CLINICAL NEWS
acute deep vein thrombosis (DVT) or
pulmonary embolism (PE).
A total of 300 patients with cancer-
associated acute VTE were assigned to
six months of treatment with either:
• apixaban 10 mg twice-daily for 7 days,
followed by 5 mg twice-daily (n=145)
• dalteparin 200 IU/kg for 1 month, fol-
lowed by 150 IU/kg once-daily (n=142)
The primary endpoint of the trial was
major bleeding events (including fatal
bleeding and intracranial hemorrhage);
secondary endpoints included recur-
rence of VTE and a composite of major
plus clinically relevant non-major
bleeding.
Participants also completed monthly
questionnaires to measure satisfaction
with the anticoagulation regimen.
In the cohort, 65.5 percent of patients
presented with metastatic disease at
baseline, and 74 percent of patients were
receiving concurrent systemic cancer
therapy. The four most prevalent types of
cancer were breast, colorectal, lung, and
pancreatic. Dr. McBane noted that only
four percent of participants had an upper
gastrointestinal malignancy, although
this was not by design or exclusion
criteria.
At the study initiation, investigators
REVLIMID [lenalidomide] capsules, for oral use
in fetal plasma and tissues; concentrations of radioactivity in fetal tissues
were generally lower than those in maternal tissues. These data indicated
that lenalidomide crossed the placenta.
8.2 Lactation
Risk Summary
There is no information regarding the presence of lenalidomide in human
milk, the effects of REVLIMID on the breastfed infant, or the effects of
REVLIMID on milk production. Because many drugs are excreted in
human milk and because of the potential for adverse reactions in
breastfed infants from REVLIMID, advise women not to breastfeed during
treatment with REVLIMID.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
REVLIMID can cause fetal harm when administered during pregnancy
[see Use in Specific Populations (8.1)]. Verify the pregnancy status of
females of reproductive potential prior to initiating REVLIMID therapy
and during therapy. Advise females of reproductive potential that they
must avoid pregnancy 4 weeks before therapy, while taking REVLIMID,
during dose interruptions and for at least 4 weeks after completing
therapy.
Females of reproductive potential must have 2 negative pregnancy tests
before initiating REVLIMID. The first test should be performed within
10-14 days, and the second test within 24 hours prior to prescribing
REVLIMID. Once treatment has started and during dose interruptions,
pregnancy testing for females of reproductive potential should occur
weekly during the first 4 weeks of use, then pregnancy testing should be
repeated every 4 weeks in females with regular menstrual cycles. If
menstrual cycles are irregular, the pregnancy testing should occur every
2 weeks. Pregnancy testing and counseling should be performed if a
patient misses her period or if there is any abnormality in her menstrual
bleeding. REVLIMID treatment must be discontinued during this
evaluation.
Contraception
Females
Females of reproductive potential must commit either to abstain
continuously from heterosexual sexual intercourse or to use 2 methods
of reliable birth control simultaneously: one highly effective form of
contraception – tubal ligation, IUD, hormonal (birth control pills,
injections, hormonal patches, vaginal rings, or implants), or partner’s
vasectomy, and 1 additional effective contraceptive method – male latex
or synthetic condom, diaphragm, or cervical cap. Contraception must
begin 4 weeks prior to initiating treatment with REVLIMID, during
therapy, during dose interruptions, and continuing for 4 weeks following
discontinuation of REVLIMID therapy. Reliable contraception is indicated
even where there has been a history of infertility, unless due to
hysterectomy. Females of reproductive potential should be referred to a
qualified provider of contraceptive methods, if needed.
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 and for up to 4 weeks after discontinuing REVLIMID, even if
they have undergone a successful vasectomy. Male patients taking
REVLIMID must not donate sperm.
8.4 Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
8.5 Geriatric Use
MM In Combination: 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 AEs,
serious AEs) was higher in older (> 75 years of age) than in younger
(≤ 75 years of age) subjects. Grade 3 or 4 AEs in the General Disorders
and Administration Site Conditions body system were consistently
reported at a higher frequency (with a difference of at least 5%) in older
subjects than in younger subjects across all treatment arms. Grade 3 or
4 TEAEs in the Infections and Infestations, Cardiac Disorders (including
cardiac failure and congestive cardiac failure), Skin and Subcutaneous
Tissue Disorders, and Renal and Urinary Disorders (including renal
failure) body systems were also reported slightly, but consistently, more
frequently (<5% difference), in older subjects than in younger subjects
across all treatment arms. For other body systems (e.g., Blood and
Lymphatic System Disorders, Infections and Infestations, Cardiac
Cosmos Communications
Disorders, Vascular Disorders), there was a less consistent trend for
increased frequency of grade 3/4 AEs in older vs younger subjects across
all treatment arms Serious AEs were generally reported at a higher
frequency in the older subjects than in the younger subjects across all
treatment arms.
MM Maintenance Therapy: Overall, 10% (106/1018) of patients were
65 years of age or older, while no patients were over 75 years of age.
Grade 3 or 4 AEs were higher in the REVLIMID arm (more than 5%
higher) in the patients 65 years of age or older versus younger patients.
The frequency of Grade 3 or 4 AEs in the Blood and Lymphatic System
Disorders were higher in the REVLIMID arm (more than 5% higher) in
the patients 65 years of age or older versus younger patients. There were
not a sufficient number of patients 65 years of age or older in REVLIMID
maintenance studies who experienced either a serious AE, or discontinued
therapy due to an AE to determine whether elderly patients respond
relative to safety differently from younger patients
MM 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.
Since elderly patients are more likely to have decreased renal function,
care should be taken in dose selection. Monitor renal function.
8.6 Renal Impairment
Adjust the starting dose of REVLIMID based on the creatinine clearance
value and for patients on dialysis [see Dosage and Administration (2.4)].
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
13.8 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.
A fertility and early embryonic development study in rats, with
administration of lenalidomide up to 500 mg/kg (approximately 200 times
the human dose of 25 mg, based on body surface area) produced no
parental toxicity and no adverse effects on fertility.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved Patient labeling (Medication
Guide)
Embryo-Fetal Toxicity
Advise patients that REVLIMID is contraindicated in pregnancy [see
Boxed Warning and Contraindications (4.1)]. REVLIMID is a thalidomide
analogue 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 2 different forms of contraception
including at least 1 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
1
Q1
Q2
assumed a six-month major bleeding
rate of 6 percent in the dalteparin group
and 1.4 percent in the apixaban group.
However, “major bleeding was quite a bit
lower in both arms than we expected,”
Dr. McBane reported. There were no
major bleeding events in the apixaban
arm, compared with two (1.4%) in the
dalteparin group (p=0.14).
Rates of the secondary safety and ef-
ficacy endpoints are presented in TABLE 3 .