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.
