Valproic acid
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From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. 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.
Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions ( 5.1 )]. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with seve re seizure disorders accompanied by mental retardation, and those with organic brain disease. When Valproic Acid products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks.
The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Valproic Acid is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications ( 4 )].
In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Valproic Acid should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Valproic Acid for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions ( 5.1 )]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida).
In addition, valproate can cause decreased IQ scores and neurodevelopmental disorders following in utero exposure. Valproate is…
Handling and access
NIOSH hazardous drug
Table 2NIOSH lists divalproex as a hazardous drug. AHFS class: 28:12.92 anticonvulsants, miscellaneous; 28:28 antimanic agents; 28:32.92 antimigraine agents, miscellaneous.
- Meets the NIOSH definition of a hazardous drug (carcinogenicity, developmental or reproductive toxicity, organ toxicity at low doses, or genotoxicity) without MSHI or a Group 1 or 2A carcinogen classification.
- Only a developmental and/or reproductive hazard: precautions matter most for workers who are pregnant, breastfeeding, or trying to conceive.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
Anti-epileptic Agent, Mood Stabilizer
Dosing in kidney impairment
This label has no separate kidney-impairment dosing section. Check warnings and clinical pharmacology in the full label.
Preparation and administration
Epilepsy Valproic Acid is intended for oral administration. Valproic Acid capsules should be swallowed whole without chewing to avoid local irritation of the mouth and throat. Patients should be informed to take Valproic Acid every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose.
If a dose is skipped, the patient should not double the next dose. Valproic Acid is indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the Valproic Acid dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions ] .
Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Valproic Acid has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.
Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day.
The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL).
No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Valproic Acid therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction.
The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Valproic Acid may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.
Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.
If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to divalproex sodium tablets, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies ] .
However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions ] . Simple and Complex Absence Seizures The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases.
The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL.
Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology ] . As the Valproic Acid dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions ] . Antiepilepsy drugs should not be abruptly discontinued 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.
The following Table is a guide for the initial daily dose of Valproic Acid (15 mg/kg/day): [See table below.] Dose 3 10 - 24.9 22 - 54.9 250 0 0 1 25 - 39.9 55 - 87.9 500 1 0 1 40 - 59.9 88 - 131.9 750 1 1 1 60 - 74.9 132 - 164.9 1,000 1 1 2 75 - 89.9 165 - 197.9 1,250 2 1 2
Drug interactions
Check valproic acid against a medication listLabel text (17 paragraphs)
Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1 ) Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives: Monitoring of valproate concentrations is recommended ( 7.1 ) Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g.
diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement ( 7.2 ) Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose ( 7.2 ) Dosage adjustment of amitriptyline/nortriptyline, propofol,warfarin, and zidovudine may be necessary if used concomitantly with Valproic Acid ( 7.2 ) Topiramate: Hyperammonemia and encephalopathy ( 5.10 , 7.3 )
7.1 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 (such as ritonavir), 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 β-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. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood.
Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions ( 5.13 ) ] . Cholestyramine Cholestyramine, when concurrently administered with valproic acid, led to, on average, a 14% decrease in plasma levels of valproic acid in a study conducted in 6 healthy subjects administered valproic acid and cholestyramine. Delaying the administration of cholestyramine relative to valproic acid administration by 3 hours may lessen the interaction.
Estrogen-Containing Hormonal Contraceptives Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen containing products. 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 mcg/mL) compared to valproate alone.
Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 mcg/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.
7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyltransferases. 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 patients. Clonazepam The concomitant use of valproate 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. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been…
Supplement interactions
Dietary supplement interactions
2 noted- Some antiepileptic drugs, including valproic acid (Depakene, Stavzor), carbamazepine (Carbatrol, Epitol, Tegretol, and others), and phenytoin (Dilantin) increase the catabolism rate of vitamin B6 vitamers, resulting in low plasma PLP concentrations and hyperhomocysteinemia.
- Antiepileptic medications, such as phenytoin (Dilantin), carbamazepine (Carbatrol, Tegretol, Equetro, Epitol), and valproate (Depacon), are used to treat epilepsy, psychiatric diseases, and other medical conditions. These medications can reduce serum folate levels.
Contraindications
Valproic Acid should not be administered to patients with hepatic disease or significant hepatic dysfunction [ see Warnings and Precautions ( 5.1 ) ] . Valproic Acid is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [ see Warnings and Precautions ( 5.1 ) ]. Valproic Acid is contraindicated in patients with known hypersensitivity to the drug [ see Warnings and Precautions ( 5.12 ) ] .
Valproic Acid is contraindicated in patients with known urea cycle disorders [ see Warnings and Precautions ( 5.6 ) ]. For use in prophylaxis of migraine headaches: Valproic Acid is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Warning and Precautions ( 5.2 , 5.3 , 5.4 ) and Use in Specific Populations ( 8.1 )].
Hepatic disease or significant hepatic dysfunction ( 4 , 5.1 ) Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ( 4 , 5.1 ) Suspected POLG-related disorder in children under two years of age ( 4 , 5.1 ) Known hypersensitivity to the drug ( 4 , 5.12 ) Urea cycle disorders ( 4 , 5.6 ) Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception ( 4 , 8.1 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
ALikelihood score A: Well known cause of several forms of clinically apparent liver injury.
Valproate or valproic acid is a branched chain organic acid that is used as therapy of epilepsy, bipolar disorders and migraine headaches and is a well known cause of several distinctive forms of acute and chronic liver injury.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Pregnancy Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including Valproic Acid, during pregnancy. Encourage women who are taking Valproic Acid during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll free 1-888-233-2334, or visiting the website,http://www.aedpregnancyregistry.org/. This must be done by the patient herself.
Risk Summary For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [ see Contraindications ( 4 )]. For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Boxed Warning and Warnings and Precautions ( 5.2 , 5.3 )].
Women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat of life. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). This risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established.
In utero exposure to valproate may also result in hearing impairment or hearing loss. Valproate polytherapy with other AEDs has been associated with an increased frequency of congenital malformations compared with AED monotherapy. The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy.
The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who use other anti-seizure monotherapies [ see Warnings and Precautions ( 5.2 ) and (Data Human)]. Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability…
Breastfeeding (LactMed)
Valproic acid levels in breastmilk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development. Breastfed infants of mothers taking valproate had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years of age in one study. A safety scoring system finds valproic acid possible to use during breastfeeding, and a computer model predicted a relatively low infant exposure, consistent with literature reports. If valproic acid is required by the mother, it is not a reason to discontinue breastfeeding. No definite adverse reactions to valproic acid in breastfed infants have been reported. Theoretically, breastfed infants are at risk for valproic acid-induced hepatotoxicity, and a questionable case of thrombocytopenia has been reported.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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