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guidance to address the problem of
drug shortages by applying metrics to
evaluate the quality of the facilities and
production processes involved in making the branded, generic, and biologic
prescription medications.
According to the draft guidance, pharmaceutical manufacturers would compile
data on the FDA’s set of metrics, and the
FDA would then collect records to conduct “risk-based inspection scheduling,”
in which facilities with highly controlled
manufacturing processes would have the
potential to be inspected less often than
similar establishments that demonstrate
uncontrolled processes.
“It is critically important for patients,
health-care professionals, caregivers, payers, and others to have confidence in how
medications are made,” according to Ashley Boam, the acting director of pharmaceutical quality policy at the FDA, and
Mary Malarkey, the director of biologics
quality compliance at the FDA. “Quality
metrics can help us achieve this goal.”
As of June 30, there were 219 active drug shortages in the United States,
representing a 44 percent increase over
the reported 152 drug shortages in 2010.
However, the shortages have decreased
since the end of 2014 when acti ve drug
shortages were reported at more than 300.
The draft letter noted, “The agency
has found that the majority of drug
shortages stem from quality concerns –
substandard manufacturing facilities or
processes are discovered, or significant
quality defects are identified in finished
product, necessitating an interruption in
production and a shortage of drugs.”
The FDA is taking public commentary on this initiative through September
2015.
Source: U.S. FDA, “Request for Quality Metrics: Guidance for Industry,” August 3, 2015.
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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 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 SOC 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) SOCs were also
reported slightly, but consistently, more frequently (<5% difference ), in
older subjects than in younger subjects across all treatment arms. For
other SOCs (e.g., Blood and Lymphatic System Disorders, Infections and
Infestations, Cardiac 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.
REVLIMID has been used in del 5q MDS clinical trials in patients up to
95 years of age.
Of the 148 patients with del 5q MDS enrolled in the major study, 38%
were age 65 and over, while 33% were age 75 and over. Although the
overall frequency of adverse events (100%) was the same in patients over
65 years of age as in younger patients, the frequency of serious adverse
events was higher in patients over 65 years of age than in younger
patients (54% vs. 33%). A greater proportion of patients over 65 years of
age discontinued from the clinical studies because of adverse events than
the proportion of younger patients (27% vs.16%). No differences in
efficacy were observed between patients over 65 years of age and younger
patients.
REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in
patients up to 83 years of age. Of the 134 patients with MCL enrolled in
the MCL trial, 63% were age 65 and over, while 22% of patients were age
75 and over. The overall frequency of adverse events was similar in
patients over 65 years of age and in younger patients (98% vs. 100%).
The overall incidence of grade 3 and 4 adverse events was also similar in
these 2 patient groups (79% vs. 78%, respectively). The frequency of
serious adverse events was higher in patients over 65 years of age than in
younger patients (55% vs. 41%). 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 Females of Reproductive Potential and Males
REVLIMID can cause fetal harm when administered during pregnancy
[see Use in Specific Populations (8.1)]. Females of reproductive potential
must avoid pregnancy 4 weeks before therapy, while taking REVLIMID,
during dose interruptions and for at least 4 weeks after completing
therapy.
Females
Females of reproductive potential must commit either to abstain
continuously from heterosexual sexual intercourse or to use two 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 one 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.
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.