Advise patients to take Lenalidomide Capsules orally at about the same time each day, either with or without food. Advise patients to swallow Lenalidomide Capsules whole with water and not to open, break, or chew them.
Recommended dosages for Lenalidomide vary by indication, with recommended dosage adjustments for certain hematologic or clinical parameters as follows:
Lenalidomide Combination Therapy
The recommended starting dose of Lenalidomide Capsules is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to Prescribing Information Section 14.1 for specific dexamethasone dosing. For patients greater than 75 years old, the starting dose of dexamethasone may be reduced. Treatment should be continued until disease progression or unacceptable toxicity.
In patients who are not eligible for auto-HSCT, treatment should continue until disease progression or unacceptable toxicity. For patients who are auto-HSCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a Lenalidomide-containing therapy.
Dose Adjustments for Hematologic Toxicities During MM 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 Lenalidomide.
Platelet counts
Thrombocytopenia in MM
Absolute Neutrophil counts (ANC)
Neutropenia in MM
Absolute Neutrophil counts (ANC)
Neutropenia in MM
Lenalidomide Maintenance Therapy Following Auto-HSCT
Following auto-HSCT, initiate Lenalidomide maintenance therapy after adequate hematologic recovery (ANC at least 1000/mcL and/or platelet counts at least 75,000/mcL). The recommended starting dose of Lenalidomide is 10 mg once daily continuously (Days 1-28 of repeated 28-day cycles) until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated.
Dose Adjustments for Hematologic Toxicities During MM 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 Lenalidomide.
Platelet counts
Thrombocytopenia in MM
Absolute Neutrophil counts (ANC)
Neutropenia in MM
The recommended starting dose of Lenalidomide Capsules is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment until disease progression or unacceptable toxicity.
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 thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS
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
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 neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS
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
The recommended starting dose of Lenalidomide Capsules is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity. Treatment is continued, modified or discontinued based upon clinical and laboratory findings.
Dose Adjustments for Hematologic Toxicities During MCL Treatment
Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to Lenalidomide.
Platelet counts
Thrombocytopenia during treatment in MCL
Absolute Neutrophil counts (ANC)
Neutropenia during treatment in MCL
The recommended starting dose of Lenalidomide Capsules is 20 mg orally once daily on Days 1-21 of repeated 28-day cycles for up to 12 cycles of treatment in combination with a rituximab-product. Refer to Prescribing Information Section 14.4 for specific rituximab dosing from the AUGMENT trial. For dose adjustments due to toxicity with rituximab, refer to the product prescribing information.
Dose Adjustments for Hematologic Toxicities during FL or MZL 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 Lenalidomide Capsules.
Platelet counts
Thrombocytopenia during treatment in FL or MZL
Absolute Neutrophil counts (ANC)
Neutropenia during treatment in FL or MZL
The recommendations for dosing patients with renal impairment are shown in the following table:
Lenalidomide Combination Therapy for MM: For CLcr of 30 to 60 mL/min, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of Lenalidomide without dose-limiting toxicity.
Lenalidomide Maintenance Therapy Following Auto-HSCT for MM and for MCL and MDS: Base subsequent Lenalidomide Capsules dose increase or decrease on individual patient treatment tolerance.
Lenalidomide Combination Therapy for FL or for MZL: For patients with CLcr of 30 to 60 mL/min, after 2 cycles, the Lenalidomide Capsules dose may be increased to 15 mg orally if the patient has tolerated therapy.
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WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, AND VENOUS AND ARTERIAL THROMBOEMBOLISM
Embryo-Fetal Toxicity
Do not use lenalidomide capsules during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting lenalidomide capsules treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after lenalidomide capsules treatment. To avoid embryo-fetal exposure to lenalidomide, lenalidomide capsules are only available through a restricted distribution program, the Lenalidomide REMS program.
Information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by calling the toll-free number 1-888-423-5436.
Hematologic Toxicity (Neutropenia and Thrombocytopenia)
Lenalidomide can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.
Venous and Arterial Thromboembolism
Lenalidomide has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with lenalidomide and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient's underlying risks.
CONTRAINDICATIONS
Pregnancy: Lenalidomide capsules can cause fetal harm when administered to a pregnant female and are contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.
Severe Hypersensitivity Reactions: Lenalidomide capsules are contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.
INDICATIONS
Lenalidomide capsules are a thalidomide analogue indicated for the treatment of adult patients with:
Limitations of Use:
Lenalidomide capsules are not indicated and are not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, AND VENOUS AND ARTERIAL THROMBOEMBOLISM
Embryo-Fetal Toxicity
Do not use lenalidomide capsules during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting lenalidomide capsules treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after lenalidomide capsules treatment. To avoid embryo-fetal exposure to lenalidomide, lenalidomide capsules are only available through a restricted distribution program, the Lenalidomide REMS program.
Information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by calling the toll-free number 1-888-423-5436.
Hematologic Toxicity (Neutropenia and Thrombocytopenia)
Lenalidomide can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.
Venous and Arterial Thromboembolism
Lenalidomide has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with lenalidomide and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient's underlying risks.
CONTRAINDICATIONS
Pregnancy: Lenalidomide capsules can cause fetal harm when administered to a pregnant female and are contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.
Severe Hypersensitivity Reactions: Lenalidomide capsules are contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity: See BOXED WARNINGS.
Lenalidomide REMS Program: See Boxed WARNINGS. Due to embryo-fetal risk, lenalidomide capsules are available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Prescribers and pharmacies must be certified with the Lenalidomide REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive lenalidomide capsules. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
Hematologic Toxicity: Lenalidomide can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. Patients may require a dose interruption and/or dose reduction. MM: Monitor complete blood counts (CBC) in patients taking lenalidomide + dexamethasone or lenalidomide as maintenance therapy, every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter.
Hematologic Toxicity: Lenalidomide can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. Patients may require a dose interruption and/or dose reduction. Patients with MM: Monitor complete blood counts (CBC) in patients taking lenalidomide + dexamethasone or lenalidomide as maintenance therapy, every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter.
Venous and Arterial Thromboembolism: See Boxed WARNINGS. Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with lenalidomide. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended and the regimen should be based on the patient's underlying risks. Erythropoietin-stimulating agents (ESAs) and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision.
Increased Mortality in Patients With CLL: In a clinical trial in the first-line treatment of patients with CLL, single-agent lenalidomide therapy increased the risk of death as compared to single-agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the lenalidomide arm. Lenalidomide is not indicated and not recommended for use in CLL outside of controlled clinical trials.
Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving lenalidomide and in patients with FL or MZL receiving lenalidomide + rituximab therapy, an increase of hematologic plus solid tumor SPM, notably AML, have been observed. In patients with MM, MDS was also observed. Monitor patients for the development of SPM. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.
Increased Mortality with Pembrolizumab: In clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide + dexamethasone. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop lenalidomide upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
Severe Cutaneous Reactions: Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive lenalidomide. Consider lenalidomide interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue lenalidomide for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN, or DRESS.
Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. Closely monitor patients at risk and take appropriate preventive approaches.
Tumor Flare Reaction (TFR): TFR, including fatal reactions, have occurred during investigational use of lenalidomide for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤Grade 1. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician's discretion.
Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with lenalidomide has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection.
Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before starting lenalidomide treatment and during therapy.
Early Mortality in Patients With MCL: In another MCL study, there was an increase in early deaths (within 20 weeks); 12.9% in the lenalidomide arm versus 7.1% in the control arm. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 109/L).
Hypersensitivity: Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to lenalidomide has been reported. Permanently discontinue lenalidomide capsules for angioedema and anaphylaxis.
ADVERSE REACTIONS
Multiple Myeloma
DRUG INTERACTIONS
Periodically monitor digoxin plasma levels due to increased Cmax and AUCinf with concomitant lenalidomide therapy. Patients taking concomitant therapies such as ESAs or estrogen-containing therapies may have an increased risk of thrombosis. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin.
USE IN SPECIFIC POPULATIONS
To report SUSPECTED ADVERSE REACTIONS, contact Apotex, Inc. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information, including BOXED WARNINGS.
