Revlimid® (Lenalidomide)

Revlimid® (Lenalidomide)

Therapeutic indication

Adult patients Multiple Myeloma, Myelodysplastic syndromes and Mantle cell lymphoma

Mechanism of action

Multiple Myeloma Lenalidomide as monotherapy is indicated for the maintenance treatment of adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplantation. Lenalidomide as combination therapy is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant. Lenalidomide in combination with dexamethasone is indicated for the treatment of multiple myeloma in adult patients who have received at least one prior therapy. Myelodysplastic syndromes Lenalidomide as monotherapy is indicated for the treatment of adult patients with transfusion-dependent 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. The lenalidomide mechanism of action includes anti-neoplastic, anti-angiogenic, pro-erythropoietic, and immunomodulatory properties. Specifically, lenalidomide inhibits proliferation of certain hematopoietic tumor cells (including MM plasma tumor 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.

Reimbursement modalities

NDMM ASCT (lenalidomide maintenance): ehealth Chapter IV 9010000

NDMM nSCT (Rd): reimbursed in Belgium: ehealth Chapter IV 7940000

NDMM nSCT (MPR-R): reimbursed in Belgium: ehealth Chapter IV 7940000

Relapsed MM (Rd): reimbursed in Belgium: paper Chapter IV 4590000

MDS: reimbursed in Belgium: ehealth/paper Chapter IV 7180000

MCL: currently in reimbursement procedure

Administration and dosage

Lenalidomide maintenance should be initiated after adequate hematologic recovery following ASCT in patients without evidence of progression. Lenalidomide must not be started if the ANC is < 1.0 x 109/L, and/or platelet counts are < 75 x 109/L.

The recommended starting dose is lenalidomide 10 mg orally once daily continuously (on days 1 to 28 of repeated 28-day cycles) given until disease progression or intolerance. After 3 cycles of lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated.

Lenalidomide treatment must not be started if the ANC is < 1.0 x 109/L, and/or platelet counts are < 50 x 109/L.

The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles.

The recommended dose of dexamethasone is 40 mg orally once daily on days 1, 8, 15 and 22 of repeated 8-day cycles. Patients may continue lenalidomide and dexamethasone therapy until disease progression or intolerance.

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.

Lenalidomide treatment must not be started if the ANC is < 1.5 x 109/L, and/or platelet counts are < 75 x 109/L.

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.

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.

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.

Lenalidomide treatment must not be started if the ANC < 0.5 x 109/L and/or platelet counts       < 25 x 109/L.

The recommended starting dose of lenalidomide is 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles.

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 hemoglobin, should discontinue lenalidomide treatment.

The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles.

Dose modifications

Toxicity


Starting dose (10 mg)

If dose increased (15 mg)*

Dose level -1

5 mg

10 mg

Dose level -2

5 mg (days 1-21 every 28 days)

5 mg

Dose level -3

Not applicable

5 mg (days 1-21 every 28 days)


Do not dose below 5 mg (days 1-21 every 28 days)

*After 3 cycles of lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated.


Lenalidomide*

Dexamethasone*

Starting dose

25 mg

40 mg

Dose level -1

20 mg

20 mg

Dose level -2

15 mg

12 mg

Dose level -3

10 mg

8 mg

Dose level -4

   5 mg

4 mg

Dose level -5

2.5 mg

Not applicable

*Dose reduction for both products can be manages independently.

 


Lenalidomide

Melphalan

Prednisone

Starting dose

10 mg*

0.18 mg/kg

2 mg/kg

Dose level -1

7.5 mg

0.14 mg/kg

1 mg/kg

Dose level -2

5 mg

0.10 mg/kg

0.5 mg/kg

Dose level -3

2.5 mg

Not applicable

0.25 mg/kg

*If neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide.


Lenalidomide

Starting dose

25 mg

Dose level -1

15 mg

Dose level -2

10 mg

Dose level -3

5 mg


Lenalidomide

Starting dose

10 mg once daily on days 1 to 21 every 28 days

Dose level -1

5 mg once daily on days 1 to 28 every 28 days

Dose level -2

2.5 mg once daily on days 1 to 28 every 28 days

Dose level -3

2.5 mg every other day 1 to 28 every 28 days


Lenalidomide

Starting dose

25 mg once daily on days 1 to 21 every 28 days

Dose level -1

20 mg once daily on days 1 to 21 every 28 days

Dose level -2

15 mg once daily on days 1 to 21 every 28 days

Dose level -3

10 mg once daily on days 1 to 21 every 28 days

Dose level -4

5 mg once daily on days 1 to 21 every 28 days

Dose level -5

2.5 mg once daily on days 1 to 21 every 28 days or

5 mg every other day on days 1 to 21 every 28 days

Hepatic impairment

Lenalidomide has not formally been studied in patients with impaired hepatic function and there are no specific dose recommendations.

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 impairment and multiple myeloma, myelodysplastic syndromes or mantle cell lymphoma.

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.    

Drug-drug interactions

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 (0.5 mg, single dose) by 14%. It is not known whether the effect will be different in the clinical use (higher lenalidomide doses and concomitant treatment with dexamethasone). Therefore, monitoring of the digoxin concentration is advised during lenalidomide treatment.

Statins

There is an increased risk of rhabdomyolysis when statins are administered with lenalidomide, which may be simply additive. Enhanced clinical and laboratory monitoring is warranted notably during the first weeks of treatment.

Dexamethasone

Co-administration of single or multiple doses of dexamethasone (40 mg once daily) has no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg once daily).

Interactions with P-glycoprotein (P-gp) inhibitors

In vitro, lenalidomide is a substrate of P-gp, but is not a P-gp inhibitor. Co-administration of multiple doses of the strong P-gp inhibitor quinidine (600 mg, twice daily) or the moderate P-gp inhibitor/substrate temsirolimus (25 mg) has no clinically relevant effect on the pharmacokinetics of lenalidomide (25 mg). Co-administration of lenalidomide does not alter the pharmacokinetics of temsirolimus.

 

Adverse events of special interest

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).

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 than in patients with multiple myeloma treated with lenalidomide in combination therapy.

Consequently, patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and 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 thrombo-embolism. 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 anti-coagulation 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.

Management of adverse events

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 cytopenias. In mantle cell lymphoma patients, the monitoring scheme should be every 2 weeks in Cycles 3 and 4, and then at the start of each cycle. 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 epistaxis, especially in patients receiving concomitant medicinal products susceptible to induce bleeding. Co-administration of lenalidomide with other myelosuppressive agents should be

undertaken with caution.

Initial work-up before start of treatment

Pregnancy warning

Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active

substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys malformations similar to those described with thalidomide. 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. 

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 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. 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.

 

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.

 

Reference: SmPC Revlimid® (lenalidomide) latest update 22/09/2017

                       Celgene Approval Number: BE-HEMA180006

For the full SmPC visit: