Written in Blood
TABLE 4.
Multivariate Landmark Analyses at Six Months for Subsequent FFS, OS, and NRM
Outcome
FFS
Number of events/
number at risk
Parameter
Change in 2005 NIH 0-3 skin score
112/211
Change in patient 0-10 skin itching
OS
Change in Lee symptom score
NRM
Change in Lee symptom score
64/308
FACT-BMT total score
48/326
Hazard ratio
p Value
1.53 (1.19-1.96)
0.001
1.15 (1.06-1.24)
0.002
1.02 (1.01-1.04)
0.005
0.98 (0.97-0.99)
0.04
1.03 (1.01-1.04)
0.001
OS, and NRM. At six months, improvements in the NIH 0-3 clinician-reported
skin score and 0-10 patient-reported
itching score predicted longer subsequent FFS. Additionally, improvements
in the Lee skin symptom score predicted
longer subsequent OS and NRM, and the
FACT BMT TOI score predicted longer
subsequent OS (TABLE 4).
Although the 2014 NIH response
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7.3 Warfarin
Co-administration of multiple dose REVLIMID (10 mg) with single dose
warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide
or R- and S-warfarin. Expected changes in laboratory assessments of PT
and INR were observed after warfarin administration, but these changes
were not affected by concomitant REVLIMID administration. It is not
known whether there is an interaction between dexamethasone and
warfarin. Close monitoring of PT and INR is recommended in multiple
myeloma patients taking concomitant warfarin.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category X [see Boxed Warnings and Contraindications (4.1).]
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Risk Summary
REVLIMID can cause embryo-fetal harm when administered to a pregnant
female and is contraindicated during pregnancy. REVLIMID is a
thalidomide analogue.
Thalidomide is a human teratogen, inducing a high frequency of severe
and life-threatening birth defects such as amelia (absence of limbs),
phocomelia (short limbs), hypoplasticity of the bones, absence of bones,
external ear abnormalities (including anotia, micropinna, small or absent
external auditory canals), facial palsy, eye abnormalities (anophthalmos,
microphthalmos), and congenital heart defects. Alimentary tract, urinary
tract, and genital malformations have also been documented and mortality
at or shortly after birth has been reported in about 40% of infants.
Lenalidomide caused thalidomide-type limb defects in monkey offspring.
If this drug is used during pregnancy, or if the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential
hazard to a fetus.
If pregnancy does occur during treatment, immediately discontinue the
drug. Under these conditions, refer patient to an obstetrician/gynecologist
experienced in reproductive toxicity for further evaluation and counseling.
Any suspected fetal exposure to REVLIMID must be reported to the FDA
via the MedWatch program at 1-800-FDA-1088 and also to Celgene
Corporation at 1-888-423-5436.
Animal data
In an embryo-fetal developmental toxicity study in monkeys, teratogenicity,
including thalidomide-like limb defects, occurred in offspring when
pregnant monkeys received oral lenalidomide during organogenesis.
Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human
exposure at the maximum recommended human dose (MRHD) of 25 mg.
Similar studies in pregnant rabbits and rats at 20 times and 200 times the
MRHD respectively, produced embryo lethality in rabbits and no adverse
reproductive effects in rats.
In a pre- and post-natal development study in rats, animals received
lenalidomide from organogenesis through lactation. The study revealed
a few adverse effects on the offspring of female rats treated with
lenalidomide at doses up to 500 mg/kg (approximately 200 times the
human dose of 25 mg based on body surface area). The male offspring
exhibited slightly delayed sexual maturation and the female offspring had
slightly lower body weight gains during gestation when bred to male
offspring. As with thalidomide, the rat model may not adequately address
the full spectrum of potential human embryo-fetal developmental effects
for lenalidomide.
8.3 Nursing Mothers
It is not known whether this drug is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for
adverse reactions in nursing infants from lenalidomide, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients below the age of 18 have not
been established.
8.5 Geriatric Use
REVLIMID has been used in multiple myeloma (MM) clinical trials in
patients up to 91 years of age.
After At Least One Prior Therapy: Of the 703 MM patients who received
study treatment in Studies 1 and 2, 45% were age 65 or over while 12%
of patients were age 75 and over. The percentage of patients age 65 or
over was not significantly different between the REVLIMID/dexamethasone
and placebo/dexamethasone groups. Of the 353 patients who received
REVLIMID/dexamethasone, 46% were age 65 and over. In both studies,
patients > 65 years of age were more likely than patients ≤ 65 years of age
to experience DVT, pulmonary embolism, atrial fibrillation, and renal
failure following use of REVLIMID. No differences in efficacy were
observed between patients over 65 years of age and younger patients.
NDMM: Overall, of the 1613 patients in the NDMM study who received
study treatment, 94% (1521 /1613) were 65 years of age or older, while
35% (561/1613) were over 75 years of age. The percentage of patients
over age 75 was similar between study arms (Rd Continuous: 33%; Rd18:
34%; MPT: 33%). Overall, across all treatment arms, the frequency in
most of the AE categories (eg, all AEs, grade 3/4 A ̰