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英文药名: Revlimid(Lenalidomide capsules) 中文药名: 来那度胺胶囊（雷利米得胶囊）
Myelodysplastic syndromes Lenalidomide treatment must not be started if the Absolute Neutrophil Counts (ANC) < 0.5 x 109/l and/or platelet counts < 25 x 109/l. Recommended dose The recommended starting dose of lenalidomide is 10 mg orally once daily on days 1-21 of repeated 28-day cycles. Dosing is continued or modified based upon clinical and laboratory findings (see section 4.4). Recommended dose adjustments during treatment and restart of treatment Dose adjustments, as summarized below, are recommended to manage grade 3 or 4 neutropenia or thrombocytopenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide. • Dose reduction steps
• Thrombocytopenia
For other grade 3 or 4 toxicities judged to be related to lenalidomide, stop treatment and restart at next lower dose level when toxicity has resolved to ≤ grade 2 depending on the physician's discretion. Lenalidomide interruption or discontinuation should be considered for grade 2 or 3 skin rash. Lenalidomide must be discontinued for angioedema, grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, and should not be resumed following discontinuation from these reactions. Discontinuation of lenalidomide Patients without at least a minor erythroid response within 4 months of therapy initiation, demonstrated by at least a 50% reduction in transfusion requirements or, if not transfused, a 1g/dl rise in haemoglobin, should discontinue lenalidomide treatment. Special populations Paediatric population The safety and efficacy of Revlimid in children aged 0-17 years have not yet been established. No data are available. Elderly population The effects of age on the pharmacokinetics of lenalidomide have not been studied. Lenalidomide has been used in clinical trials in multiple myeloma patients up to 86 years of age and in myelodysplastic syndromes patients up to 95 years of age (see section 5.1). The percentage of multiple myeloma patients aged 65 or over was not significantly different between the lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in safety or efficacy was observed between these patients and younger patients, but greater pre-disposition of older individuals cannot be ruled out. For myelodysplastic syndromes patients treated with lenalidomide, no overall difference in safety and efficacy was observed between patients aged over 65 and younger patients. 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. Patients with renal impairment Lenalidomide is substantially excreted by the kidney, therefore care should be taken in dose selection and monitoring of renal function is advised. No dose adjustments are required for patients with mild renal impairment and multiple myeloma or myelodysplastic syndromes. The following dose adjustments are recommended at the start of therapy for patients with moderate or severe impaired renal function or end stage renal disease. • Multiple myeloma
2 In countries where the 7.5 mg capsule is available. 3 The dose may be escalated to 10 mg once daily if the patient is tolerating the treatment. After initiation of lenalidomide therapy, subsequent lenalidomide dose modification in renally impaired patients should be based on individual patient treatment tolerance, as described above. • Myelodysplastic syndromes
Lenalidomide has not formally been studied in patients with impaired hepatic function and there are no specific dose recommendations. Method of administration Revlimid capsules should be taken at about the same time each day. The capsules should not be opened, broken or chewed. The capsules should be swallowed whole, preferably with water, either with or without food. If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next dose at the normal time on the following day. 4.3 Contraindications • Women who are pregnant. • Women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met (see sections 4.4 and 4.6). • Hypersensitivity to the active substance or to any of the excipients, listed in section 6.1. 4.4 Special warnings and precautions for use Pregnancy warning Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected. The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential. Criteria for women of non-childbearing potential A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria: • Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year* • Premature ovarian failure confirmed by a specialist gynaecologist • Previous bilateral salpingo-oophorectomy, or hysterectomy • XY genotype, Turner syndrome, uterine agenesis. *Amenorrhoea following cancer therapy or during lactation does not rule out childbearing potential. 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, 4 weeks before starting treatment, throughout the entire duration of treatment, and 4 weeks after the end of treatment • Even if a woman of childbearing potential has amenorrhea she must follow all the advice on effective contraception • She should be capable of complying with effective contraceptive measures • She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy • She understands the need to commence contraceptive measures as soon as lenalidomide is dispensed following a negative pregnancy test • She understands the need and accepts to undergo pregnancy testing 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, 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 1 week after dose interruptions and/or cessation of treatment. • Understand that if his female partner becomes pregnant whilst he is taking Revlimid or shortly after he has stopped taking Revlimid, 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 one effective method of contraception for 4 weeks before therapy, during therapy, and until 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 and dexamethasone, and to a lesser extent in patients with myelodysplastic syndromes 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 method 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 every 4 weeks, including 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. Men 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 not using effective contraception (even if the man has had a vasectomy). 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. Patients should not donate blood during therapy or for 1 week following discontinuation of lenalidomide. Educational materials, prescribing and dispensing restrictions In order to assist patients in avoiding foetal exposure to lenalidomide, the Marketing Authorisation Holder will provide educational material to health care professionals to reinforce the warnings about the expected teratogenicity of lenalidomide, to provide advice on contraception before therapy is started, and to provide guidance on the need for pregnancy testing. The prescriber must inform male and female patients about the expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme and provide patients with appropriate patient educational brochure, patient card and/or equivalent tool in accordance to the national implemented patient card system. A national controlled distribution system has been implemented in collaboration with each National Competent Authority. The controlled distribution system includes the use of a patient card and/or equivalent tool for prescribing and/or dispensing controls, and the collecting of detailed data relating to the indication in order to monitor closely the off-label use within the national territory. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the prescription and following a medically supervised negative pregnancy test result. Other special warnings and precautions for use Cardiovascular disorders Myocardial infarction Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors. Patients with known risk factors – including prior thrombosis – should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (eg. smoking, hypertension, and hyperlipidaemia). Venous and arterial thromboembolic events In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (predominantly myocardial infarction and cerebrovascular event) – see sections 4.5 and 4.8. In patients with myelodysplatic syndromes, treatment with lenalidomide monotherapy was also associated with a risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism), but to a lesser extent than in patients with multiple myeloma – see sections 4.5 and 4.8. Consequently, patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Concomitant administration of erythropoietic agents or previous history of thromboembolic events may also increase thrombotic risk in these patients. Therefore, erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone. A haemoglobin concentration above 12 g/dl should lead to discontinuation of erythropoietic agents. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Prophylactic antithrombotic medicines should be recommended, especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's underlying risk factors. If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, the lenalidomide treatment may be restarted at the original dose dependent upon a benefit risk assessment. The patient should continue anticoagulation therapy during the course of lenalidomide treatment. 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. 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. Co-administration of lenalidomide with other myelosuppressive agents should be undertaken with caution. • Multiple myeloma The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated patients; 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). Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in case of concomitant medication susceptible to induce bleeding (see section 4.8 Haemorrhagic disorders). • 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). Renal impairment Lenalidomide is substantially excreted by the kidney. Therefore care should be taken in dose selection and monitoring of renal function is advised in patients with renal impairment (see section 4.2). 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. At this time, the neurotoxic potential of lenalidomide associated with long-term use cannot be ruled out. Tumour lysis syndrome Because lenalidomide has anti-neoplastic activity the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Allergic reactions Cases of allergic reaction/hypersensitivity reactions have been reported (see section 4.8). Patients who had previous allergic reactions while treated with thalidomide should be monitored closely, as a possible cross-reaction between lenalidomide and thalidomide has been reported in the literature. Severe skin reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Lenalidomide must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected, and should not be resumed following discontinuation for these reactions. Interruption or discontinuation of lenalidomide should be considered for other forms of skin reaction depending on severity. Patients with a history of severe rash associated with thalidomide treatment should not receive lenalidomide. 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. Unused capsules Patients should be advised never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of the treatment. 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 patient-years) compared to controls (1.38 per 100 patient-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, a 4-fold increased incidence of SPM has been observed in patients receiving Revlimid (7.0%) compared with controls (1.8%). Among invasive SPMs, cases of AML, MDS and solid tumours were observed in patients receiving Revlimid in combination with melphalan or immediately following high dose melphalan and ASCT; cases of B-cell malignancies (including Hodgkin's lymphoma) were observed in the clinical trials where patients received Revlimid in the post ASCT setting. The risk of occurrence of SPM must be taken into account before initiating treatment with Revlimid. 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) Hepatic Disorders Hepatic failure, including fatal cases, has been reported in patients treated with lenalidomide in combination with dexamethasone: 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 side effects or hepatotoxicity. Monitoring of liver function is recommended, particularly when there is a history of or concurrent viral liver infection or when lenalidomide is combined with medications known to be associated with liver dysfunction. 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 drugs, 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 doses of 10 mg of lenalidomide had no effect on the single dose pharmacokinetics of R- and S- warfarin. Co-administration of a single 25 mg dose of warfarin had no effect on the pharmacokinetics of lenalidomide. However, it is not known whether there is an interaction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is a weak to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin concentration is advised during the treatment. Digoxin Concomitant administration with lenalidomide 10 mg/day 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 therapeutic situation (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. Interactions with other medicines Co-administration of lenalidomide, a P-gp substrate, with known P-gp inhibitors (cyclosporine, clarithromycin, itraconazole, ketoconazole, quinidine, verapamil) may increase its plasma levels and thus its toxicity. If such a combination is to be given, patients should be closely monitored for the occurrence of side- effects. Results from human in vitro metabolism studies indicate that lenalidomide is not metabolised by cytochrome P450 enzymes suggesting that administration of lenalidomide with drugs that inhibit cytochrome P450 enzymes is not likely to result in metabolic drug interactions in man. In vitro studies indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A. 4.6 Fertility, pregnancy and lactation Women of childbearing potential / Contraception in males and females Women of childbearing potential should use effective method of contraception. If pregnancy occurs in a woman treated with lenalidomide, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking lenalidomide, it is recommended to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice. Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after stopping the substance in the healthy subject (see section 5.2). As a precaution, and taking into account special populations with prolonged elimination time such as renal impairment, all male patients taking lenalidomide should use condoms throughout treatment duration, during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception. Pregnancy Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys 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 human milk. Therefore breast-feeding should be discontinued during therapy with lenalidomide. Fertility A fertility study in rats with lenalidomide doses up to 500 mg/kg (approximately 200 to 500 times the human doses of 25 mg and 10 mg, respectively, based on body surface area) produced no adverse effects on fertility and no parental toxicity. 4.7 Effects on ability to drive and use machines Lenalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, somnolence 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 Multiple myeloma In two Phase III placebo-controlled studies, 353 patients with multiple myeloma were exposed to the lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination. The most serious adverse reactions were: • Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4) • Grade 4 neutropenia (see section 4.4). The most frequently observed adverse reactions which occurred with lenalidomide 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 Revlimid in patients with myelodysplastic syndromes is based on data from a total of 286 patients from one Phase II study and one Phase III study (see section 5.1). In the Phase II, all 148 patients were on lenalidomide treatment. In the Phase III 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 events 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 frequently observed adverse reactions which occurred more frequently in the lenalidomide groups compared to the control arm in the Phase III 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%). Tabulated list of adverse reactions The adverse reactions observed in patients treated for multiple myeloma or myelodysplastic syndromes 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). The following table is derived from data gathered during the main studies in multiple myeloma and myelodysplastic syndromes and from post-marketing data for multiple myeloma only. The data were not adjusted according to the greater duration of treatment in the lenalidomide/dexamethasone versus the placebo/dexamethasone arms in the pivotal multiple myeloma studies (see section 5.1). Adverse reactions have been included under the appropriate category in the table below according to the highest frequency observed in any of the major clinical trials. Table 1: ADRs reported in clinical studies and post-marketing data in patients with multiple myeloma or in clinical trials in patients with myelodysplastic syndromes treated with lenalidomide#
†reports from post-marketing data ◊Adverse events reported as serious in myelodysplastic syndromes clinical trials. +Pneumonia was reported as a very common serious adverse event in the myelodysplastic syndromes Phase II study ~Altered mood was reported as a common serious adverse event in the myelodysplastic syndromes Phase III study; it was not reported as a grade 3 or 4 adverse event # Algorithm applied for myelodysplastic syndromes: • Myelodysplastic syndromes phase III 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 II 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 • Algorithm applied for inclusion in the SmPC: All ADRs captured by the Phase III study algorithm are included in the EU SmPC. For these ADRs, an additional check of the frequency of the ADRs captured by the Phase II study algorithm was undertaken and, if the frequency of the ADRs in the Phase II study was higher than in the Phase III study, the event was included in the EU SmPC at the frequency it occurred in the Phase II study. 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. Lenalidomide induced in monkeys malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected. Neutropenia and thrombocytopenia • Multiple myeloma The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0% in placebo/dexamethasone treated patients). The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in placebo/dexamethasone-treated patients). • Myelodysplastic syndromes 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 III 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 III study). Venous thromboembolism An increased risk of DVT and PE is associated with the use of lenalidomide with dexamethasone in patients with multiple myeloma, and to a lesser extent in patients with myelodysplastic syndromes treated with lenalidomide monotherapy (see section 4.5). Concomitant administration of erythropoietic agents or previous history of DVT may also increase thrombotic risk in these patients. Myocardial infarction Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors. Haemorrhagic disorders Haemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system disorders; nervous system disorders (intracranial haemorrhage); respiratory, thoracic and mediastinal disorders (epistaxis); gastrointestinal disorders (gingival bleeding, haemorrhoidal haemorrhage, rectal haemorrhage); renal and urinary disorders (haematuria); injury, poisoning and procedural complications (contusion) and vascular disorders (ecchymosis). Allergic reactions Cases of allergic reaction/hypersensitivity reactions have been reported. A possible cross-reaction between lenalidomide and thalidomide has been reported in the literature. Severe skin reactions SJS and TEN have been reported. Patients with a history of severe rash associated with thalidomide treatment should not receive lenalidomide. 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 high dose melphalan and ASCT (see section 4.4). • 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 Revlimid 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 hepatic disorders 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). 4.9 Overdose There is no specific experience in the management of lenalidomide overdose in patients, although in dose-ranging studies some patients were exposed to up to 150 mg, and in single-dose studies, some patients were exposed to up to 400 mg. The dose limiting toxicity in these studies was essentially haematological. In the event of overdose, supportive care is advised. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunomodulating agent. ATC code: L04AX04. Mechanism of action The lenalidomide mechanism of action includes anti-neoplastic, anti-angiogenic, pro-erythropoietic, and immunomodulatory properties. Specifically, lenalidomide inhibits proliferation of certain haematopoietic tumour cells (including MM plasma tumour cells and those with deletions of chromosome 5), enhances T cell- and Natural Killer (NK) cell-mediated immunity and increases the number of NK T cells, inhibits angiogenesis by blocking the migration and adhesion of endothelial cells and the formation of microvessels, augments foetal haemoglobin production by CD34+ haematopoietic stem cells, and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In MDS Del (5q), lenalidomide was shown to selectively inhibit the abnormal clone by increasing the apoptosis of Del (5q) cells. Clinical efficacy and safety Multiple myeloma The efficacy and safety of lenalidomide were evaluated in two Phase III multi-centre, randomised, double-blind, placebo-controlled, parallel-group controlled studies (MM-009 and MM-010) of lenalidomide plus dexamethasone therapy versus dexamethasone alone in previously treated patients with multiple myeloma. Out of 353 patients in the MM-009 and MM-010 studies who received lenalidomide/dexamethasone, 45.6% were aged 65 or over. Of the 704 patients evaluated in the MM-009 and MM-010 studies, 44.6% were aged 65 or over. In both studies, patients in the lenalidomide/dexamethasone (len/dex) group took 25 mg of lenalidomide orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22 to 28 of each 28-day cycle. Patients in the placebo/dexamethasone (placebo/dex) group took 1 placebo capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy. The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue until disease progression. In both studies, dose adjustments were allowed based on clinical and laboratory finding. The primary efficacy endpoint in both studies was time to progression (TTP). In total, 353 patients were evaluated in the MM-009 study; 177 in the lenalidomide/dexamethasone group and 176 in the placebo/dexamethasone group and, in total, 351 patients were evaluated in the MM-010 study; 176 in the lenalidomide/dexamethasone group and 175 in the placebo/dexamethasone group. In both studies, the baseline demographic and disease-related characteristics were comparable between the lenalidomide/dexamethasone and placebo/dexamethasone groups. Both patient populations presented a median age of 63 years, with a comparable male to female ratio. The ECOG performance status was comparable between both groups, as was the number and type of prior therapies. Pre-planned interim analyses of both studies showed that lenalidomide/dexamethasone was statistically significantly superior (p < 0.00001) to dexamethasone alone for the primary efficacy endpoint, TTP (median follow-up duration of 98.0 weeks). Complete response and overall response rates in the lenalidomide/dexamethasone arm were also significantly higher than the dexamethasone/placebo arm in both studies. Results of these analyses subsequently led to an unblinding in both studies, in order to allow patients in the placebo/dexamethasone group to receive treatment with the lenalidomide/dexamethasone combination. An extended follow-up efficacy analysis was conducted with a median follow-up of 130.7 weeks. Table 1 summarises the results of the follow-up efficacy analyses – pooled studies MM-009 and MM-010. In this pooled extended follow-up analysis, the median TTP was 60.1 weeks (95% CI: 44.3, 73.1) in patients treated with lenalidomide/dexamethasone (N = 353) versus 20.1 weeks (95% CI: 17.7, 20.3) in patients treated with placebo/dexamethasone (N = 351). The median progression free survival was 48.1 weeks (95% CI: 36.4, 62.1) in patients treated with lenalidomide/dexamethasone versus 20.0 weeks (95% CI: 16.1, 20.1) in patients treated with placebo/dexamethasone. The median duration of treatment was 44.0 weeks (min: 0.1, max: 254.9) for lenalidomide/dexamethasone and 23.1 weeks (min: 0.3, max: 238.1) for placebo/dexamethasone. Complete response (CR), partial response (PR) and overall response (CR+PR) rates in the lenalidomide/dexamethasone arm remain significantly higher than in the dexamethasone/placebo arm in both studies. The median overall survival in the extended follow-up analysis of the pooled studies is 164.3 weeks (95% CI: 145.1, 192.6) in patients treated with lenalidomide/dexamethasone versus 136.4 weeks (95% CI: 113.1, 161.7) in patients treated with placebo/dexamethasone. Despite the fact that 170 out of the 351 patients randomised to placebo/dexamethasone received lenalidomide after disease progression or after the studies were unblinded, the pooled analysis of overall survival demonstrated a statistically significant survival advantage for lenalidomide/dexamethasone relative to placebo/dexamethasone (hazard ratio = 0.833, 95% CI = [0.687, 1.009], p=0.045). Table 1: Summary of Results of Efficacy Analyses as of cut-off date for extended follow-up — Pooled Studies MM-009 and MM-010 (cut-offs 23 July 2008 and 2 March 2008, respectively)
b: Two-tailed continuity-corrected chi-square test. Exploratory study An open-label, randomized, multicenter, Phase 3 study was conducted in 445 patients with newly diagnosed multiple myeloma; 222 patients were randomized to the lenalidomide/low dose dexamethasone arm, and 223 were randomized to the lenalidomide/standard dose dexamethasone arm. Patients randomized to the lenalidomide/standard dose dexamethasone arm received lenalidomide 25 mg/day, Days 1 to 21 every 28 days plus dexamethasone 40 mg/day on Days 1 to 4, 9 to 12, and 17 to 20 every 28 days for the first four cycles. Patients randomized to the lenalidomide/low dose dexamethasone arm received lenalidomide 25 mg/day, Days 1 to 21 every 28 days plus low dose dexamethasone – 40 mg/day on Days 1, 8, 15, and 22 every 28 days. In the lenalidomide/low dose dexamethasone group, 20 patients (9.1%) underwent at least one dose interruption compared to 65 patients (29.3%) in the lenalidomide/standard dose dexamethasone arm. In a post-hoc analysis, lower mortality was observed in the lenalidomide/low dose dexamethasone arm 6.8% (15/220) compared to the lenalidomide/standard dose dexamethasone arm 19.3% (43/223), in the newly diagnosed multiple myeloma patient population, with a median follow up of 72.3 weeks. However with a longer follow-up, the difference in overall survival in favour of low dose dexamethasone tends to decrease. Considering that the patient population differs from the authorised indication, these results should be interpreted with caution. Myelodysplastic Syndromes The efficacy and safety of lenalidomide were evaluated in patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality, with or without additional cytogenetic abnormalities, in two main studies: a Phase III, multicentre, randomised, double-blind, placebo-controlled, 3-arm study of two doses of oral lenalidomide (10 mg and 5 mg) versus placebo (MDS-004); and a Phase II, a multicentre, single-arm, open-label study of lenalidomide (10 mg) (MDS-003). The results presented below represent the intent-to-treat population studied in MDS-003 and MDS-004; with the results in the isolated Del (5q) sub-population also shown separately (see section 4.1 for the approved indication). In study MDS-004, in which 205 patients were equally randomised to receive lenalidomide 10 mg, 5 mg or placebo, the primary efficacy analysis consisted of a comparison of the transfusion-independence response rates of the 10 mg and 5 mg lenalidomide arms versus the placebo arm (double-blind phase 16 to 52 weeks and open-label up to a total of 156 weeks). Patients who did not have evidence of at least a minor erythroid response after 16 weeks were to be discontinued from treatment. Patients who had evidence of at least a minor erythroid response could continue therapy until erythroid relapse, disease progression or unacceptable toxicity. Patients, who initially received placebo or 5 mg lenalidomide and did not achieve at least a minor erythroid response after 16 weeks of treatment were permitted to switch from placebo to 5 mg lenalidomide or continue lenalidomide treatment at higher dose (5 mg to 10 mg). In, study MDS-003, in which 148 patients received lenalidomide at a dose of 10 mg, the primary efficacy analysis consisted of an evaluation of the efficacy of lenalidomide treatments to achieve haematopoietic improvement in subjects with low- or intermediate-1 risk myelodysplastic syndromes. Table 2: Summary of efficacy results – studies MDS-004 (double-blind phase) and MDS-003, intent-to-treat population
†† Subjects treated with lenalidomide 5 mg on 28 days of 28-day cycles * The majority of patients on placebo discontinued the double-blind treatment for lack of efficacy after 16 weeks of treatment before entering the open-label phase #Associated with an increase in Hgb of ≥ 1g/dL ∞ Not reached (i.e. the median was not reached) In MDS-004, a significant larger proportion of patients with myelodysplastic syndromes achieved the primary endpoint of transfusion independence (>182 days) on lenalidomide 10 mg compared with placebo (55.1% vs. 6.0%). Amongst the 47 patients with an isolated Del (5q) cytogenetic abnormality and treated with lenalidomide 10 mg, 27 patients (57.4%) achieved red blood cell transfusion independence. The median time to transfusion independence in the lenalidomide 10 mg arm was 4.6 weeks. The median duration of transfusion independence was not reached in any of the treatment arms, but should exceed 2 years for the lenalidomide-treated subjects. The median increase in haemoglobin (Hgb) from baseline in the 10 mg arm was 6.4 g/dL. Additional endpoints of the study included cytogenetic response (in the 10 mg arm major and minor cytogenetic responses were observed in 30.0% and 24.0% of subjects, respectively), assessment of Health Related Quality of Life (HRQoL) and progression to acute myeloid leukaemia. Results of the cytogenetic response and HRQoL were consistent with the findings of the primary endpoint and in favour of lenalidomide treatment compared to placebo. In MDS-003, a large proportion of patients with myelodysplastic syndromes achieved transfusion independence (>182 days) on lenalidomide 10 mg (58.1%). The median time to transfusion independence was 4.1 weeks. The median duration of transfusion independence was 114.4 weeks. The median increase in haemoglobin (Hgb) was 5.6 g/dL. Major and minor cytogenetic responses were observed in 40.9% and 30.7% of subjects, respectively. A large proportion of subjects enrolled in MDS-003 (72.9%) and MDS-004 (52.7%) had received prior erythropoiesis-stimulating agents. The European Medicines Agency has waived the obligation to submit the results of studies with Revlimid in all subsets of the paediatric population in multiple myeloma and myelodysplastic syndromes (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Lenalidomide has an asymmetric carbon atom and can therefore exist as the optically active forms S(-) and R(+). Lenalidomide is produced as a racemic mixture. Lenalidomide is generally more soluble in organic solvents but exhibits the greatest solubility in 0.1N HCl buffer. Absorption Lenalidomide is rapidly absorbed following oral administration in healthy volunteers, under fasting conditions, with maximum plasma concentrations occurring between 0.5 and 2 hours post-dose. In patients, as well as in healthy volunteers, the maximum concentration (Cmax) and area-under-the-concentration time curve (AUC) increase proportionally with increases in dose. Multiple dosing does not cause marked drug 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 drug was administered without regard to food intake. Thus, lenalidomide can be administered with or without food. Distribution In vitro (14C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at 23% and 29% in multiple myeloma patients and healthy volunteers, respectively. Lenalidomide is present in human semen (< 0.01% of the dose) after administration of 25 mg/day and the drug is undetectable in semen of a healthy subject 3 days after stopping the substance (see section 4.4). Biotransformation and elimination In vitro studies indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. A majority of lenalidomide is eliminated through urinary excretion. The contribution of renal excretion to total clearance in subjects with normal renal function was 90%, with 4% of lenalidomide eliminated in faeces. Lenalidomide is poorly metabolized as 82% of the dose is excreted unchanged in urine. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is at least actively secreted to some extent. At doses of 5 to 25 mg/day, half-life in plasma is approximately 3 hours in healthy volunteers and ranges from 3 to 5 hours in patients with multiple myeloma or myelodysplastic syndromes. 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 drug 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 drug 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. 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 drug during pregnancy. Various visceral effects (discoloration, red foci at different organs, small colourless mass above atrio-ventricular valve, small gall bladder, malformed diaphragm) were also observed in single foetuses. Lenalidomide has a potential for acute toxicity; minimum lethal doses after oral administration were > 2000 mg/kg/day in rodents. Repeated oral administration of 75, 150 and 300 mg/kg/day to rats for up to 26 weeks produced a reversible treatment-related increase in kidney pelvis mineralisation in all 3 doses, most notably in females. The no observed adverse effect level (NOAEL) was considered to be less than 75 mg/kg/day, and is approximately 25-fold greater than the human daily exposure based on AUC exposure. Repeated oral administration of 4 and 6 mg/kg/day to monkeys for up to 20 weeks produced mortality and significant toxicity (marked weight loss, reduced red and white blood cell and platelet counts, multiple organ haemorrhage, gastrointestinal tract inflammation, lymphoid, and bone marrow atrophy). Repeated oral administration of 1 and 2 mg/kg/day to monkeys for up to 1 year produced reversible changes in bone marrow cellularity, a slight decrease in myeloid/erythroid cell ratio and thymic atrophy. Mild suppression of white blood cell count was observed at 1 mg/kg/day corresponding to approximately the same human dose based on AUC comparisons. In vitro (bacterial mutation, human lymphocytes, mouse lymphoma, Syrian Hamster Embryo cell transformation) and in vivo (rat micronucleus) mutagenicity studies revealed no drug related effects at either the gene or chromosomal level. Carcinogenicity studies with lenalidomide have not been conducted. Developmental toxicity studies were previously conducted in rabbits. In these studies, rabbits were administered 3, 10 and 20 mg/kg/day orally. An absence of the intermediate lobe of the lung was observed at 10 and 20 mg/kg/day with dose dependence and displaced kidneys were observed at 20 mg/kg/day. Although it was observed at maternotoxic levels they may be attributable to a direct effect. Soft tissue and skeletal variations in the foetuses were also observed at 10 and 20 mg/kg/day. 6. Pharmaceutical particulars 6.1 List of excipients Revlimid 2.5 mg Capsule contents: Lactose, anhydrous Cellulose, microcrystalline Croscarmellose sodium Magnesium stearate Capsule shell: Gelatin Titanium dioxide (E171) Indigo carmine (E132) Yellow iron oxide (E172) Printing ink: Shellac Propylene glycol Black iron oxide (E172) Potassium hydroxide Revlimid 5 mg Capsule contents: Lactose, anhydrous Cellulose, microcrystalline Croscarmellose sodium Magnesium stearate Capsule shell: Gelatin Titanium dioxide (E171) Printing ink: Shellac Propylene glycol Black iron oxide (E172) Potassium hydroxide Revlimid 7.5 mg Capsule contents: Lactose, anhydrous Cellulose, microcrystalline Croscarmellose sodium Magnesium stearate Capsule shell: Gelatin Titanium dioxide (E171) Yellow iron oxide (E172) Printing ink: Shellac Propylene glycol Black iron oxide (E172) Potassium hydroxide Revlimid 10 mg Capsule contents: Lactose, anhydrous Cellulose, microcrystalline Croscarmellose sodium Magnesium stearate Capsule shell: Gelatin Titanium dioxide (E171) Indigo carmine (E132) Yellow iron oxide (E172) Printing ink: Shellac Propylene glycol Black iron oxide (E172) Potassium hydroxide Revlimid 15 mg Capsule contents: Lactose, anhydrous Cellulose, microcrystalline Croscarmellose sodium Magnesium stearate Capsule shell: Gelatin Titanium dioxide (E171) Indigo carmine (E132) Printing ink: Shellac Propylene glycol Black iron oxide (E172) Potassium hydroxide Revlimid 25 mg Capsule contents: Lactose, anhydrous Cellulose, microcrystalline Croscarmellose sodium Magnesium stearate Capsule shell: Gelatin Titanium dioxide (E171) Printing ink: Shellac Propylene glycol Black iron oxide (E172) Potassium hydroxide 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 Revlimid 2.5 mg Polyvinylchloride (PVC) / Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blisters. Pack size of 7 or 21 capsules. Revlimid 5 mg Polyvinylchloride (PVC) / Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blisters. Pack size of 7 or 21 capsules Revlimid 7.5 mg Polyvinylchloride (PVC) / Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blisters. Pack size of 21 capsules. Revlimid 10 mg Polyvinylchloride (PVC) / Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blisters. Pack size of 21 capsules. Revlimid 15 mg Polyvinylchloride (PVC) / Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blisters. Pack size of 21 capsules. Revlimid 25 mg Polyvinylchloride (PVC) / Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blisters. Pack size of 21 capsules. 6.6 Special precautions for disposal and other handling Unused medicinal product should be returned to the pharmacist. 7. Marketing authorisation holder Celgene Europe Limited 1 Longwalk Road Stockley Park Uxbridge UB11 1DB United Kingdom 8. Marketing authorisation number(s) EU/1/07/391/001 EU/1/07/391/002 EU/1/07/391/003 EU/1/07/391/004 EU/1/07/391/005 EU/1/07/391/006 EU/1/07/391/007 EU/1/07/391/008 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 14 June 2007 Date of first renewal: 14 June 2012 10. Date of revision of the text 20/02/2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/. 美国食品药品管理局核准REVLIMID®（来那度胺）用于治疗复发性或难治性套细胞淋巴瘤患者 2013年6月7日，美国食品药品管理局(FDA)已核准该公司REVLIMID（来那度胺）用于治疗经2种药物（其中一种为硼替佐米）治疗后仍然复发或进展的套细胞淋巴瘤(MCL)患者的补充新药申请(sNDA)。 Hackensack UMC的John Theurer癌症中心淋巴瘤负责人、Regional Cancer Care Associates, LLC首席科学官兼研究创新总监Andre Goy, M.D., M.S.说：“既往治疗过的套细胞淋巴瘤患者有巨大的需求未获满足，来那度胺获得核准后，提供了一个新选择，它是淋巴瘤这一领域的首个口服药。” 该核准依据的是MCL-001的结果，这是一项II期多中心单组开放研究，评估来那度胺用于利妥昔单抗、环磷酰胺、阿霉素（或米托蒽醌）、硼替佐米单药或联合治疗过的134例MCL患者。患者必须有难治性（定义为硼替佐米单药或联合方案治疗中毫无缓解、部分缓解或没有好转）或复发性（定义为硼替佐米单药或联合方案治疗后1年内进展）疾病的记载。肌酐清除率≥60毫升/分钟的患者，口服来那度胺25毫克，每天1次，每28天用药21天。肌酐清除率≥30毫升/分钟但<60毫升/分钟的患者，口服来那度胺10毫克，每天1次，每28天用药21天。 该研究主要终点（经放射学扫描复核的总缓解率，由独立评审委员会按国际淋巴瘤工作组缓解标准修订版进行复核）为26% (34/133) (95% CI 18.4, 33.9)，完全缓解率(CR/CRu)为7% (9/133) (95% CI 3.1, 12.5)。中位缓解持续时间为16.6个月(95% CI, 7.7, 26.7)。 REVLIMID是沙利度胺的类似物，禁用于妊娠，妊娠期间若使用，可能导致出生缺陷或胚胎-胎儿死亡。该药仅通过一项名为REVLIMID REMS?的特别限制性分销计划供药。Revlimid可引起严重的中性粒细胞减少和血小板减少。REVLIMID治疗过的患者可发生深静脉血栓形成(DVT)和肺栓塞(PE)。REVLIMID治疗的患者中，有变态反应的报道，包括致死性病例，这些变态反应包括超敏反应、血管性水肿、Stevens-Johnson综合征、毒性表皮坏死。REVLIMID治疗的患者中，已有肿瘤溶解综合征的报道，包括致死性病例。REVLIMID治疗慢性淋巴细胞性白血病和淋巴瘤的研究性用药中，已有重度肿瘤复燃反应的报道。REVLIMID联合地塞米松治疗的患者中，曾发生肝功能衰竭，包括致死性病例。对照试验观察到，接受REVLIMID的多发性骨髓瘤患者，其第二种原发性恶性肿瘤的发病率较高。请参阅完整的处方信息，包括加框的“警示”、“禁忌症”、“警示与注意事项”和“不良反应”。 ≥5%的患者诉称的最常见3/4度不良反应有中性粒细胞减少(43%)、血小板减少(28%)、贫血(11%)、肺炎(9%)、疲乏(7%)、白细胞减少(7%)、发热性中性粒细胞减少(6%)、腹泻(6%)和呼吸困难(6%)。 REVLIMID?（来那度胺）适用于治疗经2种药物（其中一种为硼替佐米）治疗后仍然复发或进展的套细胞淋巴瘤患者(MCL)。 重要安全性信息 警示： 胚胎-胎儿毒性、血液学毒性和“静脉血栓栓塞” 胚胎-胎儿毒性 妊娠期间不得使用REVLIMID。来那度胺是沙利度胺的类似物，研究显示可导致猴子的肢体发育异常。已知沙利度胺可导致人类畸胎，引起危及生命的重度出生缺陷。妊娠期间若使用来那度胺，可引起发育中的婴儿出生缺陷或死亡。育龄女性在启用REVLIMID治疗之前须经2次妊娠试验显示阴性。育龄女性在REVLIMID治疗期间及治疗4周后须使用2种避孕方法或坚持杜绝异性性交。为避免胚胎-胎儿暴露于来那度胺，REVLIMID仅通过一项名为REVLIMID REMS（前称“RevAssist?”计划）的限制性分销计划供药。 血液学毒性（中性粒细胞减少和血小板减少） REVLIMID可引起严重的中性粒细胞减少和血小板减少。在主体研究中，80%的5q缺失骨髓增生异常综合征(MDS)患者不得不延缓给药/减量。34%的患者不得不第二次延缓给药/减量。3度或4度血液学毒性见于80%的入组患者。因 5q缺失MDS 而接受治疗的患者必须在治疗的最初8周每周监测1次全血细胞计数，然后至少每月监测1次。患者可能需要剂量歇停和/或减量。患者可能需要使用血制品支持和/或生长因子。 静脉血栓栓塞 研究显示，REVLIMID可大幅提高接受REVLIMID和地塞米松治疗的多发性骨髓瘤(MM)患者的深静脉血栓形成(DVT)和肺栓塞(PE)的风险。建议患者和医生留意血栓栓塞的体征和症状。患者若出现诸如呼吸急促、胸痛或上肢或下肢肿胀等症状，必须嘱其就医。预防性抗凝或抗血小板治疗与REVLIMID联合处方能否降低静脉血栓栓塞事件的可能性，尚属未知。采取预防性措施的决策必须慎重，事先必须评估个例患者的基础危险因素。 禁忌症 妊娠： 妊娠女性接受REVLIMID后可引起胎儿损害。来那度胺禁用于妊娠女性。妊娠期间若使用了该药、或患者在使用该药期间妊娠，须告知患者该状况可能危及胎儿 变态反应： REVLIMID禁用于对来那度胺过敏的患者（例如血管性水肿、Stevens-Johnson综合征、毒性表皮坏死） 警示与注意事项 胚胎-胎儿毒性： REVLIMID是沙利度胺的类似物，沙利度胺是一种已知的致畸原，在人类中可引起危及生命的出生缺陷或胚胎-胎儿死亡。胚胎-胎儿发育研究显示，母猴妊娠期间使用来那度胺，可引起子代畸形，类似于人类妊娠期间暴露于沙利度胺后发生的出生缺陷 育龄女性：在REVLIMID治疗启用之前、REVLIMID治疗期间、剂量歇停期间及治疗完成后至少4周内必须避孕。在REVLIMID治疗启用之前、治疗期间、剂量歇停期间及REVLIMID停药后连续4周内必须承诺坚持杜绝异性性交，或使用2种可靠的避孕方法。启用治疗之前须经2次妊娠试验显示阴性。 男性：来那度胺存在于接受该药的患者的精子中。REVLIMID用药中或REVLIMID停药后28天以内，男性在与育龄女性的任何性交中必须始终使用乳胶或合成避孕套，即使该男性已成功结扎输精管。REVLIMID用药男性不得捐赠精液。 献血： REVLIMID用药中及该药停药后1个月以内，患者不得献血，因为该血液有可能输给妊娠女性，从而使胎儿暴露于REVLIMID。 REVLIMID REMS 计划 由于胚胎-胎儿风险，REVLIMID仅通过一项名为REVLIMID REMS（前称“RevAssist?”计划）的风险评估及化解策略(REMS)限制性计划供药。处方者和药房必须经该计划认证，患者必须签署一份协议表格、遵守有关规定。有关REVLIMID REMS计划的进一步信息，可访问www.celgeneriskmanagement.com或致电1-888-423-5436。 血液学毒性：REVLIMID可引起严重的中性粒细胞减少和血小板减少。患者可能需要剂量歇停和/或减量。MCL：因MCL接受REVLIMID 的患者应在首轮疗程（28天）中每周监测1次全血细胞计数，第2~4轮周期中每2周1次，之后为每月1次。MCL试验中，3度或4度中性粒细胞减少见于43%的患者。3度或4度血小板减少见于28%的患者。 静脉血栓栓塞：来那度胺单药治疗的MCL患者曾发生静脉血栓栓塞事件（主要是深静脉血栓形成与肺栓塞）。预防性抗凝或抗血小板治疗与REVLIMID联合处方能否降低静脉血栓栓塞事件的可能性，尚属未知。采取预防性措施的决策必须慎重，事先必须评估个例患者的基础危险因素。 变态反应：血管性水肿和重度皮肤反应包括Stevens-Johnson综合征(SJS)和毒性表皮坏死(TEN)已有报道。这些事件可能是致死性的。患者若有沙利度胺关联的4度皮疹既往史，不得接受REVLIMID。发生2~3度皮疹时，应考虑暂停或停用REVLIMID。发生血管性水肿、4度皮疹、剥脱性或大泡性皮疹，或疑诊SJS或TEN时，必须停用REVLIMID，因上述原因停药后，不得重新给药。REVLIMID胶囊含乳糖。乳糖不耐受患者应评估REVLIMID治疗的风险收益比。 肿瘤溶解综合征：来那度胺治疗期间的肿瘤溶解综合征(TLS)致死病例已有报道。有TLS风险的患者在治疗之前的肿瘤负担较高。这些患者必须密切监测并采取适当的注意措施。 肿瘤复燃反应：来那度胺用于慢性淋巴细胞性白血病(CLL)和淋巴瘤的研究中曾发生肿瘤复燃反应(TFR)，其特征是淋巴结压痛肿胀、低热、疼痛和皮疹。不建议在监查良好的临床试验以外采用来那度胺治疗CLL。 MCL患者建议监测、评估TFR。肿瘤复燃可能类似于疾病进展(PD)。3度或4度TFR患者建议撤用来那度胺，直至TFR恢复至≤1度。MCL试验中，近10%的受试者出现TFR；严重程度均报道为1度或2度。这些事件全部发生在首轮疗程，1例患者在第11轮疗程中再次发生TFR。对于1度和2度TFR患者，医生可酌情可续用来那度胺，而无需歇停或调整。1度或2度TFR患者也可用皮质类固醇、非甾体抗炎药(NSAIDs)和/或麻醉镇痛剂处治TFR的症状。3度或4度TFR患者可按1度和2度TFR患者的治疗原则处治症状。 肝脏毒性： 来那度胺联合地塞米松治疗的患者中，曾发生肝功能衰竭，包括致死性病例。药物所致肝脏毒性的机制属未知。基础病毒性肝病、基线肝酶升高及合并用药可能是危险因素。应定期监测肝酶。肝酶升高时应停用Revlimid。肝酶恢复至基线值后，可考虑减量治疗。 第二种原发性恶性肿瘤：研究发现，接受来那度胺、美法仑和干细胞移植的MM患者，其第二种原发性恶性肿瘤，尤其是急性粒细胞性白血病(AML)和霍奇金淋巴瘤的发病率高于接受类似治疗但未接受来那度胺的对照组患者。必须监测患者是否发生第二种恶性肿瘤。在考虑来那度胺治疗时，必须兼顾来那度胺的潜在收益与第二种原发性恶性肿瘤的风险。 胞淋巴瘤 REVLIMID治疗MCL的试验(N=134)中，≥5%的患者诉称的3度和4度不良事件包括中性粒细胞减少(43%)、血小板减少(28%)、贫血(11%)、肺炎(9%)、白细胞减少(7%)、疲乏(7%)、腹泻(6%)、呼吸困难(6%)和发热性中性粒细胞减少(6%) REVLIMID单药治疗MCL时，≥2的患者诉称的重度不良事件包括慢性阻塞性肺病、艰难梭菌结肠炎、脓毒血症、基底细胞癌和室上性心动过速 REVLIMID治疗MCL的试验中，≥15%的患者诉称的不良事件包括中性粒细胞减少(49%)、血小板减少(36%)、疲乏(34%)、贫血(31%)、腹泻(31%)、恶心(30%)、咳嗽(28%)、发热(23%)、皮疹(22%)、呼吸困难(18%)、瘙痒(17%)、外周水肿(16%)、便秘(16%)和白细胞减少(15%) REVLIMID治疗MCL的试验中，不良事件引起76例(57%)患者至少1次剂量歇停、51例(38%)患者至少1次减量、26例(19%)患者停药。 药物相互作用 接受地高辛的患者在REVLIMID用药期间，建议按照临床判断和标准临床实践定期监测地高辛血浆水平。 特殊人群用药 妊娠：治疗期间若妊娠，应立即停药。在这种情况下，患者应转诊到生殖毒性方面经验丰富的产科/妇科医生进行进一步评估和咨询。任何疑似胎儿REVLIMID暴露必须通过MedWatch计划上报FDA，电话1-800-332-1088，同时通报Celgene公司，电话1-888-423-5436。 哺乳母亲： REVLIMID是否在人类乳汁中有分泌尚属未知。由于许多药物通过乳汁分泌、哺乳婴儿可能出现不良反应，在决定是否停止哺乳或停药时必须考虑该药对母亲的重要性。 儿科用药： 18岁以下儿科患者中的安全性和疗效尚未确立。 老年人用药： 由于老年患者易发生肾功能减退，选择剂量时应慎重。监测肾功能。 肾功能损害： 由于REVLIMID主要以原型经肾脏排泄，中度（肌酐清除率30~60毫升/分钟）或重度（肌酐清除率< 30毫升/分钟）肾功能损害患者及透析患者建议调整起始剂量，以提供适用的药物暴露量。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||