Revlimid in combination with bortezomib and dexamethasone is indicated for the treatment of adult patients with untreated multiple myeloma.

Revlimid is indicated for the treatment of adult patients with multiple myeloma as maintenance therapy after autologous stem cell transplantation.

Revlimid in combination with dexamethasone or Revlimid in combination with melphalan and predni sone, each followed by Revlimid maintenance therapy, is indicated for the treatment of adult patients with untreated multiple myeloma who are not eligible for transplant.

Revlimid in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma who have received at least one prior drug therapy.

Revlimid is indicated for the treatment of patients with transfusion-dependent anemia due to low or intermediate 1-risk myelodysplastic syndrome associated with a deletion 5q cytogenetic abnormality with or without other cytogenetic abnormalities.

Revlimid is indicated for the treatment of patients with relapsed or refractory mantle cell lymphoma (MCL) after prior therapy that included bortezomib and chemotherapy/Rituximab.

Revlimid in combination with rituximab (anti-CD20 antibody) is indicated for the treatment of adult patients with previously treated follicular lymphoma (Grade 1-3A) (see “Properties/Effects”)

The treatment must be initiated and monitored by an experienced haematologist or oncologist.

MultipleMyeloma

Revlimid in combination with bortezomib and dexamethasone in patients with untreated multiple myeloma

— Initial therapy: Revlimid in combination with bortezomib and dexamethasone

Treatment with Revlimid in combination with bortezomib and dexamethasone must not be started if the absolute neutrophil count (ANC) is < 1.0 x 10⁹/L and/or the platelet count is < 50 x 10⁹/L.

The recommended initial dose of Revlimid is 25 mg orally once daily, either a) on days 1-14 of each 21-day treatment cycle or

b) on days 1-21 of each 28-day treatment cycle.

Bortezomib should be administered as a subcutaneous injection (1.3 mg/m² body surface area) twice

weekly on days 1, 4, 8 and 11 of each 21-day or 28-day cycle.

The recommended dose of dexamethasone is

a)  20 mg orally once daily on days 1, 2, 4, 5, 8, 9, 11 and 12 or

b)  40 mg orally once daily on days 1 to 4 and 9 to 12 of each cycle.

Up to eight 21-day or six 28-day cycles (24-week initial therapy) are recommended.

Table 1: Recommended dosing schedule for Revlimid in combination with bortezomib and  dexamethasone

or

—   Continuation of treatment in patients not receiving stem cell transplantation: Revlimid in combination with dexamethasone until disease progression

Continued treatment with 25 mg Revlimid orally once daily on days 1-21 of the repeated 28-day cycles in combination with dexamethasone. The recommended dose of dexamethasone is 40 mg orally once daily on days 1, 8, 15 and 22 of the repeated 28-day cycles. Treatment may continue until disease progression or intolerance.

—   Continuation of treatment: autologous stem cell transplantation

In patients whose treatment will be continued with autologous stem cell transplantation, mobilisation of haematopoietic stem cells should performed within the first 4 cycles of initial therapy.

Revlimid in patients afterautologous stemcell transplantation

After autologous stem cell transplantation, maintenance therapy with Revlimid should be initiated after adequate hematologic recovery. Treatment with Revlimid should not be started if the ANC is < 1.0 x 10⁹/L, and/or platelet counts are < 75 x 10⁹/L.

Recommended dose

The recommended loading dose is 10 mg Revlimid orally once daily continuously (on days 1-28 of the repeated 28-day cycles) given until disease progression or intolerance. After three 28-day cycles of continuous maintenance therapy with Revlimid, the dose m ay be increased to 15 mg orally once daily if tolerated.

Revlimid incombination with dexamethasone until disease progression in untreated patients who are not eligible fortransplant

Treatment with Revlimid should 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 loading dose is 25 mg Revlimid orally once daily on days 1-21 of the 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. Treatment with Revlimid and dexamethasone may be continued until disease progression or intolerance.

Revlimid in combination with melphalan and prednisone followed by maintenance monotherapy in un-  treated non-transplant patients

Treatment with Revlimid should not be started if the ANC is < 1.5 x 10⁹/L, and/or platelet counts are < 75 x10⁹/L.

Recommended dose

The recommended loading dose is Revlimid 10 mg/day orally on days 1-21 of the repeated 28-day cycles for up to 9 cycles, melphalan 0.18 mg/kg orally on days 1-4 of the repeated 28-day cycles, prednisone 2 mg/kg orally on days 1-4 of repeated 28-day cycles.

Patients who have completed 9 cycles or who are unable to complete combination therapy due to intolerance will receive Revlimid alone,10 mg/day orally, on days 1-21 of the repeated 28-day cycles until disease progression.

Revlimid in combination with dexamethasone in patients with multiple myeloma who received at least one prior drug therapy

The recommended starting dose is 25 mg Revlimid orally once daily on days 1–21 of the repeating 28- day treatment cycles. The dose of dexamethasone recommended during the first 4 treatment cycles is 40 mg orally once daily on days 1–4, 9–12 and 17–20 of each 28-day cycle and subsequently 40 mg once daily on days 1–4. Treatment should be continued until progression or occurrence of unacceptable toxicities.

Myelodysplastic syndrome

The recommended starting dose is 10 mg Revlimid orally once daily on days 1-21 of the repeated 28- day treatment cycles. If at least a minor response, i.e. at least a 50% improvement, cannot be demonstrated 16 weeks after the start of the Revlimid therapy , discontinuation of treatment due to lack of efficacy is recommended.

Relapsed or refractory mantle cell lymphoma

The recommended starting dose of Revlimid is 25 mg orally daily on days 1-21 of repeated 28-day treatment cycles. Treatment should be continued until disease progression or occurrence of unacceptable toxicity.

Follicular lymphoma (FL) in combination with rituximab (R² regimen)

Treatment with Revlimid must not be started if the absolute neutrophil count (ANC) is <1 x 10⁹/l and/or platelet counts are <50 x 10⁹/l, unless this is the consequence of infiltration of the bone marrow by the lymphoma.

The recommended starting dose of Revlimid is 20 mg orally once daily on days 1-21 of the repeated 28- day treatment cycles for up to 12 treatment cycles. The recommended starting dose of rituximab is 375 mg/m² intravenously (i.v.) once weekly in cycle 1 (days 1, 8, 15 and 22) and on day 1 of every 28- day cycle for cycles 2 up to and including 5.

Dose adjustment

The dose of Revlimid or other medicinal products used in combination treatment (dexamethasone , melphalan , prednisone, bortezomib, rituximab) should be adjusted based on clinical findings and laboratory values.

The Summary of Product Characteristics for the respective medicinal product should be consulted for toxicity-related dose adjustments for the medicinal products used in a combination treatment other than Revlimid.

Haematotoxicity

Recommended dose adjustments during treatment and resumption of treatment

The following dose adjustments are recommended for the management of Grade 3 or Grade 4 neutropenia or thrombocytopenia, as well as any other Grade 3 or Grade 4 toxicity assessed as lenalidomide-related, as described below according to indication.

Revlimid in combination with bortezomib and dexamethasone in patients with untreated multiple myeloma

 Steps for dose redcution  

                               Dose level -5                                              2.5 mg daily or 5 mg

every 48 h

Thrombocytopenia

                               For each subsequent drop below                 Interrupt lenalidomide treatment

< 0.5 x 10⁹/L or febrile neutropenia

                                 Return to ≥ 1 x 10⁹/L                        Continuation of lenalidomide at the next

lower dose level. Do not dose below

2.5 mg once daily.

^a If neutropenia is the only toxicity at any dose level, then granulocyte colony stimulating factor (G-CSF) is given at the discretion of the physician, while maintaining the dose level of lenalidomide.

Revlimid in patients after autologous stem cell transplantation

Steps for dose reduction

                            Dose level 3                                  Not applicable              5 mg once daily on

days 1-21 of the 28-day cycles

Do not dose below 5 mg once daily on days 1-

21 of the 28-day cycles

^a After three 28-day cycles of continuous maintenance therapy with Revlimid, the dose may be increased to 15 mg orally once daily if tolerated.

Thrombocytopenia

                           For each subsequent drop below <   Interrupt lenalidomide treatment

30 x 10⁹/L

Return to ≥ 30 x 10⁹/L c on t i nua t i on o f lenalidomide at next lower dose level

Neutropenia

^a  If neutropenia is the only toxicity at any dose level, then granulocyte colony stimulating factor (G-CSF) is given at the discretion of the physician while maintaining the dose level of lenalidomide.

Revlimid in combination with dexamethasone in untreated patients who are not eligible for transplant

Steps for dose reduction

 ª If dose-limiting toxicity (DLT) occurs on Day15 of a cycle, the lenalidomide treatment will be inter-

rupted for at least the remainder of the respective 28-day cycle.

                            Neutropenia                    

^a If neutropenia is the only toxicity at any dose level, then granulocyte colony stimulating factor (G-CSF) is given at the discretion of the physician while maintaining the dose level of lenalidomide.

If lenalidomide dose was reduced due to hematologic DLT, the dose of lenalidomide may be increased again to the next higher dose level (up to the starting dose) at the discretion of the treating physician, provided that continued lenalidomide / dexamethasone therapy resulted in improved bone marrow function (no DLT for at least 2 consecutive cycles and an ANC ≥1,500/µL with a platelet count ≥ 100,000/µL at the start of a new cycle at the current dose level).

Revlimid in combination with melphalan and prednisone followed by maintenance monotherapy in non- transplant patients

Steps for dose reduction  

Thrombocytopenia

                             For each subsequent drop below                  30 x 10⁹/l

Resume lenalidomide at next lower dose level (dose level -2 or -3) once daily.

Neutropenia

^a If neutropenia is the only toxicity at any dose level, granulocyte colony stimulating factor (G-CSF) is given at the discretion of the physician while maintaining the dose level of lenalidomide. .

Multiple myeloma with at least one prior therapy, myelodysplastic syndrome and mantle cell lymphoma

For the indication MM after at least one prior therapy or MDS, treatment with lenalidomide should be interrupted for thrombocytopenia with drop of count to < 25 x 10⁹/L or neutropenia with drop of counts to < 0.5 × 10⁹/L.

The indication MCL, treatment with lenalidomide should be interrupted for thrombocytopenia with a drop of counts to < 50 x 10⁹/L or for neutropenia with a drop of count to < 0.5 × 10⁹/L or a drop to < 1 x 10⁹/L for at least 7 days or a drop to < 1 x 10⁹/L associated with a temperature of ≥ 38.5°C.

After platelet/neutrophil counts have normalised, the treatment should be continued at the next lower dose down. The dose should be reduced further in case of recurrence. If toxicity is observed below the lowest dose strength, treatment with lenalidomide should be discontinued.

For MM after at least one prior therapy, the first dose reduction is to 15 mg daily, 10 mg if toxicity recurs, and the 5 mg daily.

For MDS the first dose reduction is 5 mg daily; in case of recurrence, a second dose reduction of 2.5 mg daily or 5 mg every 2 days is recommended. A third dose reduction to 5 mg twice a week is recommended if toxicity recurs.

Switching to another therapy in MCL patients who have failed to respond to a lower dose of Revlimid for more than 3 months.

Follicular lymphoma (FL)

Steps for dose reduction

a  For loading dose for patients with renal disorders see section below

b  Only for adjusted loading dose for patients with moderate grade renal insufficiency

Thrombocytopenia

 ^a see section “Patients with renal disorders”

Neutropenia

With every further drop to under 1.0 x 10⁹/l for at Interrupt treatment with lenalidomide and least 7 days or a drop to <1.0 x 10⁹/l together with monitor complete blood counts at least fever (body temperature ≥38.5°C) or drop to <0.5 x every 7 days

                   10⁹/l                                                                                

Return to ≥0.5 x 10⁹/l

Resume lenalidomide at the next lower dose level (dose level 2 or 3). Do not dose lower than dose level 3. If the loading dose was 10 mg^b, do not dose lower than dose level 4.

 ^a If neutropenia is the only toxicity at any dose level, then granulocyte colony stimulating factor (G-CSF) is

             given at the discretion of the physician while maintaining the dose level of lenalidomide.

^b see section “Patients with renal disorders”

 Other reasons

Therapy must be interrupted If a Grade 3 non-scaly rash (with blistering), Grade 3 neuropathy, or Grade 2 allergic reaction occur. Therapy must be resumed after appropriate resolution to ≤ Grade 1 at the next lower dose level.

Revlimid must be discontinued if a scaly rash (with blistering), Grade 4 non-scaly rash (with blistering), Grade 4 neuropathy, or a ≥ Grade 3 allergic reaction occurs.

If constipation occurs (≥ Grade 3), the therapy must be interrupted and treatment of the constipation initiated. Therapy may be resumed after resolution of constipation to ≤ Grade 2 at the next lower dose level.

If venous thrombosis/embolism (≥ Grade 3) occurs, the therapy must be interrupted and anticoagulation initiated. Therapy may be resumed at the physician’s discretion ( maintaining dose level).

Revlimid must be discontinued in the case of angioedema, anaphylaxis,, Grade 4 rash, exfoliative or bullous rash, suspected Stevens- Johnson syndrome (SJS) toxic epidermal necrolysis (TEN), or drug exanthema with eosinophilia and systemic symptoms (DRESS), after discontinuation due to these reactions, treatment should not be resumed.

Other Grade 3/4 toxicities

If other Grade 3/4 toxicities attributed to Revlimid occur, treatment should be discontinued and continued at the physician’s discretion at the next lower dose level after resolution of the toxicity to ≤ Grade 2.

Special dose instructions

Patients with hepatic disorders

Revlimid has not been studied in patients with hepatic impairment, and there are no specific dose recommendations.

Patients with renal disorders

No dose adjustment is required in mild renal insufficiency (CLcr 80-50 ml/min).

The following dose adjustments are recommended for the treatment of MM patients with a starting dose of 25 mg, for patients with follicular lymphoma with a starting dose of 20 mg and for MM patients or for MDS patients with a starting dose of 10 mg at the beginning and over the course of therapy in the case of moderate (30 ≤ CLcr <50 ml/min) or severe renal insufficiency (CLcr <30 ml/min) or end-stage renal insufficiency

^a After two cycles, the dose can be increased to 15 mg daily if the patient does not respond to the treatment and tolerates the medication.

^b The dose can be increased to 10 mg daily if the patient tolerates the medication.

^c  After two cycles the dose can be increased to 15 mg daily, if the patient tolerates the medication.

In the treatment of MCL patients, an effect of renal function on the plasma level of the active substance Revlimid analogous to the observed effect in MM, MDS and FL patients is anticipated. Appropriate dose reduction should be considered in MCL patients with renal impairment. Note that the starting dose of 10 mg should not be exceeded in MCL patients with creatinine clearance between 30 and 60 ml/min.

Elderly patients

No dose adjustments are required. Since reduced renal function must be expected in elderly patients, renal function should be monitored regularly in this age group. Revlimid has been used in clinical trials in patients up to the age of 95 years.

Patients with untreated multiple myeloma who are not eligible for transplant

In patients over 75 years of age treated with lenalidomide in combination with dexamethasone, the loading dose of dexamethasone is 20 mg/day on days 1, 8, 15, and 22 of each 28-day treatment cycle.

No dose adjustment is recommended for patients over 75 years of age treated with lenalidomide in combination with melphalan and prednisone.

Paediatric patients

Revlimid has not been studied in paediatric patients. Revlimid should therefore not be used in this age group.

Method of administration

Revlimid capsules should be taken at approximately the same time of day with some water, with or without food. The capsules should not be opened or chewed. Hands should be washed immediately after contact with the capsules. Caution should be taken not to inhale the powder contained in the capsules (e.g. if a capsule is damaged) or allow it to come into contact with the skin or mucous membranes. If skin contact occurs, the area should be washed with soap and water, and eyes should be flushed with water in case of contact.

If a dose of Revlimid has been missed and it has been less than 12 hours since the missed dose, the dose can still be taken. If more than 12 hours have passed since the usual time of administration, the dose should no longer be taken. The patient should wait until the next day and then take the next dose at the usual time. 2 doses should not be taken at once.

.

Pregnancy Prevention Programme

Revlimid is available only through a restricted distribution program, called the Lenalidomide  i-SECURE program.

 Female Patient Programme

The conditions of the Pregnancy Prevention Programme must be met in all patients unless there is evidence that the patient is unable to become pregnant. Criteria for determining the potential to become pregnant.

A female patient or the female partner of a male patient is considered to have childbearing potential unless she fulfils at least one of the following conditions:

-    Age  50 years and spontaneously amenorrhoeic for  1 year*

-    Confirmed premature ovarian failure

-    Prior bilateral salpingo-oophorectomy, tubal sterilisation or hysterectomy

-    XY genotype, Turner syndrome, uterine aplasia

* Amenorrhoea after cancer therapy does not rule out childbearing potential. Counselling

Lenalidomide is contraindicated in women of childbearing potential unless all of the following conditions are met:

-         The patient understands the expected teratogenic risk to the unborn child.

-         She understands the need for effective contraception without interruption 4 weeks prior to the start of treatment, during the entire treatment period including treatment interruptions and 4 weeks after the end of treatment.

-         Even if a female patient of childbearing potential is amenorrhoeic, she must follow all of the recommendations for effective contraception.

-         she should be able to adhere to effective contraceptive measures.

-         She is informed and understands the consequences of pregnancy and the need to seek medical advice promptly if a pregnancy is suspected.

-         She understands the need and is willing to have pregnancy tests performed every 4 weeks.

-         She has confirmed that she understands the hazards and necessary safety measures associated with taking lenalidomide.

In the case of women of childbearing potential, the prescribing physician must ensure that

-         the patient meets the above conditions.

-         the patient complies with the conditions for contraception, including confirmation of sufficient understanding.

-         the patient has used adequate contraceptive measures for at least 4 weeks before the start of treatment and will continue effective contraceptive measures for the entire treatment period including treatment interruptions and for at least 4 weeks after the end of treatment. For patients who require immediate treatment with Lenalidomide, adequate contraception, including the use of condoms, must be implemented for 7 days before the start of treatment.

-         a negative result of a pregnancy test is obtained before the start of treatment.  

Contraception

Women of childbearing potential must use effective contraceptive methods for 4 weeks before starting treatment, for the entire treatment period including treatment interruptions, and for 4 weeks after completing treatment. For patients who require immediate treatment with lenalidomide, effective contraception, including condom use, must be implemented for 7 days before starting treatment. If effective contraceptive methods have not already been used previously, the patient must be referred to a medical counselling centre to receive comprehensive advise regarding effective contraceptive methods.

The following methods can be considered effective contraceptive methods:

Patient-independent methods:

-         Implant

-         Medroxyprogesterone acetate depot

-         Sterilisation

-         Patient-dependent methods:

-         Abstinence from heterosexual intercourse

-         Heterosexual intercourse only with a vasectomised male partner; vasectomy must be confirmed by two negative semen analyses

-         Oral contraceptives containing progesterone only.

Due to the increased risk of venous thromboembolism with lenalidomide, combined oral contraceptives are not recommended. If a patient is already using combined oral contraceptives, a switch to another contraceptive method should be considered. The risk of venous thromboembolism persists for 4-6 weeks after completing of treatment with combined oral contraceptives. If other methods cannot be

used, thrombosis prophylaxis should be considered during the continued use of combined oral contra- ceptives. The patient should be adequately informed about the risk of venous thromboembolism.

Intrauterine system have an increased risk of infections at the time of insertion and may cause irregular vaginal bleeding. These methods are therefore not recommended.

Pregnancy tests

Pregnancy tests with a sensitivity of at least 25 mIU/ml hCG must be performed in women of childbear ing potential.

Any case of a patient with a positive pregnancy test must be reported immediately as per the require- ments of the Pregnancy Prevention Program.

              -           Prior to starting treatment

A pregnancy test must be performed during the consultation during which lenalidomide is prescribed or within 3 days prior to the prescribing physician, after the patient has used effective contraception for at least 4 weeks. The test is intended to ensure that the patient is not preg nant when starting treatment with lenalidomide.

                    -    Before starting treatment if immediate treatment is necessary

A quantitative serum hCH test should be performed immediately. After effective contraception including use of condom for 7 days, this test must be repeated. If both tests confirm that the patient is not pregnant, treatment may be started.”

              -           During and at the end of treatment

A pregnancy test must be repeated every 4 weeks including 4 weeks after completion of treatment. These pregnancy tests should be performed during doctor’s visit for prescription of lenalidomide or in the three days before the doctor’s visit.

It is best to perform tests, the prescribing and dispensing of lenalidomide on the same day. Lenalidomide must be dispensed within a maximum of 7 days of prescription.

Male Patient Programme

Clinical data shows that this active substance passes into the sperm of male patients who take Revlimid. Patients with female partners of childbearing potential should therefore use condoms during intercourse during treatment with Revlimid and for 7 days after stopping treatment, . Men taking Revlimid must fulfil the following conditions:

-                    They must understand the expected teratogenic risk if they are having sexual intercourse with a woman of childbearing potential.

-                    They must understand and agree to use a condom during the entire treatment period, including treatment interruptions, and for at least 7 days after completion of treatment if they have sexual intercourse with a women of childbearing potential.

The prescribing physician must ensure that male patients understand the need for and agree to the use of condom, for the entire duration of treatment, including treatment interruptions and for 7 days after completing of treatment if they have sexual intercourse with a women of childbearing potential.

The patients must not donate sperm during treatment with Revlimid and for 7 days afterwards.

Additional Precautions

Patients must be instructed never to give this medicinal product to anyone else and to return unused capsules to their physician or pharmacist after the end of therapy.

Other Warnings and Precautions

HEMATOLOGIC TOXICITY. Revlimid can cause significant neutropenia and thrombocytopenia.

Neutropenia and thrombocytopenia

The major dose-limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. A complete blood count with differential blood count, platelet count, haemoglobin concentration and haematocrit should therefore be performed.

Interruption of treatment and/or dose reduction may be required (see “Dosage/Administration”). Patients with neutropenia should be monitored for signs of infection. Patients and physicians are encouraged to look out for signs and symptoms of bleeding, including petechiae and nosebleeds, particularly when medications that may increase the risk of bleeding are used concomitantly. If this type of toxicity is observed, appropriate measures should be taken. For patients with untreated multiple myeloma who are eligible for transplant and who are taking Revlimid in combination with bortezomib and dexamethasone, complete blood count should be assessed every 7 days (once weekly) during the first treatment cycle and then before the start of each subsequent cycle. Monthly monitoring (every 4 weeks) is required if treatment with Revlimid in combination with dexamethasone is continued.

For patients with multiple myeloma after autologous stem cell transplantation taking Revlimid, complete blood counts should be assessed every 7 days (once weekly) for the first two 28-day cycles, every 2 weeks (day 1 and day 15) in the third 28-day cycle and then every 28 days (4 weeks).

For patients with untreated multiple myeloma who are not eligible for transplant and are taking Revlimid in combination with melphalan and prednisone, complete blood count should be assessed every 7 days (1 week) for the first cycle (28-days), every 14 days (2 weeks) until completion of 9 cycles, and every 28 days (4 weeks) thereafter.

Complete blood count should be monitored every 7 days (weekly) for the first 2 cycles, on day 1 and day 15 of cycle 3, and every 28 days (4 weeks) thereafter in patients with untreated multiple myeloma who are not eligible for transplant and who are taking Revlimid in combination with dexamethasone.

In patients with multiple myeloma who have received at least one prior treatment and who are taking Revlimid in combination with dexamethasone, complete blood count should be checked every 14 days (2 weeks) for the first 12 weeks of therapy and once monthly thereafter.

Patients taking Revlimid for MDS with deletion 5q abnormality, should have their complete blood counts checked once weekly for the first 8 weeks of therapy and once monthly thereafter.

For Patients taking Revlimid for MCL, complete blood counts should be assessed once weekly during the first cycle (28 days), every 2 weeks during cycles 2-4, and then once monthly thereafter.

For patients with pre-treated follicular lymphoma who were treated with Revlimid and rituximab, monitoring should be carried out on a weekly basis in the first three weeks of cycle 1 (28 days), then every 14 days during cycles 2 up to and including 4, and after that, at the beginning of each subsequent cycle.

Infections with or without neutropenia

Patients with multiple myeloma are prone to developing infections including pneumonia. A higher rate of infections was observed with lenalidomide in combination with dexamethasone than with MPT. Grade ≥ 3 infections occurred in less than one-third of the patients in the context of neutropenia. Patients with known risk factors for the occurrence of infections must be closely monitored. All patients should be instructed to seek

19

immediate medical attention at the first sign of infection (e.g., cough, fever, etc.) to allow for early treatment to

reduce the severity.

In rare cases, reactivation of hepatitis B has been reported in patients who received lenalidomide and had previously been infected with the hepatitis B virus (HBV). In some cases, this resulted in acute liver failure requiring discontinuation of lenalidomide and adequate antiviral treatment. The hepatitis B virus status should be determined before starting treatment with lenalidomide. For patients who test positive for HBV infection, a physician experienced in the treatment of hepatitis B should be consulted. Appropriate caution should be exercised when lenalidomide is used in patients previously infected with HBV. These patients must be closely monitored for signs and symptoms of active HBV infection throughout treatment.

When lenalidomide was used as part of combination therapy in patients over 75 years of age, with ISS Stage III, ECOG PS ≥ 2, or CrCl < 60 mL/min, the rate of intolerance (Grade 3 or 4 adverse events, serious adverse events, treatment discontinuation) was increased. Patients should be carefully evaluated for their ability to tolerate lenalidomide in combination therapy, taking into account their age and other comorbidities.

Venous and arterial thromboembolic events (VTE/ATE)

In patients with multiple myeloma, the combination with dexamethasone or other chemotherapy (e.g., melphalan and prednisone) is associated with an increased risk of venous thromboembolic events (predominantly deep vein thrombosis and pulmonary embolism). The risk of VTE is lower in multiple myeloma maintenance therapy after autologous stem cell transplantation (ASCT), and in MDS, MCL patients with lenalidomide monotherapy and in FL patients with R² therapy.

There is an increased risk of arterial thromboembolic events (predominantly myocardial infarction and cerebrovascular events) in patients with multiple myeloma receiving combination therapy with lenalidomide and dexamethasone, and to a lesser extent, with combination of lenalidomide, melphalan and prednisone. The risk of ATE is lower in patients with multiple myeloma receiving lenalidomide as maintenance therapy after autologous stem cell transplantation than in patients with multiple myeloma receiving combination therapy of lenalidomide (either with dexamethasone or melphalan and prednisone).

Patients with known risk factors for the occurrence of thromboembolism – including previous thrombosis – must therefore be closely monitored. Patients should thus be advised to seek medical attention for symptoms such as shortness of breath, cough, chest pain or pain and/or swelling of the arms and legs. Measures should be taken to minimise all modifiable risk factors (e.g. smoking cessation, control of hypertension and hyperlipidaemia).

The concomitant administration of erythropoiesis-stimulating agents or a history of thromboembolic events may also increase thrombosis risk in these patients. Erythropoiesis-stimulating agents, or other substances that may increase the risk of thrombosis, such as hormone replacement therapy, should therefore be used with caution patients with multiple myeloma receiving lenalidomide with dexamethasone. A haemoglobin concentration above 11 g/dL should prompt discontinuation of erythropoiesis-stimulating substances.

The use of prophylactic anti-thrombotic drugs should be recommended especially in patients with additional thromboembolic risk factors.

The use of anti-thrombotic should be made for each patient individually after careful assessment.

If a thromboembolic event occurs, treatment with lenalidomide should be discontinued and standard anticoagulation therapy should be initiated . Once the patient’s condition has stabilised, lenalidomide treatment may be continued , while maintaining anticoagulation if necessary.

Myocardial infarction

There have been reports of myocardial infarction in patients treated with lenalidomide, especially in patients with known risk factors. Patients with known risk factors – including prior thrombosis – should be closely monitored and measures should be taken to minimise any modifiable risk factors (such as smoking, hypertension, and hyperlipidaemia).

Second Primary Malignancies (SPM)

Based on a small number of cases, a numerical difference was observed in clinical studies of previously treated patients with multiple myeloma on lenalidomide/dexamethasone compared with controls, whereby this occurred primarily in cases of basal cell or squamous carcinoma of the skin .

An increase in secondary primary malignancies, including AML and MDS has been observed in clinical studies of patients with newly diagnosed multiple myeloma, with cases diagnosed in patients receiving lenalidomide in combination with melphalan (frequency of 5.3%) or immediately following high- dose melphalan therapy and ASCT (frequency of 7.5%). The observed frequency of AML and MDS cases in the lenalidomide dexamethasone arm was 0.4%.

Cases of B-cell malignancies (including Hodgkin’s disease) have been observed in clinical studies in which patients received Revlimid after ASCT.

An increase in solid SPMs was observed in patients receiving lenalidomide immediately after high-dose intravenous melphalan (HDM) and ASCT (frequency of 7.7%).

In patients with newly diagnosed multiple myeloma receiving lenalidomide in combination with bortezomib and dexamethasone, the frequency of haematological SPMs was 0.0% to 0.8% and the frequency of solid SPMs was 0.4% to 4.5%.

In the case of FL patients who were being treated with a combination of lenalidomide and rituximab, the frequency of haematologic SPMs was 0.7% and the frequency of solid SPMs was 1.4%.

Before starting treatment witj lenalidomide, both the benefit achieved with lenalidomide and the risk of secondary primary malignancies should be considered. . The physician should carefully examine the patients for the occurrence of secondary primary malignancies prior to and during treatment with the aid of the usual early cancer detection measures and initiate therapy if necessary.

Liver Disorders

Liver insufficiency, including fatal cases, has been reported in patients treated with lenalidomide in combination with dexamethasone: acute liver insuffciency, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis were registered. Mechanisms of severe drug- related hepatotoxicity remain unknown, although in some cases, pre-existing viral liver disease, elevated liver enzyme baseline, and possibly antibiotics treatment may be risk factors.

Abnormal liver function values, which were generally asymptomatic and reversible treatment interruption, were reported frequently. Once liver function parameters have returned to baseline, treatment at a lower dose may be considered.

Lenalidomide is mainly excreted via the kidneys. It patients with impaired renal function, impairment dose adjustment is key to preventing plasma levels that could increase the risk of more haematologic side effects or hepatotoxicity. Monitoring of liver function is therefore recommended, especially in case of concomitant or previous viral liver infection or when lenalidomide is administered with medications known to be associated with hepatic impairment .

Allergic reactions and sever skin reactions

Cases of angioedema, anaphylaxis and severe dermatological reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)and drug exanthema with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS syndrome may manifest as a skin reaction (such as rash or exfoliative dermatitis), associated with eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These e v ent s can be fatal. In the case of Grade 2 or Grade 3 skin rash. Interruption or discontinuation of Revlimid should be considered. Revlimid must be discontinued for angioedema, anaphylaxis, Grade 4 rash, exfoliative or bullous rash suspected SJS, TEN or DRESS after discontinuation of due to these reactions, treatment should not be resumed. Patients with severe grade 4 rash associated with thalidomide treatment should not treated with Revlimid.

Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) may occur, including in lymphoma patients. Patients with a high tumor burden before the start of treatment are at risk. These patients should be monitored closely, especially during the first cycle or during dose-escalation, and appropriate precautionary measures should be taken.

Tumor Flare Reaction

Careful monitoring for signs of tumor flare reaction (TFR) is recommended. A tumor flare can mimic disease progression (PD). In the pivotal study MCL-001, occurred in approximately 10% of patients ; all cases were categorized as Grade 1 or 2 and assessed to be treatment-related. The TFR rate in the NHL-007 study was 13.0%, whereby one event corresponded to a Grade 3 event. In the NHL-008 study, the rate was 4.0% with one serious event amongst the other Grade 1-2 events. Most of the events occurred in cycle 1. In patients with Grade 1 and

2 TFR, treatment with lenalidomide may be continued at the discretion of the physicians without interruption or modification. In the clinical studies MCL-001, NHL-007 and NHL-008, patients with Grade 1 and 2 TFR were given corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for the treatment of TFR symptoms. The decision regarding therapeutic measures should be made after careful clinical assessment of the individual patient. In patients with Grade 3 or 4 TFR, treatment with lenalidomide should be withheld until the TFR has resolved to ≤ Grade

1. Patients may be treated for symptoms according to the guidance provided for Grade 1 and 2 TFR.

Early death in MCL patients

Overall, a discernible increase in early deaths (within 20 weeks) was observed in the MCL-002 study.

Patients with a high tumour burden at baseline have an increased risk of early death; which was 20% (16/81) in the lenalidomide arm and 7% (2/28) in the control arm. During the 52-week period, the corresponding figures were 40% (32/81) and 21% (6/28).

Rejection reactions after organ transplantation

Cases of organ transplant rejection during treatment with Revlimid, some of which were fatal, were reported during post-marketing surveillance.. In the majority of cases, the rejection reaction occurred within the first 2 months after the start of treatment with Revlimid. The underlying disease (e.g. amyloidosis), concomitant infections and recent discontinuation or reduction of immunosuppressive therapy were possible factors that contributed to rejection of the organ transplant in the reported cases. The incidence of rejection reactions in organ transplants cannot be reliably estimated due to the limitation of post-marketing safety data. Revlimid was generally permanently discontinued after the occurrence of the rejection reaction. Before starting treatment with Revlimid, the benefit of treatment with Revlimid should be weighed against the risk of possible organ transplant rejection in recipients of organ transplants.

Thyroid function disorder

Both hypothyroidism and hyperthyroidism have been observed with lenalidomide treatment (see “Undesirable Effects”). Therefore it is recommended to ensure optimal management of concomitant diseases that may affect thyroid function before starting Revlimid treatment. Monitoring of thyroid function is recommended at the start of treatment and during treatment.

Cardiac electrophysiology

Prolongation of the QTc interval have been observed in the ECG during treatment with lenalidomide. Concomitant treatment with drugs that prolong the QT interval and treatment in patients with long QT syndrome should only be undertaken with great caution and under regular ECG monitoring.(see

”Properties/Effects).

Immunosuppressive effect

Lenalidomide l is a strong immunosuppressant. Therefore, caution should be exercised when used concomitantly with other immunomodulating active substances. The effect of vaccination may be compromised . Vaccinations with live organisms should not be performed during treatment with lenalidomide due to the risk of infection.

Combination therapy

For information on other medicinal products used in combination with lenalidomide, please refer to the Summary of Product Characteristics of the respective medicinal product.

Lactose intolerance

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

This medicinal product contains less than 1 mmol of sodium (23 mg) per capsule, i.e., it is almost “sodium free”.

Since lenalidomide is not metabolised via phase I enzymes and is only bound to plasma proteins to a small degree , interactions via cytochrome P450 and protein binding are unlikely.

Since lenalidomide is actively eliminated via tubular secretion, interactions with other medicinal products that are actively eliminated via tubular secretion are possible. There is little experience with regard to elevated uric acid levels.

Lenalidomide (10 mg) had no effect on the pharmacokinetics of a concomitantly administered single dose of R-warfarin and S-warfarin. A single 25-mg dose of warfarin had no effect on the pharmacokinetics of concomitantly administered lenalidomide . However, it is not known whether interactions occur in clinical use. Close monitoring of warfarin concentration during treatment is therefore advised.

Treatment with coumarins is not recommended due to the high risk of thrombocytopenia.

Dexamethasone (40 mg/day) had no effect on the pharmacokinetics of Revlimid.

Concomitant administration of lenalidomide 10 mg/day increased the plasma bio-availability 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 is different in the given clinical situation (higher lenalidomide doses and concomitant therapy with dexamethasone). Monitoring of digoxin concentration is therefore indicated during treatment with lenalidomide.

Co-administration of multiple doses of the P-gp inhibitor quinidine (600 mg, twice daily) has no clinically relevant effect on the pharmacokinetics of lenalidomide (25 mg).

Co-administration of lenalidomide (25 mg) and the P-gp inhibitor/substrate temsirolimus (25 mg) does not alter the pharmacokinetics of either drug.

Erythropoiesis-stimulating agents or other active substances that may increase the risk of thrombosis, such as hormone replacement therapy, should only be used with caution in patients with multiple myeloma receiving lenalidomide with dexamethasone.

Due to the teratogenic potential, lenalidomide must be prescribed under a Pregnancy Prevention Pro- gramme (see section 4.4) unless there is reliable evidence that the patient does not have childbearing potential.

 (not in the reference label and information already in section 4.4) 

Pregnancy

There is no clinical data on the use of lenalidomide in pregnant women. Lenalidomide is structurally related to thalidomide. Thalidomide is a substance known to be teratogenic in humans, causing severe, life- threatening birth defects. In an embryo-foetal development study of pregnant female monkeys, lenalidomide caused malformations in the offspring (see also section 5.3 pre-clinical safety data). A teratogenic effect of lenalidomide is expected in humans. . For details about the pregnancy prevention programme, (see section 4.3 Warning and Precautions). For the treatment of male patients, (see section 4.3 Warning and Precautions).

 Lactation  

It is unknown whether lenalidomide passes into breast milk. Therefore, Revlimid should not be used or should be stopped in breastfeeding women.

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.

No studies have been conducted on the effects on the ability to drive and operate machinery. Adverse effects such as fatigue, light-headedness, somnolence and blurred vision may occur on Revlimid. Therefore, caution is advised when patients drive or operate machinery.  

Multiple myeloma

Patients with untreated multiple myeloma who are eligible for transplant and received lenalidomide in combination with bortezomib and dexamethasone

In the studies PETHEMA GEM2012 (pooled arms A and B (RVd), n=458) and IFM 2009 (arm A (RVd), n=356), the most common (≥ 5%) serious adverse reaction reported with lenalidomide in combination with bortezomib and dexamethasone was :

— Pneumonia (5.9%) in PETHEMA GEM2012.

In the PETHEMA GEM2012 study, the most commonly observed adverse reactions with lenalidomide in combination with subcutaneous bortezomib and dexamethasone were peripheral neuropathy (35.2%), neutropenia (31.9%) and thrombocytopenia (25.3%).

In the IFM 2009 study, the most commonly observed adverse reactions with lenalidomide in combination with intravenous bortezomib and dexamethasone were peripheral neuropathy (54.8%) and lymphopenia (52.2%).

Patients with multiple myeloma treated with lenalidomide after autologous stem cell transplantation

In two phase-3, double blind, placebo-controlled, two-arm phase III studies (IFM 2005-02 and CALGB 100104)

517 patients received lenalidomide and 501 patients received placebo. The side effects from the CALGB 100104 study included not only maintenance period events but also events reported after HDM/ASCT. In IFM 2005-02, study the information on side effects refers only to the maintenance therapy period.

The serious adverse reactions observed more frequently with lenalidomide maintenance therapy (≥5%) than with placebo were:

•        Pneumonia (10.6%; collective term)

•        Lung infections (9.4%)

The adverse reactions observed more frequently in both studies with lenalidomide maintenance therapy than with placebo were: neutropenia (79.0%), thrombocytopenia (72.3%), diarrhoea (54.5%), bronchitis

(47.4%), nasopharyngitis (34.8%), muscle spasms (33.4%), rash (31.7%), leukopenia (31.7%), asthenia (29.7%), cough (27.3%), upper respiratory tract infections (26.8%), fatigue (22.8%), gastroenteritis

(22.5%), anaemia (21.0%) and fever (20.5%).

Patients with untreated multiple myeloma who are not eligible for transplant and received lenalidomide in combination with bortezomib and dexamethasone

In the SWOG S0777 study (arm B (RVd), n = 262), the serious adverse reactions observed more frequently with lenalidomide in combination with intravenous bortezomib and dexamethasone (≥5%) than with lenalidomide in combination with dexamethasone were:

            •    Hypotension (6.5%), lung infection (5.7%), dehydration (5.0%).

Adverse reactions observed more frequently with lenalidomide in combination with bortezomib and dexamethasone than with lenalidomide in combination with dexamethasone were fatigue (73.7%), peripheral neuropathy (71.8%), thrombocytopenia (57.6%), constipation (56.1%), and hypocalcaemia

(50.0%).

Patients with untreated multiple myeloma who received lenalidomide in combination with low dose dexamethasone

In a phase-3, open-label, 3 arm study 535 patients received a combination of lenalidomide and a low dose dexamethasone until disease progression (Rd), 541 patients received the combination of lenalidomide and low-dose dexamethasone until the completion of eighteen 28-day cycles (Rd18), and 547 patients received the combination of melphalan, prednisone and thalidomide (MPT).

Serious side effects observed more frequently (≥ 5%) with lenalidomide in combination with low-dose dexamethasone (Rd and Rd18) than with melphalan, prednisone and thalidomide (MPT) were:

•        Pneumonia (9.8%)

•        Renal failure (also acute; 6.3%)

Side effects that were observed more frequently with Rd or Rd18 than with MPT were:

diarrhoea (45.5%), fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash

(24.3%), loss of appetite (23.1%), cough (22.7%), fever (21.4%), and muscle cramps (20.5%).

Patients with untreated multiple myeloma who received lenalidomide in combination with melphalan and prednisone

A phase-3, double-blind, placebo-controlled, 3-arm study evaluated the safety and efficacy of melphalan, prednisone and lenalidomide (MPR) combination therapy followed by lenalidomide maintenance monotherapy. 152 patients received induction therapy with the orally administered MPR combination followed by lenalidomide as maintenance therapy (MPR+R), 153 patients received induction therapy with orally administered MPR combination followed by maintenance therapy with placebo (MPR+p), and 154 patients received induction therapy with orally administered MPp (MP + placebo) combination followed by maintenance therapy with placebo (MPp+p).

Serious side effects observed more frequently (≥ 5%) with melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance therapy (MPR+R) or melphalan, prednisone, and lenalidomide followed by placebo (MPR+p) than with melphalan, prednisone and placebo followed by placebo (MPp+p) were:

•        Febrile neutropenia (6.0%)

•        Anaemia (5.3%)

Side effects that were observed more frequently with MPR+R or MPR+ p than with MPp+p were: neutropenia (83.3%), anaemia (70.7%), thrombocytopenia (70.0%), leukopenia (38.8%), constipation (34.0%), diarrhoea (33.3%), rash (28.9%), fever (27.0%), peripheral oedema (25.0%), cough (24.0%), loss of appetite (23.7%), and asthenia (22.0%).

Patients with multiple myeloma who received at least one prior therapy

In placebo-controlled phase-3 studies, 353 patients received the combination of lenalidomide/dexamethasone, and 350 patients received the combination of placebo/dexamethasone . 325 patients (92%) in the lenalidomide/dexamethasone group, had at least one side effect, as compared with 288 patients (82%) in the placebo/dexamethasone group.

The most serious adverse reactions observed were venous thromboembolism (deep vein thrombosis, pulmonary embolism) and Grade 4 neutropenia.

The most frequently observed adverse reaction in the lenalidomide/dexamethasone group were neutropenia (39.4%; Grade 4: 5.1%), thrombocytopenia (18.4%, Grades 3-4: 9.9%), fatigue (27.2%), constipation (23.5%), muscle cramps (20.1%), asthenia (17.6%), anaemia (17.0%), diarrhoea (14.2%) and rash (10.2%), insomnia (26.7%) and muscle weakness (10.1%). Neutropenia and thrombocytopenia occurred primarily in a dose-dependent manner, and were successfully treated by dose reduction.

Myelodysplasticsyndrome

In a placebo-controlled phase-3 study, 69 patients received lenalidomide 10 m g once daily and 67 patients received placebo.

The most serious adverse reactions observed were venous thromboembolisms (deep vein thrombosis, pulmonary embolism), Grades 3-4 neutropenia, febrile neutropenia and Grades 3-4 thrombocytopenia.

The most frequently observed adverse reactions in the lenalidomide group were neutropenia (76.8%; Grades 3-4: 75.4%), thrombocytopenia (49.3%; Grades 3-4: 40.6%), diarrhoea (37.7%), pruritus (27.5%), nausea (20.3%), fatigue (18.8%), constipation (17.4%), muscle spasm (17.4%), fever (15.9%), nasopharyngitis (14.5%), bronchitis (14.5%) and headache (14.5%). Neutropenia and thrombocytopenia occurred primarily in a dose-dependent manner and were successfully treated by dose reduction.

Mantle cell lymphoma

In the pivotal MCL study, a total of 134 patients received at least one dose of Revlimid.

Infections were the most common type of serious adverse events.

Pneumonia was most frequently reported serious infection

The most frequently observed adverse reactions were pneumonia (14.2%; Grade 3-4: 9%), upper respiratory tract infections (12.7%), neutropenia (48.5%; Grade 3-4: 43.3%), thrombocytopenia (35.8%; Grade 3-4: 27.6%), anaemia (30.6%; Grade 3-4: 11.2%), leukopenia (14.9%; Grade 3-4: 6.7%), decreased appetite (14.2%), hypokalaemia (12.7%; Grade 3-4: 2.2%), weight loss (12.7%), cough (28.4%), dyspnoea (17.9%; Grade 3-4: 6%), diarrhoea (31.3%; Grade 3-4: 6%), nausea (29.9%), constipation (15.7%), vomiting (11.9%), rash (22.4%; Grade 3-4: 1.5%), pruritus (17.2%), back pain (13.4%; Grade 3-4: 1.5%), muscle spasms (12.7%), fatigue (33.6%; Grade 3-4: 6.7%), fever 23.1%; Grade 3-4: 2.2%), peripheral oedema (15.7%), and asthenia (14.2%; Grade 3-4: 3%).

Follicular lymphoma (FL)

The general safety profile of lenalidomide in combination with rituximab in patients with pre-treated follicular lymphoma is based on data from 146 patients in the NHL-007 study and from 177 patients in the NHL-008 study.

The most serious adverse reactions observed were: febrile neutropenia (2.7%), lung embolism (2.7%) and pneumonia (2.7%).

The most frequently observed adverse reactions in the lenalidomide-rituximab group were neutropenia (58.2%), diarrhoea (30.8 %), leukopenia (28.8 %), constipation (21.9 %), cough (21.9 %) and fatigue (21.9 %).

The side effects seen in patients with multiple myeloma, myelodysplastic syndrome, mantle cell lymphoma and follicular lymphoma are listed below by organ system and frequency. Side effects are listed in order of decreasing severity within each frequency category.

Frequency information: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare: (<1/10000).

Infections and infestations

Very common:  Bronchitis (47.4%), nasopharyngitis (34.8%), upper respiratory tract infections

(26.8%), gastroenteritis (22.5%), neutropenic infections (17.9%), pneumonia (17.1%), rhinitis (15.0%), sinusitis (14.0%), influenza (13.3%), urinary tract infec tions (11.6%),

              Common:              Bacteremia, sepsis, local and systemic infections (bacterial, viral or mycoses),

cellulitis, oral candidiasis, respiratory tract infection, lung infection, lower respiratory tract infection, infectious enterocolitis .

Benign, malignant and nonspecifiic neoplasms (including cysts and polyps)

Very common: Tumour flare reaction (13.0%)

Blood and lymphatic system disorders

Very common: Neutropenia (79.0%), thrombocytopenia (72.3%), anaemia (43.8%), leukopenia (31.7%), lymphopenia (52.2%), febrile neutropenia (17.4%).

              Common:              Pancytopenia,

              Uncommon:                   Granuolytic anaemia, prolonged coagulation, monocytopenia, leukocytosis,

lymphadenophathy.

Immunesystem disorders

Endocrine Disorders

              Common:             Cushing syndrome.

Uncommon: Adrenal insufficiency, hypothyroidism, hyperthyroidism increased or decreased TSH, hirsutism.

Metabolism and nutrition disorders

              Very common:     Hypocalcaemia (50.0%), decreased appetite (34.4%, hyponatraemia (30.5%),

hypokalaemia (29.0%), dehydration (16.4%), weight loss (13.5%), hyperglycaemia (11.7%) hypoglycaemia (10.7%).

hyperphosphataemia, increased appetite.

Psychiatric disorders

              Very common:      Insomnia (32.8%), depression (10.9%).

              Common:           Delirium, hallucinations, mood swings, anxiety, irritability, sleepiness.

              Uncommon: Psychotic disorders, hypomania, delusions, decreased libido, personality changes,

nervousness, aggression, nightmares.

Nervous system disorders

irritation, dry eyes.

Ear and labyrinth disorders

bradycardia, tachycardia, QT prolongation, pulmonary oedema, arrhythmia.

Vascular disorders

Very common: Hypotension (16.4%), deep vein thrombosis (10.2%). Common:  Hypertension, flushing, haematoma

              Uncommon:         Circulatory collapse, ischaemia, phlebitis.

Respiratory ,thoracic and mediastinal disorders  

              Very common:      Dyspnoea (30.5%), cough (29.4%).

              Common:                 Pulmonary embolism, respiratory distress, pleuritic pain, hypoxia, oropharyngeal

pain, epistaxis, rhinorrhoea, dysphonia, hoarseness, hiccups.

              Uncommon:          Asthma, chest pain.

              Rare:                    Interstitial pneumonitis.

*

Hepatobiliary disorders

mixed cytolytic/cholestatic hepatitis

Gastrointestinal disorders

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

              Very common: Muscle spasms (33.4%), back pain (33.2%), muscle weakness (24.4%), muscle

cramps (20.1%), arthralgia (19.0%), limb pain (17.9%), myalgia (14.9%), skeletal muscle pain (14.8%), bone pain (11.8%), musculoskeletal chest pain (11.3%), Common: Myopathy, peripheral swelling, neck pain.

              Uncommon: Osteonecrosis, muscle atrophy, spondylitis, joint swelling, skeletal muscle

stiffness, local swelling.

Renal and urinary disorders

              Common:              Renal insufficiency, renal failure (also acute), acute renal damage

              Uncommon:        Frequent urination, renal tubular necrosis, urinary retention, acquired Fanconi

syndrome, urinary incontinence.

Reproductive system and breast disorders

              Common:             Erectile dysfunction, gynaecomastia, metrorrhagia, painful nipples.

General disorders and administration site conditions

              Very common: Fatigue (73.7%), peripheral oedema (46.6%), asthaenia (29.7%), fever (23.1%),

Common: Fall, chills, noncardiac chest pain, bruising, malaise Uncommon: Thirst, feeling cold

* = Post-marketing experience

Reporting suspected side effects after market authorisation is extremely important. This facilitates the continuous monitoring of the risk-benefit relationship of the medicinal product. Healthcare professionals are requested to report any suspicion of a new or serious side effect.

To report any side effect(s):

Saudi Arabia:

The National Pharmacovigilance Centre (NPC)

Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

Oman:

Department of Pharmacovigilance & Drug Information

Directorate General of Pharmaceutical Affairs & Drug Control

Ministry of Health, Sultanate of Oman

Phone Nos. 00968 22357686/00968 22357687

Fax: 00968 22358489

Email: pharma-vigil@moh.gov.om

Website: www.moh.gov.om

Other Countries:

- Please contact the relevant competent authority.

The main dose-limiting toxicity in studies was of haematological nature. In the case of an overdose, monitoring (symptoms, laboratory) and supportive measures are indicated.

Lenalidomide is poorly dialysable.

ATC Code: L04AX04.

Mechanism of action /

Lenalidomide is a derivative of thalidomide and is present as a racemic mixture. It has both immunomodulatory and anti-angiogenic properties.

Lenalidomide binds to the intracellular protein cereblon (CRBN.) This is part of the ubiquitin ligase complex E3, which includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), and Roc1. E3 ubiquitin ligases are responsible for the polyubiquitination of a number of different substrate proteins and may explain the pleiotropic cellular effects observed during treatment with lenalidomide .

Lenalidomide inhibits the release of pro-inflammatory cytokines including tumour necrosis factor α (TNF- α), interleukin-1β (IL-1β), IL-6 and IL-12 from peripheral blood mononuclear lipopolysaccharide (LPS) stimulated cells and increases the production of the anti-inflammatory cytokine IL-10 in LPS-stimulated cells.  

It induces the production of IL-2 and interferon-1γ (IFN-1γ) and increases T cells proliferation and cytotoxic activity of natural killer cells.

Lenalidomide inhibits the proliferation of various haematopoietic tumour cell lines.

The combination of lenalidomide with rituximab increases the NK mediated, antibody dependent cell- mediated cytotoxicity (ADCC), the formation of immune synapses and direct apoptosis in the case of follicular lymphoma, which results in an increased anti-tumour activity of the combination compare with monotherapies.

In in vitro angiogenesis models lenalidomide inhibits angiogenesis by preventing the formation of microvessels and endothelial cell channels as well as the migration of endothelial cells. Lenalidomide also inhibits the formation of the pro-angiogenic factor VEGF in PC-3 prostate tumour cells.

Pharmacodynamics

Cardiac Electrophysiology QT study

No prolongation of the QTc interval was observed in healthy male subjects receiving single doses of lenalidomide at a dose of 10 mg or 50 mg.

Clinical Efficacy  

Clinical experience in patients with untreated multiple myeloma who are eligible for transplant and receive lenalidomide in combination with bortezomib and dexamethasone.

The efficacy (according to the International Myeloma Working Group (IMWG) response criteria) and safety of lenalidomide in combination with bortezomib and dexamethasone (RVd) was evaluated in two phase-3 multicentre clinical studies: PETHEMA GEM2012 and IFM 2009.

PETHEMA GEM2012

The PETHEMA GEM2012 study was a phase-3 randomised, controlled, open-label, multicentre study comparing 2 conditioning regimens (busulfan-melphalan and MEL200), administered prior to transplantation in patients who had received RVd as initial therapy. RVd was administered in six 4-week cycles (24 weeks). Patients received lenalidomide 25 mg/day orally on days 1-21, subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8 and 11 and dexamethasone 40 mg/day orally on days 1-4 and 9- 12 of the repeated 28-day cycles. Following initial therapy, patients received either a conditioning regimen of busulfan-melphalan or MEL200 (1:1 randomisation) and ASCT. In addition, patients received two add-on treatment cycles (8 weeks) of RVd following ASCT. A total of 458 patients were enrolled in the study.

At the end of the initial treatment with RVd in the PETHEMA GEM20212 study, the ≥ VGPR rate was 67%, the CR rate was 33%, and 47% (217/458) of the study subjects were MRD negative. Of the study subjects with ≥ VGPR, 64% (196/305) were MRD negative (10^-4 sensitivity).

The ≥ post-transplant VGPR rate was 75% and the CR rate was 44%, and 59% (287/458) of the study subjects were MRD negative. Of the study subject with ≥ VGPR, 79% (271/344) were MRD negative

(10^-4 sensitivity).

IFM 2009

The IFM 2009 study was a phase 3 randomised, controlled, open-label, multicentre study comparing RVd with and without ASCT as initial therapy in transplant-eligible patients with previously untreated multiple myeloma. Patients received lenalidomide 25 mg/day orally on days 1-14, intravenous bortezomib 1.3 mg/m² on days 1, 4, 8 and 11, and dexamethasone 20 mg/day orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of the repeated 21-day cycles. RVd was administered as eight 3-week cycles (24 weeks) without immediate ASCT (arm A) or as three 3-week cycles (9 weeks) prior to ASCT (arm B). Patients in arm B also received two add-on 3-week cycles of RVd after ASCT. A of total of 700 patients were enrolled in the study.  

In the IFM 2009 study, the ≥ VGPR rate at the end of the initial therapy was 68% and the CR rate was 31%. Of the study subjects with ≥ VGPR, 57% (136/237) were MRD negative (10^-4 sensitivity).

Clinical experience with lenalidomide in patients with multiple myeloma after autologous stem cell transplantation

The efficacy and safety of lenalidomide has been evaluated in two phase 3 multicenter, randomized, double-blind placebo-controlled, parallel-group, two-arm studies: CALGB 100104 and IFM 2005-02. The primary endpoint in both studies was progression-free survival (PFS).

CALGB100104

Patients between 18 and 70 years of age with active multiple myeloma requiring treatment and no previous progression after initial therapy were included in the study.

Patients were randomized 1:1 to lenalidomide maintenance therapy or placebo within 90-100 days of ASCT. The lenalidomide maintenance dose was 10 mg once daily on days 1-28 of the repeated 28-day cycles (and was increased to 15 mg once daily after 3 months if tolerated ), and treatment was continued until disease progression.

In total 460 patients were randomised: 231 patients to lenalidomide and 229 patients to placebo. Both arms were similar in terms of demographic and disease characteristics.

The study was unblinded on the recommendation of the Data Monitoring Committee after reaching a pre- defined PFS threshold in a scheduled interim analysis. After unblinding, patients in the placebo arm were allowed to cross over to the lenalidomide treatment arm prior to disease progression.

                  The median follow-up time was 81.9 months at data cut-off      on 01 February 2016.

The risk of disease progression or death was reduced by 39% in favour of lenalidomide (HR = 0.61; 95% CI, 0.48 to 0.76; p < 0.001). The median progression-free survival was 56.9 months in the lenalidomide arm compared with 29.4 months in the placebo arm.

In the OS analysis, the observed HR was 0.61 (95% CI, 0.46 to 0.81) for lenalidomide versus placebo and indicated a 39% reduced risk of death. Median overall survival was 111.0 months in the lenalidomide arm compared with 84.2 months in the placebo arm.

IFM 2005-02

Patients who were less than 65 years of age at diagnosis and underwent high-dose chemotherapy followed by ASCT and had achieved at least disease stabilization at the time of hematologic recovery were included in the study.

Patients were randomized to lenalidomide maintenance therapy or the placebo arm within 6 months of ASCT. After two lenalidomide consolidation cycles (25 mg/day, on days 1-21 of a

28-day cycle), the lenalidomide maintenance dose was 10 mg once daily (1-28 of a 28-day cycle; and was increased to 15 mg once daily after 3 months if tolerated). Treatment was continued until disease progression. A total of 614 patients were randomised: 307 patients to lenalidomide and 307 patients to placebo.

Treatment was discontinued in the remaining 119 study subjects receiving lenalidomide maintenance therapy (minimum treatment duration of 27 months) due to an observed uneven distribution of SPMs.

The median follow-up time was 96.7 months at data cut-off on 01 February 2016. The risk of disease progression or death was reduced by 43% in favour of lenalidomide (HR = 0.57;

95% CI, 0.42 to 0.76; p < 0.001). The median PFS was 44.4 months in the lenalidomide arm compared with 23.8 months in the placebo arm.

For OS analysis, the observed HR was 0.90 (95% CI, 0.72 to 1.13) for lenalidomide versus placebo. Median overall survival was 105.9 months in the lenalidomide arm compared with 88.1 months in the placebo arm.

Clinical experience in patients with untreated multiple myeloma who are not eligible for transplant and received lenalidomide in combination with bortezomib and dexamethasone

The SWOG S0777 study evaluated the addition of bortezomib to basic treatment with lenalidomide and dexamethasone as initial therapy, followed by further treatment with Rd until disease progression in patients with treatment-naive multiple myeloma who were not due to receive stem cell transplantation in the immediate future.

Patients in the treatment arm with lenalidomide, bortezomib and dexamethasone (RVd) received lenalidomide 25 mg/day orally on days 1-14, intravenous bortezomib 1.3 mg/m² on days 1, 4, 8 and 11, and dexamethasone 20 mg/day orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of the repeated 21-day cycles for up to eight 21-day cycles (24 weeks). Patients in the treatment arm with lenalidomide and dexamethasone (Rd) received lenalidomide 25 mg/day orally on days 1-21 and dexamethasone 40 mg/day orally on days 1, 8, 15 and 22 of the repeated 28-day cycles for up to six 21-day cycles (24 weeks). Patients in both treatment arms received the Rd regimen continuously: lenalidomide 25 mg/day orally on days 1-21 and dexamethasone 40 mg/day orally on days 1, 8, 15 and 22 of the repeated 28-day cycles. Treatment was planned to continue until disease progression.

The primary efficacy endpoint of the study was progression-free survival (PFS). A total of 523 patients

were enrolled in the study, of which 263 were randomised to RVd and 260 to Rd. The demographic data and disease-related baseline characteristics of the patients were well balanced between treatment arms.

Results for PFS (IRAC review, EMA censoring rules), with data cut-off date of 01 December 2016 and a median follow-up period of 60.6 months in surviving subjects, showed a 24% reduction in the risk of disease progression or death in favour of RVd (HR = 0.76; 95% CI 0.62; 0.94). The median overall PFS was 41.7 months (95% CI 33.1; 51.5) in the RVd arm versus 29.7 months (95% CI 24.2; 37.8) in the Rd arm.

Participants in the RVd arm had a 28% reduction in the risk of death compared with the Rd arm (HR =

0.72; 95% CI = 0.56 to 0.94). Median OS was 89.1 months overall (95% CI 76.1; not evaluable) in the RVd arm compared with 67.2 months (95% CI 58.4; 90.8) in the Rd arm. Similarly, the ≥ VGPR rate was higher in the RVd arm (58%) than in the Rd arm (32%).

Clinical experience in untreated patients who are not eligible for transplant and received lenalidomide in combination with dexamethasone

The safety and efficacy of lenalidomide was evaluated in a Phase-3 , multicenter, randomized, open- label, 3-arm study (MM-020) of patients who were either 65 years of age or older or who, if younger than 65 years of age, could not undergo stem cell transplantation because they refused it or because stem cell transplantation was not available to the patient for financial or other reasons. In the study (MM-020), lenalidomide plus dexamethasone (Rd) was compared with melphalan, prednisone plus thalidomide (MPT) for a maximum of twelve 42 day-cycles (72 weeks) for 2 different durations of use (i.e., until disease progression [Rd arm] or for up to eighteen 28-day cycles [72 weeks, Rd18 arm]). Patients were randomised (1:1:1) to one of the three treatment arms. Patients were stratified at randomisation by age (≤75 years versus >75 years), stage (ISS stages I and II versus stage III), and country.

Patients in the Rd and Rd18 arms took 25 mg of lenalidomide once daily on days 1 to 21 of the 28-day cycles. Dexamethasone 40 mg was used once daily on days 1, 8, 15, and 22 of each 28-day cycle. The loading dose and regimen for Rd and Rd18 were adjusted for age and renal function. Patients over the age of 75 received a dexamethasone dose of 20 mg once daily on days 1, 8, 15, and 22 of each 28- day cycle. All patients received prophylactic anticoagulation (low molecular weight heparin, warfarin, heparin, low-dose acetylsalicylic acid) during the study.

The primary efficacy endpoint of the study was progression free survival (PFS). A total of 1,623 patients were enrolled into the study, with 535 patients randomized to Rd, 541 patients to Rd18 and

547 patients randomized to MPT. Patient demographics and disease-related characteristics were balanced between the 3 arms at baseline. In general, subjects had advanced-stage disease: 41% of the total study population had ISS stage III and 9% had severe renal impairment (creatinine clearance [CLcr] < 30 mL/min). The median age was 73 in the 3 arms

PFS was significantly longer with Rd (26.0 months) than MPT (21.9 months): HR 0.69 (95% CI: 0.59-0.80 p = < 0.001) indicating a 31% reduction in the risk of progression or death. In the two treatment arms, deaths during the study duration contributed to PFS at the same rate (10%) . There was a 4.3-month improvement in median PFS time in the Rd arm compared with the MPT arm . Myeloma response rate was significantly higher with Rd than with MPT (75.1% versus 62.3%; p < 0.00001), with

15.1% of patients in the Rd arm achieving a complete response compared with 9.3% of patients in the MPT arm. The median time to initial response was 1.8 months in the Rd arm and 2.8 months in the MPT arm.

For the analysis of overall survival (OS), the median observation time for all surviving patients is

37.0 months, with 574 death events occurring at 64% (574/896) of the last OS events. The observed HR was 0.78 in favour of Rd versus MPT (95% CI = 0.64, 0.96; nominal p-value = 0.01685) with a 22% reduction in the risk of death.

Clinical experience in untreated patients who are not eligible for transplant and received lenalidomide in combination with melphalan and prednisone

The safety and efficacy of lenalidomide was evaluated in a Phase-3 multicenter, randomized double blind 3-arm study (MM-015) in patients who were at least 65 years of age and whose serum creatinine was < 2.5 mg/dL. In the study, lenalidomide in combination with melphalan and prednisone (MPR) with or without lenalidomide maintenance monotherapy until disease progression was compared with the combination of of melphalan plus prednisone for a maximum of 9 cycles. Patients were randomized 1:1:1 to one of three treatment arms: Arm MPR+R arm – induction therapy with oral MPR combination followed by lenalidomide maintenance therapy; MPR+ p arm – induction therapy with oral MPR combination followed by maintenance therapy with placebo; MPp+ p arm – oral MPp (MP + placebo) - induction therapy with oral MPp (MP + placebo) combination followed by maintenance therapy with placebo (MPp+p).

Progression-free survival was significantly longer for MPR+R than for MPp+p, according to the blinded independent review, with an of HR 0.388 (95% CI: 0.274-0.550) indicating a 61% reduction in the risk of disease progression for MPR+R compared with MPp+p.

Clinical experience in patients with multiple myeloma who received at least one prior therapy

In two multicentre, randomised, placebo-controlled, parallel group controlled, double-blind studies with the same design (MM-009 in the US and Canada and MM-010 in Europe, Israel and Australia) 353 and 351 patients, with multiple myeloma who were previously treated with one or more chemotherapy regimens were treated with either lenalidomide plus dexamethasone or with dexamethasone.

In a pooled evaluation of both studies, the median time to progression in patients treated with lenalidomide/dexamethasone was 48 weeks (95% CI: 41.1;

60.1) and in patients on placebo/dexamethasone, it was 20.1 weeks (95% CI: 19.9, 20.7). The median duration of progression-free survival was 47.3 weeks (95% CI: 36.9, 58.4) versus 20.1 weeks (95% CI: 18.1, 20.3). Overall survival was significantly higher with lenalidomide/dexamethasone at 90.3 vs 80.2 weeks, p=0.015, (patients in the placebo arm could switch to the active drug after progression or unblinding, 50% were treated with lenalidomide/dexamethasone).

The median duration of treatment was 28.1 weeks (min: 0.1, max: 110.7). Clinical experience in myelodysplastic syndrome

In a phase-2 multicentre, single-arm, open label study (MDS-003 in Germany and the US), 120 patients with confirmed RBC transfusion dependence due to low- or intermediate-risk MDS or intermediate risk 1 with a 5q deletion cytogenic abnormality with or without further cytogenetic abnormalities were treated with lenalidomide 10 mg. The median duration of therapy was 52.5 weeks. The rate of transfusion- independence (> 56 days) was 62.8%. The median increase in haemoglobin was 5.9 g/dl. The median duration of response was 97 weeks. Significant cytogenetic response was observed in 34.6% of patients and a less pronounced cytogenetic response in 38.5% of patients.

In a phase-3 multicentre, double-blind, placebo-controlled, three-arm study (MDS-004 in Europe and Israel), 138 patients with confirmed RBC transfusion dependence due to low or intermediate-risk MDS or intermediate risk 1 with a 5q deletion cytogenetic abnormality with or without further cytogenetic abnormalities were randomised and treated with lenalidomide 10 mg, lenalidomide 5 mg or placebo. The duration of the double-blind phase was 16-52 weeks. The rate of transfusion-independence (> 182 days) was 56.1% in the 10 mg group. The corresponding transfusion-independence rates in the 5-mg and placebo groups were 41.3% and 5.9%, respectively. The median duration of response was 106 weeks in the 10-mg group; however, it could not be determined in the 5 mg and placebo groups. A clear or less clearly pronounced cytogenetic response was observed in 24.0% and 17.1% (10 mg); 10.9% and 6.5% (5 mg); and 0% and 0% (placebo) of patients.

The rate of transfusion-independence (> 56 days) was 61.0% in the 10 mg group, with a median increase in haemoglobin of 6.3 g/dl. The corresponding transfusion-independence rates and haemoglobin increases in the 5 mg and placebo groups were 50.0% and 7.8%, and 5.1 g/dl and 2.3 g/dl, respectively.

Clinical experience in mantle cell lymphoma

The phase-2 multicentre, uncontrolled MCL-001 study of lenalidomide monotherapy was designed to evaluate the safety and efficacy of lenalidomide in patients with mantle cell lymphoma who had relapsed after treatment with bortezomib or a bortezomib-containing regimen or who were refractory to this treatment. Only patients with confirmed translocation or cyclin-overexpression, as well as patients who are not eligible for stem cell transplantation were included in the study. Lenalidomide was administered on days 1-21 of the repeated 28-day treatment cycles until progression, or the occurrence of unacceptable toxicity, or withdrawal of consent.

Previous treatment of the patient with an anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib alone or in combination was a prerequisite for study participation.

Patients with an absolute neutrophil count (ANC) ≥ 1500 cells/mm³, platelet counts ≥

60,000/cells/mm³, serum SGOT/AST or SGPT/ALT < 3.0 x ULN ( upper limit of normal) except for documented evidence of hepatic involvement by lymphoma, serum total bilirubin < 1.5 x ULN except for Gilbert’s syndrome or documented hepatic involvement by lymphoma, and calculated creatinine clearance >30 ml/min (according to the Cockcroft-Gault formula) were enrolled.

The primary efficacy endpoints of the MCL-001 study were overall response rate (ORR) and duration of response (DOR). An overview of the efficacy results for the ITT (Intent to Treat) population according to the findings by the Independent Review Committee (IRC) is provided in the table below. The median time to response was 2.2 months (1.7; 13.1 month). Median overall survival was 19.0 months (95% Cl 12.5; 22.9 months). Progression-free survival in the overall study population was 3.95 months.

In the MCL-002 study, a discernible increase in deaths was observed within 20 weeks in the lenalidomide arm: 13% (22/170) compared with 7% (6/84) in the control arm, in the ITT population overall. In patients with a high tumour burden, the corresponding figures were 20% (16/81) and 7% (2/28).

Clinical experience in follicular lymphoma

NHL-007

The study CC-5013-NHL-007 (AUGMENT) is a phase-3, multicentre, double-blind, randomised study. The efficacy and safety of lenalidomide in combination with rituximab (R²) versus rituximab plus placebo was studied in patients with relapsed/refractory indolent lymphoma.

A total of 358 patients aged at least 18 with FL Grades 1, 2 or 3A (n = 295) or histologically confirmed marginal zone lymphoma (MZL) were randomised at a ratio of 1:1. The patients had been previously treated with at least one systemic chemotherapy, immunotherapy or immunochemotherapy. The patients were to have received at least 2 previous doses of rituximab and were not to be rituximab refractory.

Lenalidomide was administered at an oral dose of 20 mg once daily on the first 21 days of the repeated 28-day treatment cycles, over 12 cycles or until the occurrence of a non-acceptable toxicity. The rituximab dose was 375 mg/m² once weekly in cycle 1 (days 1, 8, 15 and 22) and on day 1 of every 28- day cycle from cycle 2 up to and including cycle 5.

The primary efficacy endpoint of the study was progression-free survival (PFS). In patients with FL, the median progression-free survial (PFS) in the R² arm was significantly longer (39.4 months; 95% CI 25.1; [NE](Not estimable)) than in the control arm (13.8 months; 95% CI: 11.2; 16.0); the risk of relapse was reduced by 60% (HR 0.40; 95% CI: 0.29; 0.55). The result of the primary endpoint was clinically and statistically significant.

In addition, the FL patients showed a higher overall response rate (ORR) in the R² arm (ORR 80.3 %; 95% CI: 72.9; 86.4) compared with the rituximab monotherapy (ORR 55.4; 95% CI: 47.0; 63.6). The median response rate was 36.6 months in the R² arm and 15.5 months in the control arm. Mortality, measured as the overall survival rate (OS) after 2 years, was reduced in the R² arm by 55% (HR 0.45; 95% CI: 0.22; 0.92), in other words, after 2 years, 94.8% of the patients in the R² arm were alive compared with 85.8% of the patients receiving rituximab monotherapy.

NHL-008

The NHL-008 study is a phase-3 open-label, randomised study in patients (n = 232) with relapsed or refractory FL (Grade 1-3B), MZL or MCL. In contrast to the NHL-007 study, the NHL-008 study included patients who were refractory to rituximab, i.e., either did not respond to the treatment or had a relapse within 6 months after treatment with rituximab, or who were refractory to rituximab as well as to chemotherapy.

After an initial combined treatment phase with rituximab + lenalidomide (R²) over 12 cycles, the patients were randomised to the subsequent maintenance therapy, to receive either the combination therapy R² (or optionally, lenalidomide monotherapy after cycle 18) or rituximab monotherapy.

During the induction treatment, lenalidomide was administered at a dose of 20 mg on days 1-21 of the repeated 28-day cycles, either for up to 12 cycles or until an unacceptable toxicity occurred or until consent to participate in the study was withdrawn. The rituximab dose was 375 mg/m² per week in cycle 1 (days 1, 8, 15 and 22) and on day 1 of every other 28-day cycle (cycles 3, 5, 7, 9 and 11) for up to

12 treatment cycles

The primary efficacy endpoint of the induction phase of the study was the overall response rate (ORR) according to the modified response criteria of the International Working Group (IWGRC) of 1999. The available results are based on the interim analysis from the initial R² treatment phase.

After the induction phase of 12 cycles, the ORR of all study participants with FL (n = 148) was 70.3%; rituximab refractory patients (n = 60) had an ORR of 58.3%, whilst rituximab non-refractory patients (n

= 88) had an ORR of 79.3%.

Absorption

Lenalidomide is rapidly absorbed with a T_max of 1 hour. The oral bioavailability is approximately 70%. The pharmacokinetics of lenalidomide are dose-proportional.

When administered concomitantly with a high-fat meal, the extent of absorption is reduced in healthy volunteers, resulting in an approximately 20% decrease in the area under the concentration-time curve (AUC) and a 50% decrease of the C_max in plasma.

Population pharmacokinetic analyses show that the oral absorption rate of lenalidomide in MCL- patients is comparable to that observed in patients with MM or MDS. Distribution

Lenalidomide binding to plasma proteins is low (<30%). Whether lenalidomide crosses the blood-brain barrier has not been studied.

Lenalidomide passes into semen (< 0.01% of the dose) after administration of a daily dose of 25 mg. Three days after discontinuation of the medicinal product, lenalidomide is no longer detectable in the semen of healthy subjects.

Metabolism

The metabolism of lenalidomide is minimal and does not occur via the phase I enzymes. The main component occurring in humans in vivo in blood is unchanged lenalidomide. 5-hydroxyl- lenalidomide and N-acetyl-lenalidomide were identified as metabolites; each of which reaches less than 5% of the blood levels of the parent substance.

Elimination

Approximately two thirds of a dose of lenalidomide is excreted unchanged via the kidneys. The renal clearance of lenalidomide exceeds the glomerular filtration rate; therefore lenalidomide is actively secreted to at least some extent.

At therapeutic doses (up to 25 mg/day), the plasma half-life is approximately 3 hours in healthy volunteers and ranges from 3 to 5 hours in patients.

Steady state concentrations are attained on day 4. There is no accumulation with multiple doses.

Kineticsinspecialpatientgroups

There is no data on pharmacokinetics in paediatric patients.

Lenalidomide is primarily el i minat ed as an unchanged active substance via glomerular filtration and active tubular secretion. After a single dose of 25 mg, the AUC is increased by 25% in mild renal insufficiency (Clcr 80-50 ml/min); three-fold in moderate renal insufficiency (Clcr 50-30 ml/min) and four to five-fold in severe renal insufficiency (ClCr <30 ml/min) and/or dialysis-dependent renal insufficiency (interdialytic period) . The elimination half-life is prolonged three-fold to 9-10 hours in moderate renal insufficiency.

Hepatic impairments

Population pharmacokinetic analysis included patients with mild hepatic impairment (n=16; total bilirubin >1.0 to ≤ 1.5 x ULN or AST > ULN) and show that mild hepatic impairment does not affect lenalidomide disposition. No data is available on patients with moderate to severe hepatic impairment .

Short-term/long-term toxicity

Lenalidomide has a low potential for acute toxicity; in rodents the lowest lethal doses after oral administration were more than 2000 mg/kg. Long-term administration of lenalidomide led to the mineralisation of the renal pelvis in rats, most notably in female animals. The dose at which no side effects occurr (no observed adverse effect level, NOAEL), is estimated to be less than 75 mg/kg in rats and is therefore approximately 25 times higher than the daily human exposure at a dose of

25 mg/day based on the AUC. In monkeys, repeated oral administration resulted in a dose-dependent decrease in the neutrophil count; this effect is due to the pharmacodynamic effect of the active substance. Repeated oral administration of 4 and 6 mg/kg to monkeys for a period of up to 20 weeks resulted in mortality and significant toxicity (marked weight loss, decrease in red and white blood cell count and in platelet counts, multiple organ bleeding , inflammation of the gastrointestinal tract, atrophy of the lymphoid tissue and bone marrow). Administration of 1 and 2 mg/kg/day for 52 weeks resulted in changes in the propotions of cells in the bone marrow in monkeys, a slight decrease in the ratio of myeloid to erythroid cells, and thymic atrophy. Minor suppression of the number of WBCs was observed at 1 mg/kg/day. The NOAEL was 1 mg/kg/day. AUC exposure at this dose is equivalent to human therapeutic exposure at 25 mg/day.

Mutagenicity/carcinogenicity

in vitro (bacterial mutations, human lymphocytes, mouse lymphoma, Syrian hamster embryonal cell transformation) and in vivo (rat micronucleus test) mutagenicity studies revealed no active substance- related effects at either the genetic or chromosomal level. Carcinogenicity studies with lenalidomide have not been performed.

Reproductive toxicity

Developmental toxicity studies (embryo-fetal toxicity/teratogenicity) were conducted in rats, rabbits and monkeys. In a study on monkeys, lenalidomide was given in doses up to 4 mg/kg/day. The study results show that the administration of lenalidomide to pregnant female monkeys resulted in malformations in the offspring that were comparable to thalidomide malformations.

In rabbits receiving oral administration of 3, 10 and 20 mg/kg/day, developmental toxicity at dos es of 10 and

20 mg/kg/day was characterized by slightly reduced foetal body weight, more frequent post-implantation loss (early and late resorption and intrauterine deaths) as well as macroscopic external findings in the foetuses, associated with morbidity and pharmacotoxic effects due to lenalidomide (purple discoloration of the skin over the whole body). At 10 mg and 20 mg/kg/day, soft tissue and skeletal changes were observed in the foetuses, which are however typical for rabbit strain used. The maternal and development--related NOAELs for lenalidomide in rabbits were 3 mg/kg/day.

As observed in previous rat thalidomide studies, an embryo-foetal development study in rats with lenalidomide administrations up to 500 mg/kg/day also showed no teratogenic effect. At doses of 100, 300 or 500 mg/kg/day, there was minimal maternal toxicity, including a small, temporary reduction in mean body weight gain and food intake.

Capsule contents

Anhydrous lactose

Microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

Not applicable.

Store below 30C. Store in the original package and out of the reach and sight of children. 

Lenalidomide capsules are provided in Polyvinylchloride (PVC) / Polychlorotrifluoroethylene (PCTFE) blisters with push-through aluminium foil.

Revlimid 5 mg/ 10 mg/ 15 mg/ 25 mg hard capsules Pack size of 21 capsules.

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

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