Effects of Co-Administered Drugs on Valproate Clearance
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels
of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and
phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have
longer half-lives and higher concentrations than patients receiving poly-therapy with antiepilepsy drugs.
In contrast,drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be
expected to have little effect on val-proate clearance because cytochrome P450 microsomal mediated oxidation is a
relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug
concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.
The following list provides information about the potential for an influence of several commonly
prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new
interactions are continuously being reported.
Drugs for which a potentially important interaction has been observed
Aspirin - A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg)
with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of
valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The
ß-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased
from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be
observed if valproate and aspirin are to be co-administered.
Felbamate - A study involving the co-administration of 1200 mg/day of felbamate with valproate to
patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115
µg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate
peak concentration to 133 µg/mL (another 16% increase). A decrease in valproate dosage may be necessary when
felbamate therapy is initiated.
Meropenem - Subtherapeutic valproic acid levels have been reported when meropenem was
Rifampin - A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after
5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate
dosage adjustment may be necessary when it is co-administered with rifampin.
Drugs for which either no interaction or a likely clinically unimportant interaction has been
Antacids - A study involving the co-administration of valproate 500 mg with commonly administered
antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of
Chlorpromazine - A study involving the administration of 100 to 300 mg/day of chlorpromazine to
schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of
Haloperidol - A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic
patients already receiving val-proate (200 mg BID) revealed no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine - Cimetidine and ranitidine do not affect the clearance of valproate.
Effects of Valproate on Other Drugs
Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and
The following list provides information about the potential for an influence of valproate
co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is
not exhaustive, since new interactions are continuously being reported.
Drugs for which a potentially important valproate interaction has been observed
Amitriptyline/Nortriptyline - Administration of a single oral 50 mg dose of amitriptyline to 15 normal
volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma
clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of
concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received.
Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline
levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be
given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide - Serum levels of carbamazepine (CBZ) decreased 17% while
that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
Clonazepam - The concomitant use of valproic acid and clonazepam may induce absence status in patients
with a history of absence type seizures.
Diazepam - Valproate displaces diazepam from its plasma albumin binding sites and inhibits its
metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in
healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%,
respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of
Ethosuximide - Valproate inhibits the metabolism of ethosuximide. Administration of a single
ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25%
increase in elimination half-life of ethosux-imide and a 15% decrease in its total clearance as compared to
ethosuximide alone. Patients receiving valproate and ethosuximide, espe-cially along with other anticonvulsants,
should be monitored for alterations in serum concentrations of both drugs.
Lamotrigine - In a steady-state study involving 10 healthy volunteers, the elimination half-life of
lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine
should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson Syndrome and
toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See
lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
Phenobarbital - Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of
valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in
half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital
dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or
valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored
for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate
dosage decreased, if appropriate.
Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with
Phenytoin - Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its
hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7)
was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of
distribution of phenytoin increased 30% in the presence of val-proate. Both the clearance and apparent volume of
distribution of free phenytoin were reduced by 25%.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the
combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical
Tolbutamide - From in vitro experiments, the unbound fraction of tolbutamide was increased from
20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this
displacement is unknown.
Warfarin - In an in vitro study, valproate increased the unbound fraction of warfarin by up to
32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if DEPAKOTE
therapy is instituted in patients taking anticoagulants.
Zidovudine - In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h)
was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was
Drugs for which either no interaction or a likely clinically unimportant interaction has been
Acetaminophen - Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when
it was concurrently administered to three epileptic patients.
Clozapine - In psychotic patients (n=11), no interaction was observed when valproate was
co-administered with clozapine.
Lithium - Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal
male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam - Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal
male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Oral Contraceptive Steroids - Administration of a single-dose of ethinyloestradiol (50
µg)/levonorgestrel (250 µg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any