Posology : מינונים

2. DOSAGE AND ADMINISTRATION
REVLIMID should be taken orally at about the same time each day, either with or without food.
REVLIMID hard capsules should be swallowed whole with water. The hard capsules should not be opened, broken, or chewed.

2.1 Newly Diagnosed Multiple Myeloma

Lenalidomide in combination with dexamethasone until disease progression in patients who are not eligible for transplant

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

Recommended dose
The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1-21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1, 8, 15 and 22 of repeated 28-day cycles. Patients may continue lenalidomide and dexamethasone therapy until disease progression or intolerance.
Dosing is continued or modified based upon clinical and laboratory findings. For patients ≥75 years of age, the starting dose of dexamethasone is 20 mg/day on days 1, 8, 15 and 22 of each 28- day treatment cycle. The recommended dose of lenalidomide for patients suffering from moderate renal impairment is 10 mg once daily.

Recommended dose adjustments during treatment and restart of treatment: Dose adjustments, as summarised below, are recommended to manage grade 3 or 4 thrombocytopenia, neutropenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide.

•   Dose reduction steps

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               NA
•   Thrombocytopenia
When platelets                                                      Recommended course Fall to < 25 x 109/L                                                Stop lenalidomide dosing for remainder of cycleª
Return to ≥ 50 x 109/L                                              Decrease by one dose level when dosing resumed at next cycle
ª If Dose Limiting Toxicity (DLT) occurs on > day15 of a cycle, lenalidomide dosing will be interrupted for at least the remainder of the current 28-day cycle.


•     Neutropenia
When neutrophils                                                    Recommended course First fall to < 0.5 x 109/L                                         Interrupt lenalidomide treatment Return to ≥ 1 x 109/L when neutropenia is                           Resume lenalidomide at Starting dose the only observed toxicity                                          once daily Return to ≥ 0.5 x 109/L when dose-                                  Resume lenalidomide at Dose level -1 dependent haematological toxicities other                           once daily than neutropenia are observed
For each subsequent drop below                                      Interrupt lenalidomide treatment < 0.5 x 109/L
Return to ≥ 0.5 x 109/L                                             Resume lenalidomide at next lower dose level once daily.

In case of neutropenia, the use of growth factors in patient management should be considered.
If the dose of lenalidomide was reduced for a hematologic DLT, the dose of lenalidomide may be re-introduced to the next higher dose level (up to the starting dose) at the discretion of the treating physician if 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 beginning of a new cycle at the current dose level).

Lenalidomide in combination with melphalan and prednisone followed by maintenance monotherapy in patients who are not eligible for transplant
Lenalidomide9 treatment must not be started if the ANC is < 1.5 x 109/L, and/or platelet counts are < 75 x 10 /L.

Recommended dose
The recommended starting dose is lenalidomide 10 mg/day orally on days 1-21 of repeated 28-day cycles for up to 9 cycles, melphalan 0.18 mg/kg orally on days 1-4 of repeated 28 day cycles, prednisone 2 mg/kg orally on days 1-4 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 alone, 10 mg/day orally on days 1-21 of repeated 28-day cycles given until disease progression. Dosing is continued or modified based upon clinical and laboratory findings.

Recommended dose adjustments during treatment and restart of treatment: Dose adjustments, as summarised below, are recommended to manage grade 3 or 4 thrombocytopenia, neutropenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide.

•    Dose reduction steps

Lenalidomide                       Melphalan                    Prednisone Starting dose                       10 mgª                          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                           NA                       0.25 mg/kg ª If neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide


•    Thrombocytopenia

When platelets                                                       Recommended course First fall to < 25 x 109/L                                           Interrupt lenalidomide treatment Return to ≥ 25 x 109/L                                               Resume lenalidomide and melphalan at Dose level -1
For each subsequent drop below                                       Interrupt lenalidomide treatment 30 x 109/L
Return to ≥ 30 x 109/L                                               Resume lenalidomide at next lower dose level (Dose level -2 or -3) once daily.

•    Neutropenia

When neutrophils                                                     Recommended course First fall to < 0.5 x 109/Lª                                         Interrupt lenalidomide treatment Return to ≥ 0.5 x 109/L when neutropenia                             Resume lenalidomide at Starting dose is the only observed toxicity                                        once daily Return to ≥ 0.5 x 109/L when dose-                                   Resume lenalidomide at Dose level -1 dependent haematological toxicities other                            once daily than neutropenia are observed
For each subsequent drop below                                       Interrupt lenalidomide treatment < 0.5 x 109/L
Return to ≥ 0.5 x 109/L                                              Resume lenalidomide at next lower dose level once daily.
ªIf the subject has not been receiving G-CSF therapy, initiate G-CSF therapy. On Day 1 of next cycle, continue G-CSF as needed and maintain dose of melphalan if neutropenia was the only DLT. Otherwise, decrease by one dose level at start of next cycle.


In case of neutropenia, the use of growth factors in patient management should be considered.
For patients older than 75 years of age treated with lenalidomide in combination with dexamethasone, the starting dose of dexamethasone is 20 mg/day on days 1, 8, 15 and 22 of each 28-day treatment cycle.

No dose adjustment is proposed for patients older than 75 years treated with lenalidomide in combination with melphalan and prednisone.

2.2 Multiple Myeloma with at least one prior therapy
The recommended starting dose of REVLIMID is 25 mg once daily on days 1-21 of repeated 28- day cycles. The recommended dose of dexamethasone is 40 mg once daily on days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily orally on days 1-4 every 28 days. Treatment is continued or modified based upon clinical and laboratory findings.
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 < 1,000/mcL, and/or platelet counts < 75,000/ mcL or, dependent on bone marrow infiltration by plasma cells, platelet counts < 30,000/mcL.

Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment Dose modification guidelines, as summarized below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID.

Platelet counts
Thrombocytopenia in MM

When Platelets                                           Recommended Course Fall to <30,000/mcL                                      Interrupt REVLIMID treatment, follow CBC weekly
Return to ≥30,000/mcL                                    Restart REVLIMID at 15 mg daily
For each subsequent drop <30,000/mcL                     Interrupt REVLIMID treatment Return to ≥30,000/mcL                                    Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily
Absolute Neutrophil counts (ANC)
Neutropenia in MM
When Neutrophils                                          Recommended Course Fall to <1000/mcL                                         Interrupt REVLIMID treatment, add G-CSF, follow
CBC weekly
Return to ≥1,000/mcL and neutropenia is the only          Resume REVLIMID at 25 mg toxicity                                                  daily
Return to ≥1,000/mcL and if other toxicity                Resume REVLIMID at 15 mg daily
For each subsequent drop <1,000/mcL                       Interrupt REVLIMID treatment
Return to ≥1,000/mcL                                      Resume REVLIMID at 5 mg less than the previous dose.
Do not dose below 5 mg daily


In case of neutropenia, the physician should consider the use of growth factors in patient management.

Starting Dose Adjustment for Renal Impairment in MM:

See Section 2.5
2.3 Myelodysplastic Syndromes
The recommended starting dose of REVLIMID is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings.
Dose Adjustments for Hematologic Toxicities During MDS Treatment
Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows:

Platelet counts
If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline ≥100,000/mcL
When Platelets                                Recommended Course
Fall to <50,000/mcL                           Interrupt REVLIMID treatment Return to ≥50,000/mcL                         Resume REVLIMID at 5 mg daily If baseline <100,000/mcL
When Platelets                                Recommended Course
Fall to 50% of the baseline value             Interrupt REVLIMID treatment If baseline ≥60,000/mcL and                   Resume REVLIMID at 5 mg daily returns to ≥50,000/mcL
If baseline <60,000/mcL and                   Resume REVLIMID at 5 mg daily returns to ≥30,000/mcL


If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS When Platelets                  Recommended Course
<30,000/mcL or <50,000/mcL      Interrupt REVLIMID treatment with platelet transfusions
Return to ≥30,000/mcL           Resume REVLIMID at 5 mg daily
(without hemostatic failure)

Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows:
If thrombocytopenia develops during treatment at 5 mg daily in MDS
When Platelets                                   Recommended Course
<30,000/mcL or <50,000/mcL                       Interrupt REVLIMID treatment with platelet transfusions
Return to ≥30,000/mcL                            Resume REVLIMID at 2.5 mg (without hemostatic failure)                     daily

Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows:
Absolute Neutrophil counts (ANC)
If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS 
If baseline ANC ≥1,000/mcL
When Neutrophils                                      Recommended Course Fall to <750/mcL                                      Interrupt REVLIMID treatment Return to ≥1,000/mcL                                  Resume REVLIMID at 5 mg daily
If baseline ANC <1,000/mcL
When Neutrophils                                      Recommended Course Fall to <500/mcL                                      Interrupt REVLIMID treatment Return to ≥500/mcL                                     Resume REVLIMID at 5 mg daily

If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS 
When Neutrophils                                         Recommended Course <500/mcL for ≥7 days or <500/mcL                         Interrupt REVLIMID treatment associated with fever (≥38.5°C)
Return to ≥500/mcL                                       Resume REVLIMID at 5 mg daily


Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows: If neutropenia develops during treatment at 5 mg daily in MDS

When Neutrophils                                           Recommended Course <500/mcL for ≥7 days or <500/mcL                           Interrupt REVLIMID associated with fever (≥38.5°C)                            treatment Return to ≥500/mcL                                         Resume REVLIMID at 2.5 mg daily
Discontinuation of lenalidomide
Patients without at least a minor erythroid response within 4 months of therapy initiation, demonstrated by at least a 50% reduction in transfusion requirements or, if not transfused, a 1g/dl rise in haemoglobin, should discontinue lenalidomide treatment.

Starting Dose Adjustment for Renal Impairment in MDS:

See Section 2.5
2.4 Mantle Cell Lymphoma
The recommended starting dose of REVLIMID is 25 mg/day orally on days 1-21 of repeated 28-day cycles.
Dosing is continued or modified based upon clinical and laboratory findings.


Dose reduction steps
Starting dose         25 mg once daily on days 1-21, every 28 days
Dose Level -1         20 mg once daily on days 1-21, every 28 days
Dose Level -2         15 mg once daily on days 1-21, every 28 days
Dose Level -3         10 mg once daily on days 1-21, every 28 days
Dose Level -4         5 mg once daily on days 1-21, every 28 days
Dose Level -5         2.5 mg once daily on days 1-21, every 28 days
5 mg every other day on days 1-21, every 28 days
Thrombocytopenia
When Platelets                                            Recommended Course Fall to <50 x 109/L                                       Interrupt REVLIMID treatment and conduct Complete Blood
Count (CBC) at least every 7 days
Return to ≥ 60 x 109/L                                    Resume lenalidomide at next lower level (Dose Level -1)
For each subsequent drop below 50 x 109/L                 Interrupt REVLIMID treatment and conduct the CBC at least every 7 days
Return to ≥60 x 109/L                                     Resume REVLIMID at next lower level (Dose Level -2, -3,
-4 or -5). Do not dose below
Dose Level -5

Neutropenia
When Neutrophils                                           Recommended Course Fall to <1 x 109/L for at least 7 days                     Interrupt REVLIMID OR                                                         treatment and conduct the Falls to <1 x 109/L with an associated fever (body         CBC at least every 7 days temperature ≥ 38.5°C)
OR
Falls to <0.5 x 109/L

Return to ≥1 x 109/L                                       Resume REVLIMID at next lower dose level (Dose Level
– 1)
For each subsequent drop below 1 x 109/L for at least 7    Interrupt REVLIMID days or drop to < 1 x 109/L with associated fever (body    treatment temperature ≥ 38.5°C) or drop to < 0.5 x 109/L

Returns to ≥1 x 109/L                                      Resume REVLIMID at next lower dose level (Dose Level -
2, -3, -4, -5). Do not dose below Dose Level -5

Tumour flare reaction
REVLIMID may be continued in patients with Grade 1 or 2 tumour flare reaction (TFR) without interruption or modification, at the physician’s discretion. In patients with Grade 3 or 4 TFR, withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1 and patients may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

Lenalidomide interruption or discontinuation should be considered for grade 2 or 3 skin rash.
Lenalidomide must be discontinued for angioedema, grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is suspected, and should not be resumed following discontinuation from these reactions.

Starting Dose Adjustment for Renal Impairment in MCL:

See Section 2.5.
2.5 Starting Dose for Renal Impairment in MM, MDS or MCL

Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with MM, MDS or MCL are as follows:

Starting Dose Adjustments for Patients with Renal Impairment in MM, MDS or MCL 
Category          Renal Function         Dose in MM or           Dose in MDS (Cockcroft-Gault)            MCL
Moderate Renal       CLcr 30-60 mL/min        10 mg              5 mg Impairment                                    Every 24 hours     Every 24 hours Severe Renal         CLcr < 30 mL/min         7.5 mg             2.5 mg Impairment           (not requiring           Every 24 hours     Every 24 hours dialysis)
End Stage Renal      CLcr < 30 mL/min         5 mg               2.5 mg Disease              (requiring dialysis)     once daily. On     Once daily. On dialysis dialysis days,     days, administer the administer the     dose following dialysis.
dose following dialysis.

After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described elsewhere (see section 2).

All patients
For other grade 3 or 4 toxicities judged to be related to lenalidomide, treatment should be stopped and only restarted at next lower dose level when toxicity has resolved to ≤ grade 2 depending on the physician’s discretion.

Lenalidomide interruption or discontinuation should be considered for grade 2 or 3 skin rash.
Lenalidomide must be discontinued for angioedema, grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is suspected, and should not be resumed following discontinuation from these reactions.

3. DOSAGE FORMS AND STRENGTHS

REVLIMID 2.5 mg, 5 mg, 7.5mg, 10 mg, 15 mg, 20 mg and 25 mg hard capsules will be supplied through the Revlimid RMP-PPP.

REVLIMID is available in the following hard capsule strengths:

2.5 mg: White and blue-green opaque hard capsules imprinted “REV” on one half and “2.5 mg” on the other half in black ink
5 mg: White opaque hard capsules imprinted “REV” on one half and “5 mg” on the other half in black ink
7.5mg: Pale yellow/white hard capsules marked “REV 7.5 mg”
10 mg: Blue/green and pale yellow opaque hard capsules imprinted “REV” on one half and “10 mg” on the other half in black ink
15 mg: Powder blue and white opaque hard capsules imprinted “REV” on one half and “15 mg” on the other half in black ink
20 mg: Powder blue and blue-green opaque hard capsules imprinted “REV” on one half and “20 mg” on the other half in black ink
25 mg: White opaque hard capsules imprinted “REV” on one half and “25 mg” on the other half in black ink