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WARNINGS and Adverse Events
Hematologic adverse events
Grade 3/4 neutropenia occurred in 21% of REVLIMID®(lenalidomide) + dex patients vs 3% of placebo + dex patients; 2% of REVLIMID® + dex patients had febrile neutropenia vs 0% of placebo + dex patients.
Grade 3/4 thrombocytopenia occurred in 10% of REVLIMID® + dex patients vs 6% of placebo + dex patients.
Grade 3/4 anemia occurred in 8% of REVLIMID® + dex patients vs 4% of placebo + dex patients.
Incidence of thrombotic events
The overall incidence of thrombotic events-including DVT, pulmonary embolism (PE), thrombosis, and thromboembolism-was higher among patients taking REVLIMID® + dex (12%; 43/346) vs placebo + dex (4%; 14/345).
Grade 3/4 DVT was significantly more frequent with REVLIMID® + dex (7%) vs placebo + dex (3%).
Grade 3/4 PE was not significantly different with REVLIMID® + dex (3%) vs placebo + dex (1%).
Prophylactic anticoagulation was not used in these 2 studies.
No significant difference between treatment arms in grade 3/4 constipation, fatigue, or neuropathy
There was no significant difference between treatment arms in neuropathy (REVLIMID® + dex, 2%; placebo + dex, 0.6%, P=NS).
Clinically relevant adverse events or those occurring in >10% of patients with multiple myeloma
REVLIMID® + dex (n=346)
Placebo + dex (n=345)
Hematologic
All grades
Grade 3/4
All grades
Grade 3/4
Neutropenia
28%*
21%*
5%
3%
Anemia NOS
24%*
8%*
17%
4%
Thrombocytopenia
17%*
10%*
10%
6%
Leukopenia NOS
__†
4%*
__†
<1%
Lymphopenia
__†
2%
__†
1%
Nonhematologic
All grades
Grade 3/4
All grades
Grade 3/4
Constipation
39%*
2%
19%
<1%
Fatigue
38%
6%
37%
4%
Insomnia
32%
__‡
37%
__‡
Muscle cramp
30%
__‡
21%
__‡
Diarrhea NOS
29%
2%
25%
1%
Asthenia
23%
4%
25%
5%
Pyrexia
23%
1%
19%
2%
Nausea
22%
__‡
19%
__‡
Headache
21%
__‡
21%
__‡
Edema peripheral
21%
__‡
19%
__‡
Dizziness
21%
__‡
15%
__‡
Dyspnea
20%
3%
15%
2%
Tremor
20%*
__‡
7%
__‡
Weight decreased
18%
__‡
14%
__‡
Rash NOS
16%*
__‡
8%
__‡
Back pain
15%
__‡
14%
__‡
Hyperglycemia NOS
15%
8%
14%
8%
Muscle weakness NOS
15%
5%
15%
3%
Vision blurred
15%
__‡
10%
__‡
Cough
15%
__‡
21%
__‡
Dyspepsia
14%
__‡
13%
__‡
Upper respiratory tract infections NOS
14%
__‡
13%
__‡
Anorexia
14%
__‡
9%
__‡
Dysgeusia
13%
__‡
9%
__‡
Parasthesia
12%
__‡
13%
__‡
Pneumonia NOS
11%
6%
8%
5%
Hypokalemia
11%
3%
5%
1%
Vomiting NOS
10%
__‡
8%
__‡
Arthralgia
10%
__‡
15%
__‡
Pooled analysis from Studies 1 and 2.
NOS=not otherwise specified.
*More frequent with REVLIMID® + dex than with placebo + dex. †Occurred in <10% of patients. ‡Occurred in <2% of patients.
In the pooled multiple myeloma studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID® and dexamethasone than in patients treated with dexamethasone alone. See ADVERSE REACTIONS Table 7 in the Prescribing Information. Patients on therapy should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients may require dose interruption and/or dose reduction.
Important Safety Information
REVLIMID®
(lenalidomide) in combination with dexamethasone is indicated for the treatment
of multiple myeloma patients who have received at least one prior therapy.
REVLIMID®
(lenalidomide) is indicated for patients with transfusion-dependent anemia due to
low- or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion
5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
WARNINGS:
1. POTENTIAL FOR HUMAN BIRTH DEFECTS.
Lenalidomide is an analogue of thalidomide. Thalidomide is a known human teratogen
that causes severe life-threatening human birth defects. If lenalidomide is taken
during pregnancy, it may cause birth defects or death to an unborn baby. Females
should be advised to avoid pregnancy while taking REVLIMID®
(lenalidomide).
Male Patients: It is not known whether lenalidomide is present in the semen of patients
receiving the drug. Therefore, males receiving REVLIMID®
(lenalidomide) must always use a latex condom during any sexual contact with females
of childbearing potential even if they have undergone a successful vasectomy.
Special Prescribing Requirements
Because of this potential toxicity and to avoid fetal
exposure to REVLIMID® (lenalidomide),
REVLIMID® (lenalidomide) is only
available under a special restricted distribution program. This program is called
“RevAssist®”. Under this program,
only prescribers and pharmacists registered with the program can prescribe and dispense
the product. In addition, REVLIMID®
(lenalidomide) must only be dispensed to patients who are registered and meet all
the conditions of the RevAssist®
program.
2. HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA).
This drug is associated with significant neutropenia and thrombocytopenia. Eighty
percent of patients with del 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 del 5q myelodysplastic syndromes should have
their complete blood counts monitored weekly for the first 8 weeks of therapy and
at least monthly thereafter. Patients may require dose interruption and/or reduction.
Patients may require use of blood product support and/or growth factors. (see DOSAGE
and ADMINISTRATION)
3. DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM.
This drug has demonstrated a significantly increased risk of deep venous thrombosis
(DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated
with REVLIMID® (lenalidomide)
combination therapy. Patients and physicians are advised to be observant for the
signs and symptoms of thromboembolism. Patients should be instructed to seek medical
care if they develop symptoms such as shortness of breath, chest pain, or arm or
leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet
therapy prescribed in conjunction with REVLIMID®
(lenalidomide) may lessen the potential for venous thromboembolic events. The decision
to take prophylactic measures should be done carefully after an assessment of an
individual patient’s underlying risk factors.
You can get the information about REVLIMID®
(lenalidomide) and the RevAssist®
program on the Internet at www.REVLIMID.com
or by calling the manufacturer's toll-free number at
1-888-423-5436.
ADDITIONAL WARNINGS: HEMATOLOGIC
TOXICITY
Multiple Myeloma
In the pooled multiple myeloma studies, Grade 3 and 4 hematologic
toxicities were more frequent in patients treated with the combination of REVLIMID® (lenalidomide) and dexamethasone
than in patients treated with dexamethasone alone
Patients on therapy should have their complete blood counts monitored
every 2 weeks for the first 12 weeks and then monthly thereafter
Patients may require dose interruption and/or dose reduction
CONTRAINDICATIONS:
Pregnancy Category X:
Lenalidomide is contraindicated in pregnant women and women capable
of becoming pregnant. When there is no alternative, females of childbearing potential
may be treated with lenalidomide provided adequate precautions are taken to avoid
pregnancy
Hypersensitivity:
REVLIMID® (lenalidomide)
is contraindicated in any patients who have demonstrated hypersensitivity to the
drug or its components
PRECAUTIONS:
Angioedema, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis:
Angioedema and serious dermatologic reactions including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events
can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide
treatment should not receive REVLIMID®
(lenalidomide). REVLIMID® (lenalidomide)
interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID® (lenalidomide) must be discontinued
for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected,
and should not be resumed following discontinuation for these reactions
Tumor Lysis Syndrome:
Lenalidomide has antineoplastic activity and therefore the complications
of tumor lysis syndrome may occur. The patients at risk of tumor lysis syndrome
are those with high tumor burden prior to treatment. These patients should be monitored
closely and appropriate precautions taken
Renal impairment:
Since lenalidomide is primarily excreted unchanged by the kidney,
adjustments to the starting dose of REVLIMID®
(lenalidomide) are recommended to provide appropriate drug exposure in patients
with moderate or severe (CLcr < 60 mL/min) renal impairment and in patients
on dialysis
Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, and it would be prudent to monitor
renal function
Nursing mothers: It is not known
whether REVLIMID® (lenalidomide)
is excreted in human milk.
Because of the potential for adverse reactions in nursing infants,
a decision should be made whether to discontinue nursing or the drug, taking into
account the importance of the drug to the mother
ADVERSE REACTIONS:
Multiple Myeloma
In the REVLIMID®
(lenalidomide)/dexamethasone treatment group, 151 patients (45%) underwent at least
one dose interruption with or without a dose reduction of REVLIMID® (lenalidomide) compared to 21% in the placebo/dexamethasone
treatment group
Of these patients who had one dose interruption with or without
a dose reduction, 50% in the REVLIMID®
(lenalidomide)/dexamethasone treatment group underwent at least one additional dose
interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone
treatment group
Most adverse events and Grade 3/4 adverse events were more frequent
in MM patients who received the combination of REVLIMID®
(lenalidomide)/dexamethasone compared to placebo/dexamethasone
Other adverse events reported in multiple myeloma
patients (REVLIMID® (lenalidomide)/dexamethasone
vs dexamethasone/placebo): constipation (39% vs 19%), fatigue (38% vs 37%),
insomnia (32% vs 37%), muscle cramp (30% vs 21%), diarrhea (29% vs 25%), neutropenia
(28% vs 5%), anemia (24% vs 17%), asthenia (23% vs 25%), pyrexia (23% vs 19%), nausea
(22% vs 19%), headache (21% vs 21%), peripheral edema (21% vs 19%), dizziness (21%
vs 15%), dyspnea (20% vs 15%), tremor (20% vs 7%), decreased weight (18% vs 14%),
thrombocytopenia (17% vs 10%), rash (16% vs 8%), back pain (15% vs 14%), hyperglycemia
(15% vs 14%), and muscle weakness (15% vs 15%).
Myelodysplastic Syndromes
Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148)
were the most frequently reported adverse events observed in the del 5q MDS population
Other adverse reactions reported in del 5q MDS patients
(REVLIMID® (lenalidomide)):
diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea
(24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%),
peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp
(18%), dyspnea (17%), and pharyngitis (16%).
DOSAGE AND ADMINISTRATION:
Dosing is continued or modified based upon clinical and laboratory
findings. Dosing modifications are recommended to manage Grade 3 or 4 neutropenia
or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID® (lenalidomide)
For other Grade 3 or 4 toxicities judged to be related to REVLIMID® (lenalidomide), hold treatment and
restart at next lower dose level when toxicity has resolved to less than or equal
to Grade 2
Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, PRECAUTIONS,
and ADVERSE REACTIONS.
