Pronunciation
(le na LID oh mide)
Index Terms
CC-5013IMid-1
Dosage Forms
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
Brand Names: U.S.
Revlimid
Pharmacologic Category
Angiogenesis InhibitorAntineoplastic AgentImmunomodulator, Systemic
Pharmacology
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 cells by inducing cell cycle arrest and cell death.
Absorption
Rapid
Excretion
Urine (~82%; as unchanged drug); Hemodialysis effect: ~30% of the drug in body is removed in a 4-hour hemodialysis session; Hemodialysis patients: 80% decrease in drug clearance compared with healthy subjects.
Time to Peak
MDS or myeloma patients: 0.5 to 6 hours
Half-Life Elimination
3 to 5 hours
Protein Binding
~30%
Special Populations: Renal Function Impairment
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.
Use: Labeled Indications
Mantle cell lymphoma: Treatment of patients with mantle cell lymphoma that has relapsed or progressed after 2 prior therapies (one of which included bortezomib).
Multiple myeloma: Treatment of multiple myeloma (in combination with dexamethasone) and as maintenance therapy following autologous hematopoietic stem cell transplantation.
Myelodysplastic syndromes: Treatment of patients 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.
Off Label Uses
Chronic lymphocytic leukemia, relapsed or refractory
Data from a phase II study in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), supports the use of lenalidomide (in combination with cyclic rituximab) in the treatment of patients with CLL [Badoux 2013]. Additional trials may be necessary to further define the role of lenalidomide in the treatment of this condition.
Diffuse large B-cell lymphoma, relapsed or refractory
Data from a phase II, single-arm, multicenter study in patients with relapsed or refractory aggressive non-Hodgkin lymphoma, supports the use of lenalidomide in the treatment of patients with this condition [Wiernik 2008]. Additional trials may be necessary to further define the role of lenalidomide in the treatment of this condition.
Myelodysplastic syndrome (MDS) without deletion 5q
Data from a phase II, multicenter study in patients with MDS, supports the use of lenalidomide in the treatment of patients with MDS without deletion 5q [Raza 2008]. Additional trials may be necessary to further define the role of lenalidomide in the treatment of this condition.
Multiple myeloma, newly diagnosed
Data from two phase II trials in patients with newly diagnosed multiple myeloma support the use of lenalidomide (in combination with bortezomib and dexamethasone) in the treatment of this condition [Kumar 2012], [Richardson 2010]. In addition, data from a small phase I/II trial supports the use of lenalidomide (in combination with carfilzomib and dexamethasone) for the treatment of newly diagnosed multiple myeloma [Jakubowiak 2012].
Systemic light chain amyloidosis
Data from two phase II studies in patients with systemic light chain amyloidosis, supports the use of lenalidomide in the treatment of patients with this condition [Nair 2012], [Sanchorawala 2007]. Additional trials may be necessary to further define the role of lenalidomide in the treatment of this condition.
Contraindications
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; women capable of becoming pregnant; breastfeeding women; male patients unable to follow or comply with required contraceptive measures
Dosing: Adult
Mantle cell lymphoma (MCL): Oral: 25 mg once daily for 21 days of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity
Multiple myeloma: Oral: 25 mg once daily for 21 days of a 28-day treatment cycle (in combination with dexamethasone). In patients not eligible for autologous stem cell transplantation, continue until disease progression or unacceptable toxicity; in transplant eligible patients, hematopoietic stem cell mobilization should occur within 4 cycles of a lenalidomide-containing therapy.
Multiple myeloma, maintenance (following autologous stem cell transplant): Oral: 10 mg once daily (begin after adequate hematologic recovery); continue until disease progression or unacceptable toxicity. If tolerated, may increase dose to 15 mg once daily after 3 cycles (each cycle is 28 days).
Off-label dosing: 10 mg once daily for 21 days of a 28-day treatment cycle until relapse (Palumbo 2010)
Myelodysplastic syndrome (MDS) with deletion 5q: Oral: 10 mg once daily
Chronic lymphocytic leukemia (CLL), 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)
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)
Multiple myeloma, newly diagnosed (off-label combination): Oral: 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 21 days of a 28-day cycle (in combination with carfilzomib and dexamethasone) for up to 8 cycles (Jakubowiak 2012)
Multiple myeloma, relapsed (off-label combinations): Adults: Oral: 25 mg once daily for 21 days of 28-day cycle (in combination with carfilzomib and dexamethasone) until disease progression or unacceptable toxicity (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; refer to the IMWG recommendations for Dosing in Renal Impairment (Dimopoulos 2016a; Dimopoulos 2016b).
Myelodysplastic syndrome (MDS), lower risk, without deletion 5q (off-label use): Oral: 10 mg once daily (Raza 2008)
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)
Dosing: Geriatric
Refer to adult dosing. Due to the potential for decreased renal function in the elderly, select dose carefully and closely monitor renal function.
Dosing: Renal Impairment
Note: Maintain appropriate number of treatment days per cycle based on indication and/or protocol. Further individualize (increase or decrease dose) based on tolerance.
Recommended initial dose adjustment in the manufacturer's labeling:
MCL and multiple myeloma (combination therapy with dexamethasone):
CrCl >60 mL/minute: No dosage adjustment necessary.
CrCl 30 to 60 mL/minute: 10 mg once daily (for multiple myeloma, may increase to 15 mg once daily after 2 cycles if nonresponsive but tolerating treatment)
CrCl <30 mL/minute (nondialysis dependent): 15 mg every 48 hours
ESRD: CrCl <30 mL/minute and dialysis dependent: 5 mg once daily (administer after dialysis on dialysis days)
MDS and multiple myeloma (maintenance treatment after autologous stem cell transplant):
CrCl >60 mL/minute: No dosage adjustment necessary.
CrCl 30 to 60 mL/minute: 5 mg once daily
CrCl <30 mL/minute (nondialysis dependent): 2.5 mg once daily
ESRD: CrCl <30 mL/minute and dialysis dependent: 2.5 mg once daily (administer after dialysis on dialysis days)
Dialysis removal: Approximately 30% removed during a 4-hour hemodialysis session
The International Myeloma Working Group (IMWG) recommendations (Dimopoulos 2016b):
The IMWG recommends use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine.
Combination therapy with dexamethasone:
CrCl ≥60 mL/minute: 25 mg once daily (no dosage adjustment necessary).
CrCl 30 to 59 mL/minute: 10 mg once daily (may increase to 15 mg once daily in the absence of toxicity).
CrCl 15 to 29 mL/minute: 15 mg once every other day; may adjust to 10 mg once daily.
CrCl <15 mL/minute: 5 mg once daily.
ESRD on dialysis: 5 mg once daily.
Dosing: Hepatic Impairment
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, lenalidomide undergoes minimal hepatic metabolism.
Dosing: Adjustment for Toxicity
NONHEMATOLOGIC toxicities:
Dermatologic toxicities:
Skin rash, grade 2 or 3: Consider interrupting or discontinuing treatment.
Angioedema, grade 4 rash, exfoliative or bullous rash, or suspected Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS): Discontinue treatment; do not rechallenge.
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, nonsteroidal anti-inflammatory drugs (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:
Adjustment for thrombocytopenia in MCL:
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
Adjustment for neutropenia in MCL:
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
Adjustment for thrombocytopenia in MDS:
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
Adjustment for neutropenia in MDS:
Neutropenia developing within 4 weeks of beginning treatment at 10 mg daily:
For baseline absolute neutrophil count (ANC) ≥1,000/mm3:
ANC <750/mm3: Hold treatment
When ANC returns to ≥1,000/mm3: Resume at 5 mg daily
For baseline absolute neutrophil count (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
Adjustment for thrombocytopenia in 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
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
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.
Adjustment for neutropenia in multiple myeloma:
Combination therapy with dexamethasone:
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
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:
ANC <500/mm3: Hold treatment, check CBC weekly
When ANC returns to ≥500/mm3: Resume at next lower dose; maintain continuous daily dosing
Additional 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.
Administration
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.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C and 30°C (59°F and 86°F).
Drug Interactions
Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. 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. Avoid combination
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).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. 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. Avoid combination
Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Dexamethasone (Systemic): May enhance the thrombogenic effect of Lenalidomide. Consider therapy modification
Digoxin: Lenalidomide may increase the serum concentration of Digoxin. Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Erythropoiesis-Stimulating Agents: May enhance the thrombogenic effect of Lenalidomide. Monitor therapy
Estrogen Derivatives: May enhance the thrombogenic effect of Lenalidomide. Monitor therapy
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. 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. Avoid combination
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy
Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Avoid combination
Tofacitinib: Anti-TNF Agents may enhance the adverse/toxic effect of Tofacitinib. Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination
Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Avoid combination
Adverse Reactions
Frequency not always defined; may vary based on indication and/or concomitant therapy.
Cardiovascular: Peripheral edema (8% to 26%), edema (10%), deep vein thrombosis (4% to 10%; grades 3/4: ≤8%), hypotension (7% to 10%), hypertension (6% to 8%), chest pain (5% to 8%), atrial fibrillation (3% to 7%; grades 3/4: ≤4%), palpitations (5%), myocardial infarction (1% to <5%), pulmonary embolism (2% to 4%; grades 3/4: 1% to 4%), syncope (grades 3/4: 1% to 3%), tachycardia (grades 3/4: 2%), cerebrovascular accident (≤2%), angina pectoris (≥1%), bradycardia (≥1%), cerebral ischemia (≥1%), cardiac failure (1%), cardiac arrest, cardiogenic shock, cardiomyopathy, cardiorespiratory arrest, cerebral infarction, increased cardiac enzymes (troponin I), ischemia, ischemic heart disease, septic shock, subarachnoid hemorrhage, supraventricular cardiac arrhythmia, tachyarrhythmia, thrombophlebitis, thrombosis, transiet ischemic attachs, ventricular dysfunction
Central nervous system: Fatigue (29% to 44%), insomnia (10% to 28%), dizziness (20% to 23%), headache (10% to 20%), depression (5% to 11%), chills (5% to 10%), falling (5% to 8%), hypoesthesia (7%), lethargy (7%), pain (7%), neuropathy (including peripheral, 5% to 7%), rigors (6%), noncardiac chest pain (3% to 6%), emotional lability (≥1%), glossalgia (≥1%), hallucination (≥1%), malaise (≥1%), abnormal gait, aphasia, cerebellar infarction, confusion, dysarthria, impaired consciousness, migraine, spinal cord compression, vertigo
Dermatologic: Pruritus (4% to 42%), skin rash (19% to 36%), xeroderma (9% to 14%), diaphoresis (7% to 10%), night sweats (8%), ecchymoses (5%), erythema (5%), cellulitis (≤5%), hyperpigmentation (≥1%), Sweet's syndrome
Endocrine & metabolic: Weight loss (9% to 20%), hypokalemia (7% to 17%), hyperglycemia (4% to 12%), hypocalcemia (3% to 11%), hypothyroidism (7%), hypomagnesemia (6% to 7%), dehydration (3% to 7%), diabetes mellitus (<5%), gout (<5%), hypophosphatemia (<5%, grades 3/4: ≤3%), hyponatremia (2% to <5%), hirsutism (≥1%), loss of libido (≥1%), Graves' disease, hypernatremia, hypoglycemia
Gastrointestinal: Diarrhea (17% to 49%), constipation (16% to 41%), nausea (24% to 30%), decreased appetite (7% to 23%), abdominal pain (8% to 21%), anorexia (10% to 16%), dysgeusia (4% to 15%), vomiting (10% to 12%), dyspepsia (5% to 11%), xerostomia (7%), loose stools (6%), gastroenteritis (2% to 6%), gastrointestinal hemorrhage (≥1%), biliary obstruction, cholecystitis, colonic polyps, diverticulitis, dysphagia, gastritis, gastroesophageal reflux disease, infection of mouth, inguinal hernia (obstructive), intestinal obstruction, intestinal perforation, irritable bowel syndrome, ischemic colitis, melena
Genitourinary: Urinary tract infection (4% to 14%), dysuria (7%), erectile dysfunction (≥1%), azotemia, hematuria, pelvic pain, perirectal obscess, urolithiasis, urosepsis
Hematologic & oncologic: Thrombocytopenia (19% to 62%; grades 3/4: 8% to 50%; MDS: Onset: 28 days [range: 8 to 290 days]; recovery: 22 days [range: 5 to 224 days]), neutropenia (33% to 61%; grades 3/4: 27% to 53%; MDS: Onset: 42 days [range: 14 to 411 days]; recovery: 17 days [range: 2 to 170 days]), anemia (12% to 44%; grades 3/4: 6% to 19%), leukopenia (8% to 15%; grades 3/4: 4% to 7%), tumor flare (10%), lymphocytopenia (5% to 7%; grades 3/4: 3% to 4%), bruise (3% to 6%), febrile neutropenia (1% to 6%; grades 3/4: 1% to 6%), second primary malignant neoplasms (≤5%, including AML, lymphomas, solid tumors), squamous cell carcinoma of skin (3% to <5%; grades 3/4: ≤3%), pancytopenia (<5%; grades 3/4: ≤2%), basal cell carcinoma (<5%; grades 3/4: <1%), granulocytopenia (grades 3/4: 2%), autoimmune hemolytic anemia (≥1%), acute leukemia, blood coagulation disorder, bone marrow depression, bronchogenic carcinoma, decreased hemoglobin, hemolysis, hemolytic anemia (including warm type), lung carcinoma, malignant lymphoma, myelocytic leukemia, neutropenic infection, pancreatitis, postoperative hemorrhage, prostate carcinoma, rectal hemorrhage, splenic infarction
Hepatic: Increased serum ALT (8%), abnormal hepatic function tests (≥1%), hepatic failure, hyperbilirubinemia
Hypersensitivity: Hypersensitivity reaction, transfusion reaction
Infection: Influenza (3% to 6%), sepsis (including Enterobacter, 3% to 6%; grades 3/4: 2% to 5%), bacteremia (1%), bacterial infection, clostridium infection, fungal infection, herpes virus infection, kidney infection, Klebsiella infection, localized infection, pseudomonas infection, staphylococcal infection
Local: Catheter infection
Neuromuscular & skeletal: Muscle cramps (18% to 33%), back pain (13% to 32%), weakness (14% to 28%), arthralgia (8% to 22%), tremor (21%), muscle spasm (11% to 21%), ostealgia (1% to 16%), limb pain (5% to 15%), musculoskeletal pain (7% to 13%), musculoskeletal chest pain (7% to 11%), myalgia (9%), myasthenia (5% to 8%), neck pain (2% to 8%), arthritis, bone fracture (femur, femoral neck, pelvis, hip, rib, spinal compression), calcium pyrophosphate deposition disease
Ophthalmic: Blurred vision (17%), cataract (≤14%; grades 3/4: ≤6%), subcapsular posterior cataract (<5%), blindness (≥1%), ocular hypertension (≥1%)
Otic: Otic infection
Renal: Renal failure (4% to 10%), increased serum creatinine
Respiratory: Cough (13% to 28%), upper respiratory tract infection (6% to 25%), dyspnea (17% to 24%), nasopharyngitis (6% to 23%), pneumonia (9% to 18%), bronchitis (6% to 17%), pharyngitis (14% to 16%), epistaxis (3% to 15%), oropharyngeal pain (3% to 10%), sinusitis (7% to 8%), pleural effusion (7%; grades 3/4: 1%), dyspnea on exertion (≤7%), respiratory tract infection (4% to 7%), rhinitis (3% to 7%), lower respiratory tract infection (2% to 6%), hypoxia (2%; grades 3/4: 1%), hoarseness (≥1%), pneumonitis (grades 3/4: 1%), pulmonary hypertension (grades 3/4: 1%), respiratory distress (1%; grades 3/4: 1% to 2%), chronic obstructive pulmonary disease, interstitial pulmonary disease, pulmonary edema, pulmonary infiltrates, respiratory failure, wheezing
Miscellaneous: Fever (14% to 28%), physical health deterioration (2%), multiorgan failure (grades 3/4: 1%), mass (renal), nodule
<1% (Limited to important or life-threatening): Angioedema, atrial flutter, circulatory shock, desquamation, drug overdose, erythema multiforme, Fanconi's syndrome, hematologic disease (impaired stem cell mobilization), hemorrhage, hepatitis, intracranial hemorrhage, leukoencephalopathy, myopathy, nephrolithiasis, orthostatic hypotension, peripheral ischemia, pseudomembranous colitis, renal tubular necrosis, Stevens-Johnson syndrome, stomatitis, toxic epidermal necrolysis, tumor lysis syndrome, urinary retention
ALERT: U.S. Boxed Warning
Fetal risk:
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 women of reproductive potential, obtain 2 negative pregnancy tests before starting lenalidomide treatment. Women of childbearing 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 Revlimid REMS.
Information about the Revlimid REMS program is available at http://www.celgeneriskmanagement.com or by calling the manufacturer's toll-free number 1-888-423-5436.
Hematologic toxicity:
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 count (CBC) monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors.
Venous and arterial thromboembolism:
Lenalidomide has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with lenalidomide and dexamethasone therapy. Monitor for and advise patients about 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.
Warnings/Precautions
Concerns related to adverse effects:
• Bone marrow suppression: [US Boxed Warning]: Hematologic toxicity (neutropenia and thrombocytopenia) occurs in a majority of patients (grade 3/4: 80% in patients with del 5q myelodysplastic syndrome) and may require dose reductions and/or delays; the use of blood product support and/or growth factors may be needed. CBC should be monitored weekly for the first 8 weeks and at least monthly thereafter in patients being treated for del 5q myelodysplastic syndromes. In patients being treated for multiple myeloma, monitor CBC weekly for the first 2 cycles, every 2 weeks during cycle 3, and monthly thereafter. In patients receiving lenalidomide for mantle cell lymphoma (MCL), monitor CBC weekly for the first cycle, every 2 weeks during cycles 2 to 4, and monthly thereafter. Monitor for signs of infection, bleeding, or bruising; may require dosage adjustment.
• CNS effects: May cause dizziness or fatigue; caution patients about performing tasks that require mental alertness (eg, operating machinery, driving).
• Dermatologic reactions: Angioedema and severe cutaneous reactions (eg, Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], 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. Consider interrupting or discontinuing treatment with grade 2 or 3 skin rash; discontinue and do not reinitiate treatment with angioedema, grade 4 rash, exfoliative or bullous rash, or for suspected SJS, TEN, or DRESS. 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. Monitor closely; interrupt therapy in patients with abnormal hepatic function tests. May consider resuming treatment at a lower dose upon return to baseline.
• Secondary malignancy: Second primary malignancies (SPMs), including hematologic (primarily AML and 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. Monitor for development of secondary malignancies.
• Thromboembolic events: [US Boxed Warning]: 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, and stroke have occurred; monitor for signs and symptoms of thromboembolism (shortness of breath, chest pain, or arm or leg swelling) and instruct patients to seek prompt medical attention with development of these symptoms. Thromboprophylaxis is recommended; the choice of regimen should be based on an assessment of the patient's underlying risk factors. The American Society of Clinical Oncology guidelines for VTE prophylaxis and treatment recommend thromboprophylaxis for patients receiving lenalidomide in combination with chemotherapy and/or dexamethasone; either aspirin or low molecular weight heparin (LMWH) is recommended for lower risk patients and LMWH is recommended for higher-risk patients (Lyman 2013; Lyman 2015). 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. Anticoagulant prophylaxis should be individualized and selected based on the thromboembolism risk of the combination treatment regimen, using the safest and easiest to administer (Palumbo 2008).
• Thyroid disorders: Both hypothyroidism and hyperthyroidism have been reported with lenalidomide use; monitor thyroid function prior to therapy initiation and periodically throughout treatment.
• Tumor flare: Observed in studies of lenalidomide for the treatment of chronic lymphocytic leukemia (CLL) and lymphoma; clinical presentation includes low grade fever, pain, rash, and tender lymph node swelling. In patients with mantle cell lymphoma (MCL), tumor flare may mimic disease progression; monitor closely. In clinical trials, the majority of tumor flare events occurred in the first cycle of therapy. Treatment with corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be considered; therapy interruption may be necessary as well.
• Tumor lysis syndrome: Patients with a high tumor burden may be at risk for tumor lysis syndrome; monitor closely; institute appropriate management for hyperuricemia. Tumor lysis syndrome (with fatalities) has been reported with lenalidomide.
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.
• 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. Initial dosage adjustments are recommended for moderate to severe and dialysis-dependent renal impairment.
• 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.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
• Elderly: Certain adverse reactions (DVT, pulmonary embolism, atrial fibrillation, renal failure) are more likely in elderly patients. Monitor renal function closely, and select dose accordingly.
• Pediatric: If used in patients between 12 to 18 years of age, the parent or legal guardian must agree to ensure compliance with the Revlimid REMS program.
• Pregnancy: [US Boxed Warning]: Do not use lenalidomide in pregnant women. Lenalidomide is an analogue of thalidomide (a human teratogen) and could potentially cause severe birth defects or embryo-fetal death; use is contraindicated during pregnancy and pregnancy must be avoided while taking lenalidomide. Obtain 2 negative pregnancy tests prior to initiation of treatment; 2 forms of contraception (or abstain from heterosexual intercourse) must be used at least 4 weeks prior to, during and for 4 weeks after lenalidomide treatment (and during treatment interruptions). In order to decrease the risk of embryo-fetal exposure, lenalidomide is available only through a restricted distribution program (Revlimid REMS). Males taking lenalidomide (even those vasectomized) must use a latex or synthetic condom during any sexual contact with women of reproductive potential and for up to 28 days following discontinuation of therapy. Males taking lenalidomide must not donate sperm.
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 Revlimid 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 Revlimid 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 Lapp lactase deficiency, glucose-galactose malabsorption, or glucose intolerance.
Monitoring Parameters
CBC with differential (MCL - weekly for the first cycle, every 2 weeks during cycles 2 to 4; MDS - weekly for first 8 weeks; Multiple myeloma - weekly for the first 2 cycles, every 2 weeks during the third cycle), then monthly thereafter; serum creatinine, liver function tests, 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), secondary malignancies, thromboembolism, dermatologic toxicity, tumor lysis syndrome, or tumor flare reaction.
Women of reproductive potential: 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.
Monitor adherence.
Pregnancy Considerations
[US Boxed Warning]: Do not use lenalidomide in pregnant women. Lenalidomide is an analogue of thalidomide (a human teratogen) and could potentially cause severe birth defects or embryo-fetal death; use is contraindicated during pregnancy and pregnancy must be avoided while taking lenalidomide. Obtain 2 negative pregnancy tests prior to initiation of treatment; 2 forms of contraception (or abstain from heterosexual intercourse) must be used at least 4 weeks prior to, during, and for 4 weeks after lenalidomide treatment (and during treatment interruptions). In order to decrease the risk of embryo-fetal exposure, lenalidomide is available only through a restricted distribution program (Revlimid REMS).
Women of reproductive potential should be treated only if they are able to comply with the conditions of the Revlimid REMS program. Women of reproductive potential 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 women with irregular menstrual cycles) thereafter is required for women 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.
Lenalidomide is also present in the semen of males. Males (including those vasectomized) should use a latex or synthetic condom during any sexual contact with women of reproductive age during treatment, during treatment interruptions, and for 4 weeks after discontinuation. Male patients should not donate sperm during, and for 4 weeks after treatment, and during therapy interruptions.
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 Celgene Corporation (1-888-423-5436).
Patient Education
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience back pain, bone pain, diarrhea, dry skin, sweating a lot, rhinitis, pharyngitis, change in taste, insomnia, constipation, nausea, vomiting, abdominal pain, dry mouth, tremors, lack of appetite, weight loss, or joint pain. Have patient report immediately to prescriber signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood); signs of a heart attack (angina; pain in arms, back, neck, jaw, or abdomen; shortness of breath; cold sweats; severe dizziness; passing out; or severe nausea or vomiting); signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit); signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes); signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea, or lack of appetite; or feel sluggish); signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight); signs of infection; signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop); signs of a low thyroid level (constipation; difficulty handling heat or cold; memory problems; mood changes; or burning, numbness, or tingling feeling); signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting); shortness of breath; burning or numbness feeling; edema; depression; severe headache; severe dizziness; passing out; severe loss of strength and energy; swollen glands; vision changes; or signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
