4.1. Therapeutic indications

Multiple myeloma

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

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

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

Myelodysplastic syndromes

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

Mantle cell lymphoma

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

Follicular lymphoma

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

4.2. Posology and method of administration

Lenalidomide treatment should be supervised by a physician experienced in the use of anti-cancer therapies. For all indications described below: - Dose is modified based upon clinical and laboratory findings (see section 4.4). - Dose adjustments, during treatment and restart of treatment, are recommended to manage Grade 3 or 4 thrombocytopenia, neutropenia, or other Grade 3 or 4 toxicity judged to be related to lenalidomide. - In case of neutropenia, the use of growth factors in patient management should be considered. - If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next dose at the normal time on the following day. Posology Newly diagnosed multiple myeloma (NDMM) • Lenalidomide in combination with dexamethasone until disease progression in patients who are not eligible for transplant Lenalidomide treatment must not be started if the Absolute Neutrophil Count (ANC) is < 1.0 x 10 9 /L, and/or platelet counts are < 50 x 10 9 /L. Recommended dose The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1, 8, 15 and 22 of repeated 28-day cycles. Patients may continue lenalidomide and dexamethasone therapy until disease progression or intolerance. - Dose reduction steps Lenalidomide a Dexamethasone a Starting dose 25 mg 40 mg Dose level -1 20 mg 20 mg Dose level -2 15 mg 12 mg Dose level -3 10 mg 8 mg Dose level -4 5 mg 4 mg Dose level -5 2.5 mg Not applicable a Dose reduction for both products can be managed independently - Thrombocytopenia When platelets Recommended course Falls to < 25 x 10 9 /L Returns to ≥ 50 x 10 9 /L Stop lenalidomide dosing for remainder of cycle a Decrease by one dose level when dosing resumed at next cycle a If Dose limiting toxicity (DLT) occurs on > day 15 of a cycle, lenalidomide dosing will be interrupted for at least the remainder of the current 28- day cycle. - Absolute neutrophil count (ANC) - neutropenia When ANC Recommended course a First falls to < 0.5 x 10 9 /L Returns to ≥ 1 x 10 9 /L when neutropenia is the only observed toxicity Interrupt lenalidomide treatment Resume lenalidomide at starting dose once daily Returns to ≥ 0.5 x 10 9 /L when dose-dependent haematological toxicities other than neutropenia are observed Resume lenalidomide at dose level -1 once daily For each subsequent drop below < 0.5 x 10 9 /L Returns to ≥ 0.5 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at next lower dose level once daily a At the physician's discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide. For hematologic toxicity the dose of lenalidomide may be re-introduced to the next higher dose level (up to the starting dose) upon improvement in bone marrow function (no hematologic toxicity for at least 2 consecutive cycles: ANC ≥ 1.5 x 10 9 /L with a platelet count ≥ 100 x 10 9 /L at the beginning of a new cycle). • Lenalidomide in combination with bortezomib and dexamethasone followed by lenalidomide and dexamethasone until disease progression in patients who are not eligible for transplant Initial treatment: Lenalidomide in combination with bortezomib and dexamethasone Lenalidomide in combination with bortezomib and dexamethasone must not be started if the ANC is < 1.0 x 10 9 /L, and/or platelet counts are < 50 x 10 9 /L. The recommended starting dose is lenalidomide 25 mg orally once daily days 1-14 of each 21-day cycle in combination with bortezomib and dexamethasone. Bortezomib should be administered via subcutaneous injection (1.3 mg/m 2 body surface area) twice weekly on days 1, 4, 8 and 11 of each 21-day. For additional information on the dose, schedule and dose adjustments of medicinal products administered with lenalidomide, see section 5.1 and the corresponding Summary of Product Characteristics. Up to eight 21-day treatment cycles (24 weeks of initial treatment) are recommended. Continued treatment: Lenalidomide in combination with dexamethasone until progression Continue lenalidomide 25 mg orally once daily on days 1-21 of repeated 28-day cycles in combination with dexamethasone. Treatment should be continued until disease progression or unacceptable toxicity. - Dose reduction steps Lenalidomide a Starting dose 25 mg Dose level -1 20 mg Dose level -2 15 mg Dose level -3 10 mg Dose level- 4 5 mg Dose level -5 2.5 mg ª Dose reduction for all products can be managed independently - Thrombocytopenia When platelets Recommended course Falls to < 30 x 10 9 /L Interrupt lenalidomide treatment Returns to ≥ 50 x 10 9 /L Resume lenalidomide at dose level -1 once daily For each subsequent drop below 30 x 10 9 /L Interrupt lenalidomide treatment Returns to ≥ 50 x 10 9 /L Resume lenalidomide at next lower dose level once daily - Absolute neutrophil count (ANC) - neutropenia When ANC Recommended course a First falls to < 0.5 x 10 9 /L Interrupt lenalidomide treatment Returns to ≥ 1 x 10 9 /L when neutropenia is the only observed toxicity Resume lenalidomide at starting dose once daily Returns to ≥ 0.5 x 10 9 /L when dose-dependent haematological toxicities other than neutropenia are observed Resume lenalidomide at dose level -1 once daily For each subsequent drop below < 0.5 x 10 9 /L Interrupt lenalidomide treatment Returns to ≥ 0.5 x 10 9 /L Resume lenalidomide at next lower dose level once daily. a At the physician's discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide. • Lenalidomide in combination with melphalan and prednisone followed by lenalidomide maintenance in patients who are not eligible for transplant Lenalidomide treatment must not be started if the ANC is < 1.5 x 10 9 /L, and/or platelet counts are < 75 x 10 9 /L. Recommended dose The recommended starting dose is lenalidomide 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles for up to 9 cycles, melphalan 0.18 mg/kg orally on days 1 to 4 of repeated 28-day cycles, prednisone 2 mg/kg orally on days 1 to 4 of repeated 28-day cycles. Patients who complete 9 cycles or who are unable to complete the combination therapy due to intolerance are treated with lenalidomide monotherapy as follows: 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles given until disease progression. - Dose reduction steps Lenalidomide Melphalan Prednisone Starting dose 10 mgª 0.18 mg/kg 2 mg/kg Dose level -1 7.5 mg 0.14 mg/kg 1 mg/kg Dose level -2 5 mg 0.10 mg/kg 0.5 mg/kg Dose level -3 2.5 mg Not applicable 0.25 mg/kg a If neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide - Thrombocytopenia When platelets Recommended course First falls to < 25 x 10 9 /L Returns to ≥ 25 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide and melphalan at dose level -1 For each subsequent drop below 30 x 10 9 /L Returns to ≥ 30 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at next lower dose level (dose level -2 or -3) once daily - Absolute neutrophil count (ANC) - neutropenia When ANC Recommended course a First falls to < 0.5 x 10 9 /L Returns to ≥ 0.5 x 10 9 /L when neutropenia is the only observed toxicity Interrupt lenalidomide treatment Resume lenalidomide at starting dose once daily Returns to ≥ 0.5 x 10 9 /L when dose-dependent haematological toxicities other than neutropenia are observed Resume lenalidomide at dose level -1 once daily For each subsequent drop below < 0.5 x 10 9 /L Returns to ≥ 0.5 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at next lower dose level once daily. a At the physician's discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide. • Lenalidomide maintenance in patients who have undergone autologous stem cell transplantation (ASCT) Lenalidomide maintenance should be initiated after adequate haematologic recovery following ASCT in patients without evidence of progression. Lenalidomide must not be started if the ANC is < 1.0 x 10 9 /L, and/or platelet counts are < 75 x 10 9 /L. Recommended dose The recommended starting dose is lenalidomide 10 mg orally once daily continuously (on days 1 to 28 of repeated 28-day cycles) given until disease progression or intolerance. After 3 cycles of lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated. - Dose reduction steps Starting dose (10 mg) If dose increased (15 mg) a Dose level -1 5 mg 10 mg Dose level -2 5 mg (days 1-21 every 28 days) 5 mg Dose level -3 Not applicable 5 mg (days 1-21 every 28 days) Do not dose below 5 mg (days 1-21 every 28 days) a After 3 cycles of lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated. - Thrombocytopenia When platelets Recommended course Falls to < 30 x 10 9 /L Returns to ≥ 30 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at dose level -1 once daily For each subsequent drop below 30 x 10 9 /L Returns to ≥ 30 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at next lower dose level once daily - Absolute neutrophil count (ANC) - neutropenia When ANC Recommended course a Falls to < 0.5 x 10 9 /L Returns to ≥ 0.5 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at dose level -1 once daily For each subsequent drop below < 0.5 x 10 9 /L Returns to ≥ 0.5 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at next lower dose level once daily a At the physician's discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide. Multiple myeloma with at least one prior therapy Lenalidomide treatment must not be started if the ANC < 1.0 x 10 9 /L, and/or platelet counts < 75 x 10 9 /L or, dependent on bone marrow infiltration by plasma cells, platelet counts < 30 x 10 9 /L. Recommended dose The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily on days 1 to 4 every 28 days. Prescribing physicians should carefully evaluate which dose of dexamethasone to use, taking into account the condition and disease status of the patient. - Dose reduction steps Starting dose 25 mg Dose level -1 15 mg Dose level -2 10 mg Dose level -3 5 mg - Thrombocytopenia When platelets Recommended course First falls to < 30 x 10 9 /L Returns to ≥ 30 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at dose level -1 For each subsequent drop below 30 x 10 9 /L Returns to ≥ 30 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at next lower dose level (dose level -2 or -3) once daily. Do not dose below 5 mg once daily. - Absolute neutrophil count (ANC) - neutropenia When ANC Recommended course a First falls to < 0.5 x 10 9 /L Returns to ≥ 0.5 x 10 9 /L when neutropenia is the only observed toxicity Interrupt lenalidomide treatment Resume lenalidomide at starting dose once daily Returns to ≥ 0.5 x 10 9 /L when dose-dependent haematological toxicities other than neutropenia are observed Resume lenalidomide at dose level -1 once daily For each subsequent drop below < 0.5 x 10 9 /L Returns to ≥ 0.5 x 10 9 /L Interrupt lenalidomide treatment Resume lenalidomide at next lower dose level (dose level -1, -2 or -3) once daily. Do not dose below 5 mg once daily a At the physician's discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide. Myelodysplastic syndromes (MDS) Lenalidomide treatment must not be started if the ANC < 0.5 x 10 9 /L and/or platelet counts < 25 x 10 9 /L. Recommended dose The recommended starting dose of lenalidomide is 10 mg orally once daily on days 1 to 21 of 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 Falls to < 25 x 10 9 /L Interrupt lenalidomide treatment Returns to ≥ 25 x 10 9 /L - < 50 x 10 9 /L on at least 2 occasions for ≥ 7 days or when the platelet count recovers to ≥ 50 x 10 9 /L at any time Resume lenalidomide at next lower dose level (dose level -1, -2 or -3) - Absolute neutrophil count (ANC) - neutropenia When ANC Recommended course Falls to < 0.5 x 10 9 /L Interrupt lenalidomide treatment Returns to ≥ 0.5 x 10 9 /L Resume lenalidomide at next lower dose level (dose level -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/dl rise 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 21 of 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 days 1 5 mg every other day on days 1 to 21, every 28 days 1 - In countries where the 2.5 mg capsule is available. - Thrombocytopenia When platelets Recommended course Falls to < 50 x 10 9 /L Interrupt lenalidomide treatment and conduct Complete Blood Count (CBC) at least every 7 days Returns to ≥ 60 x 10 9 /L Resume lenalidomide at next lower level (dose level -1) For each subsequent drop below 50 x 10 9 /L Returns to ≥ 60 x 10 9 /L Interrupt lenalidomide treatment and conduct the CBC at least every 7 days 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 10 9 /L for at least 7 days or Falls to < 1 x 10 9 /L with associated fever (body temperature ≥ 38.5 °C) or Falls to < 0.5 x 10 9 /L Interrupt lenalidomide treatment and conduct the CBC at least every 7 days Returns to ≥ 1 x 10 9 /L Resume lenalidomide at next lower dose level (dose level -1) For each subsequent drop below 1 x 10 9 /L for at least 7 days or drop to < 1 x 10 9 /L with associated fever (body temperature ≥ 38.5 °C) or drop to < 0.5 x 10 9 /L Interrupt lenalidomide treatment Returns to ≥ 1 x 10 9 /L Resume Lenalidomide at next lower dose level (dose level -2, -3, -4, -5). Do not dose below dose level -5 Follicular lymphoma (FL) Lenalidomide treatment must not be started if the ANC is < 1 x 10 9 /L, and/or platelet count < 50 x 10 9 /L, unless secondary to lymphoma infiltration of bone marrow. Recommended dose The recommended starting dose of lenalidomide is 20 mg, orally once daily on days 1 to 21 of repeated 28-day cycles for up to 12 cycles of treatment. The recommended starting dose of rituximab is 375 mg/m 2 intravenously (IV) every week in Cycle 1 (days 1, 8, 15, and 22) and day 1 of every 28-day cycle for cycles 2 through 5. - Dose reduction steps Starting dose 20 mg once daily on days 1-21, every 28 days Dose Level -1 15 mg once daily on days 1-21, every 28 days Dose Level -2 10 mg once daily on days 1-21, every 28 days Dose Level -3 5 mg once daily on days 1-21, every 28 days For dose adjustments due to toxicity with rituximab, refer to the corresponding summary of product characteristics. - Thrombocytopenia When platelets Recommended course Falls to < 50 x 10 9 /L Interrupt lenalidomide treatment and conduct CBC at least every 7 days Returns to ≥ 50 x 10 9 /L Resume at next lower dose level (dose level -1) For each subsequent drop below 50 x 10 9 /L Returns to ≥ 50 x 10 9 /L Interrupt lenalidomide treatment and conduct CBC at least every 7 days Resume lenalidomide at next lower dose level (dose level -2, -3). Do not dose below dose level -3. - Absolute neutrophil count (ANC) - neutropenia When ANC Recommended courseª Falls < 1.0 x 10 9 /L for at least 7 days or Falls to < 1.0 x 10 9 /L with associated fever (body temperature ≥ 38.5 °C) or Falls to < 0.5 x 10 9 /L Interrupt lenalidomide treatment and conduct CBC at least every 7 days Returns to ≥ 1.0 x 10 9 /L Resume lenalidomide at next lower dose level (dose level -1) For each subsequent drop below 1.0 x 10 9 /L for at least 7 days or drop to < 1.0 x 10 9 /L with associated fever (body temperature ≥ 38.5 °C) or drop to < 0.5 x 10 9 /L Returns to ≥ 1.0 x 10 9 /L Interrupt lenalidomide treatment and conduct CBC at least every 7 days Resume lenalidomide at next lower dose level (dose level -2, -3). Do not dose below dose level-3 ª At the physician's discretion, if neutropenia is the only toxicity at any dose level, add G-CSF Mantle cell lymphoma (MCL) or follicular lymphoma (FL) Tumour lysis syndrome (TLS) All patients should receive TLS prophylaxis (allopurinol, rasburicase or equivalent as per institutional guidelines) and be well hydrated (orally) during the first week of the first cycle or for a longer period if clinically indicated. To monitor for TLS, patients should have a chemistry panel drawn weekly during the first cycle and as clinically indicated. Lenalidomide may be continued (maintain dose) in patients with laboratory TLS or Grade 1 clinical TLS, or at the physician's discretion, reduce dose by one level and continue lenalidomide. Vigorous intravenous hydration should be provided and appropriate medical management according to the local standard of care, until correction of electrolyte abnormalities. Rasburicase therapy may be needed to reduce hyperuricaemia. Hospitalisation of the patient will be at physician's discretion. In patients with Grade 2 to 4 clinical TLS, interrupt lenalidomide and obtain a chemistry panel weekly or as clinically indicated. Vigorous intravenous hydration should be provided and appropriate medical management according to the local standard of care, until correction of electrolyte abnormalities. Rasburicase therapy and hospitalisation will be at physician's discretion. When the TLS resolves to Grade 0, restart lenalidomide at next lower dose per physician's discretion (see section 4.4). Tumour flare reaction At the physician's discretion, lenalidomide may be continued in patients with Grade 1 or 2 tumour flare reaction (TFR) without interruption or modification. At the physician's discretion, therapy with non-steroidal anti-inflammatory drugs (NSAIDs), limited duration corticosteroids, and/or narcotic analgesics may be administered. In patients with Grade 3 or 4 TFR, withhold treatment with lenalidomide and initiate therapy with NSAIDs, corticosteroids and/or narcotic ana

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Women who are pregnant. - Women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met (see sections 4.4 and 4.6). <summary id="CLINICAL_PRECAUTIONS" data-evt="smpcSectionOpen"

4.4. Special warnings and precautions for use

When lenalidomide is given in combination with other medicinal products, the corresponding Summary of Product Characteristics must be consulted prior to initiation of treatment. Pregnancy warning Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys' malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected. The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential. Criteria for women of non-childbearing potential A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria: - Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (Amenorrhoea following cancer therapy or during breast-feeding does not rule out childbearing potential). - Premature ovarian failure confirmed by a specialist gynaecologist - Previous bilateral salpingo-oophorectomy, or hysterectomy - XY genotype, Turner syndrome, uterine agenesis. Counselling For women of childbearing potential, lenalidomide is contraindicated unless all of the following are met: - She understands the expected teratogenic risk to the unborn child - She understands the need for effective contraception, without interruption, at least 4 weeks before starting treatment, throughout the entire duration of treatment, and at least 4 weeks after the end of treatment - Even if a woman of childbearing potential has amenorrhea she must follow all the advice on effective contraception - She should be capable of complying with effective contraceptive measures - She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy - She understands the need to commence the treatment as soon as lenalidomide is dispensed following a negative pregnancy test - She understands the need and accepts to undergo pregnancy testing at least every 4 weeks except in case of confirmed tubal sterilisation - She acknowledges that she understands the hazards and necessary precautions associated with the use of lenalidomide. For male patients taking lenalidomide, pharmacokinetic data has demonstrated that lenalidomide is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after stopping the substance in the healthy subject (see section 5.2). As a precaution and taking into account special populations with prolonged elimination time such as renal impairment, all male patients taking lenalidomide must meet the following conditions: - Understand the expected teratogenic risk if engaged in sexual activity with a pregnant woman or a woman of childbearing potential - Understand the need for the use of a condom if engaged in sexual activity with a pregnant woman or a woman of childbearing potential not using effective contraception (even if the man has had a vasectomy), during treatment and for at least 7 days after dose interruptions and/or cessation of treatment. - Understand that if his female partner becomes pregnant whilst he is taking Lenalidomide or shortly after he has stopped taking Lenalidomide, he should inform his treating physician immediately and that it is recommended to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice. The prescriber must ensure that for women of childbearing potential: - The patient complies with the conditions of the Pregnancy Prevention Programme, including confirmation that she has an adequate level of understanding - The patient has acknowledged the aforementioned conditions. Contraception Women of childbearing potential must use at least one effective method of contraception for at least 4 weeks before therapy, during therapy, and until at least 4 weeks after lenalidomide therapy and even in case of dose interruption unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated. The following can be considered to be examples of suitable methods of contraception: - Implant - Levonorgestrel-releasing intrauterine system (IUS) - Medroxyprogesterone acetate depot - Tubal sterilisation - Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses - Ovulation inhibitory progesterone-only pills (i.e. desogestrel) Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide in combination therapy, and to a lesser extent in patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma taking lenalidomide monotherapy, combined oral contraceptive pills are not recommended (see also section 4.5). If a patient is currently using combined oral contraception the patient should switch to one of the effective methods listed above. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone (see section 4.5). Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia. Copper-releasing intrauterine devices are generally not recommended due to the potential risks of infection at the time of insertion and menstrual blood loss which may compromise patients with neutropenia or thrombocytopenia. Pregnancy testing According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for women of childbearing potential as outlined below. This requirement includes women of childbearing potential who practice absolute and continuous abstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the prescription. Prior to starting treatment A medically supervised pregnancy test should be performed during the consultation, when lenalidomide is prescribed, or in the 3 days prior to the visit to the prescriber once the patient had been using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant when she starts treatment with lenalidomide. Follow-up and end of treatment A medically supervised pregnancy test should be repeated at least every 4 weeks, including at least 4 weeks after the end of treatment, except in the case of confirmed tubal sterilisation. These pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber. Additional precautions Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment for safe disposal. Patients should not donate blood, semen or sperm during treatment (including during dose interruptions) and for at least 7 days following discontinuation of lenalidomide. Healthcare professionals and caregivers should wear disposable gloves when handling the blister or capsule. Women who are pregnant or suspect they may be pregnant should not handle the blister or capsule (see section 6.6). 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 the expected 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 about the expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme and provide patients with appropriate patient educational brochure, patient card and/or equivalent tool as agreed with each National Competent Authority. In collaboration with each National Competent Authority, a controlled access programme has been implemented which includes the use of a patient card and/or equivalent tool for prescribing and/or dispensing controls, and the collection of 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 the prescription and following a medically supervised negative pregnancy test result. Prescriptions for women of childbearing potential can be for a maximum duration of treatment of 4 weeks according to the approved indications dosing regimens (see section 4.2), and prescriptions for all other patients can be for a maximum duration of treatment of 12 weeks. Other special warnings and precautions for use Myocardial infarction Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors and within the first 12 months when used in combination with dexamethasone. Patients with known risk factors – including prior thrombosis – should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Venous and arterial thromboembolic events In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism). The risk of venous thromboembolism was seen to a lesser extent with lenalidomide in combination with melphalan and prednisone. In patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma, treatment with lenalidomide monotherapy was associated with a lower risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) than in patients with multiple myeloma treated with lenalidomide in combination therapy (see sections 4.5 and 4.8). In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an increased risk of arterial thromboembolism (predominantly myocardial infarction and cerebrovascular event) and was seen to a lesser extent with lenalidomide in combination with melphalan and prednisone. The risk of arterial thromboembolism is lower in patients with multiple myeloma treated with lenalidomide monotherapy than in patients with multiple myeloma treated with lenalidomide in combination therapy. Consequently, patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Concomitant administration of erythropoietic agents or previous history of thromboembolic events may also increase thrombotic risk in these patients. Therefore, erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone. A haemoglobin concentration above 12 g/dl should lead to discontinuation of erythropoietic agents. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Prophylactic antithrombotic medicines should be recommended, especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's underlying risk factors. If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, the lenalidomide treatment may be restarted at the original dose dependent upon a benefit risk assessment. The patient should continue anticoagulation therapy during the course of lenalidomide treatment. Pulmonary hypertension Cases of pulmonary hypertension, some fatal, have been reported in patients treated with lenalidomide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during lenalidomide therapy. Neutropenia and thrombocytopenia The major dose limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. A complete blood cell count, including white blood cell count with differential count, platelet count, haemoglobin, and haematocrit should be performed at baseline, every week for the first 8 weeks of lenalidomide treatment and monthly thereafter to monitor for cytopenias. In mantle cell lymphoma patients, the monitoring scheme should be every 2 weeks in cycles 3 and 4, and then at the start of each cycle. In follicular lymphoma, the monitoring scheme should be weekly for the first 3 weeks of cycle 1 (28 days), every 2 weeks during cycles 2 through 4, and then at the start of each cycle thereafter. A dose interruption and/or a dose reduction may be required (see section 4.2). In case of neutropenia, the physician should consider the use of growth factors in patient management. Patients should be advised to promptly report febrile episodes. Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxis, especially in patients receiving concomitant medicinal products susceptible to induce bleeding (see section 4.8, Haemorrhagic disorders). Co-administration of lenalidomide with other myelosuppressive agents should be undertaken with caution. • Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with lenalidomide maintenance The adverse reactions from CALGB 100104 included events reported post-high dose melphalan and ASCT (HDM/ASCT) as well as events from the maintenance treatment period. A second analysis identified events that occurred after the start of maintenance treatment. In IFM 2005-02, the adverse reactions were from the maintenance treatment period only. Overall, Grade 4 neutropenia was observed at a higher frequency in the lenalidomide maintenance arms compared to the placebo maintenance arms in the 2 studies evaluating lenalidomide maintenance in NDMM patients who have undergone ASCT (32.1% vs 26.7% [16.1% vs 1.8% after the start of maintenance treatment] in CALGB 100104 and 16.4% vs 0.7% in IFM 2005-02, respectively). Treatment-emergent AEs of neutropenia leading to lenalidomide discontinuation were reported in 2.2% of patients in CALGB 100104 and 2.4% of patients in IFM 2005-02, respectively. Grade 4 febrile neutropenia was reported at similar frequencies in the lenalidomide maintenance arms compared to placebo maintenance arms in both studies (0.4% vs 0.5% [0.4% vs 0.5% after the start of maintenance treatment] in CALGB 100104 and 0.3% vs 0% in IFM 2005-02, respectively). Patients should be advised to promptly report febrile episodes, a treatment interruption and/or dose reduction may be required (see section 4.2). Grade 3 or 4 thrombocytopenia was observed at a higher frequency in the lenalidomide maintenance arms compared to the placebo maintenance arms in studies evaluating lenalidomide maintenance in NDMM patients who have undergone ASCT (37.5% vs 30.3% [17.9% vs 4.1% after the start of maintenance treatment] in CALGB 100104 and 13.0% vs 2.9% in IFM 2005-02, respectively). Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in patients receiving concomitant medicinal products susceptible to induce bleeding (see section 4.8, Haemorrhagic disorders). • Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with bortezomib and dexamethasone Grade 4 neutropenia was observed at a lower frequency in the lenalidomide in combination with bortezomib and dexamethasone (RVd) arm compared to the Rd comparator arm (2.7% vs 5.9%) in the SWOG S0777 study. Grade 4 febrile neutropenia was reported at similar frequencies in the RVd arm and Rd arm (0.0% vs 0.4%). Patients should be advised to promptly report febrile episodes; a treatment interruption and/or dose reduction may be required (see section 4.2). Grade 3 or 4 thrombocytopenia was observed at a higher frequency in the RVd arm compared to the Rd comparator arm (17.2 % vs 9.4%). • Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with low dose dexamethasone Grade 4 neutropenia was observed in the lenalidomide arms in combination with dexamethasone to a lesser extent than in the comparator arm (8.5% in the Rd [continuous treatment] and Rd18 [treatment for 18 four-week cycles] compared with 15% in the melphalan/prednisone/thalidomide arm, see section 4.8). Grade 4 febrile neutropenia episodes were consistent with the comparator arm (0.6 % in the Rd and Rd18 lenalidomide/dexamethasone-treated patients compared with 0.7% in the melphalan/prednisone/thalidomide arm, see section 4.8). Grade 3 or 4 thrombocytopenia was observed to a lesser extent in the Rd and Rd18 arms than in the comparator arm (8.1% vs 11.1%, respectively). • Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with melphalan and prednisone The combination of lenalidomide with melphalan and prednisone in clinical trials of newly diagnosed multiple myeloma patients is associated with a higher incidence of Grade 4 neutropenia (34.1% in melphalan, prednisone and lenalidomide arm followed by lenalidomide [MPR+R] and melphalan, prednisone and lenalidomide followed by placebo [MPR+p] treated patients compared with 7.8% in MPp+p-treated patients; see section 4.8). Grade 4 febrile neutropenia episodes were observed infrequently (1.7% in MPR+R/MPR+p treated patients compared to 0.0% in MPp+p treated patients; see section 4.8). The combination of lenalidomide with melphalan and prednisone in multiple myeloma patients is associated with a higher incidence of Grade 3 and Grade 4 thrombocytopenia (40.4% in MPR+R/MPR+p treated patients, compared with 13.7% in MPp+p-treated patients; see section 4.8). • Multiple myeloma: patients with at least one prior therapy The combination of lenalidomide with dexamethasone in multiple myeloma patients with at least one prior therapy is associated with a higher incidence of Grade 4 neutropenia (5.1% in lenalidomide/dexamethasone- treated patients compared with 0.6% in placebo/dexamethasone-treated patients; see section 4.8). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients; see section 4.8). The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated

4.5. Interaction with other medicinal products and other forms of interaction

Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone (see sections 4.4 and 4.8). Oral contraceptives No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme inducer. In an in vitro study with human hepatocytes, lenalidomide, at various concentrations tested did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. Therefore, induction leading to reduced efficacy of medicinal products, including hormonal contraceptives, is not expected if lenalidomide is administered alone. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4 and is likely to also affect other enzymes as well as transporters. It may not be excluded that the efficacy of oral contraceptives may be reduced during treatment. Effective measures to avoid pregnancy must be taken (see sections 4.4 and 4.6). Warfarin Co-administration of multiple 10 mg doses of lenalidomide had no effect on the single dose pharmacokinetics of R- and S- warfarin. Co-administration of a single 25 mg dose of warfarin had no effect on the pharmacokinetics of lenalidomide. However, it is not known whether there is an interaction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is a weak to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin concentration is advised during the treatment. Digoxin Concomitant administration with lenalidomide 10 mg once daily increased the plasma exposure of digoxin (0.5 mg, single dose) by 14% with a 90% CI (confidence interval) [0.52%-28.2%]. It is not known whether the effect will be different in the clinical use (higher lenalidomide doses and concomitant treatment with dexamethasone). Therefore, monitoring of the digoxin concentration is advised during lenalidomide treatment. Statins There is an increased risk of rhabdomyolysis when statins are administered with lenalidomide, which may be simply additive. Enhanced clinical and laboratory monitoring is warranted notably during the first weeks of treatment. Dexamethasone Co-administration of single or multiple doses of dexamethasone (40 mg once daily) has no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg once daily). Interactions with P-glycoprotein (P-gp) inhibitors In vitro , lenalidomide is a substrate of P-gp, but is not a P-gp inhibitor. Co-administration of multiple doses of the strong P-gp inhibitor quinidine (600 mg, twice daily) or the moderate P-gp inhibitor/substrate temsirolimus (25 mg) has no clinically relevant effect on the pharmacokinetics of lenalidomide (25 mg). Co-administration of lenalidomide does not alter the pharmacokinetics of temsirolimus. <summary id="PREGNANCY" data-evt="smpcSectionOpen"

4.6. Fertility, pregnancy and lactation

Due to the teratogenic potential, lenalidomide must be prescribed under a Pregnancy Prevention Programme (see section 4.4) unless there is reliable evidence that the patient does not have childbearing potential.

Women of childbearing potential / Contraception in males and females

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

Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after stopping the substance in the healthy subject (see section 5.2). As a precaution, and taking into account special populations with prolonged elimination time such as renal impairment, all male patients taking lenalidomide should use condoms throughout treatment duration, during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception.

Pregnancy

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

Lenalidomide induced malformation in monkeys similar to those described with thalidomide (see section 5.3). Therefore, a teratogenic effect of lenalidomide is expected and lenalidomide is contraindicated during pregnancy (see section 4.3).

Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

Lenalidomide has minor or moderate influence on the ability to drive and use machines.

Fatigue, dizziness, somnolence, vertigo and blurred vision have been reported with the use of lenalidomide. Therefore, caution is recommended when driving or operating machines.

4.8. Undesirable effects

Summary of the safety profile Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with lenalidomide maintenance A conservative approach was applied to determine the adverse reactions from CALGB 100104. The adverse reactions described in Table 1 included events reported post-HDM/ASCT as well as events from the maintenance treatment period. A second analysis that identified events that occurred after the start of maintenance treatment suggests that the frequencies described in Table 1 may be higher than actually observed during the maintenance treatment period. In IFM 2005-02, the adverse reactions were from the maintenance treatment period only. The serious adverse reactions observed more frequently (≥ 5%) with lenalidomide maintenance than placebo were: - Pneumonia (10.6%; combined term) from IFM 2005-02 - Lung infection (9.4% [9.4% after the start of maintenance treatment]) from CALGB 100104 In the IFM 2005-02 study, the adverse reactions observed more frequently with lenalidomide maintenance than placebo were neutropenia (60.8%), bronchitis (47.4%), diarrhoea (38.9%), nasopharyngitis (34.8%), muscle spasms (33.4%), leucopenia (31.7%), asthenia (29.7%), cough (27.3%), thrombocytopenia (23.5%), gastroenteritis (22.5%) and pyrexia (20.5%). In the CALGB 100104 study, the adverse reactions observed more frequently with lenalidomide maintenance than placebo were neutropenia (79.0% [71.9% after the start of maintenance treatment]), thrombocytopenia (72.3% [61.6%]), diarrhoea (54.5% [46.4%]), rash (31.7% [25.0%]), upper respiratory tract infection (26.8% [26.8%]), fatigue (22.8% [17.9%]), leucopenia (22.8% [18.8%]) and anaemia (21.0% [13.8%]). Newly diagnosed multiple myeloma patients who are not eligible for transplant receiving lenalidomide in combination with bortezomib and dexamethasone In the SWOG S0777 study, the serious adverse reactions observed more frequently (≥ 5%) with lenalidomide in combination with intravenous bortezomib and dexamethasone than with lenalidomide in combination with dexamethasone were: - Hypotension (6.5%), lung infection (5.7%), dehydration (5.0%) The adverse reactions observed more frequently with lenalidomide in combination with bortezomib and dexamethasone than with lenalidomide in combination with dexamethasone were: Fatigue (73.7%), peripheral neuropathy (71.8%), thrombocytopenia (57.6%), constipation (56.1%), hypocalcaemia (50.0%). Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with low dose dexamethasone The serious adverse reactions observed more frequently (≥ 5%) with lenalidomide in combination with low dose dexamethasone (Rd and Rd18) than with melphalan, prednisone and thalidomide (MPT) were: - Pneumonia (9.8%) - Renal failure (including acute) (6.3%) The adverse reactions observed more frequently with Rd or Rd18 than MPT were: diarrhoea (45.5%), fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), and muscle spasms (20.5%). Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with lenalidomide in combination with melphalan and prednisone The serious adverse reactions observed more frequently (≥ 5%) with melphalan, prednisone and lenalidomide followed by lenalidomide maintenance (MPR+R) or melphalan, prednisone and lenalidomide followed by placebo (MPR+p) than melphalan, prednisone and placebo followed by placebo (MPp+p) were: - Febrile neutropenia (6.0%) - Anaemia (5.3%) The adverse reactions observed more frequently with MPR+R or MPR+p than MPp+p were: neutropenia (83.3%), anaemia (70.7%), thrombocytopenia (70.0%), leucopenia (38.8%), constipation (34.0%), diarrhoea (33.3%), rash (28.9%), pyrexia (27.0%), peripheral oedema (25.0%), cough (24.0%), decreased appetite (23.7%), and asthenia (22.0%). Multiple myeloma: patients with at least one prior therapy In two phase 3 placebo-controlled studies, 353 patients with multiple myeloma were exposed to the lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination. The most serious adverse reactions observed more frequently in lenalidomide/dexamethasone than placebo/dexamethasone combination were: - Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4) - Grade 4 neutropenia (see section 4.4). The observed adverse reactions which occurred more frequently with lenalidomide and dexamethasone than placebo and dexamethasone in pooled multiple myeloma clinical trials (MM-009 and MM-010) were fatigue (43.9%), neutropenia (42.2%), constipation (40.5%), diarrhoea (38.5%), muscle cramp (33.4%), anaemia (31.4%), thrombocytopenia (21.5%), and rash (21.2%). Myelodysplastic syndromes The overall safety profile of lenalidomide in patients with myelodysplastic syndromes is based on data from a total of 286 patients from one phase 2 study and one phase 3 study (see section 5.1). In the phase 2, all 148 patients were on lenalidomide treatment. In the phase 3 study, 69 patients were on lenalidomide 5 mg, 69 patients on lenalidomide 10 mg and 67 patients were on placebo during the double-blind phase of the study. Most adverse reactions tended to occur during the first 16 weeks of therapy with lenalidomide. Serious adverse reactions include: - 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 section 4.4). The most commonly observed adverse reactions which occurred more frequently in the lenalidomide groups compared to the control arm in the phase 3 study were neutropenia (76.8%), thrombocytopenia (46.4%), diarrhoea (34.8%), constipation (19.6%), nausea (19.6%), pruritus (25.4%), rash (18.1%), fatigue (18.1%) and muscle spasms (16.7%). Mantle cell lymphoma The overall safety profile of lenalidomide in patients with mantle cell lymphoma is based on data from 254 patients from a phase 2 randomised, controlled study MCL-002 (see section 5.1). Additionally, adverse drug reactions from supportive study MCL-001 have been included in table 3. The serious adverse reactions observed more frequently in study MCL-002 (with a difference of at least 2 percentage points) in the lenalidomide arm compared with the control arm were: - Neutropenia (3.6%) - Pulmonary embolism (3.6%) - Diarrhoea (3.6%) The most frequently observed adverse reactions which occurred more frequently in the lenalidomide arm compared with the control arm in study MCL-002 were neutropenia (50.9%), anaemia (28.7%), diarrhoea (22.8%), fatigue (21.0%), constipation (17.4%), pyrexia (16.8%), and rash (including dermatitis allergic) (16.2%). In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths. Patients with high tumour burden at baseline are at increased risk of early death, 16/81 (20%) early deaths in the lenalidomide arm and 2/28 (7%) early deaths in the control arm. Within 52 weeks corresponding figures were 32/81 (39.5%) and 6/28 (21%) (see section 5.1). During treatment cycle 1, 11/81 (14%) patients with high tumour burden were withdrawn from therapy in the lenalidomide arm vs. 1/28 (4%) in the control group. The main reason for treatment withdrawal for patients with high tumour burden during treatment cycle 1 in the lenalidomide arm was adverse events, 7/11 (64%). High tumour burden was defined as at least one lesion ≥ 5 cm in diameter or 3 lesions ≥ 3 cm. Follicular lymphoma The overall safety profile of lenalidomide in combination with rituximab in patients with previously treated follicular lymphoma is based on data from 294 patients from a phase 3 randomised, controlled study NHL-007. Additionally, adverse drug reactions from supportive study NHL-008 have been included in Table 5. The serious adverse reactions observed most frequently (with a difference of at least 1 percentage point) in study NHL-007 in the lenalidomide/rituximab arm compared with the placebo/rituximab arm were: - Febrile neutropenia (2.7%) - Pulmonary embolism (2.7%) - Pneumonia (2.7%) In the NHL-007 study the adverse reactions observed more frequently in the lenalidomide/rituximab arm compared with the placebo/rituximab arm (with at least 2% higher frequency between arms) were neutropenia (58.2%), diarrhoea (30.8%), leucopenia (28.8%), constipation (21.9%), cough (21.9%) and fatigue (21.9%). Tabulated list of adverse reactions The adverse reactions observed in patients treated with lenalidomide are listed below by system organ class and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Adverse reactions have been included under the appropriate category in the table below according to the highest frequency observed in any of the main clinical trials. Tabulated summary for monotherapy in MM The following table is derived from data gathered during NDMM studies in patients who have undergone ASCT treated with lenalidomide maintenance. The data were not adjusted according to the longer duration of treatment in the lenalidomide-containing arms continued until disease progression versus the placebo arms in the pivotal multiple myeloma studies (see section 5.1). Table 1. ADRs reported in clinical trials in patients with multiple myeloma treated with lenalidomide maintenance therapy System Organ Class / Preferred Term All ADRs/Frequency Grade 3-4 ADRs/Frequency Infections and infestations Very Common Pneumonia ◊, a , Upper respiratory tract infection, Neutropenic infection, Bronchitis ◊ , Influenza ◊ , Gastroenteritis ◊ , Sinusitis, Nasopharyngitis, Rhinitis Common Infection ◊ , Urinary tract infection ◊, *, Lower respiratory tract infection, Lung infection ◊ Very Common Pneumonia ◊, a , Neutropenic infection Common Sepsis ◊, b , Bacteraemia, Lung infection ◊ , Lower respiratory tract infection bacterial, Bronchitis ◊ , Influenza ◊ , Gastroenteritis ◊ , Herpes zoster ◊ , Infection ◊ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Myelodysplastic syndrome ◊, * Blood and lymphatic system disorders Very Common Neutropenia^ ,◊ , Febrile neutropenia^ ,◊ , Thrombocytopenia^ ,◊ , Anaemia, Leucopenia ◊ , Lymphopenia Very Common Neutropenia^ ,◊ , Febrile neutropenia^ ,◊ , Thrombocytopenia^ ,◊ , Anaemia, Leucopenia ◊ , Lymphopenia Common Pancytopenia ◊ Metabolism and nutrition disorders Very Common Hypokalaemia Common Hypokalaemia, Dehydration Nervous system disorders Very Common Paraesthesia Common Peripheral neuropathy c Common Headache Vascular disorders Common Pulmonary embolism ◊, * Common Deep vein thrombosis^ ,◊,d Respiratory, thoracic and mediastinal disorders Very Common Cough Common Dyspnoea ◊ , Rhinorrhoea Common Dyspnoea ◊ Gastrointestinal disorders Very Common Diarrhoea, Constipation, Abdominal pain, Nausea Common Vomiting, Abdominal pain upper Common Diarrhoea, Vomiting, Nausea Hepatobiliary disorders Very Common Abnormal liver function tests Common Abnormal liver function tests Skin and subcutaneous tissue disorders Very Common Rash, Dry skin Common Rash, Pruritus Musculoskeletal and connective tissue disorders Very Common Muscle spasms Common Myalgia, Musculoskeletal pain General disorders and administration site conditions Very Common Fatigue, Asthenia, Pyrexia Common Fatigue, Asthenia ◊ Adverse reactions reported as serious in clinical trials in patients with NDMM who had undergone ASCT * Applies to serious adverse drug reactions only ^ See section 4.8 description of selected adverse reactions a “Pneumonia” combined AE term includes the following PTs: Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis b “Sepsis” combined AE term includes the following PTs: Bacterial sepsis, Pneumococcal sepsis, Septic shock, Staphylococcal sepsis c “Peripheral neuropathy” combined AE term includes the following preferred terms (PTs): Neuropathy peripheral, Peripheral sensory neuropathy, Polyneuropathy d “Deep vein thrombosis” combined AE term includes the following PTs: Deep vein thrombosis, Thrombosis, Venous thrombosis Tabulated summary for combination therapy in MM The following table is derived from data gathered during the multiple myeloma studies with combination therapy. The data were not adjusted according to the longer duration of treatment in the lenalidomide-containing arms continued until disease progression versus the comparator arms in the pivotal multiple myeloma studies (see section 5.1). Table 2. ADRs reported in clinical studies in patients with multiple myeloma treated with lenalidomide in combination with bortezomib and dexamethasone, dexamethasone, or melphalan and prednisone System Organ Class / Preferred Term All ADRs/Frequency Grade 3−4 ADRs/Frequency Infections and infestations Very Common Pneumonia ◊,◊◊ , Upper respiratory tract infection ◊ , Bacterial, viral and fungal infections (including opportunistic infections) ◊ , Nasopharyngitis, Pharyngitis, Bronchitis ◊ , Rhinitis Common Sepsis ◊,◊◊ , Lung infection ◊◊ , Urinary tract infection ◊◊ , Sinusitis ◊ Common Pneumonia ◊,◊◊ , Bacterial, viral and fungal infections (including opportunistic infections) ◊ , Cellulitis ◊ , Sepsis ◊,◊◊ , Lung infection ◊◊ , Bronchitis ◊ , Respiratory tract infection ◊◊ , Urinary tract infection ◊◊ , Enterocolitis infectious Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Basal cell carcinoma^ ,◊ , Squamous skin cancer^ ,◊, * Common Acute myeloid leukaemia ◊ , Myelodysplastic syndrome ◊ , Squamous cell carcinoma of skin^ ,◊, ** Uncommon T-cell type acute leukaemia ◊ , Basal cell carcinoma^ ,◊ , Tumour lysis syndrome Blood and lymphatic system disorders Very Common Neutropenia^ ,◊,◊◊ , Thrombocytopenia^ ,◊,◊◊ , Anaemia ◊ , Haemorrhagic disorder^, Leucopenia, Lymphopenia Common Febrile neutropenia^ ,◊ , Pancytopenia ◊ Uncommon Haemolysis, Autoimmune haemolytic anaemia, Haemolytic anaemia Very Common Neutropenia^ ,◊,◊◊ , Thrombocytopenia^ ,◊,◊◊ , Anaemia ◊ , Leucopenia, Lymphopenia Common Febrile neutropenia^ ,◊ , Pancytopenia ◊ , Haemolytic anaemia Uncommon Hypercoagulation, Coagulopathy Immune system disorders Uncommon Hypersensitivity^ Endocrine disorders Common Hypothyroidism Metabolism and nutrition disorders Very Common Hypokalaemia ◊,◊◊ , Hyperglycaemia, Hypoglycaemia, Hypocalcaemia ◊ , Hyponatraemia ,◊ , Dehydration ◊◊ , Decreased appetite ◊◊ , Weight decreased Common Hypomagnesaemia, Hyperuricaemia, Hypercalcaemia + Common Hypokalaemia ◊,◊◊ , Hyperglycaemia, Hypocalcaemia ◊ , Diabetes mellitus ◊ , Hypophosphataemia, Hyponatraemia ◊ , Hyperuricaemia, Dehydration ◊◊ , Gout, Decreased appetite ◊◊ , Weight decreased Psychiatric disorders Very Common Depression, Insomnia Uncommon Loss of libido Common Depression, Insomnia Nervous system disorders Very Common Peripheral neuropathies ◊◊ , Paraesthesia, Dizziness ◊◊ , Tremor, Dysgeusia, Headache Common Ataxia, Balance impaired, Syncope ◊◊ , Neuralgia, Dysaesthesia Very common Peripheral neuropathies ◊◊ Common Cerebrovascular accident ◊ , Dizziness ◊◊ , Syncope ◊◊ , Neuralgia Uncommon Intracranial haemorrhage ^, Transient ischaemic attack, Cerebral ischaemia Eye disorders Very Common Cataracts, Blurred vision Common Reduced visual acuity Common Cataract Uncommon Blindness Ear and labyrinth disorders Common Deafness (including Hypoacusis), Tinnitus Cardiac disorders Common Atrial fibrillation ◊,◊◊ , Bradycardia Uncommon Arrhythmia, QT prolongation, Atrial flutter, Ventricular extrasystoles Common Myocardial infarction (including acute)^ ,◊ , Atrial fibrillation ◊,◊◊ , Congestive cardiac failure ◊ , Tachycardia, Cardiac failure ◊,◊◊ , Myocardial ischaemia ◊ Vascular disorders Very Common Venous thromboembolic events^, predominantly deep vein thrombosis and pulmonary embolism^ ,◊,◊◊ , Hypotension ◊◊ Common Hypertension, Ecchymosis^ Very Common Venous thromboembolic events^, predominantly deep vein thrombosis and pulmonary embolism^ ,◊,◊◊ Common Vasculitis, Hypotension ◊◊ , Hypertension Uncommon Ischemia, Peripheral ischemia, Intracranial venous sinus thrombosis Respiratory, thoracic and mediastinal disorders Very Common Dyspnoea ◊,◊◊ , Epistaxis^, Cough Common Dysphonia Common Respiratory distress ◊ , Dyspnoea ◊,◊◊ , Pleuritic pain ◊◊ , Hypoxia ◊◊ Gastrointestinal disorders Very Common Diarrhoea ◊,◊◊ , Constipation ◊ , Abdominal pain ◊◊ , Nausea, Vomiting ◊◊ , Dyspepsia, Dry mouth, Stomatitis Common Gastrointestinal haemorrhage (including rectal haemorrhage, haemorrhoidal haemorrhage, peptic ulcer haemorrhage and gingival bleeding)^ , ◊◊ , Dysphagia Uncommon Colitis, Caecitis Common Gastrointestinal haemorrhage^ ,◊,◊◊ , Small intestinal obstruction ◊◊ , Diarrhoea ◊◊ , Constipation ◊ , Abdominal pain ◊◊ , Nausea, Vomiting ◊◊ Hepatobiliary disorders Very common Alanine aminotransferase increased, Aspartate aminotransferase increased Common Hepatocellular injury ◊◊ , Abnormal liver function tests ◊ , Hyperbilirubinaemia Uncommon Hepatic failure^ Common Cholestasis ◊ , Hepatotoxicity, Hepatocellular injury ◊◊ , Alanine aminotransferase increased, Abnormal liver function tests ◊ Uncommon Hepatic failure^ Skin and subcutaneous tissue disorders Very Common Rashes ◊◊ , Pruritus Common Urticaria, Hyperhidrosis, Dry skin, Skin hyperpigmentation, Eczema, Erythema Uncommon Drug rash with eosinophilia and systemic symptoms ◊◊ , Skin discolouration, Photosensitivity reaction Common Rashes ◊◊ Uncommon Drug rash with eosinophilia and systemic symptoms ◊◊ Musculoskeletal and connective tissue disorders Very Common Muscular weakness ◊◊ , Muscle spasms, Bone pain ◊ , Musculoskeletal and connective tissue pain and discomfort (including back pain ◊,◊◊ ), Pain in extremity, Myalgia, Arthralgia ◊ Common Joint swelling Common Muscular weakness ◊◊ , Bone pain ◊ , Musculoskeletal and connective tissue pain and discomfort (including back pain ◊,◊◊ ) Uncommon Joint swelling Renal and urinary disorders Very Common Renal failure (including acute) ◊,◊◊ Common Haematuria^, Urinary retention, Urinary incontinence Uncommon Acquired Fanconi syndrome Uncommon Renal tubular necrosis Reproductive system and breast disorders Common Erectile dysfunction General diso

4.9. Overdose

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