CLINICAL NEWS
to apoptosis. However, on electrolytic thrombosis models, the thrombi formed in
mice with these washed platelets were unstable – despite having normal time to
arterial occlusion.
Next, to investigate potential defects in platelet signaling pathways in the absence of
Bax and/or Bak, Dr. Pleines and colleagues performed in vitro platelet activation assays.
Flow cytometric measurements revealed that, in the absence of Bak and Bak/Bax, activation of the protease-activated receptor (PAR4) led to reduced platelet degranulation, a
process essential to normal platelet function and thrombus formation. Loss of Bax alone,
however, had no effect.
“In contrast, the response to activation with the platelet agonist adenosine diphos-
phate (ADP), which does not induce granule release, was similar in platelets from all
genotypes,” the researchers reported. “Similarly, platelet aggregation in response to intermediate concentrations of PAR4 was severely reduced in the absence of Bak and Bak/
Bax, but normal in response to ADP.”
Dr. Pleines and colleagues then investigated whether platelet age was a factor
behind the observed functional differences by synchronizing platelet age to three
days in both Bak and Bak/Bax-deficient mice and wild-type controls. Platelets
were then depleted in vivo by injection of anti-platelet serum, and newly generated platelets were collected at 72 hours post-injection, when platelet counts had
returned to normal levels. They found that synchronized platelet age normalized
T:7”
Males
Lenalidomide is present in the semen of males who take REVLIMID.
Therefore, males must always use a latex or synthetic condom during any
sexual contact with females of reproductive potential while taking
REVLIMID, during dose interruptions and for up to 28 days after
discontinuing REVLIMID, even if they have undergone a successful
vasectomy. Male patients taking REVLIMID must not donate sperm
8.7 Renal Impairment
Since lenalidomide is primarily excreted unchanged by the kidney,
adjustments to the starting dose of REVLIMID are recommended to
provide appropriate drug exposure in patients with moderate (CLcr
30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in
patients on dialysis [see Dosage and Administration (2.4)].
8.8 Hepatic Impairment
No dedicated study has been conducted in patients with hepatic impairment.
The elimination of unchanged lenalidomide is predominantly by the renal
route.
10 OVERDOSAGE
There is no specific experience in the management of lenalidomide
overdose in patients with MM, MDS, or MCL. In dose-ranging studies in
healthy subjects, some were exposed to up to 200 mg (administered
100 mg BID) and in single-dose studies, some subjects were exposed to
up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases
were the primary reported AEs. In clinical trials, the dose-limiting toxicity
was neutropenia and thrombocytopenia.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with lenalidomide have not been conducted.
Lenalidomide was not mutagenic in the bacterial reverse mutation assay
(Ames test) and did not induce chromosome aberrations in cultured
human peripheral blood lymphocytes, or mutations at the thymidine
kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not
increase morphological transformation in Syrian Hamster Embryo assay
or induce micronuclei in the polychromatic erythrocytes of the bone
marrow of male rats.
17 PATIENT COUNSELING INFORMATION
See FDA-approved Patient labeling (Medication Guide)
Embryo-Fetal Toxicity
Advise patients that REVLIMID is contraindicated in pregnancy [see
Contraindications (4.1)]. REVLIMID is a thalidomide analog and can cause
serious birth defects or death to a developing baby [see Warnings and
Precautions (5.1) and Use in Specific Populations (8.1)].
• Advise females of reproductive potential that they must avoid pregnancy
while taking REVLIMID and for at least 4 weeks after completing therapy.
• Initiate REVLIMID treatment in females of reproductive potential only
following a negative pregnancy test.
• Advise females of reproductive potential of the importance of monthly
pregnancy tests and the need to use two different forms of contraception
including at least one highly effective form simultaneously during
REVLIMID therapy, during dose interruption and for 4 weeks after she
has completely finished taking REVLIMID. Highly effective forms of
contraception other than tubal ligation include IUD and hormonal (birth
control pills, injections, patch or implants) and a partner’s vasectomy.
Additional effective contraceptive methods include latex or synthetic
condom, diaphragm and cervical cap.
• Instruct patient to immediately stop taking REVLIMID and contact her
doctor if she becomes pregnant while taking this drug, if she misses her
menstrual period, or experiences unusual menstrual bleeding, if she
stops taking birth control, or if she thinks FOR ANY REASON that she
may be pregnant.
• Advise patient that if her doctor is not available, she can call
1-888-668-2528 for information on emergency contraception [see
Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].
• Advise males to always use a latex or synthetic condom during any
sexual contact with females of reproductive potential while taking
REVLIMID and for up to 28 days after discontinuing REVLIMID, even
if they have undergone a successful vasectomy.
• Advise male patients taking REVLIMID that they must not donate sperm
[see Warnings and Precautions (5.1) and Use in Specific Populations
(8.6)].
Manufactured for:
Celgene Corporation
Summit, NJ 07901
REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of
Celgene Corporat