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. 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
divalproex sodium 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 divalproex sodium
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. Above this age group,
experience 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 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
´ 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 ³110 mcg/ml
(females) or ³135 mcg/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.
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 ANTIEPILEPTIC DRUGS DURING
PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF BIRTH DEFECTS
IN THE OFFSPRING. ALTHOUGH DATA ARE MORE EXTENSIVE WITH
RESPECT TO TRIMETHADIONE, PARAMETHADIONE, PHENYTOIN, AND
PHENOBARBITAL, REPORTS INDICATE A POSSIBLE SIMILAR ASSOCIATION
WITH THE USE OF OTHER ANTIEPILEPTIC DRUGS.
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 ANTIEPILEPTIC
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 THAN 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 USED IN 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 also have demonstrated valproate-induced
teratogenicity. Increased frequencies of malformation,
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
tube closure defects have been seen in mice exposed to
maternal plasma valproate concentrations exceeding 230
mcg/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 an
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 mcg/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 the pregnancy. An
oral dose of 350 mg/kg/day (approximately 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 mcg/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.
Antiepileptic 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 tube and other defects using current
accepted procedures should be considered a party 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 divalproex sodium
be monitored for platelet count and coagulation parameters
prior to planned surgery. In a clinical trial of 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
´ 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 ³110 mcg/ml
(females) or ³135 mcg/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,
divalproex sodium therapy should be modified or discontinued.
Since divalproex sodium 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.
Suicidal ideation may be a manifestation of certain psychiatric
disorders, and may persist until significant remission
of symptoms occurs. Close supervision of high risk patients
should accompany initial drug therapy.
Information for Patients
Since divalproex sodium products 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.
Migraine Patients: Since divalproex
sodium has been associated with certain types of birth
defects, female patients of child-bearing age considering
the use of divalproex sodium for the prevention of migraine
should be advised to read the PATIENT PACKAGE INSERT.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Valproic acid
was administered to Sprague Dawley rats and ICR (HA/ICR)
mice at doses of 0, 80, and 170 mg/kg/day (approximately
10-50% 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 cytogenic 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 increase in SCE frequency is not known.
Impairment of Fertility: Chronic
toxicity studies in juvenile and adult rats and dogs demonstrated
reduced spermatogenesis and testicular atrophy at 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 doses up to 350 mg/kg/day (approximately equal to
the maximum human daily dose on a mg/m2 dose) 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 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. Caution should be exercised when divalproex sodium
is administered to a nursing woman.
Pediatric Use
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 (see BOXED WARNING). When divalproex sodium
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. 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.
The safety and effectiveness of divalproex sodium for
the treatment of acute mania has not been studied in individuals
below the age of 18 years.
The safety and effectiveness of divalproex sodium for
the prophylaxis of migraines has not been studied in individuals
below the age of 16 years.
The basic toxicology and pathologic manifestations 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 patients above the age of 65 years were enrolled in
double-blind prospective clinical trials of mania associated
with bipolar illness. In a case review study of 583 patients,
72 patients (12%) were greater than 65 years of age. A
higher percentage of patients above 65 years of age reported
accidental injury, infection, pain, somnolence, and tremor.
Discontinuation of valproate was occasionally associated
with the latter two events. It is not clear whether these
events indicate additional risk or whether they result
from preexisting medical illness and concomitant medication
use among these patients.
In a double-blind, multicenter trial of valproate, in
elderly patients with dementia, doses were increased by
125 mg/day to a target dose of 20 mg/kg/day. Patients
experienced a significant increase in somnolence and discontinuations
for somnolence compared to placebo. In some patients these
events were also associated with reduced nutritional intake
and weight loss. There was a trend for the patients who
experienced these events to have lower albumin concentrations,
valproate clearance, and to be older than patients who
better tolerated a given dose. In elderly patients, dosage
should be increased more slowly and with monitoring for
possible adverse events. (See DOSAGE AND ADMINISTRATION.)
There is insufficient information available to discern
the safety and effectiveness of divalproex sodium for
the prophylaxis of migraines in patients over 65.
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