Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.
Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.
Do not use lenalidomide 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 treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after lenalidomide treatment. To avoid embryo-fetal exposure to lenalidomide, it is only available under a restricted distribution program called Lenalidomide REMS program.
Information about the Lenalidomide REMS program is available at http://www.lenalidomiderems.com or by calling the manufacturer's toll-free number 1-888-423-5436.
Lenalidomide can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with deletion 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 deletion 5q myelodysplastic syndromes should have their complete blood cell 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.
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 the 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 risk factors.
Note: Thromboprophylaxis is recommended when used in combination with chemotherapy and/or dexamethasone for the treatment of multiple myeloma and may be offered to other high-risk patients when clinically appropriate; thromboprophylaxis regimen should be based on assessment of patient- and disease-specific risk factors as well as concomitant therapy (ASCO [Key 2020]). Institute appropriate management if at risk for tumor lysis syndrome.
Chronic lymphocytic leukemia, relapsed/refractory (off-label use): Oral: 10 mg once daily beginning on day 9 of cycle 1; administer continuously in combination with cyclic rituximab (Badoux 2013). Refer to protocols for dosage adjustment details.
Diffuse large B-cell lymphoma, relapsed/refractory (off-label use): Oral: 25 mg once daily for 21 days of a 28-day treatment cycle for up to 1 year (Wiernik 2008) or 25 mg once daily for 21 days of a 28-day treatment cycle (in combination with tafasitamab) for up to 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity (Salles 2020). Refer to protocols for dosage adjustment details.
Follicular lymphoma, previously treated: Oral: 20 mg once daily for 21 days of a 28-day treatment cycle (in combination with rituximab) for up to 12 cycles (Leonard 2019).
Mantle cell lymphoma, relapsed or progressive: Oral: 25 mg once daily for 21 days of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity (Goy 2013).
Marginal zone lymphoma, previously treated: Oral: 20 mg once daily for 21 days of a 28-day treatment cycle (in combination with rituximab) for up to 12 cycles (Leonard 2019).
Multiple myeloma: Oral: 25 mg once daily for 21 days of a 28-day treatment cycle (in combination with dexamethasone [consider a reduced dexamethasone dose in patients >75 years of age]). In patients not eligible for autologous stem cell transplantation, continue until disease progression or unacceptable toxicity occurs; in transplant eligible patients, hematopoietic stem cell mobilization should occur within 4 cycles of a lenalidomide-containing therapy.
Multiple myeloma, maintenance therapy following autologous stem cell transplant: Oral: 10 mg once daily (begin after adequate hematologic recovery [ANC ≥1,000/mm3; platelets ≥75,000/mm3]); continue until disease progression or unacceptable toxicity occurs. If tolerated, may increase dose to 15 mg once daily after 3 cycles (each cycle is 28 days). A minimum of 2 years of lenalidomide maintenance therapy is recommended (ASCO/CCO [Mikhael 2019]).
Off-label dosing: 10 mg once daily for 21 days of a 28-day treatment cycle until relapse (Palumbo 2010).
Multiple myeloma, newly diagnosed (off-label combinations): Oral: 25 mg once daily for 21 days of a 28-day cycle (in combination with daratumumab and dexamethasone) until disease progression or unacceptable toxicity occurs (Facon 2019) or 25 mg once daily for 21 days of a 28-day cycle (in combination with ixazomib and dexamethasone) for 18 cycles (or until disease progression or unacceptable toxicity, whichever occurs first), followed by 10 mg once daily for 21 days of a 28-day cycle (in combination with ixazomib) until disease progression or unacceptable toxicity (Facon 2021) or 25 mg once daily for 14 days of a 21-day cycle (in combination with bortezomib and dexamethasone) for 8 cycles (Kumar 2012; Richardson 2010) or 25 mg once daily for 14 days of a 21-day cycle (in combination with bortezomib and dexamethasone) for 8 cycles, followed by 25 mg once daily for 21 days of a 28-day cycle (in combination with dexamethasone) until disease progression or unacceptable toxicity (Durie 2017; Durie 2020) or 25 mg once daily for 21 days of a 28-day cycle (in combination with carfilzomib and dexamethasone) for up to 8 cycles (Jakubowiak 2012; Kazandjian 2018; Korde 2015), followed by maintenance lenalidomide 10 mg once daily for 21 days of a 28-day cycle for 2 years (Kazandjian 2018) or 25 mg once daily for 21 days of a 28-day cycle (in combination with dexamethasone) for 9 induction cycles, followed by maintenance therapy of 10 mg once daily for 21 days of a 28-day cycle (lenalidomide monotherapy) until disease progression or unacceptable toxicity (Larocca 2021). Refer to protocols for dosage adjustment details.
Multiple myeloma, relapsed (off-label combinations): Oral: 25 mg once daily for 21 days of 28-day cycle (in combination with carfilzomib and dexamethasone) until disease progression or unacceptable toxicity occurs (Stewart 2015) or 25 mg once daily for 21 days of a 28-day cycle (in combination with daratumumab and dexamethasone) until disease progression or unacceptable toxicity occurs; refer to the International Myeloma Working Group recommendations for Dosing in Renal Impairment (Dimopoulos 2016a; Dimopoulos 2016b). Refer to protocols for dosage adjustment details.
Myelodysplastic syndrome with deletion 5q: Oral: 10 mg once daily, continue until disease progression or unacceptable toxicity occurs.
Myelodysplastic syndrome, lower risk, without deletion 5q (off-label use): Oral: 10 mg once daily (Raza 2008). Refer to protocols for dosage adjustment details.
Smoldering myeloma, high risk (off-label use): Oral: 25 mg once daily for 21 days of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity for up to 2 years (Lonial 2020).
Systemic light chain amyloidosis (off-label use): Oral: 15 mg once daily for 21 days of a 28-day cycle (in combination with dexamethasone) (Nair 2012; Sanchorawala 2007).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
|
CrCl |
If the usual dose is 25 mg once daily (eg, mantle cell lymphoma, multiple myeloma [combination therapy with dexamethasone]b) |
If the usual dose is 20 mg once daily (eg, follicular lymphoma, marginal zone lymphoma) |
If the usual dose is 15 mg once daily (eg, systemic light chain amyloidosisc) (no formal published recommendation; suggestions expert opinion only) |
If the usual dose is 10 mg once daily (eg, myelodysplastic syndrome, multiple myeloma [maintenance treatment after autologous stem cell transplant]) |
|---|---|---|---|---|
|
a Maintain appropriate number of treatment days per cycle based on indication and/or protocol. b Patients with multiple myeloma and decreased CrCl may experience an improvement in kidney function (often during the first cycle of therapy) when treatment with lenalidomide is initiated; frequent CrCl measurement and subsequent dose adjustment should be considered (Chen 2020). c Monitor kidney function closely, as acute kidney injury (usually occurring within the first 8 weeks of lenalidomide therapy) occurred in ~66% of patients in one report (Specter 2010). d It may be preferable to use full doses down to a CrCl of 50 mL/minute, as underdosing has been suggested (Chen 2020), and other multiple myeloma studies have successfully used full dose lenalidomide in patients with CrCl ≥50 mL/minute (Bridoux 2016; Dimopoulos 2010; Dimopoulos 2016; Mikhael 2018). e Approximately 30% removed during a 4-hour hemodialysis session (Chen 2007; manufacturer's labeling). f Dimopoulos 2016b. g Based on expert opinion. h Chen 2007. i Lichtman 2014. | ||||
|
CrCl >60 mL/minute |
No dosage adjustment necessary. |
No dosage adjustment necessary. |
No dosage adjustment necessary. |
No dosage adjustment necessary. |
|
CrCl 30 to 60 mL/minute |
Initial: 10 mg once daily; if treating multiple myeloma, may increase to 15 mg once daily after 2 cycles if tolerating treatment.d |
Initial: 10 mg once daily; if treating follicular lymphoma or marginal zone lymphoma may increase to 15 mg once daily after 2 cycles if tolerating treatment. |
Initial: 10 mg once daily; further individualize based on tolerance and response.g |
Initial: 5 mg once daily; further individualize dose based on tolerance and response. |
|
CrCl 15 to <30 mL/minute |
Initial: 15 mg every other day; if treating multiple myeloma, may increase dose to 10 mg once daily if tolerating treatment.f |
Initial: 5 mg once daily. |
Initial: 5 mg once daily; further individualize based on tolerance and response.g |
Initial: 2.5 mg once daily; further individualize dose based on tolerance and response. |
|
CrCl <15 mL/minute |
Initial: 5 mg once daily. |
Initial: 5 mg once daily. |
Initial: 5 mg once daily; further individualize dose based on tolerance and response.g |
Initial: 2.5 mg once daily; further individualize dose based on tolerance and response. |
|
Hemodialysis, intermittent (thrice weekly)e |
Initial: 5 mg once daily; when scheduled dose falls on a dialysis day administer after dialysis or Initial: 15 mg 3 times weekly after dialysis on dialysis days.h |
Initial: 5 mg once daily; when scheduled dose falls on a dialysis day, administer after dialysis. |
Initial: 5 mg once daily; when scheduled dose falls on a dialysis day, administer after dialysis; further individualize dose based on tolerance and response.g or Initial: 10 mg 3 times weekly after dialysis on dialysis daysi; further individualize dose based on tolerance and response.g |
Initial: 2.5 mg once daily; when scheduled dose falls on a dialysis day administer after dialysis; further individualize dose based on tolerance and response. |
|
Peritoneal dialysis |
Initial: 5 mg once daily (no data).g |
Initial: 5 mg once daily (no data).g |
Initial: 5 mg once daily (no data)g; further individualize dose based on tolerance and response.g |
Initial: 2.5 mg once daily (no data)g; further individualize dose based on tolerance and response. |
CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) and minimal residual kidney function unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neutropenia, thrombocytopenia) due to drug accumulation is important.
Oral: There are no data available to guide specific dosing recommendations. However, lenalidomide is likely removed by CRRT, therefore, dosing as for patients with CrCl 15 to <30 mL/minute is suggested with close monitoring (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, neutropenia, thrombocytopenia) due to drug accumulation is important.
Oral:
PIRRT days: There are no data available to guide specific dosing recommendations. However, lenalidomide is likely removed by PIRRT, therefore, dosing as for patients with CrCl 15 to <30 mL/minute is suggested with close monitoring; administer dose after PIRRT session has ended (expert opinion).
Non-PIRRT days: Dose as for CrCl <15 mL/minute (expert opinion).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, lenalidomide undergoes minimal hepatic metabolism.
Hepatotoxicity during treatment: Interrupt lenalidomide for abnormal hepatic function tests; may consider resuming treatment at a lower dose upon return to baseline.
Refer to adult dosing. Due to the potential for decreased renal function in the elderly, select dose carefully and closely monitor renal function.
Nonhematologic toxicities:
Dermatologic toxicities:
Skin rash, grade 2 or 3: Consider interrupting or discontinuing treatment.
Grade 4 rash, exfoliative or bullous rash, or other severe dermatologic reactions such as suspected Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms: Permanently discontinue treatment.
Hypersensitivity: Angioedema or anaphylaxis: Permanently discontinue treatment.
Thromboembolism:Signs/symptoms of thromboembolism (shortness of breath, chest pain, or arm or leg swelling): Patients should seek prompt medical attention.
Tumor flare reaction:
Grade 1 or 2: Continue therapy at physician's discretion; may consider symptom management with corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and/or analgesic therapy.
Grade 3 or 4: Interrupt therapy until resolved to ≤ grade 1; consider symptom management with corticosteroids, NSAIDs and/or analgesic therapy.
Other toxicities: For additional treatment-related grade 3/4 toxicities, hold treatment and restart (if appropriate) at next lower dose level when toxicity has resolved to ≤ grade 2.
Hematologic toxicities: Note: Hematologic toxicity may require the use of blood product support and/or growth factors.
Follicular lymphoma and marginal zone lymphoma:
Platelets <50,000/mm3: Hold treatment, check CBC weekly.
When platelets return to ≥50,000/mm3: Resume treatment at 5 mg below previous dose. If starting dose was 20 mg/day, do not dose below 5 mg daily; if starting dose was 10 mg/day, do not dose below 2.5 mg daily.
ANC <1,000/mm3 for at least 7 days or associated with fever (≥38.5°C [101°F]): Hold treatment, check CBC weekly.
ANC <500/mm3: Hold treatment, check CBC weekly.
When ANC returns to ≥1,000/mm3: Resume treatment at 5 mg below previous dose. If starting dose was 20 mg/day, do not dose below 5 mg daily; if starting dose was 10 mg/day, do not dose below 2.5 mg daily.
Mantle cell lymphoma:
Platelets <50,000/mm3: Hold treatment, check CBC weekly.
When platelets return to ≥50,000/mm3: Resume treatment at 5 mg below previous dose; do not dose below 5 mg daily.
ANC <1,000/mm3 for at least 7 days or associated with fever (≥38.5°C [101°F]): Hold treatment, check CBC weekly.
ANC <500/mm3: Hold treatment, check CBC weekly.
When ANC returns to ≥1,000/mm3: Resume treatment at 5 mg below previous dose; do not dose below 5 mg daily.
Multiple myeloma:
Combination therapy with dexamethasone:
Platelets <30,000/mm3: Hold treatment, check CBC weekly.
When platelets return to ≥30,000/mm3: Resume at next lower dose; do not dose below 2.5 mg daily.
For each additional occurrence of platelets <30,000/mm3: Hold treatment.
When platelets return to ≥30,000/mm3: Resume treatment at next lower dose; do not dose below 2.5 mg daily.
ANC <1,000/mm3: Hold treatment, check CBC weekly.
When ANC returns to ≥1,000/mm3 (with neutropenia as only toxicity): Resume at 25 mg daily or initial starting dose.
When ANC returns to ≥1,000/mm3 (with additional toxicities): Resume at next lower dose; do not dose below 2.5 mg daily.
For each additional occurrence of ANC <1,000/mm3: Hold treatment.
When ANC returns to ≥1,000/mm3: Resume treatment at next lower dose; do not dose below 2.5 mg daily.
Maintenance following autologous stem cell transplant:
Platelets <30,000/mm3: Hold treatment, check CBC weekly.
When platelets return to ≥30,000/mm3: Resume at next lower dose; maintain continuous daily dosing.
Additional occurrence of platelets <30,000/mm3 (and current dose is 5 mg once daily): Hold treatment.
When platelets return to ≥30,000/mm3 (and current dose is 5 mg once daily): Resume treatment at 5 mg daily on days 1 to 21 of a 28-day cycle; do not dose below 5 mg daily on days 1 to 21 of a 28-day cycle.
ANC <500/mm3: Hold treatment, check CBC weekly.
When ANC returns to ≥500/mm3: Resume at next lower dose; maintain continuous daily dosing.
Subsequent occurrence of ANC <500/mm3 (and current dose is 5 mg daily): Hold treatment.
When ANC returns to ≥500/mm3: Resume treatment at 5 mg daily on days 1 to 21 of a 28-day cycle; do not dose below 5 mg daily on days 1 to 21 of a 28-day cycle.
Myelodysplastic syndromes:
Thrombocytopenia developing within 4 weeks of beginning treatment at 10 mg daily:
Baseline platelets ≥100,000/mm3:
If platelets <50,000/mm3: Hold treatment.
When platelets return to ≥50,000/mm3: Resume treatment at 5 mg daily.
Baseline platelets <100,000/mm3:
If platelets fall to 50% of baseline: Hold treatment.
If baseline ≥60,000/mm3 and platelet level returns to ≥50,000/mm3: Resume at 5 mg daily.
If baseline <60,000/mm3 and platelet level returns to ≥30,000/mm3: Resume at 5 mg daily.
Thrombocytopenia developing after 4 weeks of beginning treatment at 10 mg daily:
Platelets <30,000/mm3 or <50,000/mm3 with platelet transfusions: Hold treatment.
When platelets return to ≥30,000/mm3 (without hemostatic failure): Resume at 5 mg daily.
Thrombocytopenia developing during treatment at 5 mg daily:
Platelets <30,000/mm3 or <50,000/mm3 with platelet transfusions: Hold treatment.
When platelets return to ≥30,000/mm3 (without hemostatic failure): Resume at 2.5 mg once daily.
Neutropenia developing within 4 weeks of beginning treatment at 10 mg daily:
For baseline ANC ≥1,000/mm3:
ANC <750/mm3: Hold treatment.
When ANC returns to ≥1,000/mm3: Resume at 5 mg daily.
For baseline ANC <1,000/mm3:
ANC <500/mm3: Hold treatment.
When ANC returns to ≥500/mm3: Resume at 5 mg daily.
Neutropenia developing after 4 weeks of beginning treatment at 10 mg daily:
ANC <500/mm3 for ≥7 days or associated with fever (≥38.5°C [101°F]): Hold treatment.
When ANC returns to ≥500/mm3: Resume at 5 mg daily.
Neutropenia developing during treatment at 5 mg daily:
ANC <500/mm3 for ≥7 days or associated with fever (≥38.5°C [101°F]): Hold treatment.
When ANC returns to ≥500/mm3: Resume at 2.5 mg once daily.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Revlimid: 2.5 mg [contains fd&c blue #2 (indigotine)]
Revlimid: 5 mg
Revlimid: 10 mg, 15 mg, 20 mg [contains fd&c blue #2 (indigotine)]
Revlimid: 25 mg
Generic: 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Revlimid: 2.5 mg [contains fd&c blue #2 (indigotine)]
Revlimid: 5 mg
Revlimid: 10 mg, 15 mg, 20 mg [contains fd&c blue #2 (indigotine)]
Revlimid: 25 mg
Generic: 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg
In Canada, distribution is restricted through RevAid (www.RevAid.ca or 1-888-738-2431).
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021880s065lbl.pdf#page=48, must be dispensed with this medication.
Oral: Administer at about the same time each day with water; administer with or without food. Swallow capsule whole; do not break, open, or chew.
Missed doses: May administer a missed dose if within 12 hours of usual dosing time. If greater than 12 hours, patient should skip dose for that day and resume usual dosing the following day. Patient should not take 2 doses to make up for a missed dose.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Follicular lymphoma (previously treated): Treatment of previously treated follicular lymphoma (in combination with a rituximab product) in adults.
Mantle cell lymphoma (relapsed or progressive): Treatment of mantle cell lymphoma in adults that has relapsed or progressed after 2 prior therapies (one of which included bortezomib).
Marginal zone lymphoma (previously treated): Treatment of previously treated marginal zone lymphoma (in combination with a rituximab product) in adults.
Multiple myeloma: Treatment of multiple myeloma (in combination with dexamethasone) in adults; maintenance therapy following autologous hematopoietic stem cell transplantation in adults.
Myelodysplastic syndromes: Treatment of adults with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q (del 5q) cytogenetic abnormality with or without additional cytogenetic abnormalities.
Limitations of use: Lenalidomide is not indicated and is not recommended for the treatment of chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.
Chronic lymphocytic leukemia, relapsed or refractory; Diffuse large B-cell lymphoma, relapsed or refractory; Multiple myeloma, newly diagnosed; Myelodysplastic syndrome without deletion 5q; Smoldering myeloma (high risk); Systemic light chain amyloidosis
Lenalidomide may be confused with leflunomide, pomalidomide, thalidomide.
Revlimid may be confused with revefenacin, Thalomid.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Revlimid may be confused with Revolade, a brand name for eltrombopag [Canada].
Lenalidomide may cause significant neutropenia and thrombocytopenia. Eighty percent of patients with deletion 5q myelodysplastic syndromes (MDS) had to have initial dose delay/reduction and 34% of patients had to have a second dose delay/reduction during the major study. Grade 3 or 4 hematologic toxicity occurred in 80% of patients enrolled in the study. Rates and severity of hematologic toxicity may vary by indication and dosing schedule (lowest rates with lymphoma and highest with MDS, with myeloma rates in between). Median time to documented recovery of grade 3 or 4 neutropenia was 17 days and grade 3 or 4 thrombocytopenia was 22 days. Lenalidomide is known to increase risk of fatal infections due to neutropenia (Ref).
Mechanism: Not clearly established; however, lenalidomide has multiple immunomodulatory affects that lead to decreased cell proliferation, including loss of PU.1, a key transcription factor involved in granulopoiesis, which leads to transient arrest of neutrophil maturation and subsequent neutropenia. Other mechanisms include modulation and downregulation of inflammatory cytokines, modulation of B-, T-, and NK-cells, as well as effects on the bone marrow microenvironment (Ref).
Onset: Delayed; median time to onset of grade 3 or 4 neutropenia was 42 days and grade 3 or 4 thrombocytopenia was 28 days. Data suggest incidence of infection is highest in initial months of drug treatment (Ref).
Risk factors:
• MDS deletion 5q versus other indications
• Concurrent use of other myelosuppressive therapies
• Preexisting kidney impairment
• Multiple myeloma disease-related complications that increase the risk of infection (eg, fractures, neutropenia, neurodegenerative disease) (Ref)
Lenalidomide may cause mild and self-limited abnormal hepatic function tests (Ref). Rarely, hepatic failure (including fatal) has been reported in patients treated with combination lenalidomide and dexamethasone therapy. The pattern of liver injury is usually cholestatic but may have hepatocellular or mixed characteristics (Ref).
Mechanism: Not clearly established; may have direct hepatotoxic effects. Proposed mechanisms also include changes in vascular inflow or outflow, possibly related to thrombotic effects of lenalidomide; and reduction in TNF-alpha, which is necessary for normal liver regeneration (Ref).
Onset: Varied; usually within 1 to 8 weeks after initiation (Ref)
Risk factors:
• Preexisting liver disease (Ref)
• Baseline elevations in liver enzymes
• Concurrent hepatotoxic medications
• Preexisting kidney impairment (Ref)
Immediate (eg, anaphylaxis, angioedema) (Ref) and delayed hypersensitivity reactions have been reported. Delayed hypersensitivity reactions include mild reactions most often described as maculopapular or morbilliform skin rashes or urticaria occurring in ~40% of patients (Ref). Severe cutaneous adverse reactions (SCARs), including drug rash with eosinophilia and systemic symptoms (DRESS) (Ref) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (Ref) have been documented; some events have been fatal. Lenalidomide has also been associated with other delayed hypersensitivity reactions, including myocarditis (Ref) and hypersensitivity pneumonitis (Ref).
Mechanism: Immediate hypersensitivity reactions (eg, anaphylaxis, urticaria): non–dose-related, immunologic, IgE-mediated. Delayed hypersensitivity reactions: Non–dose-related, immunologic, T-cell mediated (Ref).
Onset: Immediate hypersensitivity reactions: Rapid; occur within 1 hour of administration but may occur up to 6 hours after exposure (Ref). Delayed hypersensitivity reactions: Varied. Morbilliform and maculopapular rashes occurred a median of 3 weeks after initiation (Ref). SCARs occur 1 to 8 weeks after initiation (Ref); the median time to onset for lenalidomide-associated SJS was 24 days (Ref).
Risk factors:
• Cross-reactivity among immunomodulatory drugs (eg, thalidomide, lenalidomide, pomalidomide) is variable, despite the similarity in chemical structures (Ref)
• Systemic amyloidosis versus multiple myeloma indication (Ref)
• Possible association with specific HLA proteins (Ref)
Second primary malignancies, including hematologic (primarily acute myeloid leukemia [AML] and myelodysplastic syndrome [MDS]) and solid tumor malignancies, and non-melanoma skin cancers, have been reported with lenalidomide when used for the treatment of MDS and multiple myeloma. Overall risk is low, multifactorial, and partially related to length of patient survival and the susceptibility of multiple myeloma to additional malignancies (Ref).
Mechanism: Not clearly established; may be related to immunomodulatory effects on the tumor microenvironment, favoring the escape/growth of abnormal clones that could result in second primary malignancy development. With MDS and AML, may be related to the stem-cell damaging effects through a ubiquitin/cereblon-based inhibition pathway. Another proposal is that the increased survival benefit provided by the drug increases the likelihood of development of second primary malignancies due to time, rather than a direct drug effect itself (Ref).
Risk factors:
• Multiple myeloma as indication for treatment (Ref)
• Concurrent or previous melphalan therapy or other alkylating agents with or without previous autologous stem cell transplantation (Ref)
• History of radiotherapy (Ref)
• Older age (Ref)
• Males (Ref)
Lenalidomide and dexamethasone combination therapy has been associated with a significant increased risk for arterial and venous thromboembolic events (VTE) in patients with multiple myeloma. Deep vein thrombosis (DVT), pulmonary embolism (PE), acute myocardial infarction (MI), and cerebrovascular accident have been reported (Ref).
Mechanism: May be related to increased platelet aggregation, single-nucleotide sequence variants and altered balance between procoagulant and anticoagulant proteins on the surface of endothelial cells (Ref).
Onset: Delayed; median treatment durations prior to thromboembolic events ranged from 2 to 34 cycles (Ref).
Risk factors:
• History of arterial or VTE (Ref)
• Underlying comorbidities known to increase VTE risk (eg, infection, diabetes, cardiac disease, inherited thrombophilia) (Ref)
• Concurrent therapies (eg, higher doses of corticosteroids, doxorubicin, multi-agent chemotherapy, erythropoiesis stimulating agents, estrogen) (Ref)
• Cardiovascular comorbidities (eg, hyperlipidemia, hypertension)
• Smoking
• Older age (Ref)
• Immobilization (Ref)
• Surgery (Ref)
• Use of central venous catheters (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults receiving monotherapy and may vary based on indication. Adverse reactions are reported for newly diagnosed multiple myeloma, maintenance therapy following autologous hematopoietic stem cell transplantation (MM-auto-HSCT), myelodysplastic syndrome (MDS), or mantle cell lymphoma (MCL) unless otherwise indicated.
>10%:
Cardiovascular: Peripheral edema (MCL, MDS: 16% to 20%)
Dermatologic: Pruritus (MCL: 17%; MDS: 42%), skin rash (MCL, MDS: 22% to 36%; MM-auto-HSCT: 8%), xeroderma (MDS, MM-auto-HSCT: 11% to 14%)
Endocrine & metabolic: Hypokalemia (4% to 13%), weight loss (MCL: 13%)
Gastrointestinal: Abdominal pain (10% to 12%), constipation (13% to 24%), decreased appetite (MCL: 14%), diarrhea (MCL: 31%; MDS, MM-auto-HSCT: 39% to 49%; grades 3/4: 2% to 6%), gastroenteritis (MM-auto-HSCT: 23%), nausea (MCL, MDS: 24% to 30%; MM-auto-HSCT: 11%; grades 3/4: <4%), vomiting (MCL, MDS: 10% to 12%; grades 3/4: ≤1%)
Genitourinary: Urinary tract infection (4% to 11%)
Hematologic & oncologic: Anemia (MCL: 31%; MDS, MM-auto-HSCT: 9% to 11%, grades 3/4: 4% to 11%), leukopenia (MCL, MDS: 8% to 15%; MM-auto-HSCT: 32%; grades 3/4: MCL, MDS: 5% to 7%; MM-auto-HSCT: 24%), neutropenia (MCL: 49%; MDS, MM-auto-HSCT: 59% to 61%; grades 3/4: 43% to 54%) (table 1), thrombocytopenia (MCL, MM-auto-HSCT: 24% to 36%; MDS: 61%; grades 3/4: MCL: 28%; MDS: 50%; MM-auto-HSCT: 13%) (table 2)
|
Drug (Lenalidomide) |
Placebo |
Dose |
Indication |
Number of Patients (Lenalidomide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
All grades: 49% |
N/A |
CrCl ≥60 mL/minute: 25 mg once daily for 21 days of a 28-day treatment cycle; CrCl ≥30 mL/minute and <60 mL/minute: 10 mg once daily for 21 days of a 28-day treatment cycle |
Mantle cell lymphoma |
134 |
N/A |
|
Grades 3/4: 43% |
N/A |
CrCl ≥60 mL/minute: 25 mg once daily for 21 days of a 28-day treatment cycle; CrCl ≥30 mL/minute and <60 mL/minute: 10 mg once daily for 21 days of a 28-day treatment cycle |
Mantle cell lymphoma |
134 |
N/A |
|
All grades: 61% |
12% |
10 mg once daily |
Multiple myeloma, maintenance therapy following autologous hematopoietic stem cell transplantation |
293 |
280 |
|
Grades 3/4: 54% |
8% |
10 mg once daily |
Multiple myeloma, maintenance therapy following autologous hematopoietic stem cell transplantation |
293 |
280 |
|
All grades: 59% |
N/A |
10 mg once daily or 10 mg once daily for 21 days of a 28-day treatment cycle |
Myelodysplastic syndrome |
148 |
N/A |
|
Grades 3/4: 53% |
N/A |
10 mg once daily or 10 mg once daily for 21 days of a 28-day treatment cycle |
Myelodysplastic syndrome |
148 |
N/A |
|
Drug (Lenalidomide) |
Placebo |
Dose |
Indication |
Number of Patients (Lenalidomide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
All grades: 36% |
N/A |
CrCl ≥60 mL/minute: 25 mg once daily for 21 days of a 28-day treatment cycle; CrCl ≥30 mL/minute and <60 mL/minute: 10 mg once daily for 21 days of a 28-day treatment cycle |
Mantle cell lymphoma |
134 |
N/A |
|
Grades 3/4: 28% |
N/A |
CrCl ≥60 mL/minute: 25 mg once daily for 21 days of a 28-day treatment cycle; CrCl ≥30 mL/minute and <60 mL/minute: 10 mg once daily for 21 days of a 28-day treatment cycle |
Mantle cell lymphoma |
134 |
N/A |
|
All grades: 24% |
10% |
10 mg once daily |
Multiple myeloma, maintenance therapy following autologous hematopoietic stem cell transplantation |
293 |
280 |
|
Grades 3/4: 13% |
3% |
10 mg once daily |
Multiple myeloma, maintenance therapy following autologous hematopoietic stem cell transplantation |
293 |
280 |
|
All grades: 61% |
N/A |
10 mg once daily or 10 mg once daily for 21 days of a 28-day treatment cycle |
Myelodysplastic syndrome |
148 |
N/A |
|
Grades 3/4: 50% |
N/A |
10 mg once daily or 10 mg once daily for 21 days of a 28-day treatment cycle |
Myelodysplastic syndrome |
148 |
N/A |
Infection: Influenza (MM-auto-HSCT: 13%)
Nervous system: Asthenia (MCL, MDS: 14% to 15%; MM-auto-HSCT: 30%), dizziness (MDS: 20%), fatigue (MCL, MDS: 31% to 34%; MM-auto-HSCT: 11%), headache (MDS: 20%; MM-auto-HSCT: 9%), paresthesia (MM-auto-HSCT: 13%)
Neuromuscular & skeletal: Arthralgia (MCL: 8%; MDS: 22%), back pain (MCL, MDS: 13% to 21%), limb pain (MDS: 11%), muscle cramps (MDS: 18%), muscle spasm (MCL: 13%; MM-auto-HSCT: 33%)
Respiratory: Bronchitis (MDS: 6%; MM-auto-HSCT: 47%), cough (20% to 28%), dyspnea (including exacerbations: MCL, MDS: 17% to 18%; MM-auto-HSCT: 6%), epistaxis (MDS: 15%), nasopharyngitis (MDS: 23%; MM-auto-HSCT: 35%), pharyngitis (MDS: 16%), pneumonia (11% to 17%; can be lobar pneumonia), rhinitis (MDS, MM-auto-HSCT: 7% to 15%), sinusitis (MDS, MM-auto-HSCT: 8% to 14%; can be acute sinusitis), upper respiratory tract infection (11% to 15%)
Miscellaneous: Fever (20% to 23%)
1% to 10%:
Cardiovascular: Acute myocardial infarction (MCL: ≥2%), chest pain (MDS: 5%), deep vein thrombosis (MCL, MM-auto-HSCT: 2% to 4%) (table 3), edema (MDS: 10%), heart failure (MCL), hypertension (MDS: 6%), hypotension (MCL: 7%), palpitations (MDS: 5%), pulmonary embolism (MCL, MM-auto-HSCT: 1% to 2%) (table 4), supraventricular tachycardia (MCL: ≥2%), swelling of extremities (MDS: 8%), syncope (MDS: grades 3/4: 1%)
|
Drug (Lenalidomide) |
Placebo |
Dose |
Indication |
Number of Patients (Lenalidomide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
4% |
N/A |
CrCl ≥60 mL/minute: 25 mg once daily for 21 days of a 28-day treatment cycle; CrCl ≥30 mL/minute and <60 mL/minute: 10 mg once daily for 21 days of a 28-day treatment cycle |
Mantle cell lymphoma |
134 |
N/A |
|
2% |
<1% |
10 mg once daily |
Multiple myeloma, maintenance therapy following autologous hematopoietic stem cell transplantation |
293 |
280 |
|
Drug (Lenalidomide) |
Placebo |
Dose |
Indication |
Number of Patients (Lenalidomide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
2% |
N/A |
CrCl ≥60 mL/minute: 25 mg once daily for 21 days of a 28-day treatment cycle; CrCl ≥30 mL/minute and <60 mL/minute: 10 mg once daily for 21 days of a 28-day treatment cycle |
Mantle cell lymphoma |
134 |
N/A |
|
1% |
0% |
10 mg once daily |
Multiple myeloma, maintenance therapy following autologous hematopoietic stem cell transplantation |
293 |
280 |
Dermatologic: Basal cell carcinoma of skin (MCL: ≥2%), cellulitis (MCL, MDS: 2% to 5%), diaphoresis (MDS: 7%), ecchymoses (MDS: 5%), erythema of skin (MDS: 5%), night sweats (MDS: 8%), squamous cell carcinoma of skin (MCL: 3%)
Endocrine & metabolic: Dehydration (MCL: 7%), hypocalcemia (MCL: 3%), hypomagnesemia (MDS: 6%), hyponatremia (MCL: 2%), hypothyroidism (MDS: 7%)
Gastrointestinal: Anorexia (MDS: 10%), Clostridioides difficile colitis (MCL: ≥2%), dysgeusia (MDS: 6%), oral herpes simplex infection (MCL), upper abdominal pain (MDS, MM-auto-HSCT: 7% to 8%), xerostomia (MDS: 7%)
Genitourinary: Dysuria (MDS: 7%)
Hematologic & oncologic: Bruise (MDS: 8%), febrile neutropenia (2% to 6%; grades 3/4: 2% to 6%), granulocytopenia (MDS: grades 3/4: 2%), lymphocytopenia (MCL, MM-auto-HSCT: 4% to 7%; grades 3/4: 4%), myelodysplastic syndrome (MM-auto-HSCT: 1%; grades 3/4: <1%), pancytopenia (MM-auto-HSCT: 4%; MDS, MM-auto-HSCT: grades 3/4: 2%), tumor flare (MCL: 10%)
Hepatic: Hyperbilirubinemia (MM-auto-HSCT: 1%), increased serum alanine aminotransferase (MDS: 8%)
Infection: Bacteremia (MCL: 1%), herpes zoster infection (including reactivation; MM-auto-HSCT: 10%), infection (MM-auto-HSCT: 6%) (table 5), sepsis (MCL, MM-auto-HSCT: 1% to 2%)
|
Drug (Lenalidomide) |
Placebo |
Dose |
Indication |
Number of Patients (Lenalidomide) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
6% |
2% |
10 mg once daily |
Multiple myeloma, maintenance therapy following autologous hematopoietic stem cell transplantation |
293 |
280 |
Nervous system: Chills (MCL), depression (MDS: 5%), hypoesthesia (MDS: 7%), insomnia (MDS: 10%), lethargy (MCL), myasthenia (MCL: 6%), pain (MDS: 7%), peripheral neuropathy (MDS, MM-auto-HSCT: 5% to 10%; grades 3/4: 1%), rigors (MDS: 6%), vertigo (MCL)
Neuromuscular & skeletal: Myalgia (MDS, MM-auto-HSCT: 6% to 9%)
Renal: Renal failure syndrome (MCL: 4%)
Respiratory: Chronic obstructive pulmonary disease (MCL: ≥2%), Dyspnea on exertion (MDS: 7%), hypoxia (MCL: 2%), oropharyngeal pain (MCL: 10%), pleural effusion (MCL: 7%), respiratory distress (MCL: 1%), respiratory tract infection (MM-auto-HSCT: 3%), rhinorrhea (MM-auto-HSCT: 5%)
Miscellaneous: Multi-organ failure (MDS: grades 3/4: 1%)
Frequency not defined (any indication):
Cardiovascular: Angina pectoris, atrial fibrillation (including aggravated atrial fibrillation), bradycardia, cardiac disorder (aortic disorder), cardiogenic shock, cardiomyopathy, superficial thrombophlebitis, supraventricular cardiac arrhythmia, tachyarrhythmia, ventricular dysfunction
Dermatologic: Sweet syndrome
Endocrine & metabolic: Graves disease, hypernatremia, hypoglycemia
Gastrointestinal: Abscess of rectum and/or peri-rectal area, biliary obstruction, cholecystitis (may be acute), colonic polyps, diverticulitis of the gastrointestinal tract, dysphagia, gastritis, gastroesophageal reflux disease, gastrointestinal hemorrhage (including upper gastrointestinal hemorrhage), infection of mouth, inguinal hernia (obstructive), intestinal obstruction (small intestine), intestinal perforation, irritable bowel syndrome, ischemic colitis, melena, pancreatitis, rectal hemorrhage
Genitourinary: Azotemia, hematuria, pelvic pain, prostate carcinoma, urinary tract infection with sepsis, urolithiasis (ureter)
Hematologic & oncologic: Acquired blood coagulation disorder, acute leukemia, bone marrow depression, hemolysis, hemolytic anemia, malignant lymphoma, myeloid leukemia (acute), splenic infarction, warm antibody immunohemolytic anemia
Infection: Fungal infection, herpes virus infection, kidney infection, septic shock
Nervous system: Abnormal gait, aphasia, cerebellar infarction, cerebral infarction, cerebrovascular accident, confusion, dysarthria, falling, impaired consciousness, migraine, subarachnoid hemorrhage, transient ischemic attacks
Neuromuscular & skeletal: Arthritis (including exacerbation), bone fracture (cervical, femoral neck fracture, femur fracture, pelvic fracture, rib fracture, spinal cord compression), calcium pyrophosphate deposition disease, gout, gouty arthritis, neck pain
Otic: Otic infection
Renal: Acute kidney injury, increased serum creatinine
Respiratory: Bronchogenic carcinoma, interstitial lung disease, malignant neoplasm of lung, pulmonary edema, pulmonary infiltrates, respiratory failure, wheezing
Miscellaneous: Mass (renal), nodule
Postmarketing (any indication):
Cardiovascular: Myocarditis (Carver 2010)
Dermatologic: Stevens-Johnson syndrome (Barley 2016), toxic epidermal necrolysis (Barley 2016), urticaria (Uchiyama 2014)
Endocrine & metabolic: Hyperthyroidism (Blair 2019)
Hematologic & oncologic: Tumor lysis syndrome
Hepatic: Abnormal hepatic function tests (LiverTox 2022), cholestatic hepatitis (LiverTox 2022), hepatic cytolysis, hepatic failure (LiverTox 2022), toxic hepatitis
Hypersensitivity: Anaphylaxis, angioedema (Uchiyama 2014), drug reaction with eosinophilia and systemic symptoms (Osada 2021)
Immunologic: Graft-versus-host disease, organ transplant rejection
Infection: Reactivation of HBV
Nervous system: Progressive multifocal leukoencephalopathy (Anderson 2019)
Respiratory: Hypersensitivity pneumonitis (Lerch 2010), pneumonitis
Severe hypersensitivity (eg, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide or any component of the formulation; pregnancy
Canadian labeling: Additional contraindications (not in the US labeling): Platelet count <50,000/mm3 (in MDS patients); hypersensitivity to thalidomide or pomalidomide; females capable of becoming pregnant; breastfeeding; male patients unable to follow or comply with required contraceptive measures
Concerns related to adverse effects:
• Bone marrow suppression: Hematologic toxicity (neutropenia and thrombocytopenia) occurs in a majority of patients (grade 3/4: 80% in patients with del 5q myelodysplastic syndrome).
• CNS effects: May cause dizziness or fatigue; caution patients about performing tasks that require mental alertness (eg, operating machinery, driving).
• Dermatologic reactions: Severe cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported; may be fatal. DRESS may manifest as a cutaneous reaction (eg, rash, exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications, which may include hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Patients with a history of grade 4 rash with thalidomide should not receive lenalidomide.
• Hepatotoxicity: Hepatic failure, including fatalities, has occurred in patients treated with combination lenalidomide and dexamethasone therapy; may have hepatocellular, cholestatic, or mixed characteristics. Risk factors may include preexisting viral liver disease, elevated liver enzymes at baseline, and concomitant medications.
• Hypersensitivity: Hypersensitivity, including angioedema and anaphylactic reactions, have been reported.
• Secondary malignancy: Second primary malignancies, including hematologic (primarily acute myeloid leukemia and myelodysplastic syndrome [MDS]) and solid tumor malignancies, and non-melanoma skin cancers, have been reported with lenalidomide when used for the treatment of MDS and multiple myeloma; the incidence may be higher when lenalidomide is used in combination with an alkylating agent.
• Thromboembolic events: Lenalidomide has been associated with a significant increase in risk for arterial and venous thromboembolic events in multiple myeloma patients treated with lenalidomide and dexamethasone combination therapy. Deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), and stroke have occurred; signs and symptoms of thromboembolism include shortness of breath, chest pain, or arm or leg swelling. Erythropoietin-stimulating agents (ESAs) and estrogens may contribute to thromboembolic risk; use with caution. Patients with a prior history of arterial thromboembolic events may be at greater risk; minimize modifiable factors such as hyperlipidemia, hypertension, and smoking.
• Thyroid disorders: Both hypothyroidism and hyperthyroidism have been reported with lenalidomide use.
• Tumor flare: Tumor flare reactions, including fatalities, have been observed in studies of lenalidomide for the treatment of chronic lymphocytic leukemia (CLL) and lymphomas; clinical presentation includes low grade fever, pain, rash, and tender lymph node swelling. In patients with mantle cell lymphoma, follicular lymphoma, and/or marginal zone lymphoma, tumor flare may mimic disease progression. In clinical trials, the majority of tumor flare events occurred in the first cycle of therapy.
• Tumor lysis syndrome: Tumor lysis syndrome (with fatalities) has been reported with lenalidomide. Patients with a high tumor burden may be at risk for tumor lysis syndrome.
Disease-related concerns:
• Heart failure: In a scientific statement from the American Heart Association, lenalidomide has been determined to be an agent that may either cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).
• Mantle cell lymphoma: An increased incidence of early deaths (within 20 weeks) was reported in one study of patients receiving lenalidomide for the treatment of mantle cell lymphoma. Risk factors for early death include high tumor burden, mantle cell lymphoma international prognostic index (MIPI) score at diagnosis, and high WBC count (≥10,000/mm3) at baseline.
• Multiple myeloma: An increase in mortality was noted in 2 clinical studies in patients with multiple myeloma who received pembrolizumab in combination with a thalidomide analogue and dexamethasone. Pembrolizumab should not be used to treat multiple myeloma in combination with a thalidomide analogue and dexamethasone unless as part of a clinical trial.
• Renal impairment: Use with caution in patients with renal impairment; may experience an increased rate of toxicities due to reduced clearance and increased half-life.
• Stem cell mobilization: Lenalidomide use (≥4 cycles) may decrease the number of CD34+ cells collected for autologous stem cell transplant. Transplant eligible patients receiving lenalidomide should be referred to an appropriate transplant center in order to optimize the timing of stem cell collection. Cyclophosphamide in combination with G-CSF or G-CSF in combination with a CXC chemokine receptor 4 inhibitor (eg, plerixafor) may be considered when CD34+ cell collection is impaired.
Special populations:
• Older adult: Certain adverse reactions (DVT, PE, atrial fibrillation, renal failure) are more likely in patients >65 years of age; in some studies, the incidence of grade 3 or 4 adverse reactions was higher in older adults.
• Pediatric: If used in patients between 12 to 18 years of age, the parent or legal guardian must agree to ensure compliance with the Lenalidomide REMS program.
Other warnings/precautions:
• Appropriate use: In a clinical trial comparing lenalidomide versus chlorambucil single agent therapy in patients >65 years of age with chronic lymphocytic leukemia patients (not an FDA-approved indication), increased mortality was observed in the lenalidomide treatment arm. Atrial fibrillation, cardiac failure, and MI were observed more frequently in lenalidomide-treated patients; lenalidomide (alone or in combination) is not currently recommended for first-line treatment of CLL.
• REMS program: Due to the embryo-fetal risk, lenalidomide is only available through a restricted program under the Lenalidomide REMS program. Prescribers and pharmacies must be certified with the program to prescribe or dispense lenalidomide. Lenalidomide should only be prescribed to patients (male and female) who can understand and comply with the conditions of the Lenalidomide REMS program.
• Blood donation: Patients should be advised not to donate blood during therapy and for 1 month following completion of therapy.
• Lactose intolerance: Product may contain lactose; avoid use in patients with congenital lactase deficiency, glucose-galactose malabsorption, or glucose intolerance.
Substrate of P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abatacept: Anti-TNF Agents may enhance the immunosuppressive effect of Abatacept. Risk X: Avoid combination
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Risk C: Monitor therapy
Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Risk X: Avoid combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
DexAMETHasone (Systemic): May enhance the thrombogenic effect of Lenalidomide. Management: Consider using venous thromboembolism prophylaxis (eg, low-molecular weight heparin or warfarin [INR 2.0-3.0]) in patients with multiple myeloma who are receiving lenalidomide and dexamethasone. Risk D: Consider therapy modification
Digoxin: Lenalidomide may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Erythropoiesis-Stimulating Agents: May enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy
Estrogen Derivatives: May enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Pembrolizumab: May enhance the adverse/toxic effect of Thalidomide Analogues. Specifically, mortality may be increased when this combination is used for treatment of refractory multiple myeloma. Risk X: Avoid combination
Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
[US Boxed Warning]: In females of reproductive potential, obtain 2 negative pregnancy tests before starting lenalidomide treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after lenalidomide treatment. To avoid embryo-fetal exposure to lenalidomide, it is only available under a restricted distribution program called Lenalidomide REMS program.
Patients who could become pregnant should be treated only if they are able to comply with the conditions of the Lenalidomide REMS program. Patients who could become pregnant must avoid pregnancy beginning 4 weeks prior to therapy, during therapy, during therapy interruptions, and for at least 4 weeks after therapy is discontinued. Two forms of effective/reliable contraception (eg, tubal ligation, IUD, hormonal birth control methods, male latex or synthetic condom, diaphragm, or cervical cap) or total abstinence from heterosexual intercourse must be used by females who are not infertile or who have not had a hysterectomy. A negative pregnancy test (sensitivity of at least 50 milliunits/mL) 10 to 14 days prior to therapy, within 24 hours prior to beginning therapy, weekly during the first 4 weeks, and every 4 weeks (every 2 weeks for females with irregular menstrual cycles) thereafter is required for females of reproductive potential. Lenalidomide must be immediately discontinued for a missed period, abnormal pregnancy test or abnormal menstrual bleeding; refer patient to a reproductive toxicity specialist if pregnancy occurs during treatment. False-positive pregnancy tests have been reported during lenalidomide therapy (Castaneda 2018).
Lenalidomide is also present in semen. Patients (including those vasectomized) with partners who could become pregnant should use a latex or synthetic condom during any sexual contact with patients who could become pregnant, during lenalidomide treatment, during treatment interruptions, and for 4 weeks after discontinuation. Patients should not donate sperm during, for 4 weeks after treatment, and during lenalidomide therapy interruptions.
Use is contraindicated in pregnancy. [US Boxed Warning]: Do not use lenalidomide 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. To avoid embryo-fetal exposure to lenalidomide, it is only available under a restricted distribution program called Lenalidomide REMS program.
A pregnancy exposure registry has been created to monitor outcomes in females exposed to lenalidomide during pregnancy and female partners of male patients and to understand the root cause for the pregnancy. The pregnancy exposure registry may be contacted at 1-888-423-5436. The parent or legal guardian for patients between 12 and 18 years of age must agree to ensure compliance with the required guidelines. Any suspected fetal exposure should be reported to the FDA via the MedWatch program (1-800-FDA-1088) and to REM Call Center (1-888-423-5436).
It is not known if lenalidomide is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.
CBC with differential (mantle cell lymphoma - weekly for the first cycle, every 2 weeks during cycles 2 to 4 and monthly thereafter; myelodysplastic syndrome - weekly for first 8 weeks and at least monthly thereafter; multiple myeloma - weekly for the first 2 cycles, every 2 weeks during the third cycle and monthly thereafter; follicular and marginal zone lymphoma – weekly for the first 3 weeks in cycle 1 and every 2 weeks in cycles 2 to 4 and monthly thereafter); serum creatinine, LFTs (periodically). Thyroid function tests (TSH at baseline then every 2 to 3 months during lenalidomide treatment [Hamnvik 2011]). ECG when clinically indicated. Monitor for signs and symptoms of infection (if neutropenic), bleeding or bruising, hepatotoxicity, secondary malignancies, thromboembolism (eg, shortness of breath, chest pain, arm or leg swelling), dermatologic toxicity, tumor lysis syndrome, or hypersensitivity. Monitor for tumor flare reaction in patients with mantle cell lymphoma, follicular lymphoma, and/or marginal zone lymphoma. Monitor adherence.
Patients who could become pregnant: Pregnancy test 10 to 14 days and 24 hours prior to initiating therapy, weekly during the first 4 weeks of treatment, then every 2 to 4 weeks through 4 weeks after therapy discontinued.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Lenalidomide has immunomodulatory, antiangiogenic, and antineoplastic characteristics via multiple mechanisms. It selectively inhibits secretion of proinflammatory cytokines (potent inhibitor of tumor necrosis factor-alpha secretion); enhances cell-mediated immunity by stimulating proliferation of anti-CD3 stimulated T cells (resulting in increased IL-2 and interferon gamma secretion); inhibits trophic signals to angiogenic factors in cells. Inhibits the growth of myeloma, myelodysplastic, and lymphoma tumor cells by inducing cell cycle arrest and cell death. The addition of lenalidomide to rituximab increases antibody dependent cell-mediated cytotoxicity in follicular lymphoma and marginal zone lymphoma and increases tumor cell apoptosis in follicular lymphoma (compared to rituximab alone).
Protein binding: ~30%.
Half-life elimination: 3 to 5 hours.
Time, to peak, plasma: MDS or myeloma patients: 0.5 to 6 hours.
Excretion: Urine (~82%; as unchanged drug).
Altered kidney function: The half-life is increased 3-fold in moderate to severe renal impairment and increased ~4.5-fold in hemodialysis patients, compared to healthy patients. There is a 66% to 75% decrease in drug clearance in patients with moderate and severe renal impairment compared with healthy subjects. Hemodialysis patients had an 80% decrease in drug clearance compared with healthy subjects.
Capsules (Lenalidomide Oral)
2.5 mg (per each): $949.88
5 mg (per each): $949.88
10 mg (per each): $949.88
15 mg (per each): $949.88
20 mg (per each): $949.88
25 mg (per each): $949.88
Capsules (Revlimid Oral)
2.5 mg (per each): $999.87
5 mg (per each): $999.87
10 mg (per each): $999.87
15 mg (per each): $999.87
20 mg (per each): $999.87
25 mg (per each): $999.87
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