Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
When REVLIMID is given in combination with other medicinal products, the corresponding Summary of Product Characteristics must be consulted prior to initiation of treatment.

Embryo-Fetal Toxicity
If REVLIMID is used during pregnancy, it may cause birth defects or death to a developing baby. Females of childbearing potential must be advised to avoid pregnancy while on REVLIMID. Two reliable forms of contraception should be used simultaneously during therapy, during dose interruptions and for at least 4 weeks following discontinuation of therapy.
There are no adequate and well-controlled studies in pregnant females.

REVLIMID can be prescribed only in agreement with RMP limitations.

Reproductive Risk and Special Prescribing Requirements (Revlimid RMP-PPP) Revlimid can be prescribed and dispensed only if following the Revlimid Risk Management Program. All patients must follow the Revlimid Risk Minimization Program in order to receive Revlimid (refer to black box warning section)

Female Patients:
Two effective contraception methods must be used by female patients of childbearing potential for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for 4 weeks following discontinuation of REVLIMID therapy unless continuous abstinence from heterosexual sexual contact is the chosen method. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy, a bilateral oophorectomy, because the patient has been postmenopausal naturally for at least 24 consecutive months or in any other case indicated in Revlimid RMP. Females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature females who have not undergone a hysterectomy, have not had a bilateral oophorectomy, who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) or in any other case indicated in the Revlimid RMP, are considered to be females of childbearing potential.

Cessation of menses due to anti-cancer therapy, do not exclude the potential to become pregnant.

Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method.
Females of childbearing potential must have a negative pregnancy test (sensitivity of at least 25 mIU/mL) before starting the therapy, and then monthly thereafter (including dose interruptions and including 4 weeks following discontinuation of REVLIMID therapy). The test should be performed within 3 days prior to prescribing REVLIMID. A prescription for REVLIMID for a female of childbearing potential must not be issued by the prescriber until a negative pregnancy test has been verified by the prescriber.
Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her pregnancy test or in her menstrual bleeding. REVLIMID therapy must be discontinued during this evaluation.
Pregnancy test results should be verified by the prescriber prior to dispensing any prescription.
If pregnancy does occur during treatment, REVLIMID must be discontinued immediately.
Any suspected fetal exposure to REVLIMID must be reported to the attending physician and Neopharm. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.
Do not breastfeed during therapy (including dose interruptions).

Patients should not donate blood while taking REVLIMID, during any breaks (discontinuations) in your therapy, and for 4 weeks following discontinuation of REVLIMID therapy.

Male Patients:
Clinical data has demonstrated the presence of REVLIMID in human semen. Therefore, males receiving REVLIMID must always use a latex/ polyurethane condom during any sexual contact with females of childbearing potential, even if they have undergone a successful vasectomy. In the case of a male patient with an allergy to latex or polyurethane, at least one highly effective form of contraception should be used by any female sexual partner. Contraception should be started in this partner at least 4 weeks prior to the start of a sexual relationship with the patient and continued throughout REVLIMID therapy including dose interruptions and for 4 weeks following discontinuation of therapy.
Patients should not donate blood and semen or sperm while taking REVLIMID, during any breaks (discontinuations) in your therapy, and for 4 weeks following discontinuation of REVLIMID therapy.

Once treatment has started and during dose interruptions, pregnancy testing for females of childbearing potential should be performed every 4 weeks.

Pregnancy testing should be performed also 4 weeks following discontinuation of REVLIMID therapy.

Prescriptions for women of childbearing potential can be for a maximum duration of treatment of 4 weeks, and prescriptions for all other patients can be for a maximum duration of treatment of 12 weeks.

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.

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.

Other special warnings and precautions for use
Myocardial infarction
Myocardial infarction has been reported in patients receiving REVLIMID, particularly in those with known risk factors and within the first 12 months when used in combination with dexamethasone. Patients with known risk factors – including prior thrombosis – should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (eg. smoking, hypertension, and hyperlipidaemia).

Venous and arterial thromboembolic events
In patients with multiple myeloma, the combination of REVLIMID 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 REVLIMID in combination with melphalan and prednisone.

In patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma, treatment with REVLIMID 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 REVLIMID in combination therapy (see sections 4.5 and 4.8).

In patients with multiple myeloma, the combination of REVLIMID 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 REVLIMID in combination with melphalan and prednisone. The risk of arterial thromboembolism is lower in patients with multiple myeloma treated with REVLIMID monotherapy than in patients with multiple myeloma treated with REVLIMID 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 REVLIMID 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 REVLIMID treatment may be restarted at the original dose dependent upon a benefit risk assessment. The patient should continue anticoagulation therapy during the course of REVLIMID treatment.

Pulmonary hypertension
Cases of pulmonary hypertension, some fatal, have been reported in patients treated with REVLIMID. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during REVLIMID therapy.

Neutropenia and thrombocytopenia
The major dose limiting toxicities of REVLIMID 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 REVLIMID 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 REVLIMID with other myelosuppressive agents should be undertaken with caution.

•   Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with REVLIMID 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 REVLIMID maintenance arms compared to the placebo maintenance arms in the 2 studies evaluating REVLIMID 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 REVLIMID 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 REVLIMID 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 REVLIMID maintenance arms compared to the placebo maintenance arms in studies evaluating REVLIMID 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 treated with REVLIMID in combination with bortezomib and dexamethasone
Grade 4 neutropenia was observed at a lower frequency in the REVLIMID 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%).
Increases in the incidence of Grade 3/ 4 adverse events in the RVd arm versus the Rd arm were most notable for peripheral sensory and motor neuropathy, thrombocytopenia, hypotension, diarrhoea, syncope, hypokalaemia and dehydration.


•   Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with REVLIMID in combination with low dose dexamethasone

Grade 4 neutropenia was observed in the REVLIMID 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 REVLIMID/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 REVLIMID in combination with melphalan and prednisone
The combination of REVLIMID 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 REVLIMID arm followed by REVLIMID [MPR+R] and melphalan, prednisone and REVLIMID 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 REVLIMID 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 REVLIMID 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 REVLIMID/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 REVLIMID/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients; see section 4.8).

The combination of REVLIMID 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 REVLIMID/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients; see section 4.8).

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

The combination of REVLIMID 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 REVLIMID 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 REVLIMID. 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
REVLIMID 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 REVLIMID 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 REVLIMID 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 REVLIMID 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 REVLIMID (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. REVLIMID 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 REVLIMID 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 REVLIMID and thalidomide has been reported in the literature. Patients with a history of severe rash associated with thalidomide treatment should not receive REVLIMID.

Lactose intolerance
Revlimid capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Second primary malignancies
An increase of second primary malignancies (SPM) has been observed in clinical trials in previously treated myeloma patients receiving REVLIMID/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 REVLIMID 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 REVLIMID (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 REVLIMID 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 REVLIMID 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 REVLIMID in combination with bortezomib and dexamethasone, the hematologic SPM incidence rate was 0.00 – 0.16 per 100 person-years and the incidence rate of solid tumour SPM was 0.21 – 1.04 per 100 person-years.
The increased risk of secondary primary malignancies associated with REVLIMID 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 Revlimid 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 REVLIMID arms and 0.58 per 100 person-years for the placebo arms (1.02 per 100 person-years for patients exposed to REVLIMID after ASCT and 0.60 per 100 person-years for patients not-exposed to REVLIMID after ASCT). The incidence rate of solid tumour SPMs was 1.36 per 100 person-years for the REVLIMID arms and 1.05 per 100 person-years for the placebo arms (1.26 per 100 person-years for patients exposed to REVLIMID after ASCT and 0.60 per 100 person-years for patients not-exposed to REVLIMID after ASCT).

The risk of occurrence of hematologic SPM must be taken into account before initiating treatment with REVLIMID 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-risk MDS • 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 REVLIMID 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 REVLIMID 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 REVLIMID 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 REVLIMID/rituximab arm, compared to the placebo/rituximab arm, was observed. Hematologic SPM of AML occurred in 0.29 per 100 person-years in the REVLIMID/rituximab arm compared with 0.29 per 100 person-years in patients receiving placebo/rituximab. The incidence rate of hematologic plus solid tumour SPMs (excluding non-melanoma skin cancers) was 0.87 per 100 person-years in the REVLIMID/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 REVLIMID and the risk of SPMs should be considered when considering treatment with REVLIMID.

Hepatic disorders
Hepatic failure, including fatal cases, has been reported in patients treated with REVLIMID 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.

REVLIMID is excreted by the kidneys. It is important to dose adjust patients with renal impairment in order to avoid plasma levels which may increase the risk for higher haematological adverse reactions or hepatotoxicity.
Monitoring of liver function is recommended, particularly when there is a history of or concurrent viral liver infection or when REVLIMID 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 REVLIMID in combination with dexamethasone than with MPT in patients with NDMM who are not eligible for transplant, and with REVLIMID 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 (e.g. cough, fever, etc.) thereby allowing for early management to reduce severity.

Viral reactivation
Cases of viral reactivation have been reported in patients receiving REVLIMID, 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 REVLIMID and adequate antiviral treatment.

Reactivation of hepatitis B has been reported rarely in patients receiving REVLIMID who have previously been infected with the hepatitis B virus. Some of these cases have progressed to acute hepatic failure resulting in discontinuation of REVLIMID and adequate antiviral treatment. Hepatitis B virus status should be established before initiating treatment with REVLIMID. 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 REVLIMID 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 REVLIMID. PML was reported several months to several years after starting the treatment with REVLIMID.
Cases have generally been reported in patients taking concomitant dexamethasone or prior treatment with other immunosuppressive chemotherapy. Physicians should monitor patients at regular intervals and should consider PML in the differential diagnosis in patients with new or worsening neurological symptoms, cognitive or behavioural signs or symptoms. Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

The evaluation for PML should be based on neurological examination, magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR) or a brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additional follow-up and evaluation may be warranted if no alternative diagnosis can be established.

If PML is suspected, further dosing must be suspended until PML has been excluded. If PML is confirmed, REVLIMID 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 REVLIMID is given in combination. Patients should be carefully assessed for their ability to tolerate REVLIMID 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 REVLIMID in combination with dexamethasone particularly when used for a prolonged time. Regular monitoring of visual ability is recommended.

Effects on Driving

4.7   Effects on ability to drive and use machines

REVLIMID 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 REVLIMID. Therefore, caution is recommended when driving or operating machines.