dyspnoea◊,◊◊, Epistaxis^, Cough Respiratory distress◊, Dyspnoea◊,◊◊,

Mediastinal Pleuritic pain◊◊, Hypoxia◊◊

Disorders Common

Dysphonia

Gastrointestinal Very common Common

Disorders Diarrhoea◊,◊◊, Constipation◊, Abdominal Gastrointestinal haemorrhage^,◊,◊◊,pain◊◊, Nausea, Vomiting,◊◊, Dyspepsia, Dry Small intestinal obstruction◊◊,mouth, Stomatitis Diarrhoea◊◊, Constipation◊,

Abdominal pain◊◊, Nausea,

Common Vomiting◊◊

Gastrointestinal haemorrhage (includingrectal haemorrhage, haemorrhoidalhaemorrhage, peptic ulcer haemorrhage andgingival bleeding)^,◊◊, Dysphagia

Uncommon

Colitis, Caecitis

Hepatobiliary Very common Common

Disorders Alanine aminotransferase increased, Cholestasis◊, Hepatotoxicity,

Aspartate aminotransferase increased Hepatocellular injury◊◊, Alanineaminotransferase increased,

Common Abnormal liver function tests◊

Hepatocellular injury◊◊, Abnormal liverfunction tests◊, Hyperbilirubinaemia Uncommon

Hepatic failure^

Uncommon

Hepatic failure^

Skin and Very common Common

Subcutaneous Rashes◊◊, Pruritus Rashes◊◊

Tissue Disorders

Common Uncommon

Urticaria, Hyperhidrosis, Dry skin, Skin Drug rash with eosinophilia andhyperpigmentation, Eczema, Erythema systemic symptoms◊◊

Uncommon

Drug rash with eosinophilia and systemicsymptoms◊◊, Skin discolouration,

Photosensitivity reaction

Musculoskeletal and Very common Common

Connective Tissue Muscular weakness◊◊, Muscle spasms, Bone Muscular weakness◊◊, Bone pain◊,

Disorders pain◊, Musculoskeletal and connective tissue Musculoskeletal and connectivepain and discomfort (including back pain◊,◊◊), tissue pain and discomfort (including

Pain in extremity, Myalgia, Arthralgia◊ back pain◊,◊◊)

Common Uncommon

Joint swelling Joint swelling

Renal and Urinary Very common Uncommon

Disorders Renal failure (including acute)◊,◊◊ Renal tubular necrosis

Common

Haematuria^, Urinary retention, Urinaryincontinence

Uncommon

Acquired Fanconi syndrome

Reproductive Common

System and Breast Erectile dysfunction

Disorders

General Disorders Very common Very commonand Administration Fatigue◊,◊◊, Oedema (including peripheral Fatigue◊,◊◊

Site Conditions oedema), Pyrexia◊,◊◊, Asthenia, Influenza likeillness syndrome (including pyrexia, cough, Commonmyalgia, musculoskeletal pain, headache and Oedema peripheral, Pyrexia◊,◊◊,rigors) Asthenia

Common

Chest pain◊,◊◊, Lethargy

Investigations Very common

Blood alkaline phosphatase increased

Common

C-reactive protein increased

Injury, Poisoning Commonand Procedural Fall, Contusion^

Complications◊◊Adverse reactions reported as serious in clinical trials in patients with NDMM who had received lenalidomide in combination withbortezomib anddexamethasone^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 withdexamethasone, or with melphalan and prednisone+ Applies to serious adverse drug reactions only

* Squamous skin cancer was reported in clinical trials in previously treated myeloma patients with lenalidomide/dexamethasone comparedto controls

** Squamous cell carcinoma of skin was reported in a clinical trial in newly diagnosed myeloma patients with lenalidomide/dexamethasonecompared to controls

Tabulated summary from monotherapy

The following tables are derived from data gathered during the main studies inmonotherapy for myelodysplastic syndromes and mantle cell lymphoma.

Table 3. ADRs reported in clinical trials in patients with myelodysplastic syndromestreated with lenalidomide#

System Organ All ADRs/Frequency Grade 3−4 ADRs/Frequency

Class/Preferred

Term

Infections Very common Very commonand Bacterial, viral and fungal infections Pneumonia◊

Infestations (including opportunistic infections)◊

Common

Bacterial, viral and fungalinfections (includingopportunistic infections)◊,

Bronchitis

Blood and Very common Very common

Lymphatic System Thrombocytopenia^,◊, Thrombocytopenia^,◊,

Disorders Neutropenia^,◊, Anaemia◊, Neutropenia^,◊, Anaemia◊,

Leucopenia Leucopenia

Common

Febrile neutropenia^,◊

Endocrine Disorders Very common

Metabolism and Very common Common

Nutrition Decreased appetite Hyperglycaemia◊,

Disorders Common Decreased appetite

Iron overload, Weight decreased

Psychiatric Disorders Common

Altered mood◊,~

Nervous System Very common

Disorders Dizziness, Headache

Common

Paraesthesia

Cardiac Disorders Common

Acute myocardial infarction^,◊,

Atrial fibrillation◊, Cardiac failure◊

Vascular Disorders Common Common

Hypertension, Haematoma Venous thromboembolic events,predominantly deep veinthrombosis and pulmonaryembolism^,◊

Respiratory, Thoracic Very commonand Mediastinal Epistaxis^

Disorders

Gastrointestinal Very common Common

Disorders Diarrhoea◊, Abdominal pain (including Diarrhoea◊, Nausea, Toothacheupper), Nausea, Vomiting,

Common

Dry mouth, Dyspepsia

Hepatobiliary Common Common

Disorders Abnormal liver function tests Abnormal liver function tests

Skin and Very common Common

Subcutaneous Tissue Rashes, Dry Skin, Pruritus Rashes, Pruritus

Disorders

Musculoskeletal and Very common Common

Connective Tissue Muscle spasms, Musculoskeletal pain Back pain◊

Disorders (including back pain◊ and pain inextremity), Arthralgia, Myalgia

Renal and Urinary Common

Disorders Renal failure◊

General Disorders and Very common Common

Administration Site Fatigue, Peripheral oedema, Influenza Pyrexia

Conditions like illness syndrome (includingpyrexia, cough, pharyngitis, myalgia,musculoskeletal pain, headache)

Injury, Poisoning and Common

Procedural Fall

Complications^see section 4.8 description of selected adverse reactions◊Adverse events reported as serious in myelodysplastic syndromes clinical trials~Altered mood was reported as a common serious adverse event in the myelodysplastic syndromes phase 3 study; it was not reportedas a Grade 3 or 4 adverse event

Algorithm applied for inclusion in the SmPC: All ADRs captured by the phase 3 study algorithm are included in the EU SmPC. Forthese ADRs, an additional check of the frequency of the ADRs captured by the phase 2 study algorithm was undertaken and, if thefrequency of the ADRs in the phase 2 study was higher than in the phase 3 study, the event was included in the EU SmPC at thefrequency it occurred in the phase 2 study.# Algorithm applied for myelodysplastic syndromes:

- Myelodysplastic syndromes phase 3 study (double-blind safety population, difference between lenalidomide 5/10mg andplacebo by initial dosing regimen occurring in at least 2 subjects)o All treatment-emergent adverse events with ≥ 5% of subjects in lenalidomide and at least 2% difference inproportion betweenlenalidomide and placeboo All treatment-emergent Grade 3 or 4 adverse events in 1% of subjects in lenalidomide and at least 1%difference in proportion between lenalidomide and placeboo All treatment-emergent serious adverse events in 1% of subjects in lenalidomide and at least 1%difference in proportion between lenalidomide and placebo

- Myelodysplastic syndromes phase 2 studyo All treatment-emergent adverse events with ≥ 5% of lenalidomide treated subjectso All treatment-emergent Grade 3 or 4 adverse events in 1% of lenalidomide treated subjectso All treatment-emergent serious adverse events in 1% of lenalidomide treated subjects

Table 4. ADRs reported in clinical trials in patients with mantle cell lymphomatreated with lenalidomide

System Organ All ADRs/Frequency Grade 3−4 ADRs/Frequency

Class /

Preferred Term

Infections and Very common Common

Infestations Bacterial, viral and fungal infections Bacterial, viral and fungal infections(including opportunistic infections)◊, (including opportunistic infections)◊,

Nasopharyngitis, Pneumonia◊ Pneumonia◊

Common

Sinusitis

Neoplasms Common Common

Benign, Tumour flare reaction Tumour flare reaction, Squamous skin

Malignant and cancer^,◊, Basal cell carcinoma^,◊

Unspecified (inclcysts and polyps)

Blood and Very common Very common

Lymphatic Thrombocytopenia^, Neutropenia^,◊, Thrombocytopenia^, Neutropenia^,◊,

System Disorders Leucopenia◊, Anemia◊ Anaemia◊

Common Common

Febrile neutropenia^,◊ Febrile neutropenia^,◊, Leucopenia◊

Metabolism and Very common Common

Nutrition Decreased appetite, Weight decreased, Dehydration◊, Hyponatraemia,

Disorders Hypokalaemia Hypocalcaemia

Common

Dehydration◊

Psychiatric Common

Disorders Insomnia

Nervous System Common Common

Disorders Dysgeuesia, Headache, neuropathy Peripheral sensory neuropathy, Lethargyperipheral

Ear and Common

Labyrinth Vertigo

Disorders

Cardiac Common

Disorders Myocardial infarction (including acute)^,◊,

Cardiac failure

Vascular Common Common

Disorders Hypotension◊ Deep vein thrombosis◊, pulmonaryembolism^,◊, Hypotension◊

Respiratory, Very common Common

Thoracic and Dyspnoea◊ Dyspnoea◊

Mediastinal

Disorders

Gastrointestinal Very common Common

Disorders Diarrhoea◊, Nausea◊, Vomiting◊, Diarrhoea◊, Abdominal pain◊, Constipation

Common

Abdominal pain◊

Skin and Very common Common

Subcutaneous Rashes (including dermatitis allergic), Rashes

Tissue Disorders Pruritus

Common

Night sweats, Dry skin

Musculoskeletal Very common Commonand Connective Muscle spasms, Back pain Back pain, Muscular weakness◊,

Tissue Disorders Arthralgia, Pain in extremity

Common

Arthralgia, Pain in extremity, Muscularweakness◊

Renal and Common

Urinary Renal failure◊

Disorders

General Very common Common

Disorders and Fatigue, Asthenia◊, Peripheral oedema, Pyrexia◊, Asthenia◊, Fatigue

Administration Influenza like illness syndrome

Site Conditions (including pyrexia◊, cough)

Common

Chills^see section 4.8 description of selected adverse reactions◊Adverse events reported as serious in mantle cell lymphoma clinical trials Algorithm applied for mantle cell lymphoma:

- Mantle cell lymphoma controlled phase 2 studyo All treatment-emergent adverse events with ≥ 5% of subjects in lenalidomide arm and at least 2% difference inproportionbetween lenalidomide and control armo All treatment-emergent Grade 3 or 4 adverse events in ≥1% of subjects in lenalidomide arm and at least 1.0% differenceinproportion between lenalidomide and control armo All Serious treatment-emergent adverse events in ≥1% of subjects in lenalidomide arm and at least 1.0% differencein proportionbetween lenalidomide and control arm

- Mantle cell lymphoma single arm phase 2 studyo All treatment-emergent adverse events with ≥ 5% of subjectso All Grade 3 or 4 treatment-emergent adverse events reported in 2 or more subjectso All Serious treatment-emergent adverse events reported in 2 or more subjects

Tabulated summary for combination therapy in FL

The following table is derived from data gathered during the main studies (NHL-007 and NHL-008)using lenalidomide in combination with rituximab for patients with follicular lymphoma.

Table 5: ADRs reported in clinical trials in patients with follicular lymphoma treated withlenalidomide in combination with rituximab

System Organ Class/All ADRs/Frequency Grade 3−4 ADRs/Frequency

Preferred Term

Infections and Very common Common

Infestations Upper respiratory tract infection Pneumonia◊, Sepsis◊, Lung infection,

Bronchitis, Gastroenteritis, Sinusitis,

Common Urinary tract infection, Cellulitis◊

Pneumonia◊, Influenza, Bronchitis,

Sinusitis, Urinary tract infection

Neoplasms Benign, Very common Common

Malignant and Tumour flare^ Basal cell carcinoma^,◊

Unspecified (incl cystsand polyps) Common

Squamous Cell Carcinoma of Skin◊,^,+

Blood and Lymphatic Very common Very common

System Disorders Neutropenia^,◊, Anaemia◊, Neutropenia^,◊

Thrombocytopenia^, Leucopenia**

Lymphopenia*** Common

Anaemia◊, Thrombocytopenia^,

Febrile neutropenia◊, Pancytopenia,

Leucopenia**, Lymphopenia***

Metabolism and Very common Common

Nutrition Disorders Decreased appetite, Hypokalaemia Dehydration, Hypercalcaemia◊,

Hypokalaemia, Hypophosphataemia,

Common Hyperuricaemia

Hypophosphataemia, Dehydration

Psychiatric Disorders Common

Depression, Insomnia

Nervous System Very common Common

Disorders Headache, Dizziness Syncope

Common

Peripheral sensory neuropathy,

Dysgeusia

Cardiac Disorders Uncommon

Arrhythmia◊

Vascular Disorders Common Common

Hypotension Pulmonary embolism^,◊, Hypotension

Respiratory, Thoracic Very common Commonand Mediastinal Dyspnoea◊, Cough, Dyspnoea◊

Disorders Common

Oropharyngeal pain, Dysphonia

Gastrointestinal Very common Common

Disorders Abdominal pain◊, Diarrhoea, Abdominal pain◊, Diarrhoea,

Constipation, Nausea, Vomiting, Constipation, Stomatitis

Dyspepsia

Common

Upper abdominal pain, Stomatitis, Drymouth

Skin and Subcutaneous Very common Common

Tissue Disorders Rash*, Pruritus Rash*, Pruritus

Common

Dry skin, Night sweats, Erythema

Musculoskeletal and Very common Common

Connective Tissue Muscle spasms, Back pain, Muscular weakness, Neck pain

Disorders Arthralgia

Common

Pain in extremity, Muscular weakness,

Musculoskeletal pain, Myalgia, Neckpain

Renal and Urinary Common

Disorders Acute kidney injury◊

General Disorders and Very common Common

Administration Site Pyrexia, Fatigue, Asthenia, Peripheral Fatigue, Asthenia

Conditions oedema

Common

Malaise, Chills

Investigations Very common

Alanine aminotransferaseincreased

Common

Weight decreased, Blood Bilirubinincreased^see section 4.8 description of selected adverse reactions

Algorithm applied for follicular lymphoma:

Controlled- Phase 3 trial:

- NHL-007 ADRs- All treatment-emergent AEs with ≥ 5.0% of subjects in lenalidomide/rituximab arm and at least 2.0% higherfrequency (%) in Len arm compared to control arm - (Safety population)

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

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

FL single arm - phase 3 trial:

- NHL-008 ADRs- All treatment-emergent adverse events with ≥ 5.0% of subjects

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

- NHL-008 Serious ADRs- All serious treatment-emergent adverse events reported in ≥ 1.0% of subjects◊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 tableis derived from data gathered from post-marketing data.

Table 6. ADRs reported in post-marketing use in patients treated with lenalidomide

System Organ All ADRs/Frequency Grade 3−4 ADRs/Frequency

Class/Preferred

Term

Infections and Not known Not known

Infestations Viral infections, including herpes zoster Viral infections, including herpesand hepatitis B virus reactivation zoster and hepatitis B virusreactivation

Neoplasms Benign, Rare

Malignant and Tumour lysis syndrome

Unspecified (inclcysts and polyps)

Blood and Not known

Lymphatic System Acquired haemophilia

Disorders

Immune System Rare Rare

Disorders Anaphylactic reaction^ Anaphylactic reaction^

Not known

Endocrine Common

Disorders Hyperthyroidism

Respiratory, Uncommon Rare

Thoracic and Pulmonary hypertension Pulmonary hypertension

Mediastinal

Disorders Not known

Interstitial pneumonitis

Gastrointestinal Not known

Disorders Pancreatitis, Gastrointestinalperforation (including diverticular,intestinal and large intestineperforations)^

Hepatobiliary Not known Not known

Disorders Acute hepatic failure^, Hepatitis toxic^, Acute hepatic failure^, Hepatitis

Cytolytic hepatitis^, Cholestatic toxic^hepatitis^, Mixed cytolytic/cholestatichepatitis^

Skin and Uncommon

Subcutaneous Angioedema

Tissue Disorders

Rare

Stevens-Johnson Syndrome^, Toxicepidermal necrolysis^

Not known

Leukocytoclastic vasculitis, Drug

Reaction with Eosinophilia and

Systemic Symptoms^^see section 4.8 description of selected adverse reactions

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic activesubstance that causes severe life-threatening birth defects. In monkeys, lenalidomide inducedmalformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide istaken 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 lenalidomidemaintenance

Lenalidomide maintenance after ASCT is associated with a higher frequency of Grade 4 neutropeniacompared to placebo maintenance (32.1% vs 26.7% [16.1% vs 1.8% after the start of maintenancetreatment] 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 wasreported at similar frequencies in the lenalidomide maintenance arms compared to placebomaintenance arms in both studies (0.4% vs 0.5% [0.4% vs 0.5% after the start of maintenancetreatment] in CALGB 100104 and 0.3% vs 0% in IFM 2005-02, respectively).

Lenalidomide maintenance after ASCT is associated with a higher frequency of Grade 3 or 4thrombocytopenia compared to placebo maintenance (37.5% vs 30.3% [17.9% vs 4.1% after the startof 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 lenalidomidein 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 similarfrequencies 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 Rdcomparator arm (17.2 % vs 9.4%).

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated withlenalidomide in combination with dexamethasone

The combination of lenalidomide with dexamethasone in newly diagnosed multiple myeloma patientsis 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 comparedwith 0.7% in MPT).

The combination of lenalidomide with dexamethasone in newly diagnosed multiple myeloma patientsis associated with a lower frequency of Grade 3 and 4 thrombocytopenia (8.1% in Rd and Rd18)compared with MPT (11.1%).

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated withlenalidomide in combination with melphalan and prednisone

The combination of lenalidomide with melphalan and prednisone in newly diagnosed multiplemyeloma 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 febrileneutropenia 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 multiplemyeloma 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 witha higher incidence of Grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patientscompared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodeswere 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 witha higher incidence of Grade 3 and Grade 4 thrombocytopenia (9.9% and 1.4%, respectively, inlenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients).

Myelodysplastic syndromes patients

In myelodysplastic syndromes patients, lenalidomide is associated with a higher incidence of

Grade 3 or 4 neutropenia (74.6% in lenalidomide-treated patients compared with 14.9% inpatients on placebo in the phase 3 study). Grade 3 or 4 febrile neutropenia episodes were observedin 2.2% of lenalidomide-treated patients compared with 0.0% in patients on placebo).

Lenalidomide is associated with a higher incidence of Grade 3 or 4 thrombocytopenia (37% inlenalidomide-treated patients compared with 1.5% in patients on placebo in the phase 3 study).

Mantle cell lymphoma patients

In mantle cell lymphoma patients, lenalidomide is associated with a higher incidence of Grade 3 or4 neutropenia (43.7% in lenalidomide-treated patients compared with 33.7% in patients in thecontrol arm in the phase 2 study). Grade 3 or 4 febrile neutropenia episodes were observed in 6.0%of lenalidomide-treated patients compared with 2.4% in patients on control arm.

Follicular lymphoma patients

The combination of lenalidomide with rituximab in follicular lymphoma is associated with ahigher rate of Grade 3 or Grade 4 neutropenia (50.7% in lenalidomide/rituximab treated patientscompared with 12.2% in placebo/rituximab treated patients). All Grade 3 or 4 neutropenia werereversible through dose interruption, reduction and/or supportive care with growth factors.

Additionally, febrile neutropenia was observed infrequently (2.7% in lenalidomide/rituximabtreated patients compared with 0.7% in placebo/rituximab treated patients).

Lenalidomide in combination with rituximab is also associated with a higher incidence of Grade 3or 4 thrombocytopenia (1.4% in lenalidomide/rituximab treated patients compared to 0% inplacebo/rituximab patients).

An increased risk of DVT and PE is associated with the use of the combination of lenalidomide withdexamethasone in patients with multiple myeloma, and to a lesser extent in patients treated withlenalidomide in combination with melphalan and prednisone or in patients with multiple myeloma,myelodysplastic syndromes and mantle cell lymphoma treated with lenalidomide monotherapy (seesection 4.5).

Concomitant administration of erythropoietic agents or previous history of DVT may also increasethrombotic risk in these patients.

Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those withknown risk factors.

Haemorrhagic disorders

Haemorrhagic disorders are listed under several system organ classes: Blood and lymphatic systemdisorders; nervous system disorders (intracranial haemorrhage); respiratory, thoracic and mediastinaldisorders (epistaxis); gastrointestinal disorders (gingival bleeding, haemorrhoidal haemorrhage, rectalhaemorrhage); renal and urinary disorders (haematuria); injury, poisoning and proceduralcomplications (contusion) and vascular disorders (ecchymosis).

Allergic reactions and severe skin reactions

Cases of allergic reactions including angioedema, anaphylactic reaction and severe cutaneous reactionsincluding SJS, TEN and DRESS have been reported with the use of lenalidomide. A possible cross-reaction between lenalidomide and thalidomide has been reported in the literature. Patients with ahistory of severe rash associated with thalidomide treatment should not receive lenalidomide (seesection 4.4).

Second primary malignancies

In clinical trials in previously treated myeloma patients with lenalidomide/dexamethasone compared tocontrols, mainly comprising of basal cell or squamous cell skin cancers.

Acute myeloid leukaemia

Cases of AML have been observed in clinical trials of newly diagnosed multiple myeloma in patientstaking 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 multiplemyeloma in patients taking lenalidomide in combination with dexamethasone compared to thalidomidein combination with melphalan and prednisone.

Myelodysplastic syndromes

Baseline variables including complex cytogenetics and TP53 mutation are associated withprogression to AML in subjects who are transfusion dependent and have a Del (5q) abnormality(see section 4.4). The estimated 2-year cumulative risk of progression to AML were 13.8% inpatients with an isolated Del (5q) abnormality compared to 17.3% for patients with Del (5q) andone additional cytogenetic abnormality and 38.6% in patients with a complex karyotype.

In a post-hoc analysis of a clinical trial of lenalidomide in myelodysplastic syndromes, theestimated 2-year rate of progression to AML was 27.5 % in patients with IHC-p53 positivity and3.6% in patients with IHC- p53 negativity (p=0.0038). In the patients with IHC-p53 positivity, alower rate of progression to AML was observed amongst patients who achieved a transfusionindependence (TI) response (11.1%) compared to a non-responder (34.8%).

Hepatic disorders

The following post-marketing adverse reactions have been reported (frequency unknown): acutehepatic failure and cholestasis (both potentially fatal), toxic hepatitis, cytolytic hepatitis, mixedcytolytic/cholestatic hepatitis.

Rare cases of rhabdomyolysis have been observed, some of them when lenalidomide is administeredwith a statin.

Thyroid disorders

Cases of hypothyroidism and cases of hyperthyroidism have been reported (see section 4.4 Thyroiddisorders).

Tumour flare reaction and tumour lysis syndrome

In study MCL-002, approximately 10% of lenalidomide-treated patients experienced TFRcompared to 0% in the control arm. The majority of the events occurred in cycle 1, all wereassessed as treatment-related, and the majority of the reports were Grade 1 or 2. Patients with high

MIPI at diagnosis or bulky disease (at least one lesion that is ≥ 7 cm in the longest diameter) atbaseline may be at risk of TFR. In study MCL-002, TLS was reported for one patient in each of thetwo treatment arms. In the supportive study MCL-001, approximately 10% of subjects experienced

TFR; all reports were Grade 1 or 2 in severity and all were assessed as treatment-related. Themajority of the events occurred in cycle 1. There were no reports of TLS in study MCL-001 (seesection 4.4).

In study NHL-007, TFR was reported in 19/146 (13.0%) of patients in the lenalidomide/rituximabarm versus 1/148 (0.7%) patients in the placebo/rituximab arm. Most TFRs (18 out of 19) reportedin the lenalidomide/rituximab arm occurred during first two cycles of treatment. One FL patient inthe lenalidomide/rituximab arm experienced a Grade 3 TFR event versus no patients in theplacebo/rituximab arm. In study NHL-008, 7/177 (4.0%) of FL patients experienced TFR; (3reports 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 andno FL patients in the placebo/rituximab arm; neither patient had a Grade 3 or 4 event. TLSoccurred 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 discontinuelenalidomide/rituximab therapy due to TFR or TLS.

Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinalperforations may lead to septic complications and may be associated with fatal outcome.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting system

Iliste; d in Appendix V.

There is no specific experience in the management of lenalidomide overdose in patients, although indose-ranging studies some patients were exposed to up to 150 mg, and in single-dose studies, somepatients were exposed to up to 400 mg. The dose limiting toxicity in these studies was essentiallyhaematological. In the event of overdose, supportive care is advised.

Pharmacotherapeutic group: Other immunosuppressants, ATC code: L04AX04.

Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzymecomplex 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 cereblonrecruits substrate proteins Aiolos and Ikaros, lymphoid transcriptional factors, leading to theirubiquitination and subsequent degradation resulting in direct cytotoxic and immunomodulatoryeffects.

Specifically, lenalidomide inhibits proliferation and enhances apoptosis of certain haematopoietictumour cells (including MM plasma tumour cells, follicular lymphoma tumour cells and those withdeletions of chromosome 5), enhances T cell- and Natural Killer (NK) cell-mediated immunity andincreases the number of NK, T and NK T cells. In MDS Del (5q), lenalidomide selectively inhibits theabnormal clone by increasing the apoptosis of Del (5q) cells.

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

The lenalidomide mechanism of action also includes additional activities such as anti-angiogenic andpro-erythropoietic properties. Lenalidomide inhibits angiogenesis by blocking the migration andadhesion of endothelial cells and the formation of microvessels, augments foetal haemoglobinproduction by CD34+ haematopoietic stem cells, and inhibits production of pro-inflammatorycytokines (e.g., TNF-α and IL-6) by monocytes.

Lenalidomide efficacy and safety have been evaluated in six phase 3 studies in newly diagnosedmultiple myeloma, two phase 3 studies in relapsed refractory multiple myeloma, one phase 3 study andone phase 2 study in myelodysplastic syndromes and one phase 2 study in mantle cell lymphoma andone phase 3 and one phase 3b study in iNHL, as described below.

Newly diagnosed multiple myeloma

Lenalidomide 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 IFM2005-02.

CALGB 100104

Patients between 18 and 70 years of age with active MM requiring treatment and without priorprogression after initial treatment were eligible.

Patients were randomised 1:1 within 90-100 days after ASCT to receive either lenalidomide or placebomaintenance. 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), andtreatment was continued until disease progression.

The primary efficacy endpoint in the study was progression free survival (PFS) from randomisation tothe date of progression or death, whichever occurred first; the study was not powered for the overallsurvival endpoint. In total 460 patients were randomised: 231 patients to lenalidomide and 229 patientsto 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 surpassingthe threshold for a preplanned interim analysis of PFS. After unblinding, patients in the placebo armwere 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 ordeath favouring lenalidomide (HR = 0.38; 95% CI 0.27, 0.54; p <0.001). The median overall PFS was33.9 months (95% CI NE, NE) in the lenalidomide arm versus 19.0 months (95% CI 16.2, 25.6) in theplacebo arm.

The PFS benefit was observed both in the subgroup of patients with CR and in the subgroup of patientswho had not achieved a CR.

The results for the study, using a cut-off of 1 February 2016, are presented in Table 7.

Table 7. Summary of overall efficacy data

Lenalidomide Placebo(N = 231) (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 unblindingwas not considered as a second-line therapy.f Median follow-up post-ASCT for all surviving subjects.

Data cuts: 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 stabledisease response at the time of hematologic recovery were eligible. Patients were randomised 1:1 toreceive either lenalidomide or placebo maintenance (10 mg once daily on days 1-28 of repeated 28-daycycles 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). Treatmentwas 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 614patients were randomised: 307 patients to lenalidomide and 307 patients to placebo.

The study was unblinded upon the recommendations of the data monitoring committee after surpassingthe threshold for a preplanned interim analysis of PFS. After unblinding, patients receiving placebowere not crossed over to lenalidomide therapy prior to progressive disease. The lenalidomide arm wasdiscontinued, 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 July2010 (31.4 months follow up) showed a 48% reduction in risk of disease progression or death favouringlenalidomide (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 placeboarm.

The PFS benefit was less in the subgroup of patients with CR than in the subgroup of patients who hadnot achieved a CR.

The updated PFS, using a cut-off of 1 February 2016 (96.7 months follow up) continues to show a PFSadvantage: 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 medianoverall 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 (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 forstem cell transplantation

The SWOG S0777 study evaluated the addition of bortezomib to a foundation of lenalidomide anddexamethasone, as initial treatment, followed by continued Rd until disease progression, in patientswith previously untreated multiple myeloma who are either ineligible for transplant or eligible fortransplant with no plan to undertake immediate transplant.

Patients in the lenalidomide, bortezomib and dexamethasone (RVd) arm received lenalidomide25 mg/day orally on days 1-14, intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, anddexamethasone 20 mg/day orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of repeated 21-day cycles for up toeight 21-day cycles (24 weeks). Patients in the lenalidomide and dexamethasone (Rd) arm receivedlenalidomide 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 28-day cycles (24 weeks). Patients in both arms tookcontinued Rd: lenalidomide 25 mg/day orally on days 1-21 and dexamethasone 40 mg/day orally ondays 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 patientswere 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 balancedbetween 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 ordeath favouring RVd (HR = 0.76; 95% CI 0.61, 0.94; p = 0.010). The median overall PFS was 42.5months (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 forall surviving subjects was 69.0 months, are presented in Table 8. The benefit favouring RVd wasobserved regardless of eligibility for stem cell transplant.

Table 8. Summary of overall efficacy data

Initial treatment

RVd Rd(3-week cycles x 8) (4-week cycles x 6)(N = 263) (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-valued 0.72 (0.56, 0.94); 0.013

Response - n (%)

Overall response: CR, VGPR, or PR 199 (75.7) 170 (65.4)≥ VGPR 153 (58.2) 83 (31.9)

Follow-up (months)

Mediane (min, max): all patients I 61.6 (0.2, 99.4) I 59.4 (0.4, 99.1)

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 Kaplan-Meier estimate.b Two-sided 95% CI about the median time.c Based on unstratified Cox proportional hazards model comparing hazard functions associated with treatment arms (RVd:Rd).d The p-value is based on unstratified log-rank test.e Median follow-up was calculated from the date of randomization.

Data cutoff date = 01 Dec 2016.

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

The safety and efficacy of lenalidomide was assessed in a phase 3, 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 65years of age, were not candidates for stem cell transplantation because they declined to undergo stemcell transplantation or stem cell transplantation is not available to the patient due to cost or otherreason. The study (MM-020) compared lenalidomide and dexamethasone (Rd) given for 2 differentdurations of time (i.e., until progressive disease [Arm Rd] or for up to eighteen 28-day cycles [72weeks, Arm Rd18]) to melphalan, prednisone and thalidomide (MPT) for a maximum of twelve 42-daycycles (72 weeks). Patients were randomised (1:1:1) to 1 of 3 treatment arms. Patients were stratified atrandomisation 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 cyclesaccording to protocol arm. Dexamethasone 40 mg was dosed once daily on days 1, 8, 15, and 22 ofeach 28-day cycle. Initial dose and regimen for Rd and Rd18 were adjusted according to age and renalfunction (see section 4.2). Patients >75 years received a dexamethasone dose of 20 mg once daily ondays 1, 8, 15, and 22 of each 28-day cycle. All patients received prophylactic anticoagulation (lowmolecular weight heparin, warfarin, heparin, low-dose aspirin) during the study.

The primary efficacy endpoint in the study was progression free survival (PFS). In total 1623 patientswere enrolled into the study, with 535 patients randomised to Rd, 541 patients randomised to Rd18 and547 patients randomised to MPT. The demographics and disease-related baseline characteristics of thepatients were well balanced in all 3 arms. In general, study subjects had advanced-stage disease: of thetotal 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 9.

Table 9. Summary of overall efficacy data

Rd Rd18 MPT(N = 535) (N = 541) (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

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-offdate = 24 May 2013).

h data cut 24 May 2013

Lenalidomide in combination with melphalan and prednisone followed by maintenance therapy inpatients who are not eligible for transplant

The safety and efficacy of lenalidomide was assessed in a phase 3 multicentre, randomised doubleblind 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 andprednisone for a maximum of 9 cycles. Patients were randomised in a 1:1:1 ratio to one of 3 treatmentarms. 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 days1 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, upto 9 cycles. Patients who completed 9 cycles or who were unable to complete 9 cycles due tointolerance proceeded to maintenance therapy starting with lenalidomide 10 mg orally on days 1 to 21of repeated 28-day cycles until disease progression.

The primary efficacy endpoint in the study was progression free survival (PFS). In total 459 patientswere 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 baselinecharacteristics of the patients were well balanced in all 3 arms; notably, approximately 50% of thepatients 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 allsurviving subjects was 62.4 months, the results of the study are presented in Table 10.

Table 10. Summary of overall efficacy data

MPR+R MPR+p MPp +p(N = 152) (N = 153) (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 responsen (%)

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 ofresponse (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 3 study (ECOG E4A03) was conducted in 445 patientswith newly diagnosed multiple myeloma; 222 patients were randomised to the lenalidomide/low dosedexamethasone arm, and 223 were randomised to the lenalidomide/standard dose dexamethasone arm.

Patients randomised to the lenalidomide/standard dose dexamethasone arm received lenalidomide25 mg/day, days 1 to 21 every 28 days plus dexamethasone 40 mg/day on days 1 to 4, 9 to 12, and 17to 20 every 28 days for the first four cycles. Patients randomised to the lenalidomide/low dosedexamethasone arm received lenalidomide 25 mg/day, days 1 to 21 every 28 days plus low dosedexamethasone - 40 mg/day on days 1, 8, 15, and 22 every 28 days. In the lenalidomide/low dosedexamethasone group, 20 patients (9.1%) underwent at least one dose interruption compared to 65patients (29.3%) in the lenalidomide/standard dose dexamethasone arm.

In a post-hoc analysis, lower mortality was observed in the lenalidomide/low dose dexamethasone arm6.8% (15/220) compared to the lenalidomide/standard dose dexamethasone arm 19.3% (43/223), in thenewly 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/ lowdose dexamethasone tends to decrease.

Multiple myeloma with at least one prior therapy

The efficacy and safety of lenalidomide were evaluated in two phase 3 multicentre, randomised,double-blind, placebo-controlled, parallel-group controlled studies (MM-009 and MM-010) oflenalidomide plus dexamethasone therapy versus dexamethasone alone in previously treated patientswith multiple myeloma. Out of 353 patients in the MM-009 and MM-010 studies who receivedlenalidomide/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 oflenalidomide orally once daily on days 1 to 21 and a matching placebo capsule once daily on days 22to 28 of each 28-day cycle. Patients in the placebo/dexamethasone (placebo/dex) group took 1 placebocapsule on days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg ofdexamethasone orally once daily on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first4 cycles of therapy. The dose of dexamethasone was reduced to 40 mg orally once daily on days 1 to 4of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue untildisease progression. In both studies, dose adjustments were allowed based on clinical and laboratoryfinding.

The primary efficacy endpoint in both studies was time to progression (TTP). In total, 353 patientswere 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 theplacebo/dex group.

In both studies, the baseline demographic and disease-related characteristics were comparable betweenthe len/dex and placebo/dex groups. Both patient populations presented a median age of 63 years, witha comparable male to female ratio. The ECOG performance status was comparable between bothgroups, as was the number and type of prior therapies.

Pre-planned interim analyses of both studies showed that len/dex was statistically significantlysuperior (p < 0.00001) to dexamethasone alone for the primary efficacy endpoint, TTP (medianfollow-up duration of 98.0 weeks). Complete response and overall response rates in the len/dex armwere also significantly higher than the placebo/dex arm in both studies. Results of these analysessubsequently led to an unblinding in both studies, in order to allow patients in the placebo/dex group toreceive treatment with the len/dex combination.

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

Table 11 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) inpatients treated with len/dex (N = 353) versus 20.1 weeks (95% CI: 17.7, 20.3) in patients treated withplacebo/dex (N = 351). The median progression free survival was 48.1 weeks (95% CI: 36.4, 62.1) inpatients treated with len/dex versus 20.0 weeks (95% CI: 16.1, 20.1) in patients treated withplacebo/dex. The median duration of treatment was 44.0 weeks (min: 0.1, max: 254.9) for len/dex and23.1 weeks (min: 0.3, max: 238.1) for placebo/dex. Complete response (CR), partial response (PR) andoverall response (CR+PR) rates in the len/dex arm remain significantly higher than in the placebo/dexarm in both studies. The median overall survival in the extended follow-up analysis of the pooledstudies 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 patientsrandomised to placebo/dex received lenalidomide after disease progression or after the studies wereunblinded, the pooled analysis of overall survival demonstrated a statistically significant survivaladvantage for len/dex relative to placebo/dex (HR = 0.833, 95% CI = [0.687, 1.009], p=0.045).

Table 11. 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 placebo/dex(N=353) (N=351)

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

Time to progression 60.1 [44.3, 20.1 [17.7, 20.3] 0.350 [0.287, 0.426], p < 0.001

Median [95% CI], weeks 73.1]

Progression free survival 48.1 20.0 [16.1, 20.1] 0.393 [0.326, 0.473], p < 0.001

Median [95% CI], weeks [36.4, 62.1]

Overall survival 164.3 136.4 [113.1, 161.7] 0.833 [0.687, 1.009], p = 0.045

Median [95% CI], weeks [145.1,192.6] 75%1-year Overall survival rate 82%

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

Overall response [n, %] 212 (60.1) 75 (21.4) 5.53 [3.97, 7.71], p < 0.001

Complete response [n, %] 58 (16.4) 11 (3.1) 6.08 [3.13, 11.80], p < 0.001a Two-tailed log rank test comparing survival curves between treatment groups.b Two-tailed continuity-corrected chi-square test.

Myelodysplastic syndromes

The efficacy and safety of lenalidomide were evaluated in patients with transfusion-dependentanaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion5q cytogenetic abnormality, with or without additional cytogenetic abnormalities, in two mainstudies: a phase 3, multicentre, randomised, double-blind, placebo-controlled, 3-arm study of twodoses of oral lenalidomide (10 mg and 5 mg) versus placebo (MDS-004); and a phase 2, amulticentre, single-arm, open-label study of lenalidomide (10 mg) (MDS-003).

The results presented below represent the intent-to-treat population studied in MDS-003 and MDS-004; with the results in the isolated Del (5q) sub-population also shown separately.

In study MDS-004, in which 205 patients were equally randomised to receive lenalidomide 10 mg,5 mg or placebo, the primary efficacy analysis consisted of a comparison of the transfusion-independence response rates of the 10 mg and 5 mg lenalidomide arms versus the placebo arm(double-blind phase 16 to 52 weeks and open-label up to a total of 156 weeks). Patients who didnot have evidence of at least a minor erythroid response after 16 weeks were to be discontinuedfrom treatment. Patients who had evidence of at least a minor erythroid response could continuetherapy until erythroid relapse, disease progression or unacceptable toxicity. Patients, who initiallyreceived placebo or 5 mg lenalidomide and did not achieve at least a minor erythroid response after16 weeks of treatment were permitted to switch from placebo to 5 mg lenalidomide or continuelenalidomide treatment at higher dose (5 mg to 10 mg).

In, study MDS-003, in which 148 patients received lenalidomide at a dose of 10 mg, theprimary efficacy analysis consisted of an evaluation of the efficacy of lenalidomide treatmentsto achieve haematopoietic improvement in subjects with low- or intermediate-1 riskmyelodysplastic syndromes.

Table 12. Summary of efficacy results - studies MDS-004 (double-blind phase) and MDS-003, intent- to-treat population

Endpoint MDS-004 MDS-003

N = 205 N = 14810 mg† 5 mg†† Placebo* 10 mg

N = 69 N = 69 N = 67 N = 148

Transfusion Independence 38 (55.1%) 24 (34.8%) 4 (6.0%) 86 (58.1%)(≥ 182 days) #

Transfusion Independence 42 (60.9%) 33 (47.8%) 5 (7.5%) 97 (65.5%)(≥ 56 days) #

Median Time to Transfusion 4.6 4.1 0.3 4.1

Independence (weeks)

Median Duration of NR∞ NR NR 114.4

Transfusion

Independence (weeks)

Median Increase in Hgb, g/dL 6.4 5.3 2.6 5.6† Subjects treated with lenalidomide 10 mg on 21 days of 28-day cycles†† Subjects treated with lenalidomide 5 mg on 28 days of 28-day cycles

* The majority of patients on placebo discontinued the double-blind treatment for lack of efficacy after 16 weeks of treatmentbefore entering the open-label phase#Associated with an increase in Hgb of ≥ 1g/dL∞ Not reached (i.e. the median was not reached)

In MDS-004, a significant larger proportion of patients with myelodysplastic syndromes achieved theprimary endpoint of transfusion independence (>182 days) on lenalidomide 10 mg compared withplacebo (55.1% vs. 6.0%). Amongst the 47 patients with an isolated Del (5q) cytogenetic abnormalityand treated with lenalidomide 10 mg, 27 patients (57.4%) achieved red blood cell transfusionindependence.

The median time to transfusion independence in the lenalidomide 10 mg arm was 4.6 weeks. Themedian duration of transfusion independence was not reached in any of the treatment arms but shouldexceed 2 years for the lenalidomide-treated subjects. The median increase in haemoglobin (Hgb) frombaseline in the 10 mg arm was 6.4 g/dL.

Additional endpoints of the study included cytogenetic response (in the 10 mg arm major and minorcytogenetic responses were observed in 30.0% and 24.0% of subjects, respectively), assessment of

Health Related Quality of Life (HRQoL) and progression to acute myeloid leukaemia. Results of thecytogenetic response and HRQoL were consistent with the findings of the primary endpoint and infavour of lenalidomide treatment compared to placebo.

In MDS-003, a large proportion of patients with myelodysplastic syndromes achieved transfusionindependence (>182 days) on lenalidomide 10 mg (58.1%). The median time to transfusionindependence was 4.1 weeks. The median duration of transfusion independence was 114.4 weeks. Themedian increase in haemoglobin (Hgb) was 5.6 g/dL. Major and minor cytogenetic responses wereobserved in 40.9% and 30.7% of subjects, respectively.

A large proportion of subjects enrolled in MDS-003 (72.9%) and MDS-004 (52.7%) had receivedprior erythropoiesis-stimulating agents.

The efficacy and safety of lenalidomide were evaluated in patients with mantle cell lymphoma in aphase 2, multicentre, randomised open-label study versus single agent of investigator’s choice inpatients who were refractory to their last regimen or had relapsed one to three times (study MCL-002).

Patients who were at least 18 years of age with histologically-proven MCL and CT-measurable diseasewere enrolled. Patients were required to have received adequate previous treatment with at least oneprior combination chemotherapy regimen. Also, patients had to be ineligible for intensivechemotherapy and/or transplant at time of inclusion in the study. Patients were randomised 2:1 to thelenalidomide or the control arm. The investigator’s choice treatment was selected beforerandomisation and consisted of monotherapy with either chlorambucil, cytarabine, rituximab,fludarabine, or gemcitabine.

Lenalidomide was administered orally 25 mg once daily for the first 21 days (D1 to D21) of repeating28-day cycles until progression or unacceptable toxicity. Patients with moderate renal insufficiencywere to receive a lower starting dose of lenalidomide 10 mg daily on the same schedule.

The baseline demographic were comparable between the lenalidomide arm and control arm. Bothpatient populations presented a median age of 68.5 years with comparable male to female ratio. The

ECOG performance status was comparable between both groups, as was the number of prior therapies.

The primary efficacy endpoint in study MCL-002 was progression-free survival (PFS).

The efficacy results for the Intent-to-Treat (ITT) population were assessed by the Independent Review

Committee (IRC), and are presented in the Table 13 below.

Table 13. Summary of efficacy results - study MCL-002, intent-to-treat population

Lenalidomide Arm Control Arm

N = 170 N = 84

PFS

PFS, mediana [95% CI]b (weeks) 37.6 [24.0, 52.6] 22.7 [15.9, 30.1]

Sequential HR [95% CI]e 0.61 [0.44, 0.84]

Sequential log-rank test, p-valuee 0.004

Responsea, n (%)

Complete response (CR) 8 (4.7) 0 (0.0)

Partial response (PR) 60 (35.3) 9 (10.7)

Stable disease (SD)b 50 (29.4) 44 (52.4)

Progressive disease (PD) 34 (20.0) 26 (31.0)

Not done/Missing 18 (10.6) 5 (6.0)

ORR (CR, CRu, PR), n (%) [95% CI]c 68 (40.0) [32.58, 47.78] 9 (10.7)d [5.02, 19.37]p-valuee < 0.001

CRR (CR, CRu), n (%) [95% CI]c 8 (4.7) [2.05, 9.06] 0 (0.0) [95.70, 100.00]p-valuee 0.043

Duration of Response, mediana [95% CI] (weeks) 69.6 [41.1, 86.7] 45.1 [36.3, 80.9]

Overall Survival

HR [95% CI]c 0.89 [0.62, 1.28]

Log-rank test, p-value 0.520

CI = confidence interval; CRR = complete response rate; CR = complete response; CRu = complete response unconfirmed; DMC =

Data Monitoring Committee; ITT = intent-to-treat; HR = hazard ratio; KM = Kaplan-Meier; MIPI = Mantle Cell Lymphoma

International Prognostic Index; NA = not applicable; ORR = overall response rate; PD = progressive disease; PFS = progression-freesurvival; PR= partial response; SCT = stem cell transplantation; SD = stable disease; SE = standard error.a The median was based on the KM estimate.b Range was calculated as 95% CIs about the median survival time.c The mean and median are the univariate statistics without adjusting for censoring.d The stratification variables included time from diagnosis to first dose (< 3 years and ≥ 3 years), time from last prior systemic anti-lymphoma therapy to first dose (< 6 months and ≥ 6 months), prior SCT (yes or no), and MIPI at baseline (low, intermediate, and highrisk).e Sequential test was based on a weighted mean of a log-rank test statistic using the unstratified log-rank test for sample size increase andthe unstratified log-rank test of the primary analysis. The weights are based on observed events at the time the third DMC meeting washeld and based on the difference between observed and expected events at the time of the primary analysis. The associated sequential HRand the corresponding 95% CI are presented.

In study MCL-002 in the ITT population, there was an overall apparent increase in deaths within 20weeks in the lenalidomide arm 22/170 (13%) versus 6/84 (7%) in the control arm. In patients withhigh tumour burden, corresponding figures were 16/81 (20%) and 2/28 (7%) (see section 4.4).

AUGMENT - CC-5013-NHL-007

The efficacy and safety of lenalidomide in combination with rituximab versus rituximab plusplacebo 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 investigatoror local pathologist were randomised in a 1:1 ratio. Subjects had been previously treated with atleast one prior systemic chemotherapy, immunotherapy or chemoimmunotherapy.

Lenalidomide was administered orally 20 mg once daily for the first 21 days of repeating 28-daycycles for 12 cycles or until unacceptable toxicity. The dose of rituximab was 375 mg/m2 everyweek 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), usingactual patient weight.

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

The primary objective of the study was to compare the efficacy of lenalidomide in combinationwith 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 IRCusing the 2007 International Working Group (IWG) criteria but without positron emissiontomography (PET).

The secondary objectives of the study were to compare the safety of lenalidomide in combinationwith rituximab versus rituximab plus placebo. Further secondary objectives were to compare theefficacy of rituximab plus lenalidomide versus rituximab plus placebo using the following otherparameters 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 of28.3°months, the study met its primary endpoint of PFS with a hazard ratio (HR) (95% confidenceinterval [CI]) of 0.45 (0.33,0.61) p-value < 0.0001. The efficacy results from the follicularlymphoma population are presented in Table 14.

Table 14: Summary of follicular lymphoma efficacy data- Study CC-5013-NHL-007

FL(N = 295)

Lenalidomide and Rituximab Placebo and Rituximab(N = 147) (N = 148)

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

Median PFS a (95% CI) (months) 39.4 13.8(25.1, NE) (11.2, 16.0)

HR [95% CI] 0.40 (0.29, 0.55)bp-value < 0.0001c

Objective responsed (CR +PR), n 118 (80.3) 82 (55.4)(%) (72.9, 86.4) (47.0, 63.6)(IRC, 2007

IWGRC)95 % CIf

Complete responsed, n (%) 51 (34.7) 29 (19.6)(IRC, 2007 (27.0, 43.0) (13.5, 26.9)

IWGRC)95 % CIf

Duration of responsed (median) 36.6 15.5(months) (24.9, NE) (11.2, 25.0)95% CI a

Overall Survivald,e (OS)

OS rate at 5 years, n (%) 126 (85.9) 114 (77.0)95% CI (78.6, 90.9) (68.9, 83.3)

HR [95% CI] 0.49 (0.28, 0.85)b

Follow-up

Median duration of follow-up 67.81 65.72(min, max) (months) (0.5, 89.3) (0.6, 90.9)ª Median estimate from Kaplan-Meier analysisb Hazard ratio and its confidence interval were estimated from unstratified Cox proportional hazard model.c P-value from log-rank testd Secondary and exploratory endpoints are not α-controllede With a median follow up of 66.14 months, there were 19 deaths in the R2 arm and 38 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 treatmentperiod with 12 cycles of lenalidomide plus rituximab. Subjects who achieved CR/CRu, PR, or SD bythe 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 antilymphomatherapy. In contrast to study NHL-007, the NHL-008 study included patients who were refractory torituximab (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 diseaseprogression. The dose of rituximab was 375 mg/m2 every week in Cycle 1 (Days 1, 8, 15, and 22) andon Day 1 of every other 28-day cycle (cycles 3, 5, 7, 9, and 11) up to 12 cycles therapy. All dosagecalculations 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 treatmentperiod. Efficacy determinations are based on ORR by best response as the primary endpoint, using amodification of the 1999 International Working Group Response Criteria (IWGRC). The secondaryobjective was to evaluate other parameters of efficacy, such as DoR.

Table 15: Summary of overall efficacy data (Induction Treatment Period) - Study CC-5013-

NHL-008

All Subjects FL Subjects

Total Rituximab Rituximab Total Rituxima Rituximab

N=187 a Refractory: Refractory N=148 b Refractory

Yes : No Refractor : No

N=77 N=110 y: Yes N=88

N=60

ORR, n (%) 127 45 (58.4) 82 (75.2) 104 35 (58.3) 69 (79.3)(CR+CRu+PR) (67.9) (70.3)

CRR, n (%) 79 (42.2) 27 (35.1) 52 (47.7) 62 (41.9) 20 (33.3) 42 (48.3)(CR+Cru)

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

Responders% of Subjects with 93.0 90.4 94.5 94.3 96.0 93.5

DoR b (85.1, 96.8) (73.0, 96.8) (83.9, 98.2) (85.5, 97.9) (74.8, 99.4) (81.0, 97.9)≥ 6 months (95%

CI) c% of Subjects with 79.1 73.3 82.4 79.5 73.9 81.7

DoR b (67.4, 87.0) (51.2, 86.6) (67.5, 90.9) (65.5, 88.3) (43.0, 89.8) (64.8, 91.0)≥ 12 months (95%

CI) c

CI = confidence interval; DOR = duration of response; FL = follicular lymphomaa 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,whicheveroccurs 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 toany

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

The European Medicines Agency (EMA) has granted a product-specific waiver for the referencemedicinal product containing lenalidomide that applies to all subsets of the paediatric population formature B-cell neoplasm conditions (see section 4.2 for information on paediatric use).

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

Lenalidomide is rapidly absorbed following oral administration in healthy volunteers, under fastingconditions, with maximum plasma concentrations occurring between 0.5 and 2 hours post-dose. Inpatients, 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 doesnot 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 ofabsorption, resulting in an approximately 20% decrease in area under the concentration versus timecurve (AUC) and 50% decrease in Cmax in plasma. However, in the main multiple myeloma andmyelodysplastic syndromes registration trials where the efficacy and safety were established forlenalidomide, the medicinal product was administered without regard to food intake. Thus,lenalidomide can be administered with or without food.

Population pharmacokinetic analyses indicate that the oral absorption rate of lenalidomide is similaramong MM, MDS and MCL patients.

In vitro (14C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at23% 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 andthe medicinal product is undetectable in semen of a healthy subject 3 days after stopping the substance(see section 4.4).

Results from human in vitro metabolism studies indicate that lenalidomide is not metabolised bycytochrome P450 enzymes suggesting that administration of lenalidomide with medicinal products thatinhibit cytochrome P450 enzymes is not likely to result in metabolic medicinal product interactions inhumans. 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 anyclinically relevant medicinal product interactions when co-administered with substrates of theseenzymes.

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 aniontransporters (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 excretionto total clearance in subjects with normal renal function was 90%, with 4% of lenalidomide eliminatedin 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 leastactively secreted to some extent.

At doses of 5 to 25 mg/day, half-life in plasma is approximately 3 hours in healthy volunteers andranges from 3 to 5 hours in patients with multiple myeloma, myelodysplastic syndromes or mantle celllymphoma.

No dedicated clinical studies have been conducted to evaluate pharmacokinetics of lenalidomide in theelderly. Population pharmacokinetic analyses included patients with ages ranging from 39 to 85 yearsold and indicate that age does not influence lenalidomide clearance (exposure in plasma). Becauseelderly patients are more likely to have decreased renal function, care should be taken in dose selectionand it would be prudent to monitor renal function.

The pharmacokinetics of lenalidomide was studied in subjects with renal impairment due tononmalignant conditions. In this study, two methods were used to classify renal function: the urinarycreatinine 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 totallenalidomide clearance decreases proportionally resulting in an increase in AUC. The AUC wasincreased by approximately 2.5, 4 and 5-fold in subjects with moderate renal impairment, severe renalimpairment, and end-stage renal disease, respectively, compared to the group combining subjects withnormal renal function and subjects with mild renal impairment. The half-life of lenalidomide increasedfrom approximately 3.5 hours in subjects with creatinine clearance > 50 mL/min to more than 9 hoursin subjects with reduced renal function < 50 mL/min. However, renal impairment did not alter the oralabsorption of lenalidomide. The Cmax was similar between healthy subjects and patients with renalimpairment. 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 aredescribed in section 4.2.

Population pharmacokinetic analyses included patients with mild hepatic impairment (N=16, totalbilirubin >1 to ≤1.5 x ULN or AST > ULN) and indicate that mild hepatic impairment does notinfluence lenalidomide clearance (exposure in plasma). There are no data available for patients withmoderate to severe hepatic impairment.

Other intrinsic factors

Population pharmacokinetic analyses indicate that body weight (33- 135 kg), gender, race and type ofhaematological malignancy (MM, MDS or MCL) do not have a clinically relevant effect onlenalidomide clearance in adult patients.

An embryofoetal development study has been conducted in monkeys administered lenalidomide atdoses from 0.5 and up to 4 mg/kg/day. Findings from this study indicate that lenalidomide producedexternal 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/orpolydactyly) 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 upto 26 weeks produced a reversible treatment-related increase in kidney pelvis mineralisation in all 3doses, most notably in females. The no observed adverse effect level (NOAEL) was considered to beless 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 weeksproduced mortality and significant toxicity (marked weight loss, reduced red and white blood cell andplatelet counts, multiple organ haemorrhage, gastrointestinal tract inflammation, lymphoid, and bonemarrow atrophy). Repeated oral administration of 1 and 2 mg/kg/day to monkeys for up to 1 yearproduced reversible changes in bone marrow cellularity, a slight decrease in myeloid/erythroid cellratio and thymic atrophy. Mild suppression of white blood cell count was observed at 1 mg/kg/daycorresponding to approximately the same human dose based on AUC comparisons.

In vitro (bacterial mutation, human lymphocytes, mouse lymphoma, Syrian Hamster Embryo celltransformation) and in vivo (rat micronucleus) mutagenicity studies revealed no drug related effects ateither the gene or chromosomal level. Carcinogenicity studies with lenalidomide have not beenconducted.

Developmental toxicity studies were previously conducted in rabbits. In these studies, rabbits wereadministered 3, 10 and 20 mg/kg/day orally. An absence of the intermediate lobe of the lung wasobserved at 10 and 20 mg/kg/day with dose dependence and displaced kidneys were observed at 20mg/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.

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Lenalidomide Krka 2.5 mg hard capsules

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3 years

This medicinal product does not require any special storage conditions.

Peel open, unit dose blister (OPA/Al/PVC//PET/Al), calendar pack: 7 x 1 or 21 x 1 hard capsule, in abox.

Not all pack sizes may be marketed.

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

Healthcare professionals and caregivers should wear disposable gloves when handling the blister orcapsule. Gloves should then be removed carefully to prevent skin exposure, placed in a sealable plasticpolyethylene bag and disposed of in accordance with local requirements. Hands should then be washedthoroughly with soap and water. Women who are pregnant or suspect they may be pregnant should nothandle the blister or capsule (see section 4.4).

Any unused product or waste material should be returned to the pharmacist for safe disposal inaccordance with local requirements.

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Lenalidomide Krka 2.5 mg hard capsules7 x 1 hard capsule: EU/1/20/1519/00121 x 1 hard capsule: EU/1/20/1519/002

Lenalidomide Krka 5 mg hard capsules7 x 1 hard capsule: EU/1/20/1519/00321 x 1 hard capsule: EU/1/20/1519/004

Lenalidomide Krka 7.5 mg hard capsules7 x 1 hard capsule: EU/1/20/1519/00521 x 1 hard capsule: EU/1/20/1519/006

Lenalidomide Krka 10 mg hard capsules7 x 1 hard capsule: EU/1/20/1519/00721 x 1 hard capsule: EU/1/20/1519/008

Lenalidomide Krka 15 mg hard capsules7 x 1 hard capsule: EU/1/20/1519/00921 x 1 hard capsule: EU/1/20/1519/010

Lenalidomide Krka 20 mg hard capsules7 x 1 hard capsule: EU/1/20/1519/01121 x 1 hard capsule: EU/1/20/1519/012

Lenalidomide Krka 25 mg hard capsules7 x 1 hard capsule: EU/1/20/1519/01321 x 1 hard capsule: EU/1/20/1519/014

Date of first authorisation: 11 February 2021

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

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