A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Depacon Warnings, Precautions, Pregnancy, Nursing, Abuse - Valproate
Depacon Warnings, Precautions, Pregnancy, Nursing, Abuse - Valproate
WARNINGS
Hepatic failure resulting
in fatalities has occurred in patients receiving valproic acid.
These incidents usually have occurred during the first six months
of treatment. Serious or fatal
hepatotoxicity may be preceded by non-specific symptoms such
as malaise, weakness,
lethargy, facial edema,
anorexia, and vomiting.
In patients with epilepsy,
a loss of seizure
control may also occur.
Patients should be monitored closely for appearance
of these symptoms. Liver function
tests should be performed prior to therapy
and at frequent intervals thereafter, especially during the first
six months of valproate therapy. However, physicians should not
rely totally on serum
biochemistry since
these tests may not be abnormal
in all instances, but should also consider the results of careful
interim medical history
and physical examination.
Caution should be observed when administering valproate products
to patients with a prior history
of hepatic disease.
Patients on multiple
anticonvulsants, children, those with congenital
metabolic disorders, those with severe seizure
disorders accompanied by mental
retardation, and those with organic
brain disease
may be at particular risk. Experience has indicated that children
under the age of two years
are at a considerably increased risk
of developing fatal hepatotoxicity,
especially those with the aforementioned conditions. When DEPACON
is used in this patient
group, it should be used with extreme caution and as a sole
agent. The benefits of therapy
should be weighed against the risks. Use of DEPACON has not been
studied in children below the age
of 2 years. Above this age
group, experience
with valproate products in epilepsy
has indicated that the incidence
of fatal hepatotoxicity
decreases considerably in progressively older patient
groups.
The drug should be discontinued
immediately in the presence of significant
hepatic dysfunction,
suspected or apparent. In
some cases, hepatic
dysfunction has
progressed in spite of discontinuation of drug.
The frequency of
adverse effects (particularly elevated liver
enzymes and thrombocytopenia
[see PRECAUTIONS
]) may be dose-related.
In a clinical
trial of DEPAKOTE as monotherapy
in patients with epilepsy,
34/126 patients (27%) receiving approximately 50 mg/kg/day on average,
had at least one value
of platelets £75 x 109
/L. Approximately half of these patients had treatment
discontinued, with return of platelet
counts to normal. In the
remaining patients, platelet
counts normalized with continued treatment. In
this study, the probability
of thrombocytopenia
appeared to increase significantly at total valproate concentrations
of >110 g/mL (females) or >135 g/mL (males). The therapeutic
benefit which may accompany
the higher doses should therefore be weighed against the possibility
of a greater incidence
of adverse effects.
A study was conducted to evaluate the effect
of IV valproate in the prevention
of post-traumatic
seizures in patients with acute
head injuries. Patients
were randomly assigned to receive either IV
valproate given for one week (followed by oral
valproate products for either one or six months per
random treatment assignment)
or IV phenytoin
given for one week (followed by placebo). In
this study, the incidence
of death was found to
be higher in the two groups assigned to valproate treatment
compared to the rate in
those assigned to the IV
phenytoin treatment
group (13% vs 8.5%, respectively).
Many of these patients were critically ill
with multiple and/or
severe injuries, and evaluation
of the causes of death
did not suggest any specific
drug-related causation. Further, in the absence
of a concurrent placebo
control during the initial
week of intravenous
therapy, it is impossible
to determine if the mortality
rate in the patients treated
with valproate was greater or less than that expected in a similar
group not treated with
valproate, or whether the rate
seen in the IV phenytoin
treated patients was lower than would be expected. Nonetheless,
until further information is available, it seems prudent not to
use DEPACON in patients with acute
head trauma
for the prophylaxis
of post-traumatic
seizures.
Usage In Pregnancy
ACCORDING TO PUBLISHED AND
UNPUBLISHED REPORTS, VALPROIC ACID
MAY PRODUCE TERATOGENIC EFFECTS IN THE OFFSPRING OF HUMAN FEMALES
RECEIVING THE DRUG DURING PREGNANCY.
THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE WHICH INDICATE
THAT THE USE OF ANTIEPILEPSY
DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF BIRTH
DEFECTS IN THE OFFSPRING. ALTHOUGH DATA ARE MORE EXTENSIVE WITH
RESPECT TO TRIMETHADIONE,
PARA METHADIONE, PHENYTOIN, AND PHENOBARBITAL, REPORTS INDICATE
A POSSIBLE SIMILAR ASSOCIATION WITH THE USE OF OTHER ANTIEPILEPSY
DRUGS. THEREFORE, ANTIEPILEPSY DRUGS SHOULD BE ADMINISTERED TO
WOMEN OF CHILDBEARING POTENTIAL ONLY
IF THEY ARE CLEARLY SHOWN TO
BE ESSENTIAL IN THE MANAGEMENT OF THEIR SEIZURES.
THE INCIDENCE OF NEURAL TUBE DEFECTS IN THE FETUS MAY BE INCREASED
IN MOTHERS RECEIVING VALPROATE DURING THE FIRST TRIMESTER OF PREGNANCY.
THE CENTERS FOR DISEASE CONTROL (CDC) HAS ESTIMATED THE RISK OF
VALPROIC ACID EXPOSED WOMEN
HAVING CHILDREN WITH SPINA BIFIDA TO
BE APPROXIMATELY 1 TO 2%.
OTHER CONGENITAL ANOMALIES (E. G., CRANIOFACIAL DEFECTS, CARDIOVASCULAR
MALFORMATIONS AND ANOMALIES INVOLVING VARIOUS BODY SYSTEMS), COMPATIBLE
AND INCOMPATIBLE WITH LIFE, HAVE BEEN
REPORTED. SUFFICIENT DATA TO
DETERMINE THE INCIDENCE OF THESE CONGENITAL ANOMALIES IS NOT AVAILABLE.
THE HIGHER INCIDENCE OF CONGENITAL ANOMALIES IN ANTIEPILEPSY DRUG-TREATED
WOMEN WITH SEIZURE DISORDERS CANNOT BE REGARDED AS
A CAUSE AND EFFECT RELATIONSHIP. THERE ARE INTRINSIC METHODOLOGIC
PROBLEMS IN OBTAINING ADEQUATE DATA ON
DRUG TERATOGENICITY IN HUMANS; GENETIC FACTORS OR
THE EPILEPTIC CONDITION ITSELF, MAY BE MORE IMPORTANT T.A.
DRUG THERAPY IN CONTRIBUTING TO
CONGENITAL ANOMALIES.
PATIENTS TAKING VALPROATE MAY DEVELOP CLOTTING ABNORMALITIES. A
PATIENT WHO HAD LOW FIBRINOGEN
WHEN TAKING MULTIPLE ANTICONVULSANTS INCLUDING VALPROATE GAVE BIRTH
TO AN INFANT WITH AFIBRINOGENEMIA
WHO SUBSEQUENTLY DIED OF
HEMORRHAGE. IF VALPROATE IS SEDIN PREGNANCY, THE CLOTTING PARAMETERS
SHOULD BE MONITORED CAREFULLY.
HEPATIC FAILURE, RESULTING IN THE DEATH OF A NEWBORN AND OF AN
INFANT, HAVE BEEN REPORTED
FOLLOWING THE USE OF VALPROATE DURING PREGNANCY.
Animal studies have demonstrated valproate-induced teratogenicity.
Increased frequencies of malformations, as well as intrauterine
growth retardation
and death, have been observed
in mice, rats, rabbits, and monkeys following prenatal
exposure to valproate.
Malformations of the skeletal
system are the most common
structural abnormalities
produced in experimental animals, but neural
t.b. closure
defects have been seen in mice exposed to maternal
plasma valproate concentrations
exceeding 230 µg/mL (2.3 times the upper limit
of the human therapeutic
range) during susceptible
periods of embryonic
development. Administration of an oral
dose of 200 mg/kg/day or
greater (50% of the maximum
human daily dose
or greater on a mg/m2 basis) to pregnant
rats during organogenesis
produced malformations (skeletal, cardiac,
and urogenital) and growth
retardation in the
offspring. These doses resulted in peak maternal
plasma valproate levels
of approximately 340 µg/mL or greater (3.4 times the upper
limit of the human
therapeutic range
or greater). Behavioral deficits have been reported in the offspring
of rats given a dose of
200 mg/kg/day throughout most of pregnancy. An
oral dose
of 350 mg/kg/day (2 times the maximum
human daily dose
on a mg/m2 basis) produced skeletal
and visceral malformations
in rabbits exposed during organogenesis. Skeletal malformations,
growth retardation, and
death were observed in
rhesus monkeys following administration
of an oral dose
of 200 mg/kg/day (equal to the maximum
human daily dose
on a mg/m2 basis) during organogenesis. This dose
resulted in peak maternal
plasma valproate levels
of approximately 280 µg/mL (2.8 times the upper limit
of the human therapeutic
range).
The prescribing physician
will wish
to weigh the benefits of therapy
against the risks in treating or counseling
women of childbearing
potential. 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 the fetus.
Antiepilepsy drugs should not be discontinued abruptly in patients
in whom the drug is administered
to prevent major seizures because of the strong possibility of precipitating
status epilepticus with
attendant hypoxia
and threat to life. In individual
cases where the severity and frequency
of the seizure disorder
are such that the removal
of medication does
not pose a serious threat to the patient,
discontinuation of the drug
may be considered prior to and during pregnancy,
although it cannot be said with any confidence that even minor
seizures do not pose some hazard to the developing embryo
or fetus.
Tests to detect neural
t.b. and other defects
using current accepted
procedures should be considered a proof
of routine prenatal
care in childbearing
women receiving valproate.
PRECAUTIONS
Hepatic Dysfunction
See BOXED WARNING,
CONTRAINDICATIONS and
WARNINGS
.
General
Because of reports of thrombocytopenia
(see WARNINGS
), inhibition
of the secondary phase
of platelet aggregation,
and abnormal coagulation
parameters, (e. g., low fibrinogen), platelet
counts and coagulation tests are recommended before initiating therapy
and at periodic intervals.
It is recommended that patients receiving DEPACON be monitored for
platelet count
and coagulation parameters prior to planned surgery. In
a clinical trial of
DEPAKOTE (divalproex sodium) as monotherapy
in patients with epilepsy,
34/126 patients (27%) receiving approximately 50 mg/kg/day on average,
had at least one value
of platelets ≤ 75 x 109 /L. Approximately half of
these patients had treatment
discontinued, with return of platelet
counts to nor-9 mal. In the
remaining patients, platelet
counts normalized with continued treatment. In
this study, the probability
of thrombocytopenia
appeared to increase significantly at total valproate concentrations
of ³ 110 µg/mL (females) or ³ 135 µg/mL
(males). Evidence of hemorrhage,
bruising, or a disorder
of hemostasis/coagulation is an indication
for reduction of the
dosage or withdrawal
of therapy.
Hyperammonemia with or without lethargy
or coma has been reported
and may be present in
the absence of abnormal
liver function
tests. Asymptomatic elevations of ammonia
are more common and when present
require more frequent monitoring. If clinically significant
symptoms occur, DEPACON therapy
should be modified or discontinued.
Since DEPACON may interact with concurrently administered drugs
which are capable of enzyme
induction, periodic
plasma concentration
determinations of valproate and concomitant
drugs are recommended during the early course of therapy. (See
DRUG INTERACTIONS.)
Valproate is partially eliminated in the urine
as a keto-metabolite which may lead
to a false interpretation
of the urine ketone
test.
There have been reports of altered thyroid
function tests associated
with valproate. The clinical
significance of these is unknown.
Information for Patients
Since DEPACON may produce CNS
depression, especially
when combined with another CNS
depressant (e. g.,
alcohol), patients should be advised not to engage in hazardous
activities, such as driving
an automobile or operating dangerous machinery, until it is known
that they do not become drowsy from the drug.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Valproic acid was administered
orally to Sprague Dawley rats and ICR (HA/ICR) mice at doses of
80 and 170 mg/kg/day (approximately 10 to 50% of the maximum
human daily dose
on a mg/m2 basis) for two years. A variety
of neoplasms were observed in both species. The chief findings were
a statistically significant
increase in the incidence
of subcutaneous
fibrosarcomas in high dose
male rats receiving valproic
acid and a statistically
significant dose-related
trend for benign
pulmonary adenomas
in male mice receiving
valproic acid. The significance of these findings for humans is
unknown.
Mutagenesis
Valproate was not mutagenic in an in vitro bacterial assay
(Ames test), did not produce dominant
lethal effects in mice,
and did not increase chromosome
aberration frequency
in an in vivo cytogenetic study in rats. Increased frequencies
of sister chromatid
exchange (SCE) have
been reported in a study of epileptic
children taking valproate, but this association
was not observed in another study conducted in adults. There is
some evidence that
increased SCE frequencies
may be associated with epilepsy. The biological
significance of an increase in SCE
frequency is not known.
Fertility
Chronic toxicity studies
in juvenile and adult
rats and dogs demonstrated reduced spermatogenesis
and testicular atrophy
at oral doses of 400 mg/kg/day
or greater in rats (approximately equivalent
to or greater than the maximum
human daily dose
on a mg/m2 basis) and 150 mg/kg/day or greater in dogs
(approximately 1.4 times the maximum
human daily dose
or greater on a mg/m2 basis). Segment I fertility
studies in rats have shown oral
doses up to 350 mg/kg/day (approximately equal to the maximum
human daily dose
on a mg/m2 basis) for 60 days to have no
effect on fertility.
THE EFFECT OF VALPROATE ON
TESTICULAR DEVELOPMENT AND ON
SPERM PRODUCTION AND FERTILITY IN HUMANS IS UNKNOWN.
Pregnancy
Pregnancy Category D: See WARNINGS
.
Nursing Mothers
Valproate is excreted in breast
milk. Concentrations in breast
milk have been reported
to be 1-10% of serum concentrations.
It is not known what effect
this would have on a nursing
infant. Consideration should be given to discontinuing nursing
when valproate is administered to a nursing
woman.
Pediatric
Experience with oral valproate
has indicated that children under the age
of two years are at a considerably increased risk
of developing fatal hepatotoxicity,
especially those with the aforementioned conditions (see WARNINGS
).
The safety of DEPACON has not been studied in individuals below
the age of 2 years. If a
decision is made to use DEPACON in this age
group, it should be used with extreme caution and as a sole
agent. The benefits of therapy
should be weighed against the risks. Above the age
of 2 years, experience
in epilepsy has indicated
that the incidence
of fatal hepatotoxicity
decreases considerably in progressively older patient
groups.
Younger children, especially those receiving enzyme-inducing drugs,
will require larger maintenance
doses to attain targeted total and unbound valproic acid
concentrations.
The variability
in free fraction limits
the clinical usefulness
of monitoring total serum
valproic acid concentrations.
Interpretation of valproic acid
concentrations in children should include consideration of factors
that affect hepatic
metabolism and protein
binding.
No unique safety concerns were identified in the 24 patients age
2 to 17 years who received DEPACON in clinical
trials.
The basic toxicology
and pathologic manifestions
of valproate sodium in
neonatal (4-day old)
and juvenile (14-day
old) rats are similar to those seen in young adult
rats. However, additional findings, including renal
alterations in juvenile
rats and renal alterations
and retinal dysplasia
in neonatal rats, have
been reported. These findings occurred at 240 mg/kg/day, a dosage
approximately equivalent
to the human maximum
recommended daily dose
on a mg/m2 basis. They were not seen at 90 mg/kg, or
40% of the maximum human
daily dose on a mg/m2
basis.
Geriatric Use
No unique safety concerns were identified in the 19 patients >
65 years of age receiving
DEPACON in clinical
trials.
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