Lenalidomide Krka (previously Lenalidomide Krka d.d. Novo mesto) - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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.

3. PHARMACEUTICAL FORM

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 to yellow 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 to yellow 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 white to 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 to yellow 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 to yellow 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 to yellow 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 white to yellow white or to brown white powder. Hard capsule size: 0, length 21 ± 1 mm.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Multiple myeloma

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

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

4.2 Posology and method of administration

4.3   Contraindications

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. In monkeys, lenalidomide induced malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.

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 ifa 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 during therapy or 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 health care professionals to reinforce the warnings about the expected teratogenicity of lenalidomide, to provide advice on contraception before therapy is started, and to provide guidance on the need for pregnancy testing. The prescriber must inform male and female patients about the expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme and provide patients with appropriate patient educational brochure, patient card and/or equivalent tool in accordance to the national implemented patient card system. A national controlled distribution system has been implemented in collaboration with each National Competent Authority. The controlled distribution system includes the use of a patient card and/or equivalent tool for prescribing and/or dispensing controls, and the collecting of detailed data relating to the indication in order to monitor closely the off-label use within the national territory. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the prescription and following a medically supervised negative pregnancy test result. Prescriptions for women of childbearing potential can be for a maximum duration of treatment of 4 weeks, 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 totryto minimize all modifiable risk factors (eg. smoking, hypertension, and hyperlipidaemia).

Venous and arterial thromboembolic events

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

In patients with multiple myeloma, 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 medicinal products should be recommended, especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment ofan 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 with a higher incidence of Grade 3 and Grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in lenalidomide/de­xamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamet­hasone-treated patients; see section 4.8).

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).

Mantle cell lymphoma

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).

Follicular lymphoma

The combination of lenalidomide with rituximab in follicular lymphoma patients is associated with a higher incidence of Grade 3 or 4 neutropenia compared with patients on the placebo/rituximab arm. Febrile neutropenia and Grade 3 or 4 thrombocytopenia were more commonly observed in the lenalidomide/ri­tuximab arm (see section 4.8).

Thyroid disorders

Cases of hypothyroidism and cases of hyperthyroidism have been reported. Optimal control of co-morbid conditions influencing thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.

Peripheral neuropathy

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

The combination of lenalidomide with intravenous bortezomib and dexamethasone in multiple myeloma patients is associated with a higher frequency of peripheral neuropathy. The frequency was lower when bortezomib was administered subcutaneously. For additional information, see Section 4.8 and the SmPC for bortezomib.

Tumour flare reaction and tumour lysis syndrome

Because lenalidomide has anti-neoplastic activity, the complications of tumour lysis syndrome (TLS) may occur. 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 to treatment. Caution should be practiced when introducing these patients to lenalidomide. These patients should be monitored closely, especially during the first cycle or dose-escalation, and appropriate precautions taken.

Mantle cell lymphoma

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 in the longest diameter) at baseline may be at risk of TFR. Tumour flare reaction may mimic progression of disease (PD). Patients in studies MCL-002 and MCL-001 that experienced Grade 1 and 2 TFR were treated with corticosteroids, NSAIDs and/or narcotic analgesics for management of TFR symptoms. The decision to take therapeutic measures for TFR should be made after careful clinical assessment of the individual patient (see sections 4.2 and 4.8).

Follicular lymphoma

Careful monitoring and evaluation for TFR is recommended. Tumour flare may mimic PD. Patients who experienced Grade 1 and 2 TFR were treated with corticosteroids, NSAIDs and/or narcotic analgesics for management of TFR symptoms. The decision to take therapeutic measures for TFR should be made after careful clinical assessment of the individual patient (see sections 4.2 and 4.8).

Careful monitoring and evaluation for TLS is recommended. Patients should be well hydrated and receive TLS prophylaxis, in addition to weekly chemistry panels during the first cycle or longer, as clinically indicated (see sections 4.2 and 4.8).

Tumour burden

Mantle cell lymphoma

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

Early death

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, there were 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 (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 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%).

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 dose adjustments for TFR. High tumour burden was defined as at least one lesion >5 cm in diameter or 3 lesions >3 cm.

Allergic reactions and severe skin reactions

Cases of allergic reactions including angioedema, anaphylactic reaction and severe cutaneous reactions including SJS, TEN and DRESS have been reported in patients treated with lenalidomide (see section 4.8). Patients should be advised of the signs and symptoms of these reactions by their prescribers and should be told to seek medical attention immediately if they develop these symptoms. Lenalidomide must be discontinued for angioedema, anaphylactic reaction, exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed following discontinuation for these reactions. Interruption or discontinuation of lenalidomide should be considered for other forms of skin reaction depending on severity. Patients who had previous allergic reactions while treated with thalidomide should be monitored closely, as a possible cross-reaction between lenalidomide and thalidomide has been reported in the literature. Patients with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.

Second primary malignancies

An increase of second primary malignancies (SPM) has been observed in clinical trials in previously treated myeloma patients receiving lenalidomide/de­xamethasone (3.98 per 100 person-years) compared to controls (1.38 per 100 person-years). Non-invasive SPM comprise basal cell or squamous cell skin cancers. Most of the invasive SPMs were solid tumour malignancies.

In clinical trials of newly diagnosed multiple myeloma patients not eligible for transplant, a 4.9-fold increase in incidence rate of hematologic SPM (cases of AML, MDS) has been observed in patients receiving lenalidomide in combination with melphalan and prednisone until progression (1.75 per 100 person-years) compared with melphalan in combination with prednisone (0.36 per 100 person-years).

A 2.12-fold increase in incidence rate of solid tumour SPM has been observed in patients receiving lenalidomide (9 cycles) in combination with melphalan and prednisone (1.57 per 100 person-years) compared with melphalan in combination with prednisone (0.74 per 100 person-years).

In patients receiving lenalidomide in combination with dexamethasone until progression or for 18 months, the hematologic SPM incidence rate (0.16 per 100 person-years) was not increased as compared to thalidomide in combination with melphalan and prednisone (0.79 per 100 person-years).

A 1.3-fold increase in incidence rate of solid tumour SPM has been observed in patients receiving lenalidomide in combination with dexamethasone until progression or for 18 months (1.58 per 100 person-years) compared to thalidomide in combination with melphalan and prednisone (1.19 per 100 person-years).

In newly diagnosed multiple myeloma patients receiving lenalidomide in combination with bortezomib and dexamethasone, the hematologic SPM incidence rate was 0.00 – 0.16 per 100 personyears 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 in the context of NDMM after stem cell transplantation. Though this risk is not yet fully characterized, it should be kept in mind when considering and using lenalidomide in this setting.

The incidence rate of hematologic malignancies, most notably AML, MDS and B-cell malignancies (including Hodgkin’s lym­phoma), was 1.31 per 100 person-years for the lenalidomide arms and 0.58 per 100 person-years for the placebo arms (1.02 per 100 person-years for patients exposed to lenalidomide after ASCT and 0.60 per 100 person-years for patients not-exposed to lenalidomide after ASCT). The incidence rate of solid tumour SPMs was 1.36 per 100 person-years for the lenalidomide arms and 1.05 per 100 person-years for the placebo arms (1.26 per 100 person-years for patients exposed to lenalidomide after ASCT and 0.60 per 100 person-years for patients not-exposed to lenalidomide after ASCT).

The risk of occurrence of hematologic SPM must be taken into account before initiating treatment with lenalidomide either in combination with melphalan or immediately following high-dose melphalan and ASCT. Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of SPM and institute treatment as indicated.

Progression to acute myeloid leukaemia in low- and intermediate-1-riskMDS Karyotype

Baseline variables including complex cytogenetics are associated with progression to AML in subjects who are transfusion dependent and have a Del (5q) abnormality. In a combined analysis of two clinical trials of lenalidomide in low- or intermediate-1-risk myelodysplastic syndromes, subjects who had a complex 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 was 13.8%, 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) and complex 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 a higher risk of progression to acute myeloid leukaemia (AML). In a post-hoc analysis of a clinical trial of 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 of strong nuclear staining, using immunohistochemical assessment of p53 protein as a surrogate for TP53 mutation 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) are identified 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 arm compared with 0.29 per 100 person-years in patients receiving placebo/rituximab. The incidence rate of hematologic plus solid tumour SPMs (excluding non-melanoma skin cancers) was 0.87 per 100 personyears in the lenalidomide/ri­tuximab arm, compared to 1.17 per 100 person-years in patients receiving placebo/rituximab with a median follow-up of 30.59 months (range 0.6 to 50.9 months).

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

Physicians should monitor patients for the development of SPMs. Both the potential benefit of lenalidomide and the risk of SPMs should be considered when considering treatment with lenalidomide.

Hepatic disorders

Hepatic failure, including fatal cases, has been reported in patients treated with lenalidomide in combination therapy: acute hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cho­lestatic hepatitis have been reported. The mechanisms of severe drug-induced hepatotoxicity remain unknown although, in some cases, pre-existing viral liver disease, elevated baseline liver enzymes, and possibly treatment with antibiotics might be risk factors.

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

Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal impairment in order to avoid plasma levels which may increase the risk for higher haematological adverse reactions or hepatotoxicity. Monitoring of liver function is recommended, particularly when there is a history ofor concurrent viral liver infection or when lenalidomide is combined with medicinal products known to be associated with liver dysfunction.

Infection with or without neutropenia

Patients with multiple myeloma are prone to develop infections including pneumonia. A higher rate of infections was observed with lenalidomide in combination with dexamethasone than with MPT in patients with NDMM who are not eligible for transplant, and with lenalidomide maintenance compared to placebo in patients with NDMM who had undergone ASCT. Grade > 3 infections occurred within the context of neutropenia in less than one-third of the patients. Patients with known risk factors for infections should be closely monitored. All patients should be advised to seek medical attention promptly at the first sign of infection (eg, cough, fever, etc) thereby allowing for early management to reduce severity.

Viral reactivation

Cases of viral reactivation have been reported in patients receiving lenalidomide, including serious cases of herpes zoster or hepatitis B virus (HBV) reactivation.

Some of the cases of viral reactivation had a fatal outcome.

Some of the cases of herpes zoster reactivation resulted in disseminated herpes zoster, meningitis herpes zoster or ophthalmic herpes zoster requiring a temporary hold or permanent discontinuation of the treatment with lenalidomide and adequate antiviral treatment.

Reactivation of hepatitis B has been reported rarely in patients receiving lenalidomide who have previously been infected with the hepatitis B virus (HBV). Some of these cases have progressed to acute hepatic failure resulting in discontinuation of lenalidomide and adequate antiviral treatment. Hepatitis B virus status should be established before initiating treatment with lenalidomide. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when lenalidomide is used in patients previously infected with HBV, including patients who are anti-HBc positive but HBsAg negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy.

Progressive multifocal leukoencephalo­pathy

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

The evaluation for PML should be based on neurological examination, magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR) or a brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additional follow-up and evaluation may be warranted ifno alternative diagnosis can be established.

If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed, lenalidomide must be permanently discontinued.

Newly diagnosed multiple myeloma patients

There was a higher rate of intolerance (Grade 3 or 4 adverse events, serious adverse events, discontinuation) in patients with age > 75 years, ISS stage III, ECOG PS>2 or CLcr<60 mL/min when lenalidomide is given in combination. Patients should be carefully assessed for their ability to tolerate lenalidomide in combination, with consideration to age, ISS stage III, ECOG PS>2 or CLcr<60 mL/min (see sections 4.2 and 4.8).

Cataract

Cataract has been reported with a higher frequency in patients receiving lenalidomide in combination with dexamethasone particularly when used for a prolonged time. Regular monitoring of visual ability is recommended.

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 ofR- and S- warfarin. Co-administration ofa 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.

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 ofa 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.

In monkeys, lenalidomide induced malformations 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 of25 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

Adverse reactions reported as serious in clinical trials in patients with NDMM who had undergone ASCT

Applies to serious adverse drug reactions only

A 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

◊◊Adverse reactions reported as serious in clinical trials in patients with NDMM who had received lenalidomide in combination with bortezomib and

dexamethasone

ASee section 4.8 description of selected adverse reactions

’ Adverse reactions reported as serious in clinical trials in patients with multiple myeloma treated with lenalidomide in combination with dexamethasone, or with melphalan and prednisone

+ Applies to serious adverse drug reactions only

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

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

Tabulated summary , from monotherapy

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

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

Asee 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 reported as a Grade 3 or 4 adverse event

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

# Algorithm applied for myelodysplastic syndromes:

• – Myelodysplastic syndromes phase 3 study (double-blind safety population, difference between lenalidomide 5/10mg and placebo 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 in proportion between lenalidomide and placebo

o 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 placebo

o 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 subjects

o All treatment-emergent Grade 3 or 4 adverse events in 1% of lenalidomide treated subjects

o All treatment-emergent serious adverse events in 1% of lenalidomide treated subjects

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

Asee 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 inproportion between lenalidomide and control arm

o All treatment-emergent Grade 3 or 4 adverse events in >1% of subjects in lenalidomide arm and at least 1.0% differencein proportion between lenalidomide and control arm

o All Serious treatment-emergent adverse events in >1% of subjects in lenalidomide arm and at least 1.0% differencein proportion between lenalidomide and control arm

– Mantle cell lymphoma single arm phase 2 study

o All treatment-emergent adverse events with > 5% of subjects

o All Grade 3 or 4 treatment-emergent adverse events reported in 2 or more subjects

o 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 with lenalidomide in combination with rituximab

'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% higher frequency (%) 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/ri­tuximab arm 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 at least 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 table is derived from data gathered from post-marketing data.

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

Asee section 4.8 description of selected adverse reactions

Description of selected adverse reactions

Teratogenicity

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. In monkeys, lenalidomide induced malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.

Neutropenia and thrombocytopenia

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

Lenalidomide maintenance after ASCT is associated with a higher frequency of Grade 4 neutropenia compared to placebo maintenance (32.1% vs 26.7% [16.1% vs 1.8% after the start of maintenance treatment] in CALGB 100104 and 16.4% vs 0.7% in IFM 2005–02, respectively). Treatment-emergent AEs of neutropenia leading to lenalidomide discontinuation were reported in 2.2% of patients in CALGB 100104 and 2.4% of patients in IFM 2005–02, respectively. Grade 4 febrile neutropenia was reported at similar frequencies in the lenalidomide maintenance arms compared to placebo maintenance arms in both studies (0.4% vs 0.5% [0.4% vs 0.5% after the start of maintenance treatment] in CALGB 100104 and 0.3% vs 0% in IFM 2005–02, respectively).

Lenalidomide maintenance after ASCT is associated with a higher frequency of Grade 3 or 4 thrombocytopenia compared to placebo maintenance (37.5% vs 30.3% [17.9% vs 4.1% after the start of maintenance treatment] in CALGB 100104 and 13.0% vs 2.9% in IFM 2005–02, respectively).

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

Grade 4 neutropenia was observed in the RVd arm to a lesser extent than in the Rd comparator arm (2.7% vs 5.9%) in the SWOG S0777 study. Grade 4 febrile neutropenia was reported at similar frequencies in the RVd arm compared to the Rd arm (0.0% vs 0.4%).

Grade 3 or 4 thrombocytopenia was observed in the RVd arm to a greater extent than in the Rd comparator arm (17.2 % vs 9.4%).

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

The combination of lenalidomide with dexamethasone in newly diagnosed multiple myeloma patients is associated with a lower frequency of Grade 4 neutropenia (8.5% in Rd and Rd18, compared with MPT (15%). Grade 4 febrile neutropenia was observed infrequently (0.6% in Rd and Rd18 compared with 0.7% in MPT).

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

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

The combination of lenalidomide with melphalan and prednisone in newly diagnosed multiple myeloma patients is associated with a higher frequency of Grade 4 neutropenia (34.1% in MPR+R/MPR+p) compared with MPp+p (7.8%). There was a higher frequency of Grade 4 febrile neutropenia observed (1.7% in MPR+R/MPR+p compared to 0.0% in MPp+p).

The combination of lenalidomide with melphalan and prednisone in newly diagnosed multiple myeloma patients is associated with a higher frequency of Grade 3 and Grade 4 thrombocytopenia (40.4% in MPR+R/MPR+p) compared with MPp+p (13.7%).

Multiple myeloma: patients with at least one prior therapy

The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence ofGrade4 neutropenia (5.1% in lenalidomide/de­xamethasone-treated patients compared with 0.6% in placebo/dexamet­hasone-treated patients). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/de­xamethasone-treated patients compared to 0.0% in placebo/dexamet­hasone treated patients).

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

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

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

Mantle cell lymphoma patients

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

Follicular lymphoma patients

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

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

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

Venous thromboembolism

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

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

Myocardial infarction

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

Haemorrhagic disorders

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

Allergic reactions and severe skin reactions

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

Second primary malignancies

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

Acute myeloid leukaemia

Multiple myeloma

Cases of AML have been observed in clinical trials of newly diagnosed multiple myeloma in patients taking lenalidomide treatment in combination with melphalan or immediately following HDM/ASCT (see section 4.4). This increase was not observed in clinical trials of newly diagnosed multiple myeloma in patients taking lenalidomide in combination with dexamethasone compared to thalidomide in combination with melphalan and prednisone.

Myelodysplastic syndromes

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

In a post-hoc analysis of a clinical trial of lenalidomide in myelodysplastic syndromes, the estimated 2-year rate of progression to AML was 27.5 % in patients with IHC-p53 positivity and 3.6% in patients with IHC- p53 negativity (p=0.0038). In the patients with IHC-p53 positivity, a lower rate of progression to AML was observed amongst patients who achieved a transfusion independence (TI) response (11.1%) compared to a non-responder (34.8%).

Hepatic disorders

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

Rhabdomyolysis

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

Thyroid disorders

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

Tumour , flare reaction and tumour lysis syndrome

In study MCL-002, approximately 10% of lenalidomide-treated patients experienced TFR compared to 0% in the control arm. The majority of the events occurred in cycle 1, all were assessed as treatment-related, and the majority of the reports were Grade 1 or 2. Patients with high MIPI at diagnosis or bulky disease (at least one lesion that is > 7 cm in the longest diameter) at baseline may be at risk of TFR. In study MCL-002, TLS was reported for one patient in each of the two treatment arms. In the supportive study MCL-001, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity and all were assessed as treatment-related. The majority of the events occurred in cycle 1. There were no reports of TLS in study MCL-001 (see section 4.4).

In study NHL-007, TFR was reported in 19/146 (13.0%) of patients in the lenalidomide/ri­tuximab arm versus 1/148 (0.7%) patients in the placebo/rituximab arm. Most TFRs (18 out of 19) reported in the lenalidomide/ri­tuximab arm occurred during first two cycles of treatment. One FL patient in the lenalidomide/ri­tuximab arm experienced a Grade 3 TFR event versus no patients in the placebo/rituximab arm. In study NHL-008, 7/177 (4.0%) of FL patients experienced TFR; (3 reports were Grade 1 and 4 reports were Grade 2 severity); while 1 report was considered serious. In study NHL-007, TLS occurred in 2 FL patients (1.4%) in the lenalidomide/ri­tuximab arm and no FL patients in the placebo/rituximab arm; neither patient had a Grade 3 or 4 event. TLS occurred in 1 FL patient (0.6%) in study NHL-008. This single event was identified as a serious, Grade 3 adverse reaction. For study NHL-007 no patients had to discontinue lenalidomide/ri­tuximab therapy due to TFR or TLS.

Gastrointestinal disorders

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

5.  PHARMACOLOGICAL PROPERTIES

5.1  Pharmacodynamic properties

5.2 Pharmacokinetic properties

Lenalidomide has an asymmetric carbon atom and can therefore exist as the optically active forms S(-) and R(+). Lenalidomide is produced as a racemic mixture. Lenalidomide is generally more soluble in organic solvents but exhibits the greatest solubility in 0.1N HCl buffer.

Absorption

Lenalidomide is rapidly absorbed following oral administration in healthy volunteers, under fasting conditions, with maximum plasma concentrations occurring between 0.5 and 2 hours post-dose. In patients, as well as in healthy volunteers, the maximum concentration (Cmax) and area-under-the-concentration time curve (AUC) increase proportionally with increases in dose. Multiple dosing does not cause marked medicinal product accumulation. In plasma, the relative exposures of the S- and R-enantiomers of lenalidomide are approximately 56% and 44%, respectively.

Co-administration with a high-fat and high-calorie meal in healthy volunteers reduces the extent of absorption, resulting in an approximately 20% decrease in area under the concentration versus time curve (AUC) and 50% decrease in Cmax in plasma. However, in the main multiple myeloma and myelodysplastic syndromes registration trials where the efficacy and safety were established for lenalidomide, the medicinal product was administered without regard to food intake. Thus, lenalidomide can be administered with or without food.

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

Distribution

In vitro (14C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at 23% and 29% in multiple myeloma patients and healthy volunteers, respectively.

Lenalidomide is present in human semen (< 0.01% of the dose) after administration of 25 mg/day and the medicinal product is undetectable in semen of a healthy subject 3 days after stopping the substance (see section 4.4).

Biotransformation and elimination

Results from human in vitro metabolism studies indicate that lenalidomide is not metabolised by cytochrome P450 enzymes suggesting that administration of lenalidomide with medicinal products that inhibit cytochrome P450 enzymes is not likely to result in metabolic medicinal product interactions in humans. In vitro studies indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, or UGT1A1. Therefore, lenalidomide is unlikely to cause any clinically relevant medicinal product interactions when co-administered with substrates of these enzymes.

In vitro studies indicate that lenalidomide is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2.

In vitro studies indicate that lenalidomide has no inhibitory effect on human bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, and OCT2.

A majority of lenalidomide is eliminated through urinary excretion. The contribution of renal excretion to total clearance in subjects with normal renal function was 90%, with 4% of lenalidomide eliminated in faeces.

Lenalidomide is poorly metabolized as 82% of the dose is excreted unchanged in urine. Hydroxylenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is at least actively secreted to some extent.

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

Elderly

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

Renal impairment

The pharmacokinetics of lenalidomide was studied in subjects with renal impairment due to nonmalignant conditions. In this study, two methods were used to classify renal function: the urinary creatinine clearance measured over 24 hours and the creatinine clearance estimated by Cockcroft-Gault formula. The results indicate that as renal function decreases (< 50 mL/min), the total lenalidomide clearance decreases proportionally resulting in an increase in AUC. The AUC was increased by approximately 2.5, 4 and 5-fold in subjects with moderate renal impairment, severe renal impairment, and end-stage renal disease, respectively, compared to the group combining subjects with normal renal function and subjects with mild renal impairment. The half-life of lenalidomide increased from approximately 3.5 hours in subjects with creatinine clearance > 50 mL/min to more than 9 hours in subjects with reduced renal function < 50 mL/min. However, renal impairment did not alter the oral absorption of lenalidomide. The Cmax was similar between healthy subjects and patients with renal impairment. Approximately 30% of the medicinal product in the body was removed during a single 4-hour dialysis session. Recommended dose adjustments in patients with impaired renal function are described in section 4.2.

Hepatic impairment

Population pharmacokinetic analyses included patients with mild hepatic impairment (N=16, total bilirubin >1 to <1.5 x ULN or AST > ULN) and indicate that mild hepatic impairment does not influence lenalidomide clearance (exposure in plasma). There are no data available for patients with moderate to severe hepatic impairment.

Other intrinsic factors

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

5.3 Preclinical safety data

An embryofoetal development study has been conducted in monkeys administered lenalidomide at doses from 0.5 and up to 4 mg/kg/day. Findings from this study indicate that lenalidomide produced external malformations including non-patent anus and malformations of upper and lower extremities (bent, shortened, malformed, malrotated and/or absent part of the extremities, oligo and/or polydactyly) in the offspring of female monkeys who received the active substance during pregnancy.

Various visceral effects (discoloration, red foci at different organs, small colourless mass above atrioventricular valve, small gall bladder, malformed diaphragm) were also observed in single foetuses.

Lenalidomide has a potential for acute toxicity; minimum lethal doses after oral administration were > 2000 mg/kg/day in rodents. Repeated oral administration of 75, 150 and 300 mg/kg/day to rats for up to 26 weeks produced a reversible treatment-related increase in kidney pelvis mineralisation in all 3 doses, most notably in females. The no observed adverse effect level (NOAEL) was considered to be less than 75 mg/kg/day, and is approximately 25-fold greater than the human daily exposure based on AUC exposure. Repeated oral administration of4 and6 mg/kg/day to monkeys for up to 20 weeks produced mortality and significant toxicity (marked weight loss, reduced red and white blood cell and platelet counts, multiple organ haemorrhage, gastrointestinal tract inflammation, lymphoid, and bone marrow atrophy). Repeated oral administration of 1 and 2 mg/kg/day to monkeys for up to 1 year produced reversible changes in bone marrow cellularity, a slight decrease in myeloid/erythroid cell ratio and thymic atrophy. Mild suppression of white blood cell count was observed at 1 mg/kg/day corresponding to approximately the same human dose based on AUC comparisons.

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

Developmental toxicity studies were previously conducted in rabbits. In these studies, rabbits were administered 3, 10 and 20 mg/kg/day orally. An absence of the intermediate lobe of the lung was observed at 10 and 20 mg/kg/day with dose dependence and displaced kidneys were observed at 20 mg/kg/day. Although it was observed at maternotoxic levels they may be attributable to a direct effect. Soft tissue and skeletal variations in the foetuses were also observed at 10 and 20 mg/kg/day.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule contents

Mannitol (E421)

Microcrystalline cellulose (E460)

Pregelatinised maize starch

Tartaric acid (E334) Glycerol dibehenate

Capsule shell

Lenalidomide Krka 2.5 mg hard capsules

Hypromellose

Carrageenan (E407)

Potassium chloride (E508)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Indigo carmine (E132)

Imprinting ink:

• – shellac (E904)

• – black iron oxide (E172)

Lenalidomide Krka 5 mg hard capsules

Hypromellose

Carrageenan (E407)

Potassium chloride (E508)

Titanium dioxide (E171)

Indigo carmine (E132)

Imprinting ink:

• – shellac (E904)

• – black iron oxide (E172)

Lenalidomide Krka 7.5 mg hard capsules

Hypromellose

Carrageenan (E407)

Potassium chloride (E508)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Imprinting ink:

• – shellac (E904)

• – povidone

• – titanium dioxide (E171)

Lenalidomide Krka 10 mg hard capsules

Hypromellose

Carrageenan (E407)

Potassium chloride (E508)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Indigo carmine (E132)

Imprinting ink:

• – shellac (E904)

• – povidone

• – titanium dioxide (E171)

Lenalidomide Krka 15 mg hard capsules

Hypromellose

Carrageenan (E407)

Potassium chloride (E508)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Indigo carmine (E132)

Imprinting ink:

• – shellac (E904)

• – black iron oxide (E172)

Lenalidomide Krka 20 mg hard capsules

Hypromellose

Carrageenan (E407)

Potassium chloride (E508)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Indigo carmine (E132)

Imprinting ink: shellac (E904)

• – black iron oxide (E172)

Lenalidomide Krka 25 mg hard capsules

Hypromellose

Carrageenan (E407)

Potassium chloride (E508)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Imprinting ink:

• – shellac (E904)

• – povidone

• – titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Capsules should not be opened or crushed. If powder from lenalidomide makes contact with the skin, the skin should be washed immediately and thoroughly with soap and water. If lenalidomide makes contact with the mucous membranes, they should be thoroughly flushed with water.

Healthcare professionals and caregivers should wear disposable gloves when handling the blister or capsule. Gloves should then be removed carefully to prevent skin exposure, placed in a sealable plastic polyethylene bag and disposed of in accordance with local requirements. Hands should then be washed thoroughly with soap and water. Women who are pregnant or suspect they may be pregnant should not handle the blister or capsule (see section 4.4).

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

7. MARKETING AUTHORISATION HOLDER

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

8. MARKETING AUTHORISATION NUMBER(S)

Lenalidomide Krka 2.5 mg hard capsules 7 × 1 hard capsule: EU/1/20/1519/001 21 × 1 hard capsule: EU/1/20/1519/002

Lenalidomide Krka 5 mg hard capsules 7 × 1 hard capsule: EU/1/20/1519/003 21 × 1 hard capsule: EU/1/20/1519/004

Lenalidomide Krka 7.5 mg hard capsules 7 × 1 hard capsule: EU/1/20/1519/005 21 × 1 hard capsule: EU/1/20/1519/006

Lenalidomide Krka 10 mg hard capsules 7 × 1 hard capsule: EU/1/20/1519/007 21 × 1 hard capsule: EU/1/20/1519/008

Lenalidomide Krka 15 mg hard capsules 7 × 1 hard capsule: EU/1/20/1519/009 21 × 1 hard capsule: EU/1/20/1519/010

Lenalidomide Krka 20 mg hard capsules 7 × 1 hard capsule: EU/1/20/1519/011 21 × 1 hard capsule: EU/1/20/1519/012

Lenalidomide Krka 25 mg hard capsules 7 × 1 hard capsule: EU/1/20/1519/013 21 × 1 hard capsule: EU/1/20/1519/014

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11 February 2021