Linadex

Lenalidomide.

LINADEX Capsule 5 mg, each capsule contains: Lenalidomide 5 mg.
LINADEX Capsule 10 mg, each capsule contains: Lenalidomide 10 mg.
LINADEX Capsule 15 mg, each capsule contains: Lenalidomide 15 mg.
LINADEX Capsule 25 mg, each capsule contains: Lenalidomide 25 mg.

Pharmacology: Mechanism of action: The Lenalidomide mechanism of action includes anti-neoplastic, anti-angiogenic, pro-erythropoietic, and immunomodulatory properties. Specifically, Lenalidomide inhibits proliferation of certain hematopoietic 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 hemoglobin production by CD34+ hematopoietic 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.
Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and regulator of cullins 1 (Roc1). In the presence of Lenalidomide, cereblon binds substrate proteins Aiolos and Ikaros which are lymphoid transcriptional factors, leading to their ubiquitination and subsequent degradation resulting in cytotoxic and immunomodulatory effects.
Pharmacokinetics: The study was an open label, balanced, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study in 43 healthy, adult, human male subjects under fasting condition. The study was conducted following an oral administration of one capsule 25 mg of the test drug or one capsule 25 mg of the reference drug.
Based on the pharmacokinetic parameters of Lenalidomide (N = 43), mean ± SD for Test Drug and Reference Drug showed: T_max values were 0.750 (0.500 - 2.000) and 0.767 (0.500 - 2.750) hour, respectively; C_max values were 568.077 ± 123.4757 and 573.912 ± 141.9003 ng/mL, respectively; AUC_0-t values were 2219.402 ± 541.0999 and 2237.919 ± 503.2726 ng.h/mL, respectively; AUC_0-∞ values were 2237.632 ± 559.1299 and 2255.280 ± 518.8979 ng.h/mL, respectively; λ_z values were 0.203 ± 0.0278 and 0.209 ± 0.0298 (l/h), respectively; T_½ values were 3.469 ± 0.4813 and 3.375 ± 0.4715 hours, respectively; AUC_%Extrap_obs (%) values were 0.724 ± 0.4454 and 0.696 ± 0.4303, respectively.
Relative bioavailability results for Test Drug and Reference Drug of Lenalidomide were as following: 90.00% Confidence Intervals of C_max, AUC_0-t, AUC_0-∞ were 94.24 - 105.49, 97.39 - 100.38, 97.42 - 100.41, respectively. Intra subject CV (%) of C_max, AUC_0-t, AUC_0-∞ were 15.6, 4.2 and 4.2%, respectively.
Conclusion: These results showed that Lenalidomide capsule 25 mg was bioequivalent to the reference product.

Multiple myeloma: Lenalidomide as combination therapy with Dexamethasone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant.
Lenalidomide as combination therapy with Melphalan and prednisone is indicated for the treatment of ≥ 65 years old patients with previously untreated multiple myeloma who are not eligible for transplant.
Lenalidomide in combination with Dexamethasone is indicated for the treatment of multiple myeloma in adult patients who have relapsed or have progressive disease after receiving at least one prior therapy.
Myelodysplastic syndromes: Lenalidomide as monotherapy is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
Mantle cell lymphoma: Lenalidomide as monotherapy is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma.

Lenalidomide treatment should be supervised by a physician experienced in the use of anti-cancer therapies. For all indications described as follows: Dose is modified based upon clinical and laboratory findings.
Dose adjustments, during treatment and restart of treatment, are recommended to manage grade 3 or 4 thrombocytopenia, neutropenia, or other grade 3 or 4 toxicity judged to be related to Lenalidomide.
In case of neutropenia, the use of growth factors in patient management should be considered.
If less than 12 hours has elapsed since missing a dose, the patient can take the dose. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next dose at the normal time on the following day.
Newly diagnosed multiple myeloma (NDMM): Lenalidomide in combination with Dexamethasone until disease progression in patient who are not eligible for transplant: Lenalidomide treatment must not be started if the ANC is < 1.0 x 10⁹/L, and/or platelet counts are < 50 X 10⁹/L.
Recommended dose: The recommended starting dose of Lenalidomide is 25 mg orally once daily on days 1 - 21 of repeated 28 - day cycles. The recommended dose of Dexamethasone is 40 mg orally once daily on days 1, 8, 15 and 22 of repeated 28-day cycles. Patients may continue Lenalidomide and Dexamethasone therapy until disease progression or intolerance.
Dose reduction steps: See Table 1.


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Thrombocytopenia: See Table 2.


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Neutropenia: See Table 3.


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Lenalidomide in combination with melphalan and prednisone followed by lenalidomide maintenance in patients who are not eligible for transplant: Lenalidomide treatment must not be started if the ANC is < 1.5 x 10⁹/L, and/or platelet counts are < 75 X 10⁹/L.
Recommended dose: The recommended starting dose is lenalidomide 10 mg orally once daily on days 1 to 21 of repeated 28- day cycles for up to 9 cycles, melphalan 0.18 mg/kg orally on days 1 to 4 of repeated 28-day cycles, prednisone 2 mg/kg orally on days 1 to 4 of repeated 28-day cycles. Patients who complete 9 cycles or who are unable to complete the combination therapy due to intolerance are treated with Lenalidomide monotherapy as follows: 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles given until disease progression.
Dose reduction steps: See Table 4.


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Thrombocytopenia: See Table 5.


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Neutropenia: See Table 6.


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Multiple myeloma with at least one prior therapy: Lenalidomide treatment must not be started if the ANC < 1.0 x 10⁹/L, and/or platelet counts < 75 x 10⁹/L or, dependent on bone marrow infiltration by plasma cells, platelet counts < 30 x 10⁹/L.
Recommended dose: The recommended starting dose of Lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles. The recommended dose of Dexamethasone is 40 mg orally once daily on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily on days 1 to 4 every 28 days.
Prescribing physicians should carefully evaluate which dose of Dexamethasone to use, taking into account the condition and disease status of the patient.
Dose reduction steps: See Table 7.


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Thrombocytopenia: See Table 8.


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Neutropenia: See Table 9.


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Myelodysplastic syndromes (MDS): Lenalidomide treatment must not be started if the 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 to 21 of repeated 28-day cycles.
Dose reduction steps: See Table 10.


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Thrombocytopenia: See Table 11.


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Neutropenia: See Table 12.


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Discontinuation of Lenalidomide: Patients without at least a minor erythroid response within 4 months of therapy initiation, demonstrated by at least a 50% reduction in transfusion requirements or, if not transfused, a 1g/dl rise in haemoglobin, should discontinue lenalidomide treatment.
Mantle cell lymphoma (MCL): Recommended dose: The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles.
Dose reduction steps: See Table 13.


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Thrombocytopenia: See Table 14.


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Neutropenia: See Table 15.


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Tumour flare reaction: Lenalidomide may be continued in patients with Grade 1 or 2 tumour flare reaction (TFR) without interruption or modification, at the physician's discretion. In patients with Grade 3 or 4 TFR, withhold treatment with Lenalidomide until TFR resolves to ≤ Grade 1 and patients may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.
All indications: For other grade 3 or 4 toxicities judged to be related to lenalidomide, treatment should be stopped and only restarted 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 (SJS), toxic epidermal necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected, and should not be resumed following discontinuation from these reactions.
Special populations: Paediatric population: Lenalidomide should not be used in children and adolescents from birth to less than 18 years because of safety concerns.
Elderly: Currently available pharmacokinetic data are described in Pharmacology: Pharmacokinetics under Actions. Lenalidomide has been used in multiple myeloma patients up to 91 years of age, in myelodysplastic syndromes patients up to 95 years of age and in mantle cell lymphoma patients up to 88 years of age.
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.
Newly diagnosed multiple myeloma: patients who are not eligible for transplant: Patients with newly diagnosed multiple myeloma aged 75 years and older should be carefully assessed before treatment is considered. For patients older than 75 years of age treated with Lenalidomide in combination with Dexamethasone, the starting dose of Dexamethasone is 20 mg once daily on days 1, 8, 15 and 22 of each 28-day treatment cycle. No dose adjustment is proposed for patients older than 75 years who are treated with Lenalidomide in combination with Melphalan and Prednisone. In patients with newly diagnosed multiple myeloma aged 75 years and older who received Lenalidomide, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation.
Lenalidomide combined therapy was less tolerated in newly diagnosed multiple myeloma patients older than 75 years of age compared to the younger population. These patients discontinued at a higher rate due to intolerance (Grade 3 or 4 adverse events and serious adverse events), when compared to patients < 75 years.
Multiple myeloma: Patients with at least one prior therapy: The percentage of multiple myeloma patients aged 65 or over was not significantly different 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.
Myelodysplastic syndromes: For myelodysplastic syndromes patients treated with Lenalidomide, no overall difference in safety and efficacy was observed between patients aged over 65 and younger patients.
Mantle cell lymphoma: For mantle cell lymphoma patients treated with Lenalidomide, no overall difference in safety and efficacy was observed between patients aged 65 years or over compared with patients aged under 65 years of age.
Patients with renal impairment: Lenalidomide is primarily excreted by the kidney; patients with greater degrees of renal impairment can have impaired treatment tolerance. Care should be taken in dose selection and monitoring of renal function is advised.
No dose adjustments are required for patients with mild renal impai1ment and multiple myeloma, myelodysplastic syndromes or mantle cell lymphoma.
The following dose adjustments are recommended at the start of therapy and throughout treatment for patients with moderate or severe impaired renal function or end stage renal disease.
There are no phase III trial experiences with End Stage Renal Disease (ESRD) (CLcr < 30 mL/minute, requiring dialysis).
Multiple myeloma: See Table 16.


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Myelodysplastic syndromes: See Table 17.


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Mantle cell lymphoma: See Table 18.


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After initiation of Lenalidomide therapy, subsequent Lenalidomide dose modification in renally impaired patients should be based on individual patient treatment tolerance, as described previously.
Patients with hepatic impairment: Lenalidomide has not formally been studied in patients with impaired hepatic function and there are no specific dose recommendations.
Method of administration: Oral use.
Lenalidomide capsules should be taken orally at about the same time on the scheduled days. The capsules should not be opened, broken or chewed. The capsules should be swallowed whole, preferably with water, either with or without food.
It is recommended to press only on one end of the capsule to remove it from the blister thereby reducing the risk of capsule deformation or breakage.

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 hematological. In the event of overdose, supportive care is advised.

Hypersensitivity to the active substance or to any of the excipients.
Women who are pregnant.
Women of childbearing potential unless all of conditions of the Pregnancy Prevention Program are met.

Pregnancy warning: Lenalidomide is structurally related to Thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. If Lenalidomide is taken during pregnancy, a teratogenic effect of Lenalidomide in humans is expected.
The conditions of the pregnancy prevention program 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: a. Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (Amenorrhoea following cancer therapy or during breast-feeding does not rule out childbearing potential).
b. Premature ovarian failure confirmed by a specialist gynaecologist.
c. Previous bilateral salpingo-oophorectomy, or hysterectomy.
d. XY genotype, Turner syndrome, uterine agenesis.
Counselling: For women of childbearing potential, lenalidomide is contraindicated unless all of the following are met: a. She understands the expected teratogenic risk to the unborn child.
b. 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.
c. Even if a woman of childbearing potential has amenorrhea she must follow all the advice on effective contraception.
d. She should be capable of complying with effective contraceptive measures.
e. She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy.
f. She understands the need to commence the treatment as soon as Lenalidomide is dispensed following a negative pregnancy test.
g. She understands the need and accepts to undergo pregnancy testing every 4 weeks except in case of confirmed tubal sterilization.
h. 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. As a precaution and taking into account special populations with prolonged elimination time such as renal impairment, all male patients taking lenalidomide must meet the following conditions: a. Understand the expected teratogenic risk if engaged in sexual activity with a pregnant woman or a woman of childbearing potential.
b. 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.
c. Understand that if his female partner becomes pregnant whilst he is taking Lenalidomide or shortly after he has stopped taking LINADEX, he should inform his treating physician immediately and that it is recommended to refer the female partner to a physician specialized or experienced in teratology for evaluation and advice.
The prescriber must ensure that for women of childbearing potential: a. The patient complies with the conditions of the Pregnancy Prevention Programme, including confirmation that she has an adequate level of understanding.
b. 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: a. Implant.
b. Levonorgestrel-releasing intrauterine system (IUS).
c. Medroxyprogesterone acetate depot.
d. Tubal sterilization.
e. Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses.
f. Ovulation inhibitory progesterone-only pills (i.e. desogestrel).
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking Lenalidomide in combination therapy, and to a lesser extent in patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma taking Lenalidomide monotherapy, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception the patient should switch to one of the effective methods listed previously. 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.
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 as follows. 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 sterilization. These pregnancy tests should be performed in the day of prescribing visit or in the 3 days prior to the visit to the prescriber.
Additional precautions: Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment for safe disposal.
Patients should not donate blood during therapy or for 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 Authorization 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 care 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: a. Myocardial infarction: Myocardial infarction has been reported in patients receiving Lenalidomide, particularly in those with known risk factors and within the first 12 months when used in combination with Dexamethasone. Patients with known risk factors - including prior thrombosis - should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. Smoking, hypertension, and hyperlipidemia).
b. 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 was seen to a lesser extent with Lenalidomide in combination with Melphalan and Prednisone.
In patients with Multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma, treatment with Lenalidomide monotherapy was associated with a lower risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism), than in patients with multiple myeloma treated with Lenalidomide in combination therapy.
In patients with multiple myeloma, the combination of Lenalidomide with Dexamethasone is associated with an increased risk of arterial thromboembolism (predominantly myocardial infarction and cerebrovascular event) and was seen to a lesser extent with Lenalidomide in combination with Melphalan and Prednisone. The risk of ATE is lower in patients with multiple myeloma treated with Lenalidomide monotherapy that in patients with multiple myeloma treated with Lenalidomide in combination therapy. Consequently, patients with known risk factors for thromboembolism - including prior thrombosis - should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidemia). 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 hemoglobin 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 stabilized 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.
c. 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, hemoglobin, and hematocrit should be performed at baseline, every week for the first 8 weeks of lenalidomide treatment and monthly thereafter to monitor for cytopenia. 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. A dose reduction may be required. 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 epistaxes, especially in patients receiving concomitant medicinal products susceptible to induce bleeding. Co-administration of Lenalidomide with other myelosuppressive agents should be undertaken with caution.
Newly diagnosed multiple myeloma: Patients who are not eligible for transplant treated with Lenalidomide in combination with low dose Dexamethasone: Grade 4 neutropenia was observed in the lenalidomide arms in combination with low dose Dexamethasone to a lesser extent than in the comparator arm (in the Rd [continuous treatment] and Rd18 compared in the Melphalan/Prednisone/Thalidomide arm. Grade 4 febrile neutropenia episodes were consistent with the comparator arm (in the Rd and Rd18 Lenalidomide/Dexamethasone-treated patients compared in the Melphalan/Prednisone/Thalidomide arm.
Grade 3 or 4 thrombocytopenia was observed to a lesser extent in the Rd and Rd18 arms than in the comparator arm.
Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with Lenalidomide in combination with Melphalan and Prednisone: The combination of lenalidomide with melphalan and prednisone of newly diagnosed multiple myeloma patients is associated with a higher incidence of grade 4 neutropenia in melphalan, prednisone and lenalidomide arm followed by lenalidomide [MPR+R] and melphalan, prednisone and lenalidomide followed by placebo [MPR+p] treated patients compared in melphalan, prednisone and lenalidomide arm followed by lenalidomide [MPR+R] and melphalan, prednisone and lenalidomide followed by placebo [MPR+p] treated patients compared in MPp+p-treated patients). Grade 4 febrile neutropenia episodes were observed infrequently (in MPR+R/MPR+p treated patients compared in MPp+p treated patients).
The combination of Lenalidomide with Melphalan and Prednisone in multiple myeloma patients is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (in MPR+R/MPR+p treated patients, compared in MPp+p-treated patients).
Multiple myeloma: patients with at least one prior therapy: The combination of Lenalidomide with Dexamethasone in multiple myeloma patients with at least one prior Therapy is associated with a higher incidence of grade 4 neutropenia (in Lenalidomide/Dexamethasone- treated patients compared in placebo/Dexamethasone-treated patients). Grade 4 febrile neutropenia episodes were observed infrequently (in Lenalidomide/Dexamethasone-treated patients compared 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 (in Lenalidomide/Dexamethasone-treated patients compared in placebo/Dexamethasone-treated patients).
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.
Mantle cell lymphoma: Lenalidomide treatment in mantle cell lymphoma patients is associated with a higher incidence of grade 3 and 4 neutropenia compared with patients on the control arm.
d. 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.
e. Peripheral neuropathy: Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral neuropathy. There was no increase in peripheral neuropathy observed with long term use of lenalidomide for the treatment of newly diagnosed multiple myeloma.
f. Tumour flare reaction and tumour lysis syndrome: Because Lenalidomide has anti-neoplastic activity the complications of tumour lysis syndrome (TLS) may occur. TLS and tumour flare reaction (TFR) have commonly been observed in patients with chronic lymphocytic leukemia (CLL), and uncommonly in patients with lymphomas, who were treated with Lenalidomide. Fatal instances of TLS have been reported during treatment with Lenalidomide. The patients at risk of TLS and TFR are those with high tumour burden prior to treatment. Caution should be practiced when introducing these patients to Lenalidomide. These patients should be monitored closely, especially during the first cycle or dose-escalation, and appropriate precautions taken. There have been rare reports of TLS in patients with MM treated with Lenalidomide, and no reports in patients with MDS treated with Lenalidomide.
g. Tumour burden: Mantle cell lymphoma: Lenalidomide is not recommended for the treatment of patients with high tumour burden if alternative treatment options are available.
h. 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 early deaths in the lenalidomide arm and early deaths in the control arm.
i. Adverse events: In study MCL-002, during treatment cycle 1, patients with high tumour burden were withdrawn from therapy in the lenalidomide arm vs. in the control group. The main reason for treatment withdrawal for patients with high tumour burden during treatment cycle 1 in the lenalidomide arm was adverse events.
Patients with high tumour burden should therefore be closely monitored for adverse reactions including signs of tumour flare reaction (TFR). Refer to Dosage & Administration for dose adjustments for TFR. High tumour burden was defined as at least one lesion ≥ 5 cm in diameter or 3 lesions ≥ 3 cm.
j. Tumour flare reaction: 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, non-steroidal anti-inflammatory drugs (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.
k. Allergic reactions: Cases of allergic reaction/hypersensitivity reactions have been reported in patients treated with Lenalidomide. 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.
l. Severe skin reactions: Severe cutaneous reactions including SJS, TEN and DRESS have been reported with the use of Lenalidomide. Patients should be advised of the signs and symptoms of these reactions by their prescribers and should be told to seek medical attention immediately if they develop these symptoms. Lenalidomide must be discontinued for exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed following discontinuation for these reactions. Interruption or discontinuation of Lenalidomide should be considered for other forms of skin reaction depending on severity. Patients with a history of severe rash associated with thalidomide treatment should not receive Lenalidomide.
m. Lactose intolerance: Lenalidomide capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
n. Second primary malignancies: An increase of second primary malignancies (SPM) has been observed in previously treated myeloma patients receiving Lenalidomide/Dexamethasone compared to controls. Non-invasive SPM comprise basal cell or squamous cell skin cancers. Most of the invasive SPMs were solid tumour malignancies.
Newly diagnosed multiple myeloma patients not eligible for transplant, an increase in incidence rate of hematologic SPM (cases of AML) has been observed in patients receiving Lenalidomide in combination with melphalan and prednisone until progression compared with Melphalan in combination with Prednisone.
An increase in incidence rate of solid tumour SPM has been observed in patients receiving lenalidomide (9 cycles) in combination with melphalan and Prednisone compared with melphalan in combination with Prednisone.
In patients receiving lenalidomide in combination with Dexamethasone until progression or for 18 months, the hematologic SPM incidence rate was not increased as compared to Thalidomide in combination with Melphalan and Prednisone.
An increase in incidence rate of solid tumour SPM has been observed in patients receiving Lenalidomide in combination with Dexamethasone until progression or for 18 months compared to Thalidomide in combination with Melphalan and Prednisone.
The increased risk of secondary primary malignancies associated with Lenalidomide is relevant also in the context of NDMM after stem cell transplantation. Though this risk is not yet fully characterized, it should be kept in mind when considering and using LINADEX in this setting.
The risk of occurrence of hematologic SPM must be taken into account before initiating treatment with Lenalidomide either in combination with Melphalan or immediately following high-dose Melphalan and ASCT.
Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of SPM and institute treatment as indicated.
o. Progression to acute myeloid leukemia in low- and intermediate-1-risk MDS: Karyotype: As a consequence, the benefit/risk ratio of lenalidomide when MDS is associated with Del (5q) and complex cytogenetics is unknown.
TP53 status: A TP53 mutation is present in lower-risk MDS Del 5q patients and is associated with a higher risk of progression to acute myeloid leukemia (AML).
p. Progression to other malignancies in mantle cell lymphoma: In mantle cell lymphoma, AML, B-cell malignancies and non-melanoma skin cancer (NMSC) are potential risks.
q. Hepatic disorders: Hepatic failure, including fatal cases, has been reported in patients treated with lenalidomide in combination therapy: acute hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis have been reported. The mechanisms of severe drug-induced hepatotoxicity remain unknown although, in some cases, pre-existing viral liver disease, elevated baseline liver enzymes, and possibly treatment with antibiotics might be risk factors.
Abnormal liver function tests were commonly reported and were generally asymptomatic and reversible upon dosing interruption. Once parameters have returned to baseline, treatment at a lower dose may be considered.
Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal impairment in order to avoid plasma levels which may increase the risk for higher hematological adverse reactions 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 medicinal products known to be associated with liver dysfunction.
r. Infection with or without neutropenia: Patients with multiple myeloma are prone to develop infections including pneumonia. A higher rate of infections was observed with lenalidomide in combination with dexamethasone than with MPT in patients with NDMM who are not eligible for transplant, and with lenalidomide maintenance compared to placebo in patients with NDMM who had undergone ASCT. Grade ≥ 3 infections occurred within the context of neutropenia in less than one-third of the patients. Patients with known risk factors for infections should be closely monitored. All patients should be advised to seek medical attention promptly at the first sign of infection (e.g., cough, fever, etc) thereby allowing for early management to reduce severity.
s. Viral reactivation: Cases of viral reactivation have been reported in patients receiving Lenalidomide, including serious cases of herpes zoster or hepatitis B virus (HBV) reactivation.
Some of the cases of viral reactivation had a fatal outcome.
Some of the cases of herpes zoster reactivation resulted in disseminated herpes zoster, meningitis herpes zoster or ophthalmic herpes zoster requiring a temporary hold or permanent discontinuation of the treatment with lenalidomide and adequate antiviral treatment..
Reactivation of hepatitis B has been reported rarely in patients receiving Lenalidomide who have previously been infected with the hepatitis B virus (HBV). Some of these cases have progressed to acute hepatic failure resulting in discontinuation of Lenalidomide and adequate antiviral treatment. Hepatitis B virus status should be established before initiating treatment with Lenalidomide. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.
Caution should be exercised when Lenalidomide is used in patients previously infected with HBV, including patients who are anti-HBc positive but HBsAg negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy.
t. 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 equal or more than 2 or CLcr less than 60 mL/min when Lenalidomide is given in combination. Patients should be carefully assessed for their ability to tolerate Lenalidomide in combination, with consideration to age, ISS stage III, ECOG PS equal or more than 2 or CLcr less than 60 mL/minute.
u. Cataract: Cataract has been reported with a higher frequency in patients receiving Lenalidomide in combination with Dexamethasone particularly when used for a prolonged time. Regular monitoring of visual ability is recommended.
v. Progressive multifocal leukoencephalopathy: Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported with Lenalidomide. PML was reported several months to several years after starting the treatment with Lenalidomide. Cases have generally been reported in patients taking concomitant Dexamethasone or prior treatment with other immunosuppressive chemotherapy. Physicians should monitor patients at regular intervals and should consider PML in the differential diagnosis in patients with new or worsening neurological symptoms, cognitive or behavioural signs or symptoms. Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.
The evaluation for PML should be based on neurological examination, magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR) or a brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additional follow-up and evaluation may be warranted 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, Lenalidomide must be permanently discontinued.
Effects on ability to drive and use machines: Lenalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have been reported with the use of lenalidomide. Therefore, caution is recommended when driving or operating machines.

Due to the teratogenic potential, Lenalidomide must be prescribed under a Pregnancy Prevention Program, unless there is reliable evidence that the patient does not have childbearing potential.
a. 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. 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.
b. Pregnancy: Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects.
c. Breast-feeding: It is not known whether lenalidomide is excreted in human milk. Therefore breast-feeding should be discontinued during therapy with lenalidomide.
d. Fertility: A fertility study in rats with lenalidomide produced no adverse effects on fertility and no parental toxicity.

Summary of the safety profile: Newly diagnosed multiple myeloma: Patients who are not eligible for transplant treated with Lenalidomide in combination with low dose Dexamethasone: The serious adverse reactions observed more frequently with Lenalidomide in combination with low dose Dexamethasone (Rd and Rd18) than with Melphalan, Prednisone and Thalidomide (MPT) were: Pneumonia, Renal failure (including acute).
The adverse reactions observed more frequently with Rd or Rd18 than MPT were: Diarrhoea, fatigue, back pain, asthenia, insomnia, rash, decreased appetite, cough, pyrexia, and muscle spasms.
Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with Lenalidomide in combination with Melphalan and Prednisone: The serious adverse reactions observed more frequently with Melphalan, Prednisone and Lenalidomide followed by Lenalidomide maintenance (MPR+R) or Melphalan, Prednisone and Lenalidomide followed by placebo (MPR+p) than Melphalan, Prednisone and placebo followed by placebo (MPp+p) were: Febrile neutropenia, Anemia.
The adverse reactions observed more frequently with MPR+R or MPR+p than MPp+p were: neutropenia, anemia, thrombocytopenia, leukopenia, constipation, diarrhea, rash, pyrexia, peripheral oedema, cough, decreased appetite, and asthenia.
Multiple myeloma: patients with at least one prior therapy: The most serious adverse reactions observed more frequently in lenalidomide/dexamethasone than placebo/dexamethasone combination were: Venous thromboembolism (deep vein thrombosis, pulmonary embolism), Grade 4 neutropenia.
The observed adverse reactions which occured more frequently with lenalidomide and dexamethasone than placebo and dexamethasone in pooled multiple myeloma (MM-009 and MM-010) were fatigue, neutropenia, constipation, diarrhoea, muscle cramp, anemia, thrombocytopenia and rash.
Myelodysplastic syndromes: Most adverse reactions tended to occur during the first 16 weeks of therapy with lenalidomide.
Serious adverse reactions include: Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see PRECAUTIONS); Grade 3 or 4 neutropenia, febrile neutropenia and grade 3 or 4 thrombocytopenia (see PRECAUTIONS).
The most commonly observed adverse reactions which occurred more frequently in the lenalidomide groups compared to the control arm in the phase III study were neutropenia, thrombocytopenia, diarrhea, constipation, nausea, pruritus, rash, fatigue and muscle spasms.
Mantle cell lymphoma: The serious adverse reactions observed more frequently (with a difference of at least 2 percentage points) in the Lenalidomide arm compared with the control arm were: Neutropenia, Pulmonary embolism, Diarrhea.
The most frequently observed adverse reactions which occurred more frequently in the Lenalidomide arm compared with the control arm were neutropenia, anemia, diarrhea, fatigue, constipation, pyrexia, and rash (including dermatitis allergic).
There was overall an apparent increase in early (within 20 weeks) deaths. Patients with high tumor burden at baseline are at increased risk of early death, early death in the Lenalidomide arm and early death in the control arm. Within 52 weeks corresponding figures.
During treatment cycle 1, patients with high tumor burden were withdrawn from therapy in the Lenalidomide arm vs. 1/28 (4%) in the control group. The main reason for treatment withdrawal for patients with high tumor burden during treatment cycle 1 in the lenalidomide arm was adverse events. High tumor burden was defined as at least one lesion ≥ 5 cm in diameter or 3 lesions ≥ 3 cm.
Tabulated list of adverse reactions: The adverse reactions observed in patients treated with Lenalidomide are listed as follows 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, common, uncommon, rare, very rare, not known (be estimated from the available data).
Adverse reactions have been included under the appropriate category in the table according to the highest frequency observed.
Tabulated summary for combination therapy in MM: See Tables 19 A and B.


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Tabulated summary from monotherapy: The following tables are derived from data gathered during the main studies in monotherapy for myelodysplastic syndromes and mantle cell lymphoma. (See Tables 20 and 21.)


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Tabulated summary of post-marketing adverse reactions: In addition to the previously mentioned adverse reactions identified, the following table is derived from data gathered from post-marketing data. (See Table 22.)


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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. If Lenalidomide is taken during pregnancy, a teratogenic effect of Lenalidomide in humans is expected.
Neutropenia and thrombocytopenia: a. Newly diagnosed multiple myeloma: Patients who are not eligible for transplant treated with Lenalidomide in combination with low dose Dexamethasone: The combination of Lenalidomide with low dose Dexamethasone in newly diagnosed multiple myeloma patients is associated with a lower frequency of grade 3 and 4 thrombocytopenia.
b. Newly diagnosed multiple myeloma: Patients who are not eligible for transplant treated with Lenalidomide in combination with Melphalan and Prednisone: The combination of Lenalidomide with Melphalan and Prednisone in newly diagnosed multiple myeloma patients is associated with a higher frequency of grade 4 neutropenia.
The combination of Lenalidomide with melphalan and prednisone in newly diagnosed multiple myeloma patients is associated with a higher frequency of grade 3 and grade 4 thrombocytopenia.
c. Multiple myeloma: Patients with at least one prior therapy: The combination of Lenalidomide with Dexamethasone in multiple myeloma patients is associated with a higher incidence of grade 4 neutropenia. Grade 4 febrile neutropenia episodes were observed infrequently.
The combination of Lenalidomide with Dexamethasone in multiple myeloma patients is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia.
d. Myelodysplastic syndromes patients: In myelodysplastic syndromes patients, Lenalidomide is associated with a higher incidence of grade 3 or 4 neutropenia. Grade 3 or 4 febrile neutropenia episodes were observed in lenalidomide-treated patients compared with in patients on placebo). Lenalidomide is associated with a higher incidence of grade 3 or 4 thrombocytopenia.
e. Mantle cell lymphoma patients: In mantle cell lymphoma patients, Lenalidomide is associated with a higher incidence of grade 3 or 4 neutropenia. Grade 3 or 4 febrile neutropenia episodes were observed in lenalidomide-treated patients compared with in patients on control arm.
Venous thromboembolism: An increased risk of DVT and PE is associated with the use of the combination of lenalidomide with dexamethasone in patients with multiple myeloma, and to a lesser extent in patients treated with melphalan and prednisone or as monotherapy in patients with myelodysplastic syndromes and mantle cell lymphoma treated with lenalidomide monotherapy (see INTERACTIONS). 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.
Hemorrhagic disorders: Hemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system disorders; nervous system disorders (intracranial hemorrhage); respiratory, thoracic and mediastinal disorders (epistaxis); gastrointestinal disorders (gingival bleeding, hemorrhoidal hemorrhage, rectal hemorrhage); renal and urinary disorders (hematuria); 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: Severe cutaneous reactions including SJS, TEN and DRESS have been reported with the use of Lenalidomide. Patients with a history of severe rash associated with Thalidomide treatment should not receive Lenalidomide (see PRECAUTIONS).
Second primary malignancies: In previously treated myeloma patients with lenalidomide/dexamethasone compared to controls, mainly comprising of basal cell or squamous cell skin cancers.
Acute myeloid leukemia: a. Multiple myeloma: Cases of AML have been observed in newly diagnosed multiple myeloma in patients taking lenalidomide treatment in combination with Melphalan or immediately following HDM/ASCT (see PRECAUTIONS). This increase was not observed in newly diagnosed multiple myeloma in patients taking Lenalidomide in combination with low dose Dexamethasone compared to Thalidomide in combination with Melphalan and Prednisone.
b. 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 PRECAUTIONS). The estimated 2- year cumulative risk of progression to AML were in patients with an isolated Del (5q) abnormality compared to patients with Del (5q) and one additional cytogenetic abnormality and in patients with a complex karyotype.
Hepatic disorders: The following post-marketing adverse reactions have been reported (frequency unknown): acute hepatic failure and cholestasis (both potentially fatal), toxic hepatitis, cytolytic hepatitis, mixed cytolytic/cholestatic hepatitis.
Rhabdomyolysis: Rare cases of rhabdomyolysis have been observed, some of them when lenalidomide is administered with a statin.
Thyroid disorders: Cases of hypothyroidism and cases of hyperthyroidism have been reported.
Tumour flare reaction and tumour lysis syndrome: In Lenalidomide-treated patients experienced TFR, the majority of the events occurred in cycle 1, all were assessed as treatment-related, and the majority of the reports were Grade 1 or 2. Patients with high MIPI at diagnosis or bulky disease at baseline may be at risk of TFR. TLS was reported for one patient in each of the two treatment arms.
Gastrointestinal disorders: Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinal perforations may lead to septic complications and may be associated with fatal outcome.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

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.
Oral contraceptives: No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme inducer. In an in vitro study with human hepatocytes, lenalidomide, at various concentrations tested did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. Therefore, induction leading to reduced efficacy of medicinal products, including hormonal contraceptives, is not expected if lenalidomide is administered alone. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4 and is likely to also affect other enzymes as well as transporters. It may not be excluded that the efficacy of oral contraceptives may be reduced during treatment. Effective measures to avoid pregnancy must be taken.
Warfarin: Co-administration of multiple 10 mg doses of Lenalidomide had no effect on the single dose pharmacokinetics of R- and S- warfarin. Co-administration of a single 25 mg dose of Warfarin had no effect on the pharmacokinetics of Lenalidomide. However, it is not known whether there is an interaction during clinical use (concomitant treatment with Dexamethasone). Dexamethasone is a weak to moderate enzyme inducer and its effect on Warfarin is unknown. Close monitoring of Warfarin concentration is advised during the treatment.
Digoxin: Concomitant administration with Lenalidomide 10 mg once daily increased the plasma exposure of digoxin. It is not known whether the effect will be different in the use (higher Lenalidomide doses and concomitant treatment with Dexamethasone). Therefore, monitoring of the Digoxin concentration is advised during Lenalidomide treatment.
Statins: There is an increased risk of rhabdomyolysis when statins are administered with Lenalidomide, which may be simply additive. Enhanced clinical and laboratory monitoring is warranted notably during the first weeks of treatment.
Dexamethasone: Co-administration of single or multiple doses of Dexamethasone (40 mg/once daily) has no clinically relevant effect on the multiple dose pharmacokinetics of Lenalidomide (25 mg/once daily).
Interactions with P-glycoprotein (P-gp) inhibitors: In vitro, Lenalidomide is a substrate of P-gp, but is not a P-gp inhibitor. Co-administration of multiple doses of the strong P-gp inhibitor Quinidine (600 mg, twice daily) or the moderate P-gp inhibitor/substrate Temsirolimus (25 mg) has no clinically relevant effect on the pharmacokinetics of Lenalidomide (25 mg). Co-administration of Lenalidomide does not alter the pharmacokinetics of Temsirolimus.

Store below 30°C.

Cancer Immunotherapy

L04AX04 - lenalidomide ; Belongs to the class of other immunosuppressants.

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