THALOMID® (thalidomide) Capsules 50 mg, 100 mg, & 200mg
WARNING: SEVERE,
LIFE-THREATENING HUMAN BIRTH DEFECTS.
IF THALIDOMIDE IS TAKEN
DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN
BABY. THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD
BECOME PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE DOSE [1 CAPSULE (50 mg,
100 mg or 200 mg)] TAKEN BY A PREGNANT WOMAN
DURING HER PREGNANCY CAN CAUSE SEVERE BIRTH DEFECTS. BECAUSE OF THIS TOXICITY AND IN AN EFFORT TO MAKE THE CHANCE OF FETAL
EXPOSURE TO THALOMID® (thalidomide) AS NEGLIGIBLE AS POSSIBLE,
THALOMID® (thalidomide) IS APPROVED FOR MARKETING ONLY UNDER A
SPECIAL RESTRICTED DISTRIBUTION PROGRAM APPROVED BY THE FOOD AND DRUG
ADMINISTRATION. THIS PROGRAM IS CALLED THE "SYSTEM FOR THALIDOMIDE
EDUCATION AND PRESCRIBING SAFETY (S.T.E.P.S. ®)."
UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND
PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE
THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY
WITH THE REQUIREMENTS OF THE S.T.E.P.S. ® PROGRAM IN ORDER TO RECEIVE PRODUCT. PLEASE SEE THE FOLLOWING BOXED WARNINGS CONTAINING SPECIAL
INFORMATION FOR PRESCRIBERS, FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS
RESTRICTED DISTRIBUTION PROGRAM. |
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THALOMID®
(thalidomide) may be prescribed only by licensed prescribers who are
registered in the S.T.E.P.S. ®
program and understand the risk of teratogenicity if thalidomide is used
during pregnancy. Major human fetal
abnormalities related to thalidomide administration during pregnancy have
been documented: amelia (absence of
limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of
bones, external ear abnormalities (including anotia, micro pinna, 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.1
Mortality at or shortly after birth has been reported at about 40%.2 Effective contraception
(see CONTRAINDICATIONS) must be
used for at least 4 weeks before beginning
thalidomide therapy, during thalidomide therapy, and for 4 weeks following
discontinuation of thalidomide therapy. Reliable contraception is indicated
even where there has been a history of infertility, unless due to
hysterectomy or because the patient has been postmenopausal for at least 24
months. Two reliable forms of contraception must be used simultaneously unless
continuous abstinence from heterosexual sexual contact is the chosen method.
Women of childbearing potential should be referred to a qualified provider of
contraceptive methods, if needed. Sexually mature women who have not
undergone a hysterectomy or who have not been postmenopausal for at least 24
consecutive months (i.e., who have had menses at some time in the preceding
24 consecutive months) are considered to be women of childbearing potential. Before starting treatment, women of childbearing potential should have a
pregnancy test (sensitivity of at least 50 mIU/mL). The test should be
performed within the 24 hours prior to beginning thalidomide therapy. A prescription for thalidomide for a woman
of childbearing potential must not be issued by the prescriber until a
written report of a negative pregnancy test has been obtained by the
prescriber. Male Patients: Because thalidomide is present in the semen of patients receiving
the drug, males receiving thalidomide must always use a latex condom during
any sexual contact with women of childbearing potential even if he has
undergone a successful vasectomy. Once treatment has started, pregnancy testing should occur weekly during the
first 4 weeks of use, then pregnancy testing should be repeated at 4 weeks in
women 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 menstrual bleeding. If pregnancy does occur
during thalidomide treatment, thalidomide must be discontinued immediately. Any suspected fetal exposure to THALOMID® (thalidomide) must be
reported immediately to the FDA via
the MedWatch number at 1-800-FDA-1088 and also
to Celgene Corporation. The patient should be referred to an
obstetrician/gynecologist experienced in reproductive toxicity for further
evaluation and counseling. |
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FEMALE PATIENTS |
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Thalidomide
is contraindicated in WOMEN of childbearing potential unless alternative
therapies are considered inappropriate AND the patient MEETS ALL OF THE
FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant
while on thalidomide therapy): ·
she understands and can reliably carry out instructions. ·
she is capable of complying with the mandatory contraceptive
measures, pregnancy testing, patient registration, and patient survey as
described in the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S. ®) program. ·
she has received both oral and written warnings of the hazards of
taking thalidomide during pregnancy and of exposing a fetus to the drug. ·
she has received both oral and written warnings of the risk of
possible contraception failure and of the need to use two reliable forms of
contraception simultaneously (see CONTRAINDICATIONS), unless continuous
abstinence from heterosexual sexual contact is the chosen method. Sexually
mature women who have not undergone a hysterectomy or who have not been
postmenopausal for at least 24 consecutive months (i.e., who have had menses
at some time in the preceding 24 consecutive months) are considered to be
women of childbearing potential. ·
she acknowledges, in writing, her understanding of these warnings and
of the need for using two reliable methods of contraception for 4 weeks prior
to beginning thalidomide therapy, during
thalidomide therapy, and for 4 weeks after discontinuation of thalidomide
therapy. ·
she has had a negative pregnancy test with a sensitivity of at least
50 mIU/mL, within the 24 hours prior to beginning therapy. (See PRECAUTIONS, CONTRAINDICATIONS.) ·
if the patient is between 12 and 18 years of age, her parent or legal
guardian must have read this material and agreed to ensure compliance with
the above. |
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MALE
PATIENTS |
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Thalidomide is contraindicated in sexually mature
MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS: ·
he understands and can reliably carry out instructions. ·
he is capable of complying with the mandatory contraceptive measures
that are appropriate for men, patient registration, and patient survey as
described in the S.T.E.P.S. ®
program. ·
he has received both oral and written warnings of the hazards of
taking thalidomide and exposing a fetus to the
drug. ·
he has received both oral and written warnings of the
risk of possible contraception failure and of the presence of thalidomide in
semen. He has been instructed that he must always use a
latex condom during any sexual contact with women of childbearing potential,
even if he has undergone a successful
vasectomy. ·
he acknowledges, in writing, his understanding of these warnings and
of the need to use a latex condom during any sexual contact with women of childbearing
potential, even if he has undergone a successful vasectomy. Sexually mature
women who have not undergone a hysterectomy or who have not been
postmenopausal for at least 24 consecutive months (i.e., who have had menses
at any time in the preceding 24 consecutive months) are considered to be
women of childbearing potential. ·
if the patient is between 12 and 18 years of age, his parent or legal
guardian must have read this material and agreed to ensure compliance with
the above. |
DESCRIPTION
THALOMID®
(thalidomide), a-(N-phthalimido)glutarimide,
is an immunomodulatory agent. The empirical formula for thalidomide is C13H10N2O4
and the gram molecular weight is 258.2. The CAS number of thalidomide is
50-35-1.
Chemical
Structure of thalidomide
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Note: ·
= asymmetric carbon atom
Thalidomide
is an off-white to white, odorless, crystalline powder that is soluble at 25°C in dimethyl
sulfoxide and sparingly soluble in water and ethanol. The glutarimide moiety
contains a single asymmetric center and, therefore, may exist in either of two
optically active forms designated S-(-) or R-(+). THALOMID®
(thalidomide) is an equal mixture of the S-(-) and R-(+) forms and, therefore,
has a net optical rotation of zero.
THALOMID®
(thalidomide) is available in 50 mg, 100 mg and 200 mg capsules for oral
administration. Active ingredient: thalidomide. Inactive ingredients:
pregelatinized starch and magnesium stearate. The 50 mg capsule shell contains
gelatin, titanium dioxide, and black ink. The 100 mg capsule shell contains
black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black
ink. The 200 mg capsule shell contains
FD&C blue #2, titanium dioxide, gelatin, and white ink.
CLINICAL PHARMACOLOGY
Mechanism of Action
Thalidomide is an
immunomodulatory agent with a spectrum of activity that is not fully
characterized. In patients with erythema nodosum leprosum (ENL) the mechanism
of action is not fully understood.
Available
data from in vitro studies and
preliminary clinical trials suggest that the immunologic effects of this compound
can vary substantially under different conditions, but may be related to
suppression of excessive tumor necrosis factor-alpha (TNF-a) production
and down-modulation of selected cell surface adhesion molecules involved in
leukocyte migration.3-6 For example, administration of thalidomide
has been reported to decrease circulating levels of TNF-a in patients
with ENL, 3 however, it has also been shown to increase plasma TNF-a levels in
HIV-seropositive patients.7
Pharmacokinetics and
Drug Metabolism
Absorption
The absolute bioavailability of
thalidomide from THALOMID® (thalidomide) capsules has not yet been
characterized in human subjects due to its poor aqueous solubility. In studies
of both healthy volunteers and subjects with Hansen’s disease, the mean time to
peak plasma concentrations (Tmax) of THALOMID®
(thalidomide) ranged from 2.9 to 5.7 hours indicating that THALOMID®
(thalidomide) is slowly absorbed from the gastrointestinal tract. While the
extent of absorption (as measured by area under the curve [AUC]) is
proportional to dose in healthy subjects, the observed peak concentration (Cmax)
increased in a less than proportional manner (see Table 1 below). This lack of
Cmax dose proportionality, coupled with the observed increase in Tmax
values, suggests that the poor solubility of thalidomide in aqueous media may
be hindering the rate of absorption.
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Table 1 Pharmacokinetic Parameter Values for THALOMID®
(thalidomide) Mean (%CV) |
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|
Population/ Single Dose |
AUC0¥ µg·hr/mL |
Cmax µg/mL |
Tmax (hrs) |
Half‑life (hrs) |
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Healthy Subjects (n=14) |
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50 mg |
4.9 (16%) |
0.62 (52%) |
2.9 (66%) |
5.52 (37%) |
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200
mg |
18.9 (17%) |
1.76 (30%) |
3.5 (57%) |
5.53 (25%) |
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400
mg |
36.4 (26%) |
2.82 (28%) |
4.3 (37%) |
7.29 (36%) |
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Patients with Hansen’s Disease (n=6) |
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400
mg |
46.4 (44.1%) |
3.44 (52.6%) |
5.7 (27%) |
6.86 (17%) |
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Coadministration
of THALOMID® (thalidomide) with a high fat meal causes minor
(<10%) changes in the observed AUC and Cmax values; however, it
causes an increase in Tmax to approximately 6 hours.
Distribution
In human blood plasma,
the geometric mean plasma protein binding was 55% and 66%, respectively, for
(+)-(R)- and (-)-(S)-thalidomide.8 In a pharmacokinetic study of
thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100
mg/day, thalidomide was detectable in the semen.
Metabolism
At
the present time, the exact metabolic route and fate of thalidomide is not
known in humans. Thalidomide itself does not appear to be hepatically
metabolized to any large extent, but appears to undergo non-enzymatic
hydrolysis in plasma to multiple metabolites. In a repeat dose study in which
THALOMID® (thalidomide) 200 mg was administered to 10 healthy
females for 18 days, thalidomide displayed similar pharmacokinetic profiles on
the first and last day of dosing. This suggests that thalidomide does not
induce or inhibit its own metabolism.
Elimination
As
indicated in Table 1 (above) the mean half-life of elimination ranges from
approximately 5 to 7 hours following a single dose and is not altered upon
multiple dosing. As noted in the metabolism subsection, the precise metabolic
fate and route of elimination of thalidomide in humans is not known at this
time. Thalidomide itself has a renal clearance of 1.15 mL/minute with less than
0.7% of the dose excreted in the urine as unchanged drug. Following a single
dose, urinary levels of thalidomide were undetectable 48 hrs after dosing.
Although thalidomide is thought to be hydrolyzed to a number of metabolites,9
only a very small amount (0.02% of the administered dose) of 4-OH-thalidomide
was identified in the urine of subjects 12 to 24 hours after dosing.
Pharmacokinetic
Data in Special Populations
HIV-seropositive Subjects:
There is no apparent significant difference in measured pharmacokinetic
parameter values between healthy human subjects and HIV-seropositive subjects
following single dose administration of THALOMID® (thalidomide)
capsules.
Patients with Hansen’s Disease:
Analysis of data from a small study in Hansen’s patients suggests that these
patients, relative to healthy subjects, may have an increased bioavailability
of THALOMID® (thalidomide). The increase is reflected both in an
increased area under the curve and in increased peak plasma levels. The
clinical significance of this increase is unknown.
Patients with Renal Insufficiency:
The pharmacokinetics of thalidomide in patients with renal dysfunction have not
been determined.
Patients with Hepatic Disease:
The pharmacokinetics of thalidomide in patients with hepatic impairment have
not been determined.
Age: Analysis of
the data from pharmacokinetic studies in healthy volunteers and patients with
Hansen’s disease ranging in age from 20 to 69 years does not reveal any
age-related changes.
Pediatric:
No pharmacokinetic data are available in subjects below the age of 18 years.
Gender: While a
comparative trial of the effects of gender on thalidomide pharmacokinetics has
not been conducted, examination of the data for thalidomide does not reveal any
significant gender differences in pharmacokinetic parameter values.
Race: Pharmacokinetic
differences due to race have not been studied.
Clinical Studies
The primary data
demonstrating the efficacy of thalidomide in the treatment of the cutaneous
manifestations of moderate to severe ENL are derived from the published medical
literature and from a retrospective study of 102 patients treated by the U.S.
Public Health Service.
Two
double-blind, randomized, controlled trials reported the dermatologic response
to a 7-day course of 100 mg thalidomide (four times daily) or control. Dosage
was lower for patients under 50 kg in weight.
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Table 2 Double-Blind, Controlled Clinical Trials of Thalidomide in Patients
with ENL: Cutaneous Response
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Reference
|
No. of Patients |
No. Treatment Courses* |
Percent Responding** |
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Iyer et al.10 Bull World Health Organization 1971;45:719 |
92 |
204 |
Thalidomide 75% |
Aspirin 25% |
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Sheskin et al.11 Int J Lep 1969;37:135 |
52 |
173 |
Thalidomide 66% |
Placebo 10% |
*In
patients with cutaneous lesions
**Iyer:
Complete response or lesions absent
**Sheskin:
Complete improvement + “striking” improvement (i.e., >50% improvement)
Waters12 reported the results
of two studies, both double-blind, randomized, placebo-controlled, crossover
trials in a total of 10 hospitalized, steroid-dependent patients with chronic
ENL treated with 100 mg thalidomide or placebo (three times daily). All
patients also received dapsone. The primary endpoint was reduction in weekly
steroid dosage.
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Table 3 Double
Blind, Controlled Trial of Thalidomide in Patients with ENL: Reduction in
Steroid Dosage |
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Reference
|
Duration of |
No. of Patients |
Number Responding |
|
|
|
Treatment |
|
Thalidomide |
Placebo |
|
Waters12 |
4 weeks |
9 |
4/5 |
0/4 |
|
Lep Rev 1971;42:26 |
6 weeks (crossover) |
8 |
8/8 |
1/8 |
Data
on the efficacy of thalidomide in prevention of ENL relapse were derived from a
retrospective evaluation of 102 patients treated under the auspices of the U.S.
Public Health Service. A subset of patients with ENL controlled on thalidomide
demonstrated repeated relapse upon drug withdrawal and remission with
reinstitution of therapy.
Twenty
U.S. patients between the ages of 11 and 17 years were treated with
thalidomide, generally at 100 mg daily. Response rates and safety profiles were
similar to that observed in the adult population.
Thirty-two
other published studies containing over 1600 patients consistently report
generally successful treatment of the cutaneous manifestations of moderate to
severe ENL with thalidomide.
INDICATIONS AND USAGE
THALOMID®
(thalidomide) is indicated for the acute treatment of the cutaneous
manifestations of moderate to severe erythema nodosum leprosum (ENL).
THALOMID®
(thalidomide) is not indicated as monotherapy for such ENL treatment in the
presence of moderate to severe neuritis.
THALOMID®
(thalidomide) is also indicated as maintenance therapy for prevention and suppression
of the cutaneous manifestations of ENL recurrence.
CONTRAINDICATIONS (See BOXED WARNINGS.)
Pregnancy: Category X
Due to its known human
teratogenicity, even following a single dose, thalidomide is contraindicated in
pregnant women and women capable of becoming pregnant. (See BOXED WARNINGS.) When there is no
alternative treatment, women of childbearing potential may be treated with
thalidomide provided adequate precautions are taken to avoid pregnancy. Women
must commit either to abstain continuously from heterosexual sexual contact or
to use two methods of reliable birth control, including at least one highly
effective method (e.g., IUD, hormonal contraception, tubal ligation, or
partner’s vasectomy) and one additional effective method (e.g., latex condom,
diaphragm, or cervical cap), beginning 4 weeks prior to initiating treatment
with thalidomide, during therapy with thalidomide, and continuing for 4 weeks
following discontinuation of thalidomide therapy. If hormonal or IUD
contraception is medically contraindicated (see also PRECAUTIONS: Drug Interactions), two other effective or highly
effective methods may be used.
Women
of childbearing potential being treated with thalidomide should have a
pregnancy test (sensitivity of at least 50 mIU/mL). The test should be
performed within the 24 hours prior to beginning
thalidomide therapy and then weekly during the first 4 weeks of thalidomide therapy, then at 4 week intervals in
women with regular menstrual cycles or every 2 weeks in women with irregular
menstrual cycles. Pregnancy testing and counseling should be performed if a
patient misses her period or if there is any abnormality in menstrual bleeding.
If pregnancy occurs during thalidomide treatment, thalidomide must be
discontinued immediately. Under these conditions, the patient should be
referred to an obstetrician/gynecologist experienced in reproductive toxicity
for further evaluation and counseling.
Because
thalidomide is present in the semen of patients receiving the drug, males
receiving thalidomide must always use a latex condom during any sexual contact
with women of childbearing potential. The risk to the fetus from the semen of male patients
taking thalidomide is unknown.
THALOMID®
(thalidomide) is contraindicated in patients who have demonstrated
hypersensitivity to the drug and its components.
WARNINGS (See BOXED
WARNINGS.)
Birth Defects:
Thalidomide
can cause severe birth defects in humans. (See BOXED WARNINGS and CONTRAINDICATIONS.)
Patients should be instructed to take thalidomide only as prescribed and not to
share their thalidomide with anyone else. Because thalidomide is present in the
semen of patients receiving the drug, males receiving thalidomide must always
use a latex condom during any sexual contact with women of childbearing
potential. The risk to
the fetus from the semen of male patients taking thalidomide is unknown.
Drowsiness and
Somnolence:
Thalidomide
frequently causes drowsiness and somnolence. Patients should be instructed to
avoid situations where drowsiness may be a problem and not to take other
medications that may cause drowsiness without adequate medical advice. Patients
should be advised as to the possible
impairment of mental and/or physical abilities required for the performance of
hazardous tasks, such as driving a car or operating other complex or dangerous
machinery.
Peripheral Neuropathy:
Thalidomide is known
to cause nerve damage that may be permanent. Peripheral neuropathy is a common,
potentially severe, side effect of treatment with thalidomide that may be
irreversible. Peripheral neuropathy generally occurs following chronic use over
a period of months; however, reports following
relatively short-term use also exist. The correlation with cumulative dose is
unclear. Symptoms may occur some time after thalidomide treatment has been
stopped and may resolve slowly or not at all. Few reports of neuropathy have
arisen in the treatment of ENL despite long-term thalidomide treatment.
However, the inability clinically to differentiate thalidomide neuropathy from
the neuropathy often seen in Hansen’s disease makes it difficult to determine
accurately the incidence of thalidomide-related neuropathy in ENL patients
treated with thalidomide.
Patients
should be examined at monthly intervals for the first 3 months of thalidomide
therapy to enable the clinician to detect early signs of neuropathy, which
include numbness, tingling or pain in the hands and feet. Patients should be
evaluated periodically thereafter during treatment. Patients should be
regularly counseled, questioned, and evaluated for signs or symptoms of
peripheral neuropathy. Consideration should be given to electrophysiological
testing, consisting of measurement of sensory nerve action potential (SNAP)
amplitudes at baseline and thereafter every 6 months in an effort to detect
asymptomatic neuropathy. If symptoms of drug-induced neuropathy develop,
thalidomide should be discontinued immediately to limit further damage, if
clinically appropriate. Usually, treatment with thalidomide should only be
reinitiated if the neuropathy returns to baseline status. Medications known to
be associated with neuropathy should be used with caution in patients receiving
thalidomide.
Thrombotic Events:
Thrombotic
events have been reported in patients treated with THALOMID®
(thalidomide). Patients with neoplastic
and various inflammatory conditions being treated with THALOMID®
(thalidomide) may have an increased incidence of pulmonary embolism, deep vein
thrombophlebitis, thrombophlebitis, or thrombosis. It is not known if concomitant therapy with other medications
including anticancer agents, are a contributing factor.
Dizziness and
Orthostatic Hypotension:
Patients should also
be advised that thalidomide may cause dizziness and orthostatic hypotension and
that, therefore, they should sit upright for a few minutes prior to standing up
from a recumbent position.
Neutropenia:
Decreased white blood
cell counts, including neutropenia, have been reported in association with the
clinical use of thalidomide. Treatment should not be initiated with an absolute
neutrophil count (ANC) of <750/mm3. White blood cell count and
differential should be monitored on an ongoing basis, especially in patients
who may be more prone to neutropenia, such as patients who are
HIV-seropositive. If ANC decreases to below 750/mm3 while on
treatment, the patient’s medication regimen should be re-evaluated and, if the
neutropenia persists, consideration should be given to withholding thalidomide
if clinically appropriate.
Increased HIV Viral Load:
In a randomized,
placebo controlled trial of thalidomide in an HIV-seropositive patient
population, plasma HIV RNA levels were found to increase (median change = 0.42
log10 copies HIV RNA/mL, p = 0.04 compared to placebo). 7
A similar trend was observed in a second, unpublished study conducted in
patients who were HIV- seropositive13 The clinical significance of
this increase is unknown. Both studies were conducted prior to availability of
highly active antiretroviral therapy. Until the clinical significance of this
finding is further understood, in HIV-seropositive patients, viral load should
be measured after the first and third months of treatment and every 3 months
thereafter.
PRECAUTIONS
General:
The only type of thalidomide exposure known to result in drug
associated birth defects are as a result of direct oral ingestion of
thalidomide. Currently no specific data
are available regarding the cutaneous absorption or inhalation of thalidomide
in women of child-bearing potential and whether these exposures may result in
any birth defects. Patients should be
instructed to not extensively handle or open THALOMID® (thalidomide)
Capsules and to maintain storage of capsules in blister packs until
ingestion. If there is contact with
non-intact thalidomide capsules or the powder contents, the exposed area should
be washed with soap and water.
Thalidomide has been shown to be present in the serum and semen of
patients receiving thalidomide. If
healthcare providers or other care givers are exposed to body fluids from
patients receiving THALOMID® (thalidomide), appropriate precautions
should be utilized, such as wearing gloves to prevent the potential cutaneous
exposure to THALOMID® (thalidomide) or the exposed area should be
washed with soap and water.
Hypersensitivity:
Hypersensitivity to
THALOMID® (thalidomide) has been reported. Signs and symptoms have
included the occurrence of erythematous macular rash, possibly associated with
fever, tachycardia, and hypotension, and if severe, may necessitate
interruption of therapy. If the reaction recurs when dosing is resumed,
THALOMID® (thalidomide) should be discontinued.
Bradycardia:
Bradycardia
in association with thalidomide use has been reported. Cases
of bradycardia have been reported, some required medical interventions. The clinical significance and underlying etiology of
the bradycardia noted in some thalidomide-treated patients are presently
unknown.
Stevens-Johnson Syndrome
and Toxic Epidermal Necrolysis:
Serious dermatologic
reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis,
which may be fatal, have been reported.
THALOMID® (thalidomide) should be discontinued if a skin rash
occurs and only resumed following appropriate clinical evaluation. If the rash
is exfoliative, purpuric, or bullous or if Stevens-Johnson syndrome or toxic
epidermal necrolysis is suspected, use of THALOMID® (thalidomide)
should not be resumed.
Seizures:
Although not reported
from pre-marketing controlled clinical trials, seizures, including grand mal
convulsions, have been reported during post-approval use of THALOMIDÒ
(thalidomide) in clinical practice. Because these events are reported
voluntarily from a population of unknown size, estimates of frequency cannot be
made. Most patients had disorders that may have predisposed them to seizure
activity, and it is not currently known whether thalidomide has any
epileptogenic influence. During therapy with thalidomide, patients with a
history of seizures or with other risk factors for the development of seizures
should be monitored closely for clinical changes that could precipitate acute
seizure activity.
Information for Patients
(See BOXED WARNINGS.)
Patients should be
instructed about the potential teratogenicity of thalidomide and the
precautions that must be taken to preclude fetal exposure as per the S.T.E.P.S. ® program and
boxed warnings in this package insert. Patients should be instructed to take
thalidomide only as prescribed in compliance with all of the provisions of the S.T.E.P.S. ® Restricted
Distribution Program.
Patients
should be instructed to not extensively handle or open THALOMID® (thalidomide)
Capsules and to maintain storage of capsules in blister packs until ingestion.
Patients
should be instructed not to share medication with anyone else.
Patients
should be instructed that thalidomide frequently causes drowsiness and
somnolence. Patients should be instructed to avoid situations where drowsiness
may be a problem and not to take other medications that may cause drowsiness
without adequate medical advice. Patients should be advised as to the possible
impairment of mental and/or physical abilities required for the performance of
hazardous tasks, such as driving a car or operating other complex machinery.
Patients should be instructed that thalidomide may potentiate the somnolence
caused by alcohol.
Patients
should be instructed that thalidomide can cause peripheral neuropathies that
may be initially signaled by numbness, tingling, or pain or a burning sensation
in the feet or hands. Patients should be instructed to report such occurrences
to their prescriber immediately.
Patients
should also be instructed that thalidomide may cause dizziness and orthostatic
hypotension and that, therefore, they should sit upright for a few minutes
prior to standing up from a recumbent position.
Patients
should be instructed that they are not permitted to donate blood while taking
thalidomide. In addition, male patients should be instructed that they are not
permitted to donate sperm while taking thalidomide.
Laboratory
Tests
Pregnancy
Testing:
(See BOXED WARNINGS.) Women of childbearing potential should
have a pregnancy test performed (sensitivity of
at least 50 mIU/mL). The test should be performed within the 24 hours prior to
beginning thalidomide therapy and then weekly during the first 4 weeks of use, then at 4 week intervals in women with
regular menstrual cycles or every 2 weeks in women with irregular menstrual
cycles. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any
abnormality in menstrual bleeding.
Neutropenia: (See WARNINGS.)
Increased HIV Viral Load:
(See WARNINGS.)
Drug
Interactions
Thalidomide
has been reported to enhance the sedative activity of barbiturates, alcohol,
chlorpromazine, and reserpine.
Peripheral
Neuropathy: Medications known to be associated with
peripheral neuropathy should be used with caution in patients receiving
thalidomide.
Oral
Contraceptives: In 10 healthy women, the pharmacokinetic
profiles of norethindrone and ethinyl estradiol following administration of a
single dose containing 1.0 mg of norethindrone acetate and 75 µg of ethinyl
estradiol were studied. The results were similar with and without
coadministration of thalidomide 200 mg/day to steady-state levels.
Important Non-Thalidomide Drug Interactions
Drugs
That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease
inhibitors, griseofulvin, modafinil, pencillins,
rifampin, rifabutin, phenytoin, or carbamazepine, or certain herbal
supplements such as St. John’s Wort with hormonal contraceptive agents,
may reduce the effectiveness of the contraception and up to one month after
discontinuation of these concomitant therapies. Therefore, women requiring
treatment with one or more of these drugs must use two OTHER effective or
highly effective methods of contraception or abstain from heterosexual sexual
contact while taking thalidomide.
Carcinogenesis,
Mutagenesis, Impairment of Fertility
Long-term
carcinogenicity tests have not been conducted using thalidomide. Thalidomide
gave no evidence of mutagenic effects when assayed in in vitro bacterial (Salmonella
typhimurium and Escherichia coli;
Ames mutagenicity test), in vitro
mammalian (AS52 Chinese hamster ovary cells; AS52/XPRT mammalian cell forward
gene mutation assay) and in vivo
mammalian (CD-1 mice; in vivo
micronucleus test) test systems.
Animal
studies to characterize the effects of thalidomide on fertility have not been
conducted.
Pregnancy
Pregnancy Category X (See BOXED WARNING
and CONTRAINDICATIONS.)
Because of the known
human teratogenicity of thalidomide, thalidomide is contraindicated in women
who are or may become pregnant and who are not using the two required types of
birth control or who are not continually abstaining from heterosexual sexual
contact. If thalidomide is taken during pregnancy, it can cause severe birth
defects or death to an unborn baby. Thalidomide should never be used by women
who are pregnant or who could become pregnant while taking the drug. Even a
single dose [1 capsule (50 mg, 100 mg, or a 200 mg)] taken by a pregnant woman
can cause birth defects. If pregnancy does occur during treatment, the drug
should be immediately discontinued. Under these conditions, the patient should
be referred to an obstetrician/gynecologist experienced in reproductive
toxicity for further evaluation and counseling. Any suspected fetal exposure to
THALOMID® (thalidomide) must be reported to the FDA via the MedWatch program at
1-800-FDA-1088 and also to Celgene Corporation.
Because
thalidomide is present in the semen of patients receiving the drug, males
receiving thalidomide must always use a latex condom during any sexual contact
with women of childbearing potential. The risk to the
fetus from the semen of male patients taking thalidomide is unknown.
Animal
studies to characterize the effects of thalidomide on late-stage pregnancy have not been conducted.
Use in Nursing Mothers
It is not known
whether thalidomide is excreted in human milk. Because many drugs are excreted
in human milk and because of the potential for serious adverse reactions in
nursing infants from thalidomide, 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.
Pediatric
Use
Safety and effectiveness in pediatric patients
below the age of 12 years have not been established.
Geriatric Use
No systematic studies
in geriatric patients have been conducted. Thalidomide has been used in
clinical trials in patients up to 90 years of age. Adverse events in patients over
the age of 65 years did not appear to differ in kind from those reported for
younger individuals.
ADVERSE REACTIONS
The most serious
toxicity associated with thalidomide is its documented human teratogenicity.
(See BOXED WARNINGS and CONTRAINDICATIONS.) The risk of severe
birth defects, primarily phocomelia or death to the fetus, is extremely high
during the critical period of pregnancy. The critical period is estimated,
depending on the source of information, to range from 35 to 50 days after the
last menstrual period. The risk of other potentially severe birth defects
outside this critical period is unknown, but may be significant. Based on
present knowledge, thalidomide must not be used at any time during pregnancy.
Because
thalidomide is present in the semen of patients receiving the drug, males
receiving thalidomide must always use a latex condom during any sexual contact
with women of childbearing potential.
Thalidomide
is associated with drowsiness/somnolence, peripheral neuropathy,
dizziness/orthostatic hypotension, neutropenia, and HIV viral load increase.
(See WARNINGS.)
Hypersensitivity
to THALOMID® (thalidomide) and bradycardia in patients treated with
thalidomide have been reported. (See PRECAUTIONS.)
Somnolence,
dizziness, and rash are the most commonly observed adverse events associated
with the use of thalidomide. Thalidomide has been studied in controlled and
uncontrolled clinical trials in patients with ENL and in people who are
HIV-seropositive. In addition, thalidomide has been administered
investigationally for more than 20 years in numerous indications. Adverse event
profiles from these uses are summarized in the sections that follow.
Other Adverse Events
Due to the nature of
the longitudinal data that form the basis of this product’s safety evaluation,
no determination has been made of the causal relationship between the reported
adverse events listed below and thalidomide. These lists are of various adverse
events noted by investigators in patients to whom they had administered
thalidomide under various conditions. The use of
thalidomide may not limit disease progression and/or death.
Incidence in Controlled Clinical Trials
Table
4 lists treatment-emergent signs and symptoms that occurred in THALOMID®
(thalidomide)-treated patients in controlled clinical trials in ENL. Doses
ranged from 50 to 300 mg/day. All adverse events were mild to moderate in
severity, and none resulted in discontinuation. Table 4 also lists
treatment-emergent adverse events that occurred in at least three of the
THALOMID® (thalidomide)-treated HIV-seropositive patients who
participated in an 8-week, placebo-controlled clinical trial. Events that were
more frequent in the placebo-treated group are not included. (See WARNINGS, PRECAUTIONS, and Drug Interactions.)
|
Table 4 Summary of
Adverse Events (AEs) Reported in
Celgene-sponsored Controlled Clinical Trials |
||||
|
|
All AEs
Reported |
AEs Reported in ³3 HIV-seropositive Patients
|
||
|
Body System/Adverse Event |
in ENL Patients |
Thalidomide |
Placebo |
|
|
|
50 to 300
mg/day (N=24) |
100 mg/day (N=36) |
200 mg/day (N=32) |
(N=35) |
Body as a Whole
|
16 (66.7%) |
18 (50.0%) |
19 (59.4%) |
13 (37.1%) |
|
Abdominal pain |
1 (4.2%) |
1 (2.8%) |
1 (3.1%) |
4 (11.4%) |
|
Accidental injury |
1 (4.2%) |
2 (5.6%) |
0 |
1 (2.9%) |
|
Asthenia |
2 (8.3%) |
2 (5.6%) |
7 (21.9%) |
1 (2.9%) |
|
Back pain |
1 (4.2%) |
2 (5.6%) |
0 |
0 |
|
Chills |
1 (4.2%) |
0 |
3 (9.4%) |
4 (11.4%) |
|
Facial edema |
1 (4.2%) |
0 |
0 |
0 |
|
Fever |
0 |
7 (19.4%) |
7 (21.9%) |
6 (17.1%) |
|
Headache |
3 (12.5%) |
6 (16.7%) |
6 (18.7%) |
4 (11.4%) |
|
Infection |
0 |
3 (8.3%) |
2 (6.3%) |
1 (2.9%) |
|
Malaise |
2 (8.3%) |
0 |
0 |
0 |
|
Neck pain |
1 (4.2%) |
0 |
0 |
0 |
|
Neck rigidity |
1 (4.2%) |
0 |
0 |
0 |
|
Pain |
2 (8.3%) |
0 |
1 (3.1%) |
2 (5.7%) |
|
Digestive System |
5 (20.8%) |
16 (44.4%) |
16 (50.0%) |
15 (42.9%) |
|
Anorexia |
0 |
1 (2.8%) |
3 (9.4%) |
2 (5.7%) |
|
Constipation |
1 (4.2%) |
1 (2.8%) |
3 (9.4%) |
0 |
|
Diarrhea |
1 (4.2%) |
4 (11.1%) |
6 (18.7%) |
6 (17.1%) |
|
Dry mouth |
0 |
3 (8.3%) |
3 (9.4%) |
2 (5.7%) |
|
Flatulence |
0 |
3 (8.3%) |
0 |
2 (5.7%) |
|
Liver
function tests multiple abnormalities |
0 |
0 |
3 (9.4%) |
0 |
|
Nausea |
1 (4.2%) |
0 |
4 (12.5%) |
1 (2.9%) |
|
Oral moniliasis |
1 (4.2%) |
4 (11.1%) |
2 (6.3%) |
0 |
|
Tooth pain |
1 (4.2%) |
0 |
0 |
0 |
|
Hemic and Lymphatic |
0 |
8 (22.2%) |
13 (40.6%) |
10 (28.6%) |
|
Anemia |
0 |
2 (5.6%) |
4 (12.5%) |
3 (8.6%) |
|
Leukopenia |
0 |
6 (16.7%) |
8 (25.0%) |
3 (8.6%) |
|
Lymphadenopathy |
0 |
2 (5.6%) |
4 (12.5%) |
3 (8.6%) |
|
Metabolic and Endocrine
Disorders |
1 (4.2%) |
8 (22.2%) |
12 (37.5%) |
8 (22.9%) |
|
Edema peripheral |
1 (4.2%) |
3 (8.3%) |
1 (3.1%) |
0 |
|
Hyperlipemia |
0 |
2 (5.6%) |
3 (9.4%) |
1 (2.9%) |
|
SGOT increased |
0 |
1 (2.8%) |
4 (12.5%) |
2 (5.7%) |
|
Nervous System |
13 (54.2%) |
19 (52.8%) |
18 (56.3%) |
12 (34.3%) |
|
Agitation |
0 |
0 |
3 (9.4%) |
0 |
|
Dizziness |
1 (4.2%) |
7 (19.4%) |
6 (18.7%) |
0 |
|
Insomnia |
0 |
0 |
3 (9.4%) |
2 (5.7%) |
|
Nervousness |
0 |
1 (2.8%) |
3 (9.4%) |
0 |
|
Neuropathy |
0 |
3 (8.3%) |
0 |
0 |
|
Paresthesia |
0 |
2 (5.6%) |
5 (15.6%) |
4 (11.4%) |
|
Somnolence |
9 (37.5%) |
13 (36.1%) |
12 (37.5%) |
4 (11.4%) |
|
Tremor |
1 (4.2%) |
0 |
0 |
0 |
|
Vertigo |
2 (8.3%) |
0 |
0 |
0 |
|
Respiratory System |
3 (12.5%) |
9 (25.0%) |
6 (18.7%) |
9 (25.7%) |
|
Pharyngitis |
1 (4.2%) |
3 (8.3%) |
2 (6.3%) |
2 (5.7%) |
|
Rhinitis |
1 (4.2%) |
0 |
0 |
4 (11.4%) |
|
Sinusitis |
1 (4.2%) |
3 (8.3%) |
1 (3.1%) |
2 (5.7%) |
|
Skin and Appendages |
10 (41.7%) |
17 (47.2%) |
18 (56.3%) |
19 (54.3%) |
|
Acne |
0 |
4 (11.1%) |
1 (3.1%) |
0 |
|
Dermatitis fungal |
1 (4.2%) |
2 (5.6%) |
3 (9.4%) |
0 |
|
Nail disorder |
1 (4.2%) |
0 |
1 (3.1%) |
0 |
|
Pruritus |
2 (8.3%) |
1 (2.8%) |
2 (6.3%) |
2 (5.7%) |
|
Rash |
5 (20.8%) |
9 (25.0%) |
8 (25.0%) |
11 (31.4%) |
|
Rash maculo‑papular |
1 (4.2%) |
6 (16.7%) |
6 (18.7%) |
2 (5.7%) |
|
Sweating |
0 |
0 |
4 (12.5%) |
4 (11.4%) |
|
Urogenital System |
2 (8.3%) |
6 (16.7%) |
2 (6.3%) |
4 (11.4%) |
|
Albuminuria |
0 |
3 (8.3%) |
1 (3.1%) |
2 (5.7%) |
|
Hematuria |
0 |
4 (11.1%) |
0 |
1 (2.9%) |
|
Impotence |
2 (8.3%) |
1 (2.8%) |
0 |
0 |