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The physician’s psychoactive medication resource guide
25% of your patients taking an antidepressant will have
weight gain and the weight gain is directly caused by the antidepressant.
Depakote has anticonvulsant properties, and is chemically related to valproic acid. Although its
mechanism of action has not yet been established, it has been suggested that its activity is
related to increased brain levels of gamma-aminobutyric acid (GABA). The effect on the neuronal
membrane is unknown. It dissociates into valproic acid in the gastrointestinal tract.
Peak serum levels of valproic acid occur in 3 to 4 hours.
The serum half-life of valproic acid is typically in the range of 6 to 16 hours. Half-lives in the
lower part of the above range are usually found in patients taking other drugs capable of enzyme
induction. Enzyme induction may result in enhanced clearance of valproic acid by
glucuronidation and microsomal oxidation. Because of these changes in valproic acid clearance
monitoring of valproate and concomitant drug concentrations should be intensified whenever
enzyme inducing drugs are introduced or withdrawn.
A slight delay in absorption occurs when the drug is administered with meals but this does not
affect the total absorption. Valproic acid is rapidly distributed throughout the body and the drug is
strongly bound (90%) to human plasma proteins. Increases in dose may result in decreases in
the extent of protein binding and variable changes in valproic acid clearance and elimination. In
epilepsy, the therapeutic plasma concentration range is believed to be from 50 to 100 mcg/mL.
Occasional patients may be controlled with serum levels lower or higher than this range. A good
correlation has not been established between daily dose, serum level and therapeutic effect.
In placebo controlled clinical studies in acute mania, 79% of patients were dosed to a plasma
concentration between 50 and 125 mcg/mL. Protein binding of valproate is saturable ranging
from 90% at 50 mcg/mL to 82% at 125 mcg/mL.
Elimination of valproic acid and its metabolites occurs principally in the urine, with minor
amounts in the feces and expired air. Very little unmetabolized parent drug is excreted in the
urine. The principal metabolite formed in the liver is the glucuronide conjugate.
Other metabolites in the urine are products of C-3, C-4 and C-5 oxidation. The major oxidative
metabolite in the urine is 2-propyl-3-keto-pentanoic acid; minor metabolites are 2-propyl-glutaric
acid, 2-propyl-5-hydroxy-pentanoic acid, 2-propyl-3-hydroxy-pentanoic acid and 2-propyl-4-
See Warnings regarding statement on fatal hepatic dysfunction.
Depakote is indicated for use as sole or adjunctive therapy in the treatment of simple or complex
absence seizures, including petit mal and is useful in primary generalized seizures with tonic-
clonic manifestations. Depakote may also be used adjunctively in patients with multiple seizure
types which include either absence or tonic-clonic seizures.
Depakote is indicated in the treatment of the manic episodes associated with bipolar disorder
The effectiveness of Depakote in long-term use, that is for more than 3 weeks, has not been
systematically evaluated in controlled trials.
Depakote is not indicated for use as a mood stabilizer in patients under 18 years of age.
Patients with hepatic disease or significant dysfunction. Hypersensitivity to the drug.
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its
derivatives. These incidences usually occurred during the first 6 months of treatment with
valproic acid. Experience has indicated that children under the age of 2 years are at a
considerably increased risk of developing fatal hepatotoxicity, especially those on multiple
anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders
accompanied by mental retardation, and those with organic brain disease.
The risk in this age group decreased considerably in patients receiving valproate as monotherapy. Similarly, patients aged 3 to 10
years were at somewhat greater risk if they received multiple anticonvulsants than those who received only valproate. Risk
generally declined with increasing age. No deaths have been reported in patients over 10 years of age who received valproate
If Depakote is to be used for the control of seizures in children 2 years old or younger, it should be used with extreme caution and
as a sole agent. The benefits of therapy should be weighed against the risks.
Serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema,
anorexia, vomiting, and in epileptic patients, loss of seizure control. Patients and parents should be instructed to report such
symptoms. Because of the nonspecific nature of some of the early signs, hepatotoxicity should be suspected in patients who
become unwell, other than through obvious cause, while taking Depakote.
Liver function tests should be performed prior to therapy and at frequent intervals thereafter especially during the first 6 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 Depakote to patents with a prior history of hepatic disease. Patients with various unusual congenital disorders, those
with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.
In high-risk patients, it might also be useful to monitor serum fibrinogen and albumin for decreases in concentrations and serum
ammonia for increases in concentration. If changes occur, Depakote should be discontinued. Dosage should be titrated to and
maintained at the lowest dose consistent with optimal seizure control.
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) may increase with increasing dose. The benefit of improved symptom control at higher doses should
therefore be weighed against the possibility of a greater incidence of adverse effects.
According to recent reports in the medical literature, valproic acid may produce teratogenicity in the offspring of human females
receiving the drug during pregnancy. The incidence of neural tube defects in the fetus may be increased in mothers receiving
valproic acid during the first trimester of pregnancy. Based upon a single report, it was estimated that the risk of valproic acid
exposed women having children with spina bifida is approximately 1 to 2%. This risk is similar to that which applies to nonepileptic
women who have had children with neural tube defects (anencephaly and spina bifida).
Animal studies have demonstrated valproic acid-induced teratogenicity, and studies in human females have demonstrated placental
transfer of the drug.
Multiple reports in the clinical literature indicate an association between the use of antiepileptic drugs and an elevated incidence of
birth defects in children born to epileptic women taking such medication during pregnancy. The incidence of congenital
malformations in the general population is regarded to be approximately 2%; in children of treated epileptic women, this incidence
may be increased 2- to 3-fold. The increase is largely due to specific defects, e.g., congenital malformations of the heart, cleft lip
and/or palate, craniofacial abnormalities and neural tube defects. Nevertheless, the great majority of mothers receiving antiepileptic
medications deliver normal infants.
Data are more extensive with respect to phenytoin and phenobarbital, but these drugs are also the most commonly prescribed
antiepileptics. Some reports indicate a possible similar association with the use of other antiepileptic drugs, including trimethadione,
paramethadione, and valproic acid. However, the possibility also exists that other factors, e.g., genetic predisposition or the
epileptic condition itself may contribute to or may be mainly responsible for the higher incidence of birth defects.
Patients taking valproic acid may develop clotting abnormalities. If valproic acid is used in pregnancy, the clotting parameters
should be monitored carefully.
Antiepileptic drugs should not be discontinued in patients to whom the drug is administered to prevent major seizures, because of
the strong possibility of precipitating status epilepticus with attendant hypoxia and risks to both the mother and the unborn child.
With regard to drugs given for minor seizures, the risks of discontinuing medication prior to or during pregnancy should be weighed
against the risk of congenital defects in the particular case and with the particular family history.
Epileptic women of childbearing age should be encouraged to seek the counsel of their physician and should report the onset of
pregnancy promptly to him. Where the necessity for continued use of antiepileptic medication is in doubt, appropriate consultation
Risk-benefit must be carefully considered when treating women of childbearing age for bipolar disorder.
Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal
care in childbearing women receiving valproate.
Valproic acid is excreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentrations.
As a general rule, nursing should not be undertaken while a patient is receiving divaiproex. It is not known what effect this may
have on a nursing infant.
The effect of valproate on testicular development and on sperm production and fertility in humans is unknown.
Long-term animal toxicity studies indicate that valproic acid is a weak carcinogen or promoter in rats and mice. The significance of
these findings for man is unknown at present.
Hepatic dysfunction (see Contraindications and Warnings).
Because of reports of thrombocytopenia, inhibition of the second phase of platelet aggregation, platelet counts and coagulation
tests are recommended before instituting therapy and at periodic intervals. It is recommended that patients receiving Depakote be
monitored for platelet count and coagulation parameters prior to planned surgery.
Clinical evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for dosage reduction or
withdrawal of therapy pending investigation.
Hyperammonemia with or without lethargy or coma has been reported and may be present in the absence of abnormal liver
function tests; if elevation occurs the Depakote should be discontinued.
Depakote is partially eliminated in the urine as a ketone-containing metabolite which may lead to a false interpretation of the urine
There have been reports of altered thyroid function tests associated with valproic acid: the clinical significance of these is unknown.
Renal impairment is associated with an increase in the unbound fraction of valproate. In several studies, the unbound fraction of
valproate in plasma from renally impaired patients was approximately double that for subjects with normal renal function.
Hemodialysis in renally impaired patients may remove up to 20% of the circulating valproate.
The safety and efficacy of Depakote in elderly patients with epilepsy and mania has not been systematically evaluated in clinical
trials. Caution should thus be exercised in dose selection for an elderly patient, recognizing the more frequent hepatic and renal
dysfunctions, and limited experience with Depakote in this population.
Depakote may produce CNS depression, especially when combined with another CNS depressant, such as alcohol. Therefore,
patients should be advised not to engage in hazardous occupations, such as driving a car or operating dangerous machinery, until
it is known that they do not become drowsy from the drug.
Depakote may potentiate the CNS depressant action of alcohol.
The concomitant administration of valproic acid with drugs that exhibit extensive protein binding (e.g., aspirin, carbamazepine and
dicumarol) may result in alteration of serum drug levels.
Aspirin and Warfarin:
Caution is recommended when Depakote is administered with drugs affecting coagulation, (e.g., aspirin and warfarin) (see Adverse
There is evidence that valproic acid may cause an increase in serum phenobarbital levels, by impairment of nonrenal clearance.
This phenomenon can result in severe CNS depression. The combination of valproic acid and phenobarbital has also been reported
to produce CNS depression without significant elevations of barbiturate or valproic acid serum levels. Patients receiving
concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate drug levels should be
obtained, if possible, and the barbiturate dosage decreased, if indicated.
Primidone is metabolized into a barbiturate and, therefore, may also be involved in a similar or identical interaction.
There is conflicting evidence regarding the interaction of valproic acid with phenytoin. It is not known if there is a change in
unbound (free) phenytoin serum levels. The dosage of phenytoin should be adjusted as required by the clinical situation. There
have been reports of breakthrough seizures occurring with the combination of valproic acid and phenytoin.
Because Depakote may interact with concurrently administered drugs which are capable of enzyme induction, periodic serum level
determinations of these drugs are recommended during the early part of therapy.
The concomitant use of valproic acid and clonazepam may produce absence status in patients with a history of absence type
Evidence suggests that there is an association between the use of certain drugs capable of enzyme induction and failure of oral
contraceptives. One explanation for this interaction is that enzyme-inducing antiepileptic drugs effectively lower plasma
concentrations of the relevant steroid hormones, resulting in unimpaired ovulation. However, other mechanisms, not related to
enzyme induction, may contribute to the failure of oral contraceptives. Valproic acid is not a significant enzyme inducer and would
not be expected to decrease concentrations of steroid hormones. However, clinical data about the interaction of valproic acid with
oral contraceptives are minimal.
In addition to enhancing CNS depression when used concurrently with valproic acid, tricyclic antidepressants, MAO inhibitors, and
antipsychotics, may lower the seizure threshold. Dosage adjustments may be necessary to control seizures.
Concomitant use of carbamazepine with valproic acid may result in decreased serum concentrations and half-life of valproate due
to increased metabolism induced by hepatic microsomal enzyme activity. Valproate causes an increase in the active 10, 11-epoxide
metabolite of carbamazepine by inhibition of its breakdown. Monitoring of serum concentrations is recommended when either
medication is added to or withdrawn from an existing regimen. Changes in the serum concentration of the 10, 11-epoxide
metabolite of carbamazepine, however, will not be detected by routine serum carbamazepine assay.
Cimetidine may decrease the clearance and increase the half-life of valproic acid by altering its metabolism. In patients receiving
valproic acid, serum valproic acid levels should be monitored when treatment with cimetidine is instituted, increased, decreased, or
discontinued. The valproic acid dose should be adjusted accordingly.
A single study has shown that the concomitant use of chlorpromazine with valproic acid may result in a decrease in valproic acid
clearance. Valproic acid serum concentrations and effects should be monitored when valproic acid is unadministered
chlorpromazine due to possible inhibition of valproic acid metabolism.
Selective serotonin re-uptake inhibitors (SSRIs):
Some evidence suggests that SSRIs inhibit the metabolism of valproate, resulting in higher than expected levels of valproate.
The metabolism of amitriptyline and nortriptyline after a single dose of amitriptyline (50 mg) was inhibited by multiple dosing with
valproic acid (500 mg twice daily) in 16 healthy male and female volunteers. For the sum of amitriptyline and nortriptyline plasma
concentrations, in the presence of valproic acid, the mean C
and AUC were increased by 19 and 42%, respectively.
In a double-blind placebo-controlled multiple dose crossover study in 16 healthy male volunteers, pharmacokinetic parameters of
lithium were not altered by the presence or absence of Depakote. The presence of lithium, however, resulted in an 11 to 12%
increase in the AUC and C
of valproate. T
was also reduced. Although these changes were statistically significant, they are
not likely to have clinical importance.
Valproic acid may decrease oxidative liver metabolism of some benzodiazepines, resulting in increased serum concentrations. In
two small studies in healthy volunteers, valproate produced a 17% decrease in the clearance of lorazepam, and 26% decrease in
the clearance of unbound diazepam. Displacement of diazepam from plasma protein binding sites may also occur. During valproate
administration the unbound fraction of diazepam in the senum increased approximately two-fold.
The most commonly reported adverse reactions are nausea, vomiting and indigestion. Since valproic acid has usually been used
with other antiepileptics, it is not possible in most cases to determine whether the adverse reactions mentioned in this section are
due to valproic acid alone or to the combination of drugs.
Nausea, vomiting and indigestion are the most commonly reported side effects at the initiation of therapy. These effects are usually
transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps and constipation have also been reported.
Anorexia with some weight loss and increased appetite with some weight gain have also been seen.
Sedative effects have been noted in patients receiving valproic acid alone but are found most often in patients on combination
therapy. Sedation usually disappears upon reduction of other antiepileptic medication. Ataxia, headache, nystagmus, diplopia,
asterixis, "spots before the eyes", tremor (may be dose-related), dysarthria, dizziness, and incoordination have rarely been noted.
Rare cases of coma have been reported in patients receiving valproic acid alone or in conjunction with phenobarbital.
Transient increases in hair loss have been observed. Skin rash, photosensitivity, generalized pruritus, erythema multiforms,
Stevens-Johnson syndrome and petechiae have rarely been noted.
There have been reports of irregular menses and secondary amenorrhea, breast enlargement, galactorrhea and parotid gland
swelling in patients receiving valproic acid. Abnormal thyroid function tests have been reported (see Precautions).
Emotional upset, depression, psychosis, aggression, hyperactivity and behavioral deterioration have been reported.
Weakness has been reported.
Thrombocytopenia has been reported. Valproic acid inhibits the second phase of platelet aggregation (see Precautions). This may
be reflected in altered bleeding time. Petechiae, bruising, hematoma formation and frank hemorrhage have been reported. Relative
lymphocytosis macrocytosis and hypofibrinogenemia have been noted. Leukopenia and eosinophilia have also been reported.
Anemia, including macrocytic with or without folate deficiency, bone marrow suppression and acute intermittent porphyria have
Minor elevations of transaminases (e.g., AST and ALT) and LDH are frequent and appear to be dose related. Occasionally,
laboratory tests also show increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect
potentially serious hepatotoxicity (see Warnings).
Hyperammonemia (see Precautions), hyponatremia and inappropriate ADH secretion. Hyperglycinemia has been reported and
associated with a fall outcome in a patient with pre-existing nonketotic hyperglycinemia.
There have been reports of acute pancreatitis occurring in association with therapy with valproic acid.
Hearing loss, either reversible or irreversible, has been reported however, a cause and effect relationship has not been established.
Edema of extremities has been reported.
The incidence of adverse events has been ascertained based on data from 2 short-term (21 day) placebo-controlled clinical trials of
Depakote in the treatment of acute mania, and from 2 long-term (up to 3 years) retrospective open trials.
Most Commonly Observed:
During the short-term placebo-controlled trials, the 6 most commonly reported adverse events in patients (N=89) exposed to
Depakote were nausea (22%), headache (21%), somnolence (19%), pain (15%), vomiting (12%), and dizziness (12%).
In the long-term retrospective trials (634 patients exposed to Depakote), the 6 most commonly reported adverse events were
somnolence (31%), tremor (29%), headache (24%), asthenia (23%), diarrhea (22%) and nausea (20%).
Associated With Discontinuation of Treatment:
In the placebo-controlled trials, adverse events which resulted in valproate discontinuation in at least 1% of patients were nausea
(4%) abdominal pain (3%), somnolence (2%) and rash (2%).
In the long-term retrospective trials, adverse events which resulted in valproate discontinuation in at least 1% of patients were
alopecia (2.4%), somnolence (1.9%), nausea (1.7%) and tremor (1.4%). The time to onset of these events was generally within the
first 2 months of initial exposure to valproate. A notable exception was alopecia, which was first experienced after 3 to 6 months of
exposure by 8 of the 15 patients who discontinued valproate in response to the event.
Table I summarizes those treatment emergent adverse events reported for patients in the placebo-controlled trials when the
incidence rate in the Depakote group was at least 5%. (Maximum treatment duration was 21 days; maximum dose in 83% of
patients was between 1000 to 2500 mg/day).
Treatment-Emergent Adverse Event Incidence (>=5%)
In Short-Term Placebo-Controlled Trials
Percentage of Patients
Body as a Whole
Skin and Appendages
*Statistically significant at P <= 0.05 level.
In elderly patients (above 65 years of age), there were more frequent reports of accidental injury, infection pain, and to a lesser
degree, somnolence and tremor, when compared to patients 18 to 65 years of age. Somnolence and tremor tended to be
associated with the discontinuation of valproate.
Symptoms and Treatment:
In a reported case of overdosage with valproic acid after ingesting 36 g in combination with phenobarbital and phenytoin, the
patient presented in deep coma. An EEG recorded diffuse slowing, compatible with the state of consciousness. The patient made
an uneventful recovery.
Naloxone has been reported to reverse the CNS depressant effects of valproic acid overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of Depakote, it should be used with caution in patients
Since Depakote tablets are enteric-coated, the benefit of gastric ravage or emesis will vary with the time since ingestion. General
supportive measures should be applied with particular attention to the prevention of hypovolemia and the maintenance of adequate
Administered orally. The recommended initial dosage is 15 mg/kg/day, increasing at 1-week intervals by 5 to 10 mg/kg/day until
seizures are controlled or side effects preclude further increases.
The maximal recommended dosage is 60 mg/kg/day. When the total daily dose is 125 mg or greater, it should be given in a divided
regimen (see Table II).
The frequency of adverse effects (particularly elevated liver enzymes) may increase with increasing dose. Therefore, the benefit
gained by improved seizure control must be weighed against the increased incidence of adverse effects.
Table II - Epival
Initial Doses by Weight (based on 15 mg/kg/day)
equivalent to valproic acid
As the dosage of Depakote is raised, blood levels of phenobarbital and/or phenytoin may be affected (see Precautions, Drug
Patients who experience gastrointestinal irritation may benefit from administration of the drug with food or by a progressive
increase of the dose from an initial low level. The tablets should be swallowed without chewing.
The recommended initial dose is 250 mg 3 times a day. The dose should be increased as rapidly as possible to achieve the lowest
therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations.
In placebo-controlled trials, 84% of patients received and tolerated maximum daily doses of between 1000 mg/day to 2500 mg/day.
The maximum recommended dosage is 60 mg/kg/day.
The relationship of plasma concentration to clinical response has not been established for Depakote. In controlled clinical studies,
79% of patients achieved and tolerated serum valproate concentrations between 50 and 125 mcg/mL.
When changing therapy involving drugs known to induce hepatic microsomal enzymes (e.g., carbamazepine) or other drugs with
valproate interactions (see Precautions, Drug Interactions), it is advisable to monitor serum valproate concentrations.
Conversion from Valproic Acid to Depakote:
Depakote dissociates into valproic acid in the gastrointestinal tract. Depakote tablets are uniformly and reliably absorbed, however,
because of the enteric-coating, absorption is delayed by an hour when compared with valproic acid capsules. The bioavailability of
Depakote tablets is equivalent to that of valproic acid capsules.
In patients previously receiving valproic acid therapy, Depakote should be initiated at the same daily dose and dosing schedule.
After the patient is stabilized on Depakote, a dosing schedule of 2 to 3 times a day may be elected in selected patients.
Each enteric-coated, salmon-pink tablet contains: Depakote equivalent to valproic acid 125 mg. Nonmedicinal ingredients:
cellulosic polymers, diacetylated monoglycendes, FD&C Blue No. 1, FD&C Red No. 40, povidone, pregelatinized starch (contains
cornstarch), silica gel, talc, titanium dioxide and vanillin. Bottles of 100.
Each enteric-coated, peach-colored tablet contains: Depakote equivalent to valproic acid 250 mg. Nonmedicinal ingredients:
cellulosic polymers, diacetylated monoglycendes, FD&C Yellow No. 6, iron oxide, povidone, preyelatinized starch (contains
cornstarch), silica gel, talc, titanium dioxide and vanillin. Bottles of 100 and 500.
Each enteric-coated, lavender-colored tablet contains: Depakote equivalent to valproic acid 500 mg. Nonmedicinal ingredients:
cellulosic polymers, D&C Red No. 30, diacetylated monoglycerides, FD&C Blue No. 2, iron oxide, povidone, pregelatinized starch
(contains cornstarch), silica gel, talc, titanium dioxide and vanillin. Bottles of 100 and 500.
Alcohol-, gluten-, lactose-, paraben-, sucrose-, sulfite- and tartrazine-free. Store between 15 and 30°C.