Revlimid treatment should be supervised by a physician experienced in the use of anti-cancer therapies (see section 4.4, karyotype).

Posology

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 (see section 4.4). 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

• Thrombocytopenia

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

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

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

Recommended dose

The recommended starting dose is lenalidomide 10 mg/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 (see section 4.4).

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

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

• Neutropenia

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.

Multiple myeloma with at least one prior therapy

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 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily on days 1-4 every 28 days. Dosing is continued or modified based upon clinical and laboratory findings (see section 4.4). Prescribing physicians should carefully eva luate 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 < 1.0 x 10⁹/L, and/or platelet counts < 75 x 10⁹/L or, dependent on bone marrow infiltration by plasma cells, platelet counts < 30 x 10⁹/L.

Recommended dose adjustments during treatment and restart of treatment:

Dose adjustments, as summarised below, are recommended to manage grade 3 or 4 neutropenia or thrombocytopenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide.

• Dose reduction steps

• Thrombocytopenia

• Neutropenia

In case of neutropenia, the use of growth factors in patient management should be considered.

Myelodysplastic syndromes

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

Recommended dose

The recommended starting dose of lenalidomide is 10 mg orally once daily on days 1-21 of repeated 28-day cycles. Dosing is continued or modified based upon clinical and laboratory findings (see section 4.4).

Recommended dose adjustments during treatment and restart of treatment:

Dose adjustments, as summarized below, are recommended to manage grade 3 or 4 neutropenia or thrombocytopenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide.

• Dose reduction steps

For patients who are dosed initially at 10 mg and who experience thrombocytopenia or neutropenia:

• Thrombocytopenia

• Neutropenia

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.

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.

Special populations

Paediatric population

Revlimid should not be used in children and adolescents from birth to less than 18 years because of safety concerns (see section 4.4).

Older people

Currently available pharmacokinetic data are described in section 5.2. Lenalidomide has been used in clinical trials in multiple myeloma patients up to 91 years of age and in myelodysplastic syndromes patients up to 95 years of age (see section 5.1).

In patients with newly diagnosed multiple myeloma aged 75 years and older who received lenalidomide, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation (see section 4.4). Patients with newly diagnosed multiple myeloma aged 75 years and older should be carefully assessed before treatment is considered (see section 4.4).

• Newly diagnosed multiple myeloma

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 who are treated with lenalidomide in combination with melphalan and prednisone.

In clinical trials of newly diagnosed multiple myeloma in transplant non eligible patients, lenalidomide combined therapy was less tolerated in patients older than 75 years of age compared to the younger population. These patients discontinued at a higher rate due to intolerance (Grade 3 or 4 adverse events and serious adverse events), when compared to patients < 75 years (see section 4.4).

• Multiple myeloma with at least one prior therapy

The percentage of multiple myeloma patients aged 65 or over was not significantly different between the lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in safety or efficacy was observed between these patients and younger patients, but greater pre-disposition of older individuals cannot be ruled out.

For myelodysplastic syndromes patients treated with lenalidomide, no overall difference in safety and efficacy was observed between patients aged over 65 and younger patients.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it would be prudent to monitor renal function.

Patients with renal impairment

Lenalidomide is substantially excreted by the kidney; patients with greater degrees of renal impairment can have impaired treatment tolerance (see section 4.4). Care should be taken in dose selection and monitoring of renal function is advised.

No dose adjustments are required for patients with mild renal impairment and multiple myeloma or myelodysplastic syndromes. The following dose adjustments are recommended at the start of therapy and throughout treatment for patients with moderate or severe impaired renal function or end stage renal disease.

There are no Phase III trial experiences with End Stage Renal Disease (ESRD) (CLcr < 30 mL/min, requiring dialysis).

• Multiple myeloma