Brands, Medical Use, Clinical Data
Drug Category
- Antimanic Agents
- GABA Agents
- Enzyme Inhibitors
- Anticonvulsants
Dosage Forms
- Capsule (250 mg)
- Syrup (250 mg drug/5mL syrup)
Brands / Synonyms
2 PP (base); Alti-Valproic; Bruceine D; Convulex; Delepsine; Depakene; Depakine; Deproic; Di-n-propylacetic acid; Di-n-propylessigsaure; Dipropylacetic acid; Dom-Valproic; DPA; DPA (VAN); Epilex; Epilim; Epival; Ergenyl; Kyselina 2-propylvalerova; Med Valproic; Mylproin; Myproic Acid; n-Dipropylacetic acid
; n-DPA; Novo-Valproic; Nu-Valproic; Penta-Valproic; Pentanoic acid, 2-propyl-; PMS-Valproic Acid; Propylvaleric acid; Sodium hydrogen divalproate; Sprinkle; Valcote; Valeric acid, 2-propyl-; Valparin; Valproate semisodique [French]; Valproate semisodium; Valproato semisodico [Spanish]; Valproatum seminatricum [Latin]; Valproic acid semisodium salt (2:1); Valproic acid USP; Valproic acid USP24
Indications
For use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.
Pharmacology
Valproic Acid is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat migraine headaches and schizophrenia. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures associated with Lennox-Gastaut syndrome. Valproic Acid is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain. Valproic Acid dissociates to the valproate ion in the gastrointestinal tract. Valproic acid has also been shown to be an inhibitor of an enzyme called histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. A study published in August 2005 revealed that patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a 75% reduction in latent HIV infection.
Mechanism of Action
Valproic Acid binds to and inhibits GABA transaminase. The drug's anticonvulsant activity may be related to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Valproic Acid may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.
Absorption
Rapid absorption from gastrointestinal tract.
Toxicity
Oral, mouse: LD50 = 1098 mg/kg; Oral, rat: LD50 = 670 mg/kg. Symptoms of overdose may include coma, extreme drowsiness, and heart problems.
Biotrnasformation / Drug Metabolism
Valproic Acid is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial ß-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
Contraindications
VALPROIC ACID SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT
DYSFUNCTION.
Valproic acid is contraindicated in patients with known hypersensitivity to the drug.
Drug Interactions
Effects of Co-Administered Drugs on Valproate Clearance : Drugs that affect the level of expression of
hepatic enzymes, particularly those that elevate levels of glucuronosyltrans-ferases, 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 polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e. g. , antidepressants, may be expected to
have little effect on valproate 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.
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 observed:
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 valproate.
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 valproate.
Haloperidol - A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients
already receiving valproate (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 glucuronosyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on the
pharma-cokinetics 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:
Carbamazepine/carbamazepine-10, 11-Epoxide - Serum levels of carbamazepine (CBZ) decreased 17% while that of
carba-mazepine-10, 11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic
patients.
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
valproate.
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 ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone.
Patients receiving valproate and ethosuximide, especially 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.
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 con-centrations. 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 valproate.
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 valproate. 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 situation.
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 unaffected.
Drugs for which either no interaction or a likely clinically unimportant interaction has been observed:
Acetaminophen - Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was
concurrently administered to three epileptic patients.
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.
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 pharmacokinetic
interaction.
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