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Lenalidomide

Pronunciation

(le na LID oh mide)

Index Terms

  • CC-5013
  • IMid-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 Inhibitor
  • Antineoplastic Agent
  • Immunomodulator, Systemic

Pharmacology

Immunomodulatory, antiangiogenic, and antineoplastic characteristics via multiple mechanisms. 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; Moderate to severe renal impairment: Increased threefold; Hemodialysis patients: Increased ~4.5-fold

Protein Binding

~30%

Special Populations: Renal Function Impairment

The AUC was 56% greater in patients with multiple myeloma with mild renal impairment compared with those with normal renal function. 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

US labeling:

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)

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

Canadian labeling:

Multiple myeloma: Treatment of multiple myeloma (in combination with dexamethasone) in patients who have received at least one prior therapy

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: In the US and in Canada, lenalidomide is not indicated and is not recommended for the treatment of chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

Use: Unlabeled

Treatment of non-Hodgkin lymphoma (diffuse large B-cell lymphoma); relapsed or refractory chronic lymphocytic leukemia (CLL), systemic light chain amyloidosis; lower-risk myelodysplastic syndrome (MDS) in transfusion-dependent patients without deletion 5q (del 5q); maintenance treatment for multiple myeloma (after response to primary treatment or following autologous stem cell transplant), newly diagnosed multiple myeloma

Contraindications

Hypersensitivity (eg, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide or any component of the formulation; pregnancy

Canadian labeling: Additional contraindications (not in US labeling): Platelet count <50,000/mm3 (in MDS patients); hypersensitivity to thalidomide or pomalidomide; women capable of becoming pregnant; breast-feeding women; male patients unable to follow or comply with required contraceptive measures

Dosage

Mantle cell lymphoma (MCL): Adults: Oral: 25 mg once daily for 21 days of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity

Multiple myeloma: Adults: 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.

Myelodysplastic syndrome (MDS) with deletion 5q: Adults: Oral:

US labeling: 10 mg once daily

Canadian labeling: 10 mg once daily for 21 days of 28-day treatment cycle; discontinue therapy if within 4 months of initiation, patient fails to achieve a rise in hemoglobin ≥1 g/dL (if not transfused) or ≥50% reduction in transfusion requirements.

Chronic lymphocytic leukemia (CLL), relapsed/refractory (off-label use): Adults: 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): Adults: 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): Adults: 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)

Multiple myeloma, relapsed (off-label combination): 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)

Multiple myeloma, maintenance (following autologous stem cell transplant; off-label use): Adults: Oral: 10 mg once daily for 3 months, then increased to 15 mg daily if tolerated; continue until relapse (Attal, 2012; McCarthy, 2012) or 10 mg once daily for 21 days of a 28-day treatment cycle until relapse (Palumbo, 2010)

Myelodysplastic syndrome (MDS), lower risk, without deletion 5q (off-label use): Adults: Oral: 10 mg once daily (Raza, 2008)

Systemic light chain amyloidosis (off-label use): Adults: Oral: 15 mg once daily for 21 days of a 28-day cycle (in combination with dexamethasone) (Nair, 2012; Sanchorawala, 2007)

Elderly: Refer to adult dosing; due to the potential for decreased renal function in the elderly, select dose carefully and closely monitor renal function

Dosage adjustment in renal impairment:

Recommended initial dose adjustment in the FDA-approved labeling; further individualize based on tolerance:

MCL:

CrCl >60 mL/minute: No adjustment required

CrCl 30 to 60 mL/minute: 10 mg once daily

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:

CrCl >60 mL/minute: No adjustment required

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)

Multiple myeloma:

CrCl >50 mL/minute: No adjustment required

CrCl 30 to 50 mL/minute: 10 mg once daily (may increase to 15 mg once daily after 2 cycles if nonresponsive but tolerating treatment; Chen, 2007)

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)

Recommended adjustment in Canadian labeling:

MDS:

CrCl ≥60 mL/minute: No adjustment required

CrCl 30 to 59 mL/minute: 5 mg once daily

CrCl <30 mL/minute (nondialysis dependent): 5 mg every 48 hours

ESRD: CrCl <30 mL/minute and dialysis dependent: 5 mg 3 times weekly (administer after each dialysis)

Multiple myeloma:

CrCl ≥60 mL/minute: No adjustment required

CrCl 30 to 59 mL/minute: 10 mg once daily (may increase to 15 mg once daily after 2 cycles if nonresponsive but tolerating treatment; Chen, 2007)

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)

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). However, lenalidomide undergoes minimal hepatic metabolism.

Dosage adjustment for 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 or toxic epidermal necrolysis: 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 at next lower dose level when toxicity has resolved to ≤ grade 2.

Dosage adjustment for 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 with 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):

US labeling: Resume at 2.5 mg once daily

Canadian labeling: Resume at 5 mg every other day

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 with 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:

US labeling: Resume at 2.5 mg once daily

Canadian labeling: Resume at 5 mg every other day

Adjustment for thrombocytopenia in multiple myeloma:

US labeling:

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

Canadian labeling:

Platelets <30,000/mm3: Hold treatment, check CBC weekly

When platelets return to ≥30,000/mm3: Resume at 15 mg daily

Additional occurrence of platelets <30,000/mm3: Hold treatment

When platelets return to ≥30,000/mm3: Resume treatment at 5 mg less than previous dose; do not dose below 5 mg daily

Adjustment for neutropenia in multiple myeloma:

US labeling:

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

Canadian labeling:

ANC <1,000/mm3: Hold treatment, initiate granulocyte-colony stimulating factor (G-CSF), check CBC weekly

When ANC returns to ≥1,000/mm3 (with neutropenia as only toxicity): Resume at 25 mg daily

When ANC returns to ≥1,000/mm3 (with additional toxicities): Resume at 15 mg daily

Additional occurrence of ANC <1,000/mm3: Hold treatment

When ANC returns to ≥1,000/mm3: Resume treatment at 5 mg less than previous dose; do not dose below 5 mg daily

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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

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: Systemic Angiogenesis Inhibitors 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

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

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

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

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. 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%), cerebrovascular tachycardia (grades 3/4: 2%), 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 embryofetal 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 embryofetal 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 which require mental alertness (eg, operating machinery or driving).

• Dermatologic reactions: Angioedema, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported; may be fatal. 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 or TEN. 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 (AML, MDS, and B-cell malignancies, including Hodgkin lymphoma) and solid tumor malignancies, and 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. 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).

• 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:

• 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]: Lenalidomide is an analogue of thalidomide (a human teratogen) and could potentially cause severe birth defects or embryo-fetal death; do not use during pregnancy (contraindication); avoid pregnancy 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 childbearing potential and for up to 28 days following discontinuation of therapy. Males taking lenalidomide must not donate sperm.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

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, tumor lysis syndrome, or tumor flare reaction

Women of childbearing 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

Pregnancy Risk Factor

X

Pregnancy Considerations

[US Boxed Warning]: Lenalidomide is an analogue of thalidomide (a human teratogen) and could potentially cause severe birth defects or embryo-fetal death; do not use during pregnancy (contraindication); avoid pregnancy 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). Animal reproduction studies with lenalidomide in nonhuman primates have demonstrated malformations similar to those observed in humans with thalidomide.

Women of childbearing 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 4 weeks prior to therapy, during therapy, during therapy interruptions, and for ≥4 weeks after therapy is discontinued. Two forms of effective 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 childbearing 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 childbearing 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.

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, osteodynia, diarrhea, xeroderma, hyperhidrosis, rhinitis, pharyngitis, dysgeusia, insomnia, constipation, nausea, dyspepsia, xerostomia, tremors, lack of appetite, weight loss, or arthralgia. Have patient report immediately to prescriber signs of infection, signs of hemorrhaging, signs of electrolyte imbalance, paresthesia, edema, depression, significant headache, severe dizziness, syncope, considerable asthenia, enlarged lymph nodes, vision changes, signs of tumor lysis syndrome, signs of Stevens-Johnson syndrome/toxic epidermal necrolysis, or signs of hepatic impairment (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 healthcare 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.

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