PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Immunomodulators, Angiogenesis Inhibitors

    BOXED WARNING

    Hyperlipidemia, hypertension, thromboembolism, tobacco smoking

    Venous (e.g., deep vein thrombosis, pulmonary embolism) and arterial (e.g., myocardial infarction, stroke) thromboembolism has been reported with lenalidomide use. There was an increased incidence of venous and arterial thrombotic events in patients with multiple myeloma who received lenalidomide in combination with dexamethasone compared with dexamethasone alone in clinical trials. Patients with hyperlipidemia, hypertension, tobacco smoking, or a history of thrombosis may be at greater risk; minimize modifiable risk factors when possible. In clinical trials that did not use thromboprophylaxis, the overall rate of thrombotic events was higher in patients with refractory or relapsed multiple myeloma who received lenalidomide plus dexamethasone compared with dexamethasone alone; the median time to first thrombotic event was 2.8 months. Thromboprophylaxis is recommended in patients with multiple myeloma who receive lenalidomide and dexamethasone; the agent used for prophylaxis may be chosen based on an assessment of the patient’s underlying risks. Monitor for signs of thromboembolism and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.

    Bleeding, infection, neutropenia, thrombocytopenia

    Hematologic toxicity, including severe thrombocytopenia and neutropenia, has been reported with lenalidomide therapy. Monitor complete blood counts (CBC) in patients receiving lenalidomide therapy as follows: for myelodysplastic syndrome, obtain a CBC weekly for 8 weeks and then monthly thereafter; for multiple myeloma, obtain a CBC weekly for the first 2 cycles, on days 1 and 15 of cycle 3, and then every 4 weeks thereafter; for mantle cell lymphoma, obtain a CBC weekly for the first 4 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter; and for follicular or marginal zone lymphoma, obtain a CBC weekly for the first 3 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter. Monitor neutropenic patients for signs of infection. Advise patients to report unusual bleeding or bruising, especially if they are also receiving other agents that increase the risk of bleeding. Therapy interruption and dose adjustments are necessary in patients who develop significant hematologic toxicity.

    Contraception requirements, dysfunctional uterine bleeding, male-mediated teratogenicity, menstrual irregularity, pregnancy testing, reproductive risk, sperm donation

    Counsel patients about the reproductive risk and contraception requirements during lenalidomide treatment. Do not initiate therapy in females of reproductive potential (e.g., sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months) until pregnancy testing is performed twice with confirmed negative results. Administer the first test within 10 to 14 days and the second test 24 hours prior to prescribing lenalidomide. Once treatment is started, continue pregnancy testing weekly during the first 4 weeks of treatment, then every 4 weeks in females with regular menstrual cycles and every 2 weeks in females with irregular menstrual cycles. Effective contraception must be used by all females of reproductive potential for at least 4 weeks before beginning treatment, during therapy and dosage interruptions, and for 4 weeks following discontinuation of therapy. Women must commit to abstain from heterosexual intercourse or to use 2 methods of reliable birth control, including at least 1 highly effective method (e.g., intrauterine device (IUD), hormonal contraception, tubal ligation, or partner's vasectomy) and 1 additional effective method (e.g., latex condom, diaphragm, or cervical cap). Follow these contraceptive requirements even in patients with a history of infertility, unless a hysterectomy has been performed. Discontinue treatment, test for pregnancy, and counsel any woman of reproductive potential who experiences menstrual irregularity (e.g., dysfunctional uterine bleeding) or misses her period. Advise patients that if her doctor is not available, she can call 1-888-423-5436 for information on emergency contraception. Lenalidomide passes into semen and there is potential for male-mediated teratogenicity. Male patients must use barrier contraception (latex condom) during sexual intercourse with a woman of reproductive potential while on therapy, during interruptions, and for 4 weeks after discontinuing therapy, even if he has undergone successful vasectomy. Male patients should be warned against sperm donation during lenalidomide therapy and for 4 weeks after stopping it.[58806]

    DEA CLASS

    Rx

    DESCRIPTION

    Biologic response modifier with immunomodulatory, antiangiogenic, and antineoplastic properties
    Used for the treatment of adult patients with myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma
    Risk of birth defects or embryo-fetal death if used during pregnancy; prescribers, pharmacies, and patients must register in the REVLIMID REMS program (1-888-423-5436)

    COMMON BRAND NAMES

    Revlimid

    HOW SUPPLIED

    Revlimid Oral Cap: 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg

    DOSAGE & INDICATIONS

    For the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndrome (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
    Oral dosage
    Adults

    10 mg orally daily; adjust the dose based on clinical toxicity and laboratory findings. Transfusion independence was reported in 67% of patients with red blood cell transfusion-dependent anemia in low- or intermediate-1-risk myelodysplastic syndromes with a deletion 5q cytogenetic abnormality who received lenalidomide in a clinical study (n = 148). Transfusion independence was defined as the absence of a red blood cell transfusion during any consecutive 56 days during the treatment period. The median transfusion-free period in responding patients was 44 weeks; 90% of responding patients achieved a transfusion benefit within 3 months of starting lenalidomide treatment.

    For the treatment of multiple myeloma.
    NOTE: The FDA has designated lenalidomide as an orphan drug for the treatment of multiple myeloma.
    for the treatment of multiple myeloma following at least 1 prior therapy, in combination with dexamethasone.
    Oral dosage
    Adults

    25 mg orally once daily for 21 days; repeat treatment cycles every 28 days until disease progression. For the first 4 cycles, administer lenalidomide in combination with dexamethasone 40 mg orally on days 1, 2, 3, and 4; days 9, 10, 11, and 12; and days 17, 18, 19, and 20; thereafter, give lenalidomide in combination with dexamethasone 40 mg orally on days 1, 2, 3, and 4 of each 28-day cycle. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. Treatment with lenalidomide plus dexamethasone led to significantly improved median time to disease progression (TTP) and overall survival (OS) time compared with dexamethasone alone in patients with relapsed or refractory multiple myeloma in 2 multinational, placebo-controlled, phase 2 trials (MM-009 and MM-010 trials); both trials were stopped early based on favorable efficacy results demonstrated in the lenalidomide arm at an interim analysis. In a pooled analysis of these trials, the median age was 63 years (range, 33 to 86 years), about 20% of patients had received 1 prior therapy, about 80% had received 2 or more prior therapies, and approximately 58% had previously received a stem-cell transplantation. At a median follow-up time of 17.6 months, treatment with lenalidomide and dexamethasone resulted in a significantly longer median TTP (primary endpoint) compared with placebo plus dexamethasone (11.1 months vs. 4.7 months; hazard ratio [HR] = 0.35; 95% CI, 0.27 to 0.37; p less than 0.001) in patients with relapsed or refractory multiple myeloma in a multicenter, randomized, double-blind, phase III trial (n = 353; the MM-009 trial). At a median follow-up time of 26.2 months in the lenalidomide/dexamethasone arm and 12.9 months in the placebo/dexamethasone arm, the median OS time was significantly improved with lenalidomide/dexamethasone treatment (29.6 months vs. 20.2 months; HR = 0.44; 95% CI, 0.3 to 0.65; p less than 0.001); 58% of patients from the placebo/dexamethasone arm crossed over to receive treatment with lenalidomide/dexamethasone. At a median follow-up time of 16.4 months, treatment with lenalidomide and dexamethasone resulted in a significantly longer median TTP (primary endpoint) compared with placebo plus dexamethasone (11.3 months vs. 4.7 months; p less than 0.001) in patients with relapsed or refractory multiple myeloma in a multicenter, randomized, phase 3 trial (n = 351; the MM-010 trial). The median OS time was significantly improved in the lenalidomide/dexamethasone arm (median time not reached vs. 20.6 months; HR = 0.66; 95% CI, 0.45 to 0.96; p = 0.03). In a pooled analysis of the MM-009 and MM-010 trials (n = 703), the median OS time continued to be significantly improved in patients who received lenalidomide plus dexamethasone (38 months) compared with patients who received placebo plus dexamethasone (31.6 months; p = 0.045) at a median follow-up time of 48 months; 47.6% of patients from the placebo/dexamethasone arm crossed over to receive treatment with lenalidomide/dexamethasone.

    for the treatment of newly diagnosed multiple myeloma, in combination with dexamethasone.
    Oral dosage
    Adults and Geriatric patients 75 years or younger

    25 mg orally once daily for 21 days in combination with dexamethasone 40 mg orally on days 1, 8, 15, and 22. In patients who are ineligible for autologous stem-cell transplantation, repeat treatment cycles every 28 days until disease progression. In patients who are eligible for autologous stem-cell transplantation, hematopoietic stem-cell mobilization should occur within four 28-day treatment cycles. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.

    Geriatric patients older than 75 years

    25 mg orally once daily for 21 days in combination with dexamethasone 20 mg orally on days 1, 8, 15, and 22. Repeat treatment cycles every 28 days until disease progression. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.

    for the treatment of relapsed multiple myeloma in patients who have received 1 to 3 prior lines of therapy, in combination with carfilzomib and dexamethasone†.
    NOTE: Carfilzomib is FDA approved in combination with lenalidomide and dexamethasone for the treatment of relapsed multiple myeloma in patients who have received 1 to 3 prior lines of therapy.
    Oral dosage
    Adults

    25 mg orally once daily for 21 days in combination with dexamethasone (40 mg orally or intravenously on days 1, 8, 15, and 22) and carfilzomib. Treatment cycles are repeated every 28 days until disease progression or unacceptable toxicity; maximum of 18 cycles for carfilzomib only. Cycle 1: carfilzomib 20 mg/m2 intravenous over 10 minutes on days 1 and 2; if tolerated, increase to a target dose of 27 mg/m2 intravenous over 10 minutes on days 8, 9, 15, and 16. Cycles 2 to 12: carfilzomib 27 mg/m2 intravenous over 10 minutes on days 1, 2, 8, 9, 15, and 16. Cycles 13 to 18: carfilzomib 27 mg/m2 intravenous over 10 minutes on days 1, 2, 15, and 16. Dose carfilzomib at a maximum body surface area of 2.2 m2; dose adjustment is not necessary for patients with a weight change of 20% or less. Premedication: Give dexamethasone 30 minutes to 4 hours before carfilzomib (on carfilzomib dosing days only). Supportive care: Prehydrate with both oral and intravenous fluids before each carfilzomib dose in cycle 1. Additional intravenous hydration may be given after the carfilzomib infusion in cycle 1. Oral and/or intravenous hydration may be continued as needed in subsequent cycles; adjust hydration to individual patient needs. Thromboprophylaxis is recommended. Consider giving an antiviral agent and an antacid medication. In a prespecified interim analysis of a multinational, randomized, open-label, phase 3 trial (n = 792; the ASPIRE trial), the median progression-free survival time (primary endpoint) was significantly increased with carfilzomib plus lenalidomide/dexamethasone (26.3 months) compared with lenalidomide/dexamethasone alone (17.6 months; hazard ratio (HR) = 0.69; 95% CI, 0.57 to 0.83; p = 0.0001) in patients with relapsed multiple myeloma who had received 1 to 3 prior therapies (age range, 31 to 91 years; median of 2 prior therapies). In this study, some patients had previously received bortezomib (65.8%) and/or lenalidomide (19.8%). The median overall survival (OS) time had not been reached in either study arm at the time of the interim analysis (median follow-up: carfilzomib arm, 32.3 months; lenalidomide/dexamethasone alone, 31.5 months). The estimated 24-month OS rates were 73.3% and 65% in the carfilzomib/lenalidomide/dexamethasone and lenalidomide/dexamethasone arms, respectively (HR = 0.79; 95% CI, 0.63 to 0.99; p = 0.04); prespecified criteria for stopping the study due to OS benefit was not met and this study is ongoing.

    For the treatment multiple myeloma in patients who have received at least 1 prior therapy, in combination with daratumumab and dexamethasone†.
    NOTE: Daratumumab is FDA approved in combination with lenalidomide and dexamethasone for this indication.
    Oral dosage
    Adults

    25 mg orally daily for 21 days in patients with creatinine clearance (CrCl) greater than 60 mL/min (or 10 mg orally daily for 21 days in patients with a CrCl of 30 to 60 mL/min) in combination with daratumumab and dexamethasone repeated every 28 days until disease progression or unacceptable toxicity was evaluated in a multinational, randomized, open-label, phase 3 trial (n = 569; POLLUX trial). The daratumumab dosage is 16 mg/kg (actual body weight) intravenous weekly on weeks 1 to 8 (8 doses), 16 mg/kg intravenous every other week on weeks 9 to 24 (8 doses), and then 16 mg/kg intravenous every 4 weeks starting on week 25 until disease progression. Administer standard pre- and post-infusion medications with daratumumab infusions. The dexamethasone dosage is 40 mg orally once weekly (or 20 mg orally once weekly for patients older than 75 years or with a BMI lower than 18.5).

    As maintenance therapy following autologous hematopoietic stem-cell transplantation (HSCT) in patients with multiple myeloma.
    Oral dosage
    Adults and Geriatric patients 70 years and younger

    10 mg orally once daily as continuous therapy until disease progression. Begin therapy following adequate hematologic recovery (defined as an absolute neutrophil count of 1,000 cells/mcL or more and/or platelet count of 75,000 cells/mcL or more) after an autologous hematopoietic stem cell transplantation (HSCT). After three 28-day treatment cycles, the dose can be increased to lenalidomide 15 mg once daily, if tolerated. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. The progression-free survival (PFS) time was significantly improved in patients who had nonprogressive disease after first line autologous HSCT and who received maintenance therapy with lenalidomide compared with placebo (41 months vs. 23 months; hazard ratio [HR] = 0.5; p < 0.001) in a multinational, randomized, double-blind, placebo-controlled, phase 3 trial (n = 614; median age, 55 years; range, 22 to 67 years). At a median follow-up time of 45 months, the estimated 4-year PFS rates were 43% and 22% (HR = 0.5; p less than 0.001), and the estimated 4-year overall survival (OS) rates were 73% and 75% in the lenalidomide and placebo arms, respectively. At a planned interim analysis (median follow-up of 18 months), the time to disease progression (TTP) was significantly improved in patients who had stable disease or better at 100 days after an autologous HSCT and received maintenance therapy with lenalidomide compared with placebo (39 months vs. 21 months; p less than 0.001) in a randomized, double-blind, placebo-controlled, phase 3 trial (n = 460; median age, 59 years; range, 29 to 71 years). Based on these results, the trial was stopped and cross-over from placebo to the lenalidomide arm was permitted. At a median follow-up of 34 months, the median TTP were 46 months and 27 months (p less than 0.001), the 3-year PFS rates were 66% and 39% (HR = 0.5; p less than 0.001), and the 3-year OS rates were 88% and 80% (HR = 0.62; 95% CI, 0.4 to 0.95) in the lenalidomide and placebo arms, respectively.

    For the treatment of newly diagnosed multiple myeloma, in combination with bortezomib and dexamethasone†.
    Oral dosage
    Adults

    25 mg orally daily on days 1 to 14; bortezomib 1.3 mg/m2 intravenous on days 1, 4, 8, and 11; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 repeated every 21 days (VRd regimen) for 8 cycles was evaluated in a randomized, phase 3 trial (n = 471; SWOG S0777 trial). Following induction therapy, patients received maintenance therapy with lenalidomide 25 mg orally daily on days 1 to 21 and dexamethasone 40 mg orally on days 1, 8, 15, and 22 repeated every 28 days; the median duration of maintenance therapy was 385 days. All patients received herpes simplex virus prophylaxis and thromboembolic prophylaxis with aspirin 325 mg/day.

    For the treatment of multiple myeloma in patients who have received 1 to 3 prior therapies, in combination with elotuzumab and dexamethasone†.
    NOTE: Elotuzumab is FDA approved in combination with lenalidomide and dexamethasone for this indication.
    Oral dosage
    Adults

    25 mg orally daily on days 1 through 21 in combination with elotuzumab 10 mg/kg IV once weekly on cycles 1 and 2 (on days 1, 8, 15, and 22), then 10 mg/kg IV every 2 weeks (on days 1 and 15) thereafter and dexamethasone 28 mg orally (taken 3 to 24 hours prior to elotuzumab) on days 1, 8, 15, and 22 on cycles 1 and 2 and on days 1 and 15 of subsequent cycles. Give dexamethasone 40 mg orally on days 8 and 22 of cycles 3 and beyond. Repeat treatment cycles every 28 days until disease progression. Administer the following premedications 45 to 90 minutes prior to each elotuzumab infusion: acetaminophen 650 to 1,000 mg orally, diphenhydramine 25 to 50 mg orally or IV (or equivalent), ranitidine 50 mg IV or 150 mg orally (or equivalent), and dexamethasone 8 mg IV.[60354] Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.[58806] At a median follow-up time of 24.5 months, the median progression-free survival time was significantly improved with elotuzumab plus lenalidomide and dexamethasone (median duration of therapy, 17 months) compared with lenalidomide and dexamethasone alone (19.4 months vs. 14.9 months; hazard ratio (HR) = 0.7; 95% CI, 0.57 to 0.85; p less than 0.001) in patients with relapsed and/or refractory multiple myeloma in a planned interim analysis of a multicenter, randomized, open-label, phase 3 trial (n = 646; the ELOQUENT-2 trial). In this study, patients had received a median of 2 prior therapies (range, 1 to 4 therapies); 35% of patients had refractory disease to the last therapy and 54% of patients had previously received an autologous stem cell transplantation.[60353] The overall survival time was improved in the elotuzumab-containing arm (48.3 months vs. 39.6 months; HR = 0.82; 95% CI, 0.68 to 1) at the final analysis (minimum follow-up time of 70.6 months).

    For the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant, in combination with daratumumab and dexamethasone†.
    NOTE: Daratumumab is FDA approved in combination with lenalidomide and dexamethasone for this indication.
    Oral dosage
    Adults

    25 mg orally daily for 21 days in patients with creatinine clearance (CrCl) greater than 50 mL/min (or 10 mg orally daily for 21 days in patients with a CrCl of 30 to 50 mL/min) in combination with daratumumab and dexamethasone repeated every 28 days until disease progression or unacceptable toxicity was evaluated in a multinational, randomized, open-label, phase 3 trial (n = 737; MAIA trial). The daratumumab dosage is 16 mg/kg (actual body weight) intravenous weekly on weeks 1 to 8 (8 doses), 16 mg/kg intravenous every 2 weeks on weeks 9 to 24 (8 doses), and then 16 mg/kg intravenous every 4 weeks starting on week 25 until disease progression. Administer standard pre- and post-infusion medications with daratumumab infusions. The dexamethasone dosage is 40 mg orally once weekly (or 20 mg orally once weekly for patients older than 75 years or with a BMI lower than 18.5).[60311] In the MAIA trial (median follow-up time, 28 months), the median progression-free survival time was significantly improved in the daratumumab plus lenalidomide and dexamethasone arm compared with the lenalidomide and dexamethasone arm (time not reached vs. 31.9 months; hazard ratio = 0.56; 95% CI, 0.43 to 0.73, p less than 0.001) in patients (median age, 73 years; range, 45 to 90 years) with newly diagnosed multiple myeloma who were ineligible for a stem-cell transplant.[64365]

    For the treatment of mantle cell lymphoma (MCL).
    NOTE: There was an increased risk of early death in the lenalidomide arm compared with the control arm (12.9% vs. 7.1%) in a clinical trial in patients with MCL. Risk factors for early death included a high tumor burden, a high MCL International Prognostic Index (MIPI) score at diagnosis, and a high white blood cell count (greater than 10 X 109 cells/L) at baseline.
    For the treatment of relapsed or progressive MCL following 2 prior therapies, including bortezomib.
    Oral dosage
    Adults

    25 mg orally once daily for 21 days repeated every 28 days; continue therapy until disease progression. Therapy interruption, dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. In patients with relapsed or refractory mantle-cell lymphoma (MCL), treatment with lenalidomide has resulted in overall response rates (ORR) of 28% to 53% in phase 2 trials. At a median follow-up of 13.2 months, treatment with lenalidomide led to a median progression-free survival (PFS) time of 4 months and a median overall survival (OS) time of 20.9 months in patients with relapsed or refractory MCL who had received prior treatment including bortezomib in a multinational, open-label, phase 2 trial (n = 134; MCL-001 [EMERGE] trial). Patients (median age, 67 years; range, 43 to 83 years) in this study had previously received a median of 4 therapies (range, 2 to 10 therapies). At a median follow-up of 15.9 months, the median PFS time was significantly improved with lenalidomide compared with investigator’s choice therapy (8.7 months vs. 5.2 months; hazard ratio [HR] = 0.61; 95% CI, 0.44 to 0.84; p = 0.004) in patients with relapsed or refractory MCL who were ineligible for intensive chemotherapy or stem-cell transplantation in a multinational, randomized (2:1), open-label, phase 2 trial (n = 254; MCL-002 [SPRINT] trial). The median OS times were not significantly different between the lenalidomide and investigator’s choice arms (27.9 months vs. 21.2 months; HR = 0.89; 95% CI, 0.62 to 1.28); however, 46% of patients in the investigator’s choice arm crossed over to the lenalidomide arm upon disease progression. Investigator’s choice chemotherapy consisted of monotherapy with rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Patients (median age, 68.5 years; range, 44 to 88 years) who received lenalidomide in this study had previously received a median of 2 regimens (range, 1 to 3 regimens); 12% of patients had received prior treatment with bortezomib.

    For the treatment of MCL, in combination with rituximab†.
    Oral dosage
    Adults

    20 mg orally once daily on days 1 to 21 repeated every 28 days in combination rituximab was evaluated in phase II trials. In patients with relapsed or refractory mantle-cell lymphoma (MCL), lenalidomide was continued until disease progression (median of 2 cycles; range, 1 to 26 cycles) and rituximab 375 mg/m2 intravenous was administered weekly starting on day 1 for a total of 4 doses on cycle 1 only. In patients with newly diagnosed MCL, induction therapy (weeks 1 to 48) consisted of 12 cycles of lenalidomide; rituximab 375 mg/m2 IV was given once on weeks 1, 2, 3, 4, 13, 21, 29, 37, and 45 for a total of 9 doses. The lenalidomide dose could be escalated to 25 mg after the first cycle if no dose-limiting adverse events occurred. Maintenance therapy consisted of lenalidomide 15 mg PO daily on days 1 to 21 repeated every 28 days (starting week 49) plus rituximab 375 mg/m2 intravenous once every 8 weeks (starting week 52); treatment was continued for up to 36 cycles or until disease progression.

    For the treatment of non-Hodgkin's lymphoma (NHL).
    NOTE: The FDA has designated lenalidomide as an orphan drug for the treatment of follicular lymphoma and marginal zone lymphoma.
    For the treatment of previously untreated follicular lymphoma, in combination with rituximab†.
    Oral dosage
    Adults

    20 mg orally once daily on days 2 to 22 repeated every 28 days for 6 cycles in combination with rituximab (375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1 and 375 mg/m2 IV on day 1 only of cycles 2 to 6) was evaluated in a multinational, randomized, open-label, phase 3 trial (the RELEVANCE trial; n = 1,030). Patients who had a complete response (CR) after 6 cycles of therapy received lenalidomide 10 mg orally once daily on days 2 to 22 for another 12 cycles of therapy. Patients who had a partial response received lenalidomide 20 mg orally once daily on days 2 to 22 for 3 or 6 additional cycles until a CR was achieved and then lenalidomide 10 mg orally daily on days 2 to 22 for a total of 18 cycles of therapy. Additionally, patients who had a response continued to receive rituximab 375 mg/m2 IV every 8 weeks for 12 cycles.[63644] Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity.[58806]

    For the treatment of previously treated marginal zone lymphoma, in combination with rituximab.
    Oral dosage
    Adults

    20 mg orally once daily for 21 days repeated every 28 days for a maximum of 12 cycles; give in combination with rituximab as follows: 375 mg/m2 IV weekly in cycle 1 (on days 1, 8, 15, and 22) and then 375 mg/m2 IV on day 1 of every 28-day cycle on cycles 2, 3, 4 and 5. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. At a median follow-up of 28.3 months, the median progression-free survival (PFS) time was significantly improved in patients (median age, 63; range, 26 to 88 years) with relapsed or refractory grades 1 to 3a  follicular lymphoma (n = 295) or marginal zone lymphoma (n = 63) who received lenalidomide plus rituximab compared with placebo plus rituximab (39.4 months vs. 14.1 months; hazard ratio (HR) = 0.46; 95% CI, 0.34 to 0.62) in a multinational, randomized, phase 3 trial (the AUGMENT trial). Patients had received a median of 1 prior regimen (range, 1 to 12 regimens) in this trial. Overall survival (OS) was not significantly different between treatment arms (HR = 0.61; 95% CI, 0.33 to 1.13); however, OS data was not mature at the time of analysis. PFS was not significantly improved with lenalidomide plus rituximab (HR = 1; 95% CI, 0.47 to 2.13) in the subgroup of patients with marginal zone lymphoma.

    For the treatment of previously treated follicular lymphoma, in combination with rituximab.
    Oral dosage
    Adults

    20 mg orally once daily for 21 days repeated every 28 days for a maximum of 12 cycles; give in combination with rituximab as follows: 375 mg/m2 IV weekly in cycle 1 (on days 1, 8, 15, and 22) and then 375 mg/m2 IV on day 1 of every 28-day cycle on cycles 2, 3, 4 and 5. Therapy interruption, a dose adjustment, or discontinuation may be necessary in patients who develop severe toxicity. At a median follow-up of 28.3 months, the median progression-free survival (PFS) time was significantly improved in patients (median age, 63; range, 26 to 88 years) with relapsed or refractory grades 1 to 3a  follicular lymphoma (n = 295) or marginal zone lymphoma (n = 63) who received lenalidomide plus rituximab compared with placebo plus rituximab (39.4 months vs. 14.1 months; hazard ratio (HR) = 0.46; 95% CI, 0.34 to 0.62) in a multinational, randomized, phase 3 trial (the AUGMENT trial). Patients had received a median of 1 prior regimen (range, 1 to 12 regimens) in this trial. Overall survival (OS) was not significantly different between treatment arms (HR = 0.61; 95% CI, 0.33 to 1.13); however, OS data was not mature at the time of analysis. PFS was also significantly improved with lenalidomide plus rituximab (HR = 0.4; 95% CI, 0.29 to 0.56) in the subgroup of patients with follicular lymphoma.

    For the treatment of amyloidosis†.
    For the treatment of systemic amyloid light-chain amyloidosis, in combination with cyclophosphamide and dexamethasone†.
    Oral dosage
    Adults

    15 mg orally daily on days 1 to 21 in combination with cyclophosphamide and dexamethasone repeated every 28 days has been evaluated in nonrandomized, phase II studies. Treatment duration, drug dosages of cyclophosphamide and dexamethasone, and thromboprophylaxis agents/recommendations varied in these studies. In one study, 12 cycles of lenalidomide, cyclophosphamide (300 mg/m2 IV on days 1 and 8 for 6 cycles; then 300 mg/m2 IV on day 1 for an additional 6 cycles), and dexamethasone (20 mg PO on days 1, 2, 3, 4, 9, 10, 11, and 12 for 6 cycles; then 20 mg PO on days 1, 2, 3, and 4 for an additional 6 cycles) were given and then maintenance therapy with lenalidomide and dexamethasone was administered for 3 additional years or until disease progression. Patients with a glomerular filtration rate (GFR) less than 50 mL/min received a reduced lenalidomide dose of 10 mg and patients with a GFR less than 30 mL/min received a reduced lenalidomide dose of 5 mg. Patients with cardiac stage III had an upfront dose modification of dexamethasone. In another study, lenalidomide, cyclophosphamide (500 mg PO on days 1, 8, and 15), and dexamethasone (40 mg PO on days 1, 8, 15, and 22) therapy was given for a maximum of 9 cycles; treatment was discontinued after cycle 6 if a complete response or partial response/very good partial response plus organ response was obtained. In this study, patients with fluid retention over 3% of body weight despite optimal diuretic use received a lower dose of dexamethasone (20 mg once weekly). In a third study, cycles of lenalidomide, cyclophosphamide (300 mg/m2 PO on days 1, 8, and 15), and dexamethasone (40 mg PO on days 1, 8, 15, and 22) were continued until disease progression, unacceptable toxicity, or up to 2 years; however, cyclophosphamide was given for up to a maximum of 12 cycles only.]

    For the treatment of systemic amyloid light-chain amyloidosis, in combination with melphalan and dexamethasone†.
    Oral dosage
    Adults

    10 mg orally daily on days 1 to 21 in combination with melphalan and dexamethasone repeated every 28 days has been evaluated in nonrandomized studies. Treatment duration, the melphalan dosage, and thromboprophylaxis agents/recommendations varied in these studies. In 1 study, lenalidomide plus melphalan (0.18 mg/kg PO daily on days 1, 2, 3, and 4) and dexamethasone (40 mg PO on days 1, 8, 15, and 22) therapy was given for a maximum of 9 cycles; single-agent lenalidomide was continued in responding patients. In another study, lenalidomide, melphalan (5 mg/m2 PO daily on days 1, 2, 3, and 4), and dexamethasone (40 mg PO on days 1, 8, 15, and 22) were continued until disease progression, unacceptable toxicity, or up to 12 cycles.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    25 mg/day PO.

    Geriatric

    25 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline hepatic impairment: no dosage adjustment is necessary for mild hepatic impairment (defined as total bilirubin level of greater than 1 to 1.5-times upper limit normal (ULN) or any AST level greater than the ULN). Lenalidomide use has not been evaluated in patients with moderate to severe hepatic impairment.
    Treatment-related hepatotoxicity: interrupt lenalidomide therapy; when the toxicity resolves to baseline values, may resume therapy at a lower dose.

    Renal Impairment

    Adjust the starting dose of lenalidomide in patients with renal impairment based on baseline creatinine clearance (CrCl) values and indication for use. Subsequent dose adjustments are based on individual patient tolerance.
    Mantle cell lymphoma (MCL) and Combination Therapy in Multiple Myeloma
    CrCl 30 to 60 mL/min: 10 mg PO once daily; in patients with multiple myeloma, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10-mg dose without dose-limiting toxicity. CrCl less than 30 mL/min (not requiring dialysis): 15 mg PO every other day. CrCl less than 30 mL/min (requiring dialysis): 5 mg PO once daily; administer the dose following dialysis on dialysis days.
    Myelodysplastic syndromes (MDS) and Maintenance Therapy in Multiple Myeloma
    CrCl 30 to 60 mL/min: 5 mg PO once daily. CrCl less than 30 mL/min (not requiring dialysis): 2.5 mg PO once daily. CrCl less than 30 mL/min (requiring dialysis): 2.5 mg PO once daily; administer the dose following dialysis on dialysis days.
    Follicular Lymphoma or Marginal Zone LymphomaCrCl 30 to 60 mL/min: 10 mg PO once daily; consider escalating the dose to 15 mg/day after 2 cycles if the patient tolerates 10 mg/day.CrCl less than 30 mL/min (not requiring dialysis): 5 mg PO once daily.CrCl less than 30 mL/min (requiring dialysis): 5 mg PO once daily; administer the dose following dialysis on dialysis days.

    ADMINISTRATION

    Observe and exercise usual cautions for handling, administering, and disposal of cytotoxic drugs. Wash the exposed area immediately and thoroughly with soap and water if powder from lenalidomide capsules come into contact with skin; flush thoroughly with water if lenalidomide come into contact with mucous membranes.

    Oral Administration
    Oral Solid Formulations

    Take lenalidomide with or without food at approximately the same time each day.
    Swallow capsules whole; do not crush, break, or chew.
    If a dose is missed, take within 12 hours of missing the dose. If more than 12 hours have passed, skip the dose of the day and take the dose the next day at the scheduled time.
    No more than a 28-day supply should be dispensed at one time.

    STORAGE

    Revlimid:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema, serious rash, thalidomide hypersensitivity

    Severe hypersensitivity reactions including serious rash (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with lenalidomide therapy; some cases were fatal. Use is contraindicated in patients who have experienced an allergic reaction (e.g., angioedema, SJS, TEN) to lenalidomide. Do not administer lenalidomide in patients with a history of grade 4 rash with thalidomide therapy (thalidomide hypersensitivity). Therapy interruption or discontinuation should be considered in lenalidomide-treated patients who develop a grade 2 or 3 skin rash. Permanently discontinue lenalidomide if a patient develops angioedema, anaphylaxis, grade 4 rash, exfoliative or bullous rash, or SJS, TEN, or DRESS.

    Hyperlipidemia, hypertension, thromboembolism, tobacco smoking

    Venous (e.g., deep vein thrombosis, pulmonary embolism) and arterial (e.g., myocardial infarction, stroke) thromboembolism has been reported with lenalidomide use. There was an increased incidence of venous and arterial thrombotic events in patients with multiple myeloma who received lenalidomide in combination with dexamethasone compared with dexamethasone alone in clinical trials. Patients with hyperlipidemia, hypertension, tobacco smoking, or a history of thrombosis may be at greater risk; minimize modifiable risk factors when possible. In clinical trials that did not use thromboprophylaxis, the overall rate of thrombotic events was higher in patients with refractory or relapsed multiple myeloma who received lenalidomide plus dexamethasone compared with dexamethasone alone; the median time to first thrombotic event was 2.8 months. Thromboprophylaxis is recommended in patients with multiple myeloma who receive lenalidomide and dexamethasone; the agent used for prophylaxis may be chosen based on an assessment of the patient’s underlying risks. Monitor for signs of thromboembolism and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.

    Bleeding, infection, neutropenia, thrombocytopenia

    Hematologic toxicity, including severe thrombocytopenia and neutropenia, has been reported with lenalidomide therapy. Monitor complete blood counts (CBC) in patients receiving lenalidomide therapy as follows: for myelodysplastic syndrome, obtain a CBC weekly for 8 weeks and then monthly thereafter; for multiple myeloma, obtain a CBC weekly for the first 2 cycles, on days 1 and 15 of cycle 3, and then every 4 weeks thereafter; for mantle cell lymphoma, obtain a CBC weekly for the first 4 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter; and for follicular or marginal zone lymphoma, obtain a CBC weekly for the first 3 weeks (cycle 1), every 2 weeks during cycles 2 to 4, and then monthly thereafter. Monitor neutropenic patients for signs of infection. Advise patients to report unusual bleeding or bruising, especially if they are also receiving other agents that increase the risk of bleeding. Therapy interruption and dose adjustments are necessary in patients who develop significant hematologic toxicity.

    Renal disease, renal failure, renal impairment

    Renal failure has been reported with lenalidomide therapy. Use lenalidomide with caution in patients with pre-existing renal disease. An initial dose reduction is necessary in patients with moderate (creatinine clearance (CrCl) of 30 to 60 mL/min) and severe (CrCl less than 30 mL/min) renal impairment including patients on dialysis; base subsequent lenalidomide dosage adjustments on individual patient tolerance.

    Hepatic disease, hepatitis, hepatotoxicity

    Hepatotoxicity has been reported with lenalidomide use, including hepatic failure resulting in death. Use caution in patients with moderate or severe hepatic disease/impairment; lenalidomide has not been evaluated in these patients. Monitor liver function tests periodically during treatment. Therapy interruption and a dose reduction may be necessary in patients who develop elevated hepatic enzymes during treatment. Patients with viral hepatitis, elevated hepatic enzymes at baseline, or who are receiving concomitant medications may have an increased risk for developing hepatotoxicity.

    Blood donation

    Avoid blood donation during lenalidomide therapy, during dosage interruptions, and for 4 weeks after the last lenalidomide dose due to the risk of blood being given to a pregnant female patient.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has been reported with lenalidomide therapy; some cases resulted in death. Monitor patients at risk for TLS (e.g., high tumor burden prior to treatment) and take precautionary measures (e.g., hydration, uric acid lowering therapy). Tumor flare reaction (TFR) has been reported in lenalidomide-treated patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (unapproved use), and follicular and marginal zone lymphoma; TFR may mimic progressive disease. In a clinical trial in patients with MCL, most cases of TFR occurred in the first cycle. Monitor MCL and lymphoma patients for TFR symptoms during lenalidomide therapy (e.g., lymph node swelling, low-grade fever, pain, and rash). Hold therapy in patients who develop grade 3 or 4 TFR. Administer symptomatic treatment with corticosteroids, non-steroidal anti-inflammatory drugs (NSAID), and/or narcotic analgesics in patients who develop TFR.

    New primary malignancy

    New primary malignancy (e.g., acute myelogenous leukemia, myelodysplastic syndrome, lymphomas, squamous cell and basal cell carcinoma of the skin, lung cancer, and prostate cancer) has been reported with lenalidomide therapy. Initiate lenalidomide after performing a benefit/risk assessment. Monitor patients for the development of new primary malignancies.

    Hyperthyroidism, hypothyroidism

    Hypothyroidism and hyperthyroidism have been reported with lenalidomide use. Obtain baseline thyroid function tests and monitor thyroid function during lenalidomide therapy.

    Lactase deficiency

    Lenalidomide capsules contain lactose. Use lenalidomide with caution in patients with lactose intolerance or lactase deficiency.

    Peripheral blood stem cell (PBSC) mobilization

    Reduced CD34+ cell collection has been reported in patients who received more than 4 cycles of lenalidomide therapy. Peripheral blood stem cell (PBSC) mobilization should occur within four 28-day treatment cycles in patients who are eligible for an autologous stem-cell transplant. Refer eligible patients to a transplant center. If inadequate CD 34+ cells are collected in patients who have received more than 4 cycles of lenalidomide, consider using granulocyte colony-stimulating factor (G-CSF) plus cyclophosphamide or G-CSF plus a CXCR4 inhibitor (e.g., plerixafor) for PBSC mobilization.

    Geriatric

    Use lenalidomide with caution in geriatric patients; serious adverse events have been reported more frequently in elderly patients compared with younger patients who received lenalidomide. Additionally, closely monitor renal function in these patients.

    Treatment outside of a clinical trial

    The use of a PD-1 or PDL1 blocking antibody with a thalidomide analogue plus dexamethasone is not recommended for multiple myeloma treatment outside of a clinical trial. Two clinical trials were halted due to an increased risk of death in patients who received pembrolizumab and dexamethasone in combination with an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of multiple myeloma.

    Intrauterine fetal death, pregnancy

    Lenalidomide is contraindicated for use during pregnancy. Lenalidomide is structurally similar to thalidomide, which is a known teratogen that causes severe, life-threatening human birth defects. Lenalidomide produced limb malformations in the offspring of pregnant female monkeys. It may cause birth defects or intrauterine fetal death if administered during pregnancy. In order to prevent fetal exposure, it is only available through a restricted distribution program, the REVLIMID REMS program. This program requires prescribers, pharmacists, and patients to comply with certain conditions prior to prescribing, dispensing, or receiving lenalidomide. It can be prescribed only by licensed prescribers who are registered in the REVLIMID REMS program and understand the potential risk of teratogenicity if used during pregnancy. If pregnancy does occur during treatment, immediately discontinue lenalidomide. Prescribers are encouraged to report all cases of pregnancy to Celgene Corporation at 1-888-423-5436 or to the FDA MedWatch program at 1-800-332-1088. Refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

    Contraception requirements, dysfunctional uterine bleeding, male-mediated teratogenicity, menstrual irregularity, pregnancy testing, reproductive risk, sperm donation

    Counsel patients about the reproductive risk and contraception requirements during lenalidomide treatment. Do not initiate therapy in females of reproductive potential (e.g., sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months) until pregnancy testing is performed twice with confirmed negative results. Administer the first test within 10 to 14 days and the second test 24 hours prior to prescribing lenalidomide. Once treatment is started, continue pregnancy testing weekly during the first 4 weeks of treatment, then every 4 weeks in females with regular menstrual cycles and every 2 weeks in females with irregular menstrual cycles. Effective contraception must be used by all females of reproductive potential for at least 4 weeks before beginning treatment, during therapy and dosage interruptions, and for 4 weeks following discontinuation of therapy. Women must commit to abstain from heterosexual intercourse or to use 2 methods of reliable birth control, including at least 1 highly effective method (e.g., intrauterine device (IUD), hormonal contraception, tubal ligation, or partner's vasectomy) and 1 additional effective method (e.g., latex condom, diaphragm, or cervical cap). Follow these contraceptive requirements even in patients with a history of infertility, unless a hysterectomy has been performed. Discontinue treatment, test for pregnancy, and counsel any woman of reproductive potential who experiences menstrual irregularity (e.g., dysfunctional uterine bleeding) or misses her period. Advise patients that if her doctor is not available, she can call 1-888-423-5436 for information on emergency contraception. Lenalidomide passes into semen and there is potential for male-mediated teratogenicity. Male patients must use barrier contraception (latex condom) during sexual intercourse with a woman of reproductive potential while on therapy, during interruptions, and for 4 weeks after discontinuing therapy, even if he has undergone successful vasectomy. Male patients should be warned against sperm donation during lenalidomide therapy and for 4 weeks after stopping it.[58806]

    Breast-feeding

    It is not known if lenalidomide is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during lenalidomide therapy.

    Vaccination

    Vaccination with live vaccines should be avoided due to the potential risk of severe neutropenia and thrombocytopenia during lenalidomide therapy.[43236] [49472]

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 28.0-59.0
    thrombocytopenia / Delayed / 8.0-50.0
    leukopenia / Delayed / 4.0-24.0
    thromboembolism / Delayed / 0-21.5
    anemia / Delayed / 4.0-18.0
    lymphopenia / Delayed / 2.8-17.0
    hepatotoxicity / Delayed / 0-15.0
    new primary malignancy / Delayed / 0.4-14.9
    infection / Delayed / 0-12.0
    diarrhea / Early / 2.0-10.0
    thrombosis / Delayed / 2.0-10.0
    heart failure / Delayed / 0-10.0
    renal failure (unspecified) / Delayed / 0-9.0
    fatigue / Early / 1.0-9.0
    asthenia / Delayed / 0-8.0
    nausea / Early / 0-7.0
    atrial fibrillation / Early / 0-7.0
    back pain / Delayed / 0-7.0
    hypokalemia / Delayed / 0-7.0
    pleural effusion / Delayed / 0-7.0
    rash / Early / 1.0-7.0
    weakness / Early / 0-6.0
    hypophosphatemia / Delayed / 0-6.0
    dyspnea / Early / 0-6.0
    cataracts / Delayed / 0-6.0
    pancytopenia / Delayed / 0-4.0
    abdominal pain / Early / 0-4.0
    vomiting / Early / 0-4.0
    pulmonary embolism / Delayed / 1.0-4.0
    peripheral neuropathy / Delayed / 0-4.0
    elevated hepatic enzymes / Delayed / 0-4.0
    hypocalcemia / Delayed / 0-4.0
    anorexia / Delayed / 0-3.0
    syncope / Early / 0-3.0
    dizziness / Early / 0-3.0
    hypotension / Rapid / 0-3.0
    bone pain / Delayed / 0-3.0
    dehydration / Delayed / 0-3.0
    fever / Early / 0-3.0
    pruritus / Rapid / 0-2.8
    myocardial infarction / Delayed / 0-2.4
    stroke / Early / 0-2.3
    constipation / Delayed / 0-2.0
    headache / Early / 0-2.0
    chest pain (unspecified) / Early / 0-2.0
    sinus tachycardia / Rapid / 0-2.0
    arthralgia / Delayed / 0-2.0
    muscle cramps / Delayed / 0-2.0
    hyperbilirubinemia / Delayed / 0-2.0
    gout / Delayed / 0-2.0
    hyponatremia / Delayed / 0-2.0
    weight loss / Delayed / 0-2.0
    depression / Delayed / 0-2.0
    diabetes mellitus / Delayed / 0-2.0
    nephrotoxicity / Delayed / 0-1.7
    supraventricular tachycardia (SVT) / Early / 0-1.1
    cough / Delayed / 0-1.1
    tumor lysis syndrome (TLS) / Delayed / 0-1.1
    dysgeusia / Early / 0-1.0
    dyspepsia / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    myalgia / Early / 0-1.0
    hyperhidrosis / Delayed / 0-1.0
    hypoxia / Early / 0-1.0
    pulmonary hypertension / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    pharyngitis / Delayed / 0-1.0
    influenza / Delayed / 0-1.0
    tumor flare / Delayed / 0-1.0
    hyperuricemia / Delayed / 0-1.0
    hemolytic anemia / Delayed / 1.0
    GI bleeding / Delayed / 1.0
    bradycardia / Rapid / 1.0
    ocular hypertension / Delayed / 1.0
    coagulopathy / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    biliary obstruction / Delayed / Incidence not known
    skin cancer / Delayed / Incidence not known
    lymphoma / Delayed / Incidence not known
    leukemia / Delayed / Incidence not known
    spinal cord compression / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    bone fractures / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    graft-versus-host disease (GVHD) / Delayed / Incidence not known
    organ transplant rejection / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 0-26.0
    blurred vision / Early / 0-17.0
    edema / Delayed / 0-10.0
    hypertension / Early / 0-8.0
    hypothyroidism / Delayed / 0-7.0
    dysuria / Early / 0-7.0
    hypomagnesemia / Delayed / 0-7.0
    hyperglycemia / Delayed / 0-7.0
    stomatitis / Delayed / 0-5.0
    palpitations / Early / 0-5.0
    erythema / Early / 0-5.0
    pneumonitis / Delayed / 0-1.0
    insomnia / Early / 0-1.0
    angina / Early / 1.0
    impotence (erectile dysfunction) / Delayed / 1.0
    hallucinations / Early / 1.0
    hemolysis / Early / Incidence not known
    bleeding / Early / Incidence not known
    colitis / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    melena / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known
    dysarthria / Delayed / Incidence not known
    migraine / Early / Incidence not known
    aphasia / Delayed / Incidence not known
    hyperthyroidism / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hypernatremia / Delayed / Incidence not known
    wheezing / Rapid / Incidence not known
    interstitial lung disease / Delayed / Incidence not known
    confusion / Early / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    impaired stem cell mobilization / Delayed / Incidence not known

    Mild

    ecchymosis / Delayed / 0-55.0
    tremor / Early / 0-21.0
    rhinitis / Early / 0-15.0
    xerosis / Delayed / 0-14.0
    sinusitis / Delayed / 0-14.0
    hypoesthesia / Delayed / 0-10.0
    night sweats / Early / 0-10.0
    vertigo / Early / 1.0-10.0
    chills / Rapid / 0-10.0
    lethargy / Early / 0-10.0
    xerostomia / Early / 0-7.0
    malaise / Early / 0-7.0
    rhinorrhea / Early / 0-5.0
    hirsutism / Delayed / 1.0
    skin hyperpigmentation / Delayed / 1.0
    libido decrease / Delayed / 1.0
    gastroesophageal reflux / Delayed / Incidence not known
    hoarseness / Early / Incidence not known
    pelvic pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Darbepoetin Alfa: (Moderate) Concomitant use of lenalidomide with erythropoietic agents such as epoetin alfa and darbepoetin alfa may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and erythropoietic agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
    Denosumab: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
    Digoxin: (Moderate) Concomitant use of lenalidomide and digoxin may result in increased digoxin levels and exposure; use these drugs together with caution. Monitor digoxin levels periodically and as clinically indicated in patients who require both lenalidomide and digoxin. The Cmax and AUC values of digoxin were increased by 14% in patients who received digoxin following multiple oral doses of lenalidomide 10 mg/day.
    Epoetin Alfa: (Moderate) Concomitant use of lenalidomide with erythropoietic agents such as epoetin alfa and darbepoetin alfa may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and erythropoietic agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
    Estrogens: (Moderate) Concomitant use of lenalidomide with estrogens may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and estrogen-containing agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Warfarin: (Minor) According to the manufacturer, the use of warfarin in patients with blood dyscrasias is contraindicated. Therefore, to minimize the bleeding risk, warfarin should be used cautiously in patients receiving antineoplastic agents that cause myelosuppression or blood dyscrasias. In addition, effects of antineoplastic agents on protein synthesis as well as protein binding may lead to transient changes in a patient's INR while receiving warfarin. The INR may increase and/or decrease throughout the chemotherapy cycle leading to supra- or sub-therapeutic values; monitor warfarin therapy closely. There was no change in pharmacokinetic parameters for either agent when a single dose of warfarin 25 mg PO was administered following multiple oral doses of lenalidomide 10 mg/day. Expected PT and INR changes from warfarin use occurred. However, close monitoring of PT levels and INR in patients with multiple myeloma who require both lenalidomide and warfarin is recommended.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Counsel patients about the reproductive risk and contraception requirements during lenalidomide treatment. Do not initiate therapy in females of reproductive potential (e.g., sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months) until pregnancy testing is performed twice with confirmed negative results. Administer the first test within 10 to 14 days and the second test 24 hours prior to prescribing lenalidomide. Once treatment is started, continue pregnancy testing weekly during the first 4 weeks of treatment, then every 4 weeks in females with regular menstrual cycles and every 2 weeks in females with irregular menstrual cycles. Effective contraception must be used by all females of reproductive potential for at least 4 weeks before beginning treatment, during therapy and dosage interruptions, and for 4 weeks following discontinuation of therapy. Women must commit to abstain from heterosexual intercourse or to use 2 methods of reliable birth control, including at least 1 highly effective method (e.g., intrauterine device (IUD), hormonal contraception, tubal ligation, or partner's vasectomy) and 1 additional effective method (e.g., latex condom, diaphragm, or cervical cap). Follow these contraceptive requirements even in patients with a history of infertility, unless a hysterectomy has been performed. Discontinue treatment, test for pregnancy, and counsel any woman of reproductive potential who experiences menstrual irregularity (e.g., dysfunctional uterine bleeding) or misses her period. Advise patients that if her doctor is not available, she can call 1-888-423-5436 for information on emergency contraception. Lenalidomide passes into semen and there is potential for male-mediated teratogenicity. Male patients must use barrier contraception (latex condom) during sexual intercourse with a woman of reproductive potential while on therapy, during interruptions, and for 4 weeks after discontinuing therapy, even if he has undergone successful vasectomy. Male patients should be warned against sperm donation during lenalidomide therapy and for 4 weeks after stopping it.[58806]

    MECHANISM OF ACTION

    Mechanism of Action: The mechanism of action of lenalidomide is not completely understood. Lenalidomide possesses immunomodulatory properties. Lenalidomide inhibited the secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory cytokines from peripheral blood mononuclear cells. It inhibited cell proliferation with varying effectiveness (IC50s) in some but not all cell lines. Of cell lines tested, lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) but was much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and other cell lines without chromosome 5 deletions. Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.In addition to immunomodulatory properties, lenalidomide possesses antiangiogenic properties. Lenalidomide attenuates growth factor induced angiogenesis and inhibits growth factor induced endothelial cell migration. The antimigratory and thus, antiangiogenic effects of lenalidomide may be a result of Akt phosphorylation inhibition. The inhibition of of growth factor induced Akt phosphorylation correlated with the inhibition of growth factor induced endothelial cell migration. Growth factor induced endothelial cell migration and subsequent tube formation are known to be P13K-Akt-dependent. Activation of the Akt pathway plays a crucial role in malignant transformation, chemoresistance, and invasiveness by inducing angiogenesis and cell survival, growth, and migration. Lenalidomide inhibits the phosphorylation of Akt in response to basic fibroblast growth factor.Lenalidomide appears to cause cytogenetic changes that correlate with hematologic response in patients with myelodysplastic syndromes. Myelodysplastic syndromes associated with a 5q31.1 deletion appear to be very sensitive to lenalidomide. An absence of the pretreatment cytogenetic abnormality on standard metaphase analysis occurred in 9 of 12 patients with del(5)(q31.1) who received lenalidomide 25 mg daily, 10 mg daily, or 10 mg daily for each 21 of 28 days for 4 months. Eight of the nine patients had an isolated del(5)(q31.1); the other patient also had trisomy 21. The one patient in the study with the chromosomal abnormality t(1;22)(q21p11.2) also had a complete cytogenetic response. In addition to a complete cytogenetic response, an additional patient with del(5)(q31.1) had a reduction in abnormal cells by at least 50%. Thus, 10 of the 12 patients with del(5)(q31.1) had a cytogenetic response, and these 10 patients also had an erythroid response defined as at least a sustained hemoglobin concentration increase of 1 g/dl or at least a 50% reduction in transfusion need. Neither of the 2 patients with del (20)(q11.2) nor any of the 5 patients with other chromosomal abnormalities (+19, t(3;3)(q21;q26.3), +8, -X, and complex) had even a 50% reduction in abnormal cells. Three patients with a 5q31.1 deletion acquired new translocations involving chromosome 7 despite the complete suppression of the initial karyotypic abnormality. An additional patient with a normal karyotype before lenalidomide receipt had deletion 20 (q21q13.1). The clinical significance of the acquired translocations is unknown. Although 3 of the 4 patients remained free from the need for transfusion, one patient had cytogenetic and disease progression.

    PHARMACOKINETICS

    Lenalidomide is administered orally. Lenalidomide is approximately 30% bound to plasma proteins. It does pass into semen. Metabolism is limited with unchanged lenalidomide representing most of the drug present in circulation; 2 metabolites (hydroxy-lenalidomide and N-acetyl-lenalidomide) represent less than 5% of the parent drug found in circulation. Lenalidomide is primarily eliminated renally; the renal clearance exceeds the glomerular filtration rate. Following a radiolabeled dose of lenalidomide 25 mg in healthy subjects, about 82% of the dose was excreted in the urine within 24 hours, and 90% and 4% of the dose was excreted in the urine and feces, respectively, within 10 days. The metabolites hydroxy-lenalidomide and N-acetyl-lenalidomide accounted for 4.6% and 1.8% of the excreted dose, respectively. The mean elimination half-life is 3 hours in healthy subjects and 3 to 5 hours in patients with multiple myeloma, myelodysplastic syndrome, or mantle cell lymphoma. Multiple dosing at the recommended dose does not result in drug accumulation.
     
    Affected cytochrome P450 (CYP450) isoenzymes or drug transporters: P-gp
    Lenalidomide is not metabolized by the CYP450 pathway; therefore, it is not expected to inhibit or induce CYP450 isoenzymes. In vitro, lenalidomide is a P-glycoprotein (P-gp) substrate but not a P-gp inhibitor. However, the pharmacokinetic values (i.e., Cmax, AUC) of lenalidomide were not significantly altered when lenalidomide 25 mg was administered concurrently with multiple doses of the potent P-gp inhibitor quinidine 600 mg twice daily in healthy volunteers. When lenalidomide 25 mg was administered with the P-gp inhibitor/substrate temsirolimus 25 mg, the pharmacokinetic values of lenalidomide, temsirolimus, and the temsirolimus metabolite (i.e., sirolimus) were not significantly changed. Lenalidomide is not a substrate of human breast cancer resistance protein (BCRP); multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3; organic anion transporters (OAT) OAT1 and OAT3; organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2); organic cation transporters (OCT) OCT1 and OCT2; multidrug and toxin extrusion protein (MATE) MATE1; and organic cation transporters novel (OCTN) OCTN1 and OCTN2. Additionally, it is not an inhibitor of bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. Lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes with UGT1A1 genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28.

    Oral Route

    Oral lenalidomide is rapidly absorbed with the maximum plasma concentrations occurring 0.5 to 6 hours post-dose following single and multiple doses in patients with multiple myeloma (MM) or myelodysplastic syndromes (MDS). Both the Cmax and AUC values increased proportionally with dose following single and multiple doses. The oral absorption rate in patients with mantle cell lymphoma was similar to that of patients with MM or MDS. In healthy subjects, the administration of a single 25-mg lenalidomide dose with a high-fat meal resulted in a decrease in Cmax by about 20% and a decrease in AUC by about 50%. However, lenalidomide may be taken with or without food.