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Valproate: Drug information

Valproate: Drug information
(For additional information see "Valproate: Patient drug information" and see "Valproate: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Hepatotoxicity:

Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first 6 months of treatment. Serious or fatal hepatotoxicity may be preceded by nonspecific 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 6 months.

Children <2 years of age are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple antiseizure medications, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When these 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 gamma (POLG) gene (eg, Alpers-Huttenlocher syndrome). Valproate is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children younger than 2 years who are clinically suspected of having a mitochondrial disorder. In patients >2 years of age who are clinically suspected of having a hereditary mitochondrial disease, only use after other antiseizure medications have failed. This older group of patients should be closely monitored during treatment with valproate 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.

Fetal risk:

Valproate can cause major congenital malformations, particularly neural tube defects (eg, spina bifida). In addition, valproate can cause decreased IQ scores and neurodevelopmental disorders following in utero exposure. Valproate is therefore contraindicated for prophylaxis of migraine headaches in pregnant women and in women of childbearing potential who are not using effective contraception. Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. In such situations, effective contraception should be used.

A Medication Guide describing the risks of valproate is available for patients.

Pancreatitis:

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

Brand Names: US
  • Depacon [DSC];
  • Depakene [DSC];
  • Depakote;
  • Depakote ER;
  • Depakote Sprinkles
Brand Names: Canada
  • APO-Divalproex;
  • APO-Valproic Acid;
  • Depakene;
  • DOM-Divalproex;
  • DOM-Valproic Acid;
  • DOM-Valproic Acid EC;
  • Epival;
  • MYLAN-Divalproex;
  • NOVO-Valproic [DSC];
  • PMS-Divalproex;
  • PMS-Valproic;
  • PMS-Valproic Acid;
  • RATIO-Valproic [DSC];
  • SANDOZ Valproic [DSC];
  • TEVA-Divalproex [DSC]
Pharmacologic Category
  • Anticonvulsant, Miscellaneous;
  • Antimanic Agent;
  • Histone Deacetylase Inhibitor
Dosing: Adult

Note: The dosing recommendations in this monograph are expressed as the total daily dose (ie, per 24 hours) unless stated otherwise. The total daily oral dose is given in 1 to 4 divided doses per day depending on the type of preparation. Available preparations include: Oral immediate release (usually dosed 3 to 4 times daily [Koch-Weser 1980]), delayed release (DR) (usually dosed 2 to 3 times daily) and extended release (ER) (commonly dosed once daily; may also be dosed twice daily) formulations and an IV injection (Bialer 2007). The ER oral formulation is not available in Canada. Available formulations of valproate (active moiety) include valproic acid, valproate sodium, and divalproex sodium (also known as valproate semisodium) salts. All doses in this monograph are expressed as the equivalent amounts of valproic acid.

Bipolar disorder

Bipolar disorder:

Acute mania or acute episodes with mixed features (in combination with or as an alternative to an antipsychotic) (BAP [Goodwin 2016]):

Fixed dose: Oral: Initial: 500 to 750 mg/day (BAP [Goodwin 2016]; Tohen 2008); increase by 250 to 500 mg every 1 to 3 days to reach desired clinical effect and therapeutic serum concentration (BAP [Goodwin 2016]; Stovall 2018); therapeutic serum levels generally occur with daily doses of 1.5 to 2.5 g (Stovall 2018). Maximum recommended dosage: 60 mg/kg/day (manufacturer's labeling).

Weight-based loading dose for rapid symptom control: Oral: Initial: 20 to 30 mg/kg/day. After 2 to 3 days, adjust dose upward or downward to reach desired clinical effect and therapeutic serum concentration (BAP [Goodwin 2016]; Bowden 2006; Bowden 2010; Hirschfeld 1999); therapeutic serum levels generally occur with daily doses of 1.5 to 2.5 g. To avoid intolerable adverse effects, some experts limit the initial rapid loading dose to 20 mg/kg/day (up to 2 g/day if body weight exceeds 100 kg) and then adjust based on response and serum concentration (Stovall 2018). Maximum recommended dosage: 60 mg/kg/day (manufacturer's labeling).

Bipolar major depression (alternative agent) (mono- or adjunctive therapy) (off-label use): Based on limited data: Oral: Initial: 500 to 750 mg/day; increase by 250 to 500 mg every 1 to 3 days to reach desired clinical effect and therapeutic serum concentration; therapeutic serum levels generally occur with daily doses of 1.5 to 2.5 g (CANMAT/ISBD [Yatham 2018]; Davis 2005; Ghaemi 2007; Muzina 2011; Shelton 2021).

Maintenance treatment of bipolar disorder (off-label): Oral: Continue dose and combination regimen that was used to achieve control of the acute episode (Gyulai 2003; McElroy 2008).

Focal onset seizures and generalized onset seizures

Focal (partial) onset seizures and generalized onset seizures (FDA-approved for monotherapy or adjunctive therapy of complex partial and absence seizures, and as adjunctive therapy for multiple seizure types; may be used off-label as monotherapy for other seizure types):

Oral: Initial monotherapy or adjunctive therapy: 10 to 15 mg/kg/day for complex partial seizures or 15 mg/kg/day for absence seizures; increase by 5 to 10 mg/kg/day at weekly intervals until optimal clinical response and/or therapeutic levels are achieved; maximum recommended dose: 60 mg/kg/day (manufacturer's labeling). Some experts suggest checking serum level ~1 to 2 weeks after initial dose to help guide dose adjustment (Schachter 2020a).

Conversion to monotherapy from valproate adjunctive therapy: Initial oral dosage as above. Dosage reduction of the concomitant antiseizure drug may begin when valproate therapy is initiated or 1 to 2 weeks following valproate initiation; taper the concomitant antiseizure drug over 8 weeks (ie, by ~25% every 2 weeks).

IV (for non-status epilepticus): Total daily IV dose should be equivalent to the total daily oral valproate dose (expressed as valproic acid) and divided every 6 hours. Administer each dose as a 60-minute infusion (rate ≤20 mg/minute). Note: In non-status epilepticus, IV formulation should be used only for those who temporarily cannot use oral formulations; switch to oral formulation as soon as appropriate.

Migraine, intractable and status migrainosus

Migraine, intractable and status migrainosus (alternative agent) (off-label use): IV: 500 mg to 1 g as a single dose as part of an appropriate combination regimen (Edwards 2001, Friedman 2014; Rozen 2015).

Migraine prophylaxis

Migraine prophylaxis: Oral: Initial: 500 mg once daily (ER) or in 2 divided doses (DR or ER); increase dose gradually based on response and tolerability in increments of 250 mg/day at intervals >3 days up to 1 g/day. Based on clinical experience, some patients require doses up to 1.5 g/day for sufficient response; however, adverse effects are increased (Bajwa 2018; Klapper 1997; Linde 2013; Pringsheim 2010).

Status epilepticus

Status epilepticus (off-label use): Note: Given in combination with an IV benzodiazepine: IV: Loading dose: 20 to 40 mg/kg administered at a rate up to 10 mg/kg/minute (maximum dose: 3 g) (AES [Glauser 2016]; Limdi 2007; NCS [Brophy 2012]). In non-convulsive status epilepticus, some experts recommend a maximal infusion rate of 5 mg/kg/minute (Jirsch 2020).

Discontinuation of therapy: In patients receiving valproic acid chronically, unless safety concerns require a more rapid withdrawal, valproic acid should be withdrawn gradually over 2 to 6 months to minimize the potential of increased seizure frequency (in patients with epilepsy) or other withdrawal symptoms (Medical Research Council Antiepileptic Drug Withdrawal Study Group 1991; Schachter 2020b). In patients discontinuing therapy for treatment of bipolar disorder, close monitoring for several weeks to months for reemergence of mania/hypomania is recommended (Post 2021).

Dosing conversions: Note: The ER formulation is not available in Canada:

Conversion from immediate release to DR or ER : When converting to DR, use the same total daily dose as the immediate release and divide into 2 to 3 daily doses. When converting from immediate release to ER, increase the total daily dose of ER by 8% to 20% and dose once daily (most common) or twice daily (Bialer 2007).

Conversion from DR to ER: For patients on a stable dose of DR, increase the total daily dose of ER by 8% to 20% to maintain similar serum concentrations, and dose once daily (most common) or twice daily (Bialer 2007).

Conversion to IV valproate preparations : To continue therapy IV in patients temporarily unable to receive oral therapy, total daily IV dose should be equivalent to the total daily oral dose (expressed as valproic acid) and divided every 6 hours. Trough levels may fall below the equivalent oral regimen when administered less frequently than every 6 hours; in these cases, closely monitor trough plasma concentrations.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: IV, Oral:

CrCl ≥10 mL/minute: No dosage adjustment necessary.

CrCl <10 mL/minute: No specific dosage adjustment necessary; however, free valproate clearance may be reduced up to ~30%. Closely monitor clinical response and tolerability in addition to valproic acid serum concentrations, when appropriate. Monitoring of free valproic acid concentrations (when available) is preferred due to decreased protein binding in severe kidney impairment. Total valproate concentrations may be misleading (manufacturer’s labeling).

Hemodialysis, intermittent (thrice weekly):

IV, Oral: No specific dosage adjustment necessary. At therapeutic concentrations, dialysis decreases valproic acid concentrations by 20% (manufacturer’s labeling); supplemental doses are typically unnecessary as concentrations rebound within a few hours after dialysis (Israni 2006; Kandrotas 1990). Closely monitor clinical response and tolerability in addition to valproic acid serum concentrations, when appropriate; monitoring of free valproic acid concentrations (when available) is preferred due to decreased protein binding in severe kidney impairment. Total valproate concentrations may be misleading (manufacturer’s labeling).

Peritoneal dialysis: Minimally dialyzed (~4.5%) (Orr 1983):

IV, Oral: No specific dosage adjustment necessary. Closely monitor clinical response and tolerability in addition to valproic acid serum concentrations, when appropriate; monitoring of free valproic acid concentrations (when available) is preferred due to decreased protein binding in severe kidney impairment. Total valproate concentrations may be misleading (manufacturer’s labeling).

CRRT:

IV, Oral: No specific dose adjustment necessary. However, critically ill patients receiving CRRT may exhibit reduced protein binding and increased free valproic acid concentrations, leading to increased removal. Closely monitor clinical response and tolerability in addition to valproic acid serum concentrations, when appropriate; monitoring of free valproic acid concentrations (when available) is preferred. Total valproate concentrations may be misleading (De Maat 2011; Mahmoud 2017).

PIRRT (eg, sustained, low-efficiency diafiltration):

IV, Oral: No specific dose adjustment necessary. However, critically ill patients receiving PIRRT may exhibit reduced protein binding and increased free valproic acid concentrations, leading to increased removal. Closely monitor clinical response and tolerability in addition to valproic acid serum concentrations, when appropriate; monitoring of free valproic acid concentrations (when available) is preferred. Total valproate concentrations may be misleading (expert opinion).

Dosing: Hepatic Impairment: Adult

Mild to moderate impairment: Not recommended for use in hepatic disease; clearance is decreased with liver impairment. Hepatic disease is also associated with decreased albumin concentrations and 2- to 2.6-fold increase in the unbound fraction. Free concentrations of valproate may be elevated while total concentrations appear normal, therefore, monitoring only total valproate concentrations may be misleading.

Severe impairment: Use is contraindicated.

Dosing: Pediatric

(For additional information see "Valproate: Pediatric drug information")

Note: Use of Depakote ER in pediatric patients <10 years of age is not recommended; do not confuse Depakote ER with Depakote. Erroneous substitution of Depakote (delayed-release tablets) for Depakote ER has resulted in toxicities; only Depakote ER is intended for once daily administration.

Migraine, prophylaxis:

Divalproex sodium (eg, Depakote tablets):

Children ≥5 years and Adolescents ≤16 years: Limited data available: Oral: Initial 10 to 15 mg/kg/day in 2 divided doses; maximum initial dose: 250 mg/dose. Titrate as needed over 4 to 6 weeks to 40 to 45 mg/kg/day in 2 divided doses; maximum daily dose: 1,000 mg/day (AAN [Lewis 2004]; Ashrafi 2005; Caruso 2000; Gunner 2008). Dosing based on multiple pediatric trials. In one open-label trial of divalproex sodium (DVS) (n=42; age range: 7 to 16 years); dose was initiated at 15 mg/kg/day in 2 divided doses and increased as needed over 6 weeks to 45 mg/kg/day in 2 divided doses. After 4 months, 78.5% of subjects had a 50% decrease in headaches frequency, 14.2% had a 75% decrease in headache frequency, and 9.5% became headache free (Caruso 2000). In a randomized comparative trial of pediatric patients aged 4 to 15 years, sodium valproate (n=54) was initiated at 10 mg/kg/day in 2 divided doses and titrated based on clinical response and tolerability up to a maximum dose of 40 mg/kg/day in divided doses; similar efficacy to propranolol (n=56) was observed with regards to decrease in headache frequency by >50%, mean headache duration, headache severity, and improved response to rescue medications (Ashrafi 2005). A small (n=10) open-label trial of pediatric patients 9 to 17 years showed a statistically significant decrease in mean frequency of headache attacks, severity, and duration with divalproex sodium therapy using a daily dose range of 500 to 1,000 mg/day (Serdaroglu 2002).

Adolescents ≥17 years: Depakote: Oral: 250 mg twice daily; adjust dose based on patient response; maximum daily dose: 1,000 mg/day.

Depakote ER: Limited data available: Children ≥12 years and Adolescents: Oral: 500 mg once daily for 15 days, may increase to 1,000 mg once daily; adjust dose based on patient response; usual dosage range: 250 to 1,000 mg/day; dose should be individualized; if smaller dosage adjustments are needed, use Depakote delayed-release tablets; results from a Phase 3, long-term (12 months) open-label trial of 241 patients (age: 12 to 17 years) showed a 75% decrease in median 4-week headache days between the first and fourth months of the trial (Apostol 2009a). In a short-term (12 weeks), double-blind, randomized placebo-controlled trial of 304 patients (age: 12 to 17 years), Depakote ER (250 to 1,000 mg/day) was no different than placebo at reducing the 4-week headache rate; however, a large placebo effect was observed in the study population (Apostol 2008).

Migraine, treatment; refractory: Limited data available, efficacy results variable, optimal regimen not established:

Intermittent IV: Adolescents 500 or 1,000 mg infused at 50 mg/minute; a repeat dose of 500 mg may be administered if pain relief not observed (Reiter 2005; Sheridan 2015); dosing based on two retrospective reports that evaluated experience in 43 patients treated for acute migraine attack(s) (n=60; some subjects presented with multiple attacks); the mean age in both reports was 15 years and the majority of patients received 1,000 mg doses. One trial evaluated 48 clinic visits for acute migraine attack in 31 patients; adequate pain relief was reported in 77.6% of visits (n=45) after a single valproic acid dose; the mean time to achieve maximum pain relief was 63 ± 31 minutes (range: 15 to 160 minutes) after a single dose of valproic acid; maximum pain reduction following a repeat 500 mg dose was observed at 124 ± 62 minutes (range: 20 to 250 minutes) (Reiter 2005).

Continuous IV infusion: Children ≥4 years and Adolescents:

Loading dose: IV: 20 mg/kg; maximum dose: 2,000 mg/dose infused over 30 to 60 minutes.

Continuous infusion: IV: Initial: 1 mg/kg/hour; adjust to maintain target serum concentrations of 80 to 100 mcg/mL (assessed at 2 to 4 hours and at 24 hours after loading dose) (Cook 2016; Taylor 2007; Zafar 2018). Dosing based on a retrospective report including 83 patients (mean age: 12.9 years; range: 4 to 18 years) who received IV valproate for status migrainosus after failing home oral therapy and initial IV therapy in the emergency department (diphenhydramine, metoclopramide, and ketorolac); the mean reported rate was 1 mg/kg/hour, and an excellent response (100% pain reduction) was reported in 55 (66.3%) patients; within the responder group, 56% reported response within 16 hours and 76% within 24 hours. Patients were then transitioned to oral valproic acid therapy migraine prophylaxis therapy on the delayed-released formulation initiated at the same dosage as last 24 hours of IV infusion (Zafar 2018).

Seizures disorders: Note: Due to the increased risk of valproic acid and derivatives-associated hepatotoxicity in patients <2 years, valproic acid and derivatives are not preferred agents in this population.

Oral:

General dosing (including focal onset seizures with impaired consciousness or awareness [complex partial seizures], mixed seizure disorders, tonic-clonic): Children and Adolescents: Limited data available for some seizure types and ages <10 years (Piña-Garza 2013): Initial: 10 to 15 mg/kg/day in 1 to 3 divided doses; increase by 5 to 10 mg/kg/day at weekly intervals until seizures are controlled or side effects preclude further increases; daily doses >250 mg should be given in divided doses; maintenance: 30 to 60 mg/kg/day in 2 to 3 divided doses; Depakote and Depakote Sprinkle can be given twice daily; Note: Children receiving more than 1 antiseizure medication (ie, polytherapy) may require doses up to 100 mg/kg/day in 3 to 4 divided doses.

Generalized nonmotor (absence) seizures, focal onset seizures with or without impaired consciousness or awareness (simple and complex): Children and Adolescents: Initial: 15 mg/kg/day in 1 to 3 divided doses; increase by 5 to 10 mg/kg/day at weekly intervals until seizures are controlled or side effects preclude further increases; daily doses >250 mg should be given in divided doses; maintenance: 30 to 60 mg/kg/day in 2 to 3 divided doses; Depakote and Depakote Sprinkle can be given twice daily.

Conversion to Depakote ER from a stable dose of immediate release or delayed release: May require an increase in the total daily dose between 8% and 20% administered once daily to maintain similar serum concentrations (Kernitsky 2005; manufacturer's labeling). For doses that do not directly convert to a Depakote ER dose form, clinicians may consider increasing to the next highest dose of the immediate or delayed-release (eg, Depakote) formulation before converting to the appropriate daily dose of Depakote ER.

Conversion to monotherapy from adjunctive therapy: The concomitant antiseizure drug (AED) can be decreased by ~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.

Parenteral: Children and Adolescents: Limited data available in some cases depending on seizure types and age (Piña-Garza 2013): IV: Total daily IV dose is equivalent to the total daily oral dose; however, IV dose should be divided with a frequency of every 6 hours; if IV form is administered 2 to 3 times/day, close monitoring of trough concentrations is recommended; switch patients to oral product as soon as clinically possible as IV use >14 days has not been studied.

Rectal: Limited data available: Children and Adolescents: Dilute oral syrup 1:1 with water for use as a retention enema (Graves 1987):

Loading dose: 17 to 20 mg/kg once.

Maintenance: 10 to 15 mg/kg/dose every 8 hours.

Status epilepticus; urgent therapy/second-line therapy or refractory: Limited data available:

Loading dose: Initial:

American Epilepsy Society guidelines (AES [Glauser 2016]): Infants, Children, and Adolescents: IV: 40 mg/kg as a single dose; maximum dose: 3,000 mg/dose.

Neurocritical care guidelines (NCS [Brophy 2012]): Infants, Children, and Adolescents: IV: 20 to 40 mg/kg; may be followed by an additional 20 mg/kg after 10 minutes if needed.

Maintenance dose: Continuous IV infusion: 5 mg/kg/hour after the loading dose was used in pediatric continuous IV infusion studies (Mehta 2007; Uberall 2000); once patients were seizure-free for 6 hours, the infusion rate was decreased by 1 mg/kg/hour every 2 hours (Mehta 2007). Lower initial infusion rates of 1 mg/kg/hour have also been described (Malamiri 2012).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

All patients: Mild to severe impairment: No dosage adjustment required (including patients on hemodialysis); however, protein binding is reduced in patients with renal impairment; monitoring only total valproate serum concentrations may be misleading.

Dosing: Hepatic Impairment: Pediatric

All patients:

Mild to moderate impairment: Not recommended for use in hepatic disease; clearance is decreased with liver impairment. Hepatic disease is also associated with decreased albumin concentrations and 2- to 2.6-fold increase in the unbound fraction of valproate. Free concentrations of valproate may be elevated while total concentrations appear normal; therefore, monitoring only total valproate concentrations may be misleading.

Severe impairment: Use is contraindicated.

Dosing: Older Adult

Note: The dosing recommendations in this monograph are expressed as the total daily dose (ie, per 24 hours) unless stated otherwise. The total daily oral dose is given in 1 to 4 divided doses per day depending on the type of preparation. Available preparations include: Oral immediate release (usually dosed 3 to 4 times daily [Koch-Weser 1980]), delayed release (DR) (usually dosed 2 to 3 times daily) and extended release (ER) (commonly dosed once daily; may also be dosed twice daily) formulations and an IV injection. The ER oral formulation is not available in Canada. Available valproate formulations include valproic acid, valproate sodium, and divalproex sodium (also known as valproate semisodium) salts. All doses in this monograph are expressed as the equivalent amounts of valproic acid.

Oral, IV: Lower initial doses are recommended due to decreased elimination and increased incidences of somnolence in the elderly. No specific dosage recommendations are provided by the manufacturer; however, some experts suggest initial doses of 125 to 250 mg/day and gradually increasing the dose by 125 to 250 mg/day every 2 to 5 days up to a usual daily dose of 500 to 1,000 mg/day (Sajatovic 2002). Monitor closely for adverse events (eg, sedation, dehydration, decreased nutritional intake). Safety and efficacy for use in patients >65 years of age have not been studied for migraine prophylaxis.

Dosing conversions: Note: The ER formulation is not available in Canada:

Conversion from immediate release to DR or ER: Refer to adult dosing.

Conversion from DR to ER: Refer to adult dosing.

Conversion to IV valproate preparations : Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, Immediate Release, as valproic acid:

Depakene: 250 mg [DSC]

Generic: 250 mg

Capsule Delayed Release Sprinkle, Oral, as divalproex sodium:

Depakote Sprinkles: 125 mg [contains brilliant blue fcf (fd&c blue #1)]

Generic: 125 mg

Solution, Oral, Immediate Release, as valproate sodium:

Depakene: 250 mg/5 mL (480 mL [DSC])

Generic: 250 mg/5 mL (5 mL, 10 mL, 473 mL)

Solution, Intravenous, as valproate sodium:

Depacon: 100 mg/mL (5 mL [DSC]) [contains edetate (edta) disodium]

Solution, Intravenous, as valproate sodium [preservative free]:

Generic: 100 mg/mL (5 mL)

Tablet Delayed Release, Oral, as divalproex sodium:

Depakote: 125 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Depakote: 250 mg [contains fd&c yellow #6 (sunset yellow)]

Depakote: 500 mg [contains fd&c blue #2 (indigotine)]

Generic: 125 mg, 250 mg, 500 mg

Tablet Extended Release 24 Hour, Oral, as divalproex sodium:

Depakote ER: 250 mg, 500 mg

Generic: 250 mg, 500 mg

Generic Equivalent Available: US

Yes

Dosage Forms Considerations

Strengths of divalproex sodium and valproate sodium products are expressed in terms of valproic acid

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, Immediate Release, as valproic acid:

Generic: 250 mg

Capsule Delayed Release, Oral, as valproic acid:

Generic: 500 mg

Solution, Oral, Immediate Release, as valproate sodium:

Depakene: 250 mg/5 mL (240 mL, 480 mL) [contains fd&c red #40, methylparaben, propylparaben]

Generic: 250 mg/5 mL (450 mL)

Tablet Delayed Release, Oral, as divalproex sodium:

Epival: 125 mg [contains corn starch, fd&c red #40]

Epival: 250 mg [contains corn starch, fd&c yellow #6 (sunset yellow)]

Epival: 500 mg [contains corn starch, fd&c blue #2 (indigotine)]

Generic: 125 mg, 250 mg, 500 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Depakene, Depakote, Depakote ER: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021168s042lbl.pdf#page=48

Administration: Adult

Oral: Oral valproate products may cause GI upset; taking with food or slowly increasing the dose may decrease GI upset should it occur.

Divalproex sodium tablets (delayed release, extended release, and enteric coated [Canadian product]) and valproic acid capsules (immediate release): Swallow whole; do not crush or chew.

Divalproex sodium delayed release sprinkle capsules: May be swallowed whole or capsule opened and sprinkled on small amount (1 teaspoonful) of soft food (eg, pudding, applesauce) to be used immediately (do not store or chew).

Bariatric surgery: Tablet, extended and delayed release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Delayed-release and extended-release tablets should be swallowed whole. Do not crush or chew. Immediate-release capsule formulation is available but should not be chewed or crushed. Sprinkle capsules, oral solution, and injectable formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, close clinical monitoring is advised in the immediate postoperative phase for the theoretical circumstance of reduced absorption after bariatric surgery. Conversion to oral solution should be considered for high-risk labeled and off-label clinical indications (ie, seizure, mania, agitation).

IV: For IV use only.

Seizures: Following dilution to final concentration, manufacturer's labeling recommends administering over 60 minutes at a rate ≤20 mg/minute.

Status epilepticus: Loading dose: 3 to 6 mg/kg/minute (NCS [Brophy 2012]); however, evidence suggest rates of 10 mg/kg/minute may be safely used with doses up to 30 mg/kg (Limdi 2007).

Administration: Pediatric

Oral: May administer with food to decrease adverse GI effects; do not administer with carbonated drinks.

Depakote ER: Swallow whole; do not crush or chew.

Depakote sprinkle capsules: May be swallowed whole or capsule may be opened and sprinkled on small amount (1 teaspoonful) of soft food (eg, pudding, applesauce) to be used immediately; do not crush or chew sprinkle beads; do not store drug food mixture for later use.

Depakene capsule: Swallow whole; do not break, crush, or chew.

Parenteral: IV:

Migraine, acute therapy:

Intermittent IV doses: Adolescents: In trials, doses were infused at 50 mg/minute (Reiter 2005).

Continuous IV (including loading doses): Children ≥4 and Adolescents: In trials, loading dosing were infused over 30 to 60 minutes followed by a continuous infusion (Cook 2016; Taylor 2007; Zafar 2018).

Status epilepticus:

Manufacturer recommendations: Dilute dose prior to administration; infuse over 60 minutes; maximum infusion rate: 20 mg/minute; Note: Rapid infusions may be associated with an increase in adverse effects; infusions of ≤15 mg/kg administered over 5 to 10 minutes (1.5 to 3 mg/kg/minute) were generally well tolerated (Ramsay 2003). In pediatric patients, an infusion rate of 1.5 to 3 mg/kg/minute has been recommended (NCS [Brophy 2012]).

Rapid IV loading doses: Infants and Children: Dilute dose prior to administration; administer at 1.5 to 3 mg/kg/minute (NCS [Brophy 2012]; Yu 2003). Faster infusion rates have been used in some studies; doses of 20 to 40 mg/kg have been administered over 1 to 5 minutes (Mehta 2007; Uberall 2000).

Rectal: Dilute oral solution or syrup prior to rectal administration (Graves 1987).

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 3]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends single gloving for administration of intact tablets or capsules. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration. For IV preparation, double gloves, a protective gown, ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator), and closed system transfer devices (CSTDs) are recommended. Double gloving, a gown, and (if dosage form allows) CSTDs are required during administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Use: Labeled Indications

Bipolar disorder: Treatment of mania (delayed release) or acute mania or acute episodes with mixed features with or without psychotic features (extended release) associated with bipolar disorder, as monotherapy or in combination with atypical antipsychotics (BAP [Goodwin 2016]).

Focal (partial) onset and generalized onset seizures: Monotherapy and adjunctive therapy in the treatment of patients with focal onset seizures with impairment of consciousness or awareness (complex partial) and generalized onset nonmotor seizures (absence), and as adjunctive therapy for multiple seizure types. May be used off-label as monotherapy for other seizure types.

Migraine prophylaxis (excluding IV formulation): Prophylaxis of migraine headaches

Limitation of use: Do not administer to pregnant patients, patients who plan to become pregnant, or patients of childbearing potential for the treatment of epilepsy or bipolar disorder unless essential for the management of their condition.

Use: Off-Label: Adult

Bipolar major depression (alternative agent); Maintenance treatment of bipolar disorder; Migraine, intractable and status migrainosus; Status epilepticus

Medication Safety Issues
Sound-alike/look-alike issues:

Depakene may be confused with Depakote

Depakote may be confused with Depakene, Depakote ER, Senokot

Depakote ER may be confused with divalproex enteric coated

Valproate sodium may be confused with vecuronium

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.

Pediatric patients: High-risk medication:

KIDs List: Valproic acid and derivatives, when used in pediatric patients <6 years of age, are identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided in infants and used with caution in children <6 years of age due to risk of pancreatitis and fatal hepatotoxicity (strong recommendation; high quality of evidence) (PPA [Meyers 2020]).

Adverse Reactions (Significant): Considerations
CNS effects

Valproate may cause CNS effects, mostly related to CNS depression (including dizziness and drowsiness). However, nervous system stimulation (eg, nervousness, insomnia, tremor) may also occur at a high frequency in some patients. More severe reactions, including delirium (Ref) and hallucinations have also been reported. Parkinsonism and cognitive dysfunction are also concerns associated with several antiseizure medications, including valproate (Ref). Cognitive decline has particularly been a concern in patients with bipolar disorder (Ref). In general, valproate appears to have less effect on cognitive abilities compared to other older antiseizure medications (Ref).

Mechanism: Dose-related; decreases neuronal excitation in the CNS by enhancing the activity of gamma-amino butyric acid (GABA). Valproate also has a direct effect on voltage gated sodium channels, may regulate the excitatory activity of NMDA glutamate receptors, and regulates neuronal gene expression (Ref). Of note, cognitive function does not appear to correspond with ammonia levels in patients receiving valproate (Ref).

Onset: Varied; with respect to common (dose-related) CNS effects, the onset and duration correlate with the increase in concentration. Identification of patients with Parkinsonism and cognitive decline have been described after several years of therapy (Ref).

Risk factors:

• Increased unbound valproate concentrations (decreased albumin) (Ref)

• Use of multiple antiseizure medications (Ref)

Hematologic effects

Valproate is associated with a range of hematologic effects. Coagulopathy including thrombocytopenia, decreased platelet aggregation, and acquired von Willebrand disease type I may result in hemorrhage in patients receiving valproate. Severe complications including hemorrhagic stroke have occurred (Ref). In some cases, platelet counts may normalize with continued treatment. Thrombocytopenia is generally reversible with dose reduction or discontinuation (Ref). Other blood disorders including aplastic anemia, neutropenia, and pure red cell aplasia have been reported infrequently (Ref).

Mechanism: Dose-related; thrombocytopenia may result from direct bone marrow toxicity, increased platelet destruction, or antibody-mediated depletion of thrombocytes (Ref). Valproate may inhibit erythroid differentiation and may activate the myelo-monocytic pathway (Ref). Direct suppression of bone marrow by an idiosyncratic mechanism is responsible for the most severe reactions (eg, aplastic anemia) (Ref).

Onset: Varied; thrombocytopenia may occur between 8 days to 16 months after initiation. In one study, the mean time to onset was 82 days (range: 38 to 170 days); may develop more quickly depending on dose/valproate levels (Ref). Neutropenia may occur in the first few weeks of treatment (Ref).

Risk factors:

Thrombocytopenia corresponds to:

• Females (Ref)

• Higher dosage (Ref). Probability of thrombocytopenia increases with total valproate levels ≥110 mcg/mL in females or ≥135 mcg/mL in males.

• Older adults (Ref)

Hepatotoxicity/hepatic failure

Valproate is associated with hepatotoxicity and hepatic failure, including fatal cases in adult and pediatric patients (Ref). May progress despite discontinuation.

Mechanism: Non-dose-related; idiosyncratic. Drug-mediated hepatotoxicity can be the result of direct toxicity/hepatocyte necrosis or the formation of a neoantigen, which results in an immunologic reaction (Ref). Direct hepatotoxic reactions may be caused by reactive valproate metabolites, inhibition of fatty acid β-oxidation, excessive oxidative stress, and a susceptibility to these effects may be encoded by genetic variants of key enzymes (Ref). Valproate can cause significant mitochondrial toxicity which may underlie many of these events (Ref).

Onset: Varied. In patients with defined susceptibility mutations, including mitochondrial DNA polymerase gamma (POLG), hepatotoxicity commonly occurs within the first 3 months of treatment (Ref). The manufacturer’s labeling notes the onset of hepatotoxicity is most common in the first 6 months of therapy; however, clinicians should note these effects may occur at any time during therapy. Idiosyncratic drug-induced liver injury tends to occur with a more delayed onset (weeks to months) as complex mechanisms, including adaptive immune responses, have been implicated in these reactions (Ref).

Risk factors:

Pediatric patients; neonates, infants, and children <2 years of age are at higher risk (Ref)

Hereditary mutations of the POLG gene (eg, Alpers-Huttenlocher syndrome [AHS]) (Ref)

Neurologic disorders

Seizure disorder accompanied by developmental delay (Ref)

Metabolic disorders (Ref)

Patients on multiple antiseizure medications (Ref)

Genetic variants of some enzymes, such as carbamoyl phosphate synthetase (CPS1), glutathione S-transferase (GST), superoxide dismutase-2 (SOD2), UDP-glucuronosyl transferase (UGT), and cytochrome P450 isoenzymes (Ref)

Hyperammonemia and encephalopathy

Hyperammonemia and/or hyperammonemic encephalopathy have been reported following the initiation of valproate therapy. This may be characterized by drowsiness, lethargy, changes in level of consciousness, slowing of cognition, vomiting, and focal neurological deficits (Ref). Several types of hyperammonemia and encephalopathy have been suggested to occur, based on whether they occur in the presence or absence of hepatic dysfunction (Ref).

Mechanism: Non-dose-related; idiosyncratic. In the presence of risk factors (eg, urea cycle disorders, deficiency of carnitine, or high concentrations), valproate metabolism is shunted to a greater proportion of metabolism by omega-oxidation leading to the formation of 4-en-valproic acid, which decreases the function of carbamoyl-phosphate synthetase-1, a critical step in the urea cycle (Ref). Valproate therapy may induce carnitine deficiency in some individuals, particularly in children and adolescents (Ref). Valproate may also decrease the formation of N-acetyl-glutamic acid which is an allosteric activator of carbamoyl-phosphate synthetase 1 (Ref). Ammonia accumulation leads to glutamine and swelling of astrocytes with associated cerebral edema (Ref).

Onset: Varied; may generally occur in the first week of therapy in patients with susceptibility (Ref). However, in some cases the first detection of encephalopathy has occurred after several years of therapy (Ref).

Risk factors:

• Concurrent therapy with antipsychotic drugs (Ref)

• Concurrent therapy with liver enzyme-inducing antiseizure medications (Ref)

• Concurrent therapy with topiramate (even in patients who previously tolerated monotherapy)

• Nutritional status or a deficiency of carnitine (Ref)

• Overdose or higher doses (Ref)

• Sex (inconsistent data; some studies have shown a higher risk in males whereas others have shown a higher risk in females) (Ref)

Hypersensitivity reactions (delayed)

Valproate is associated with several forms of delayed hypersensitivity including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS) (Ref).

Mechanism: Non-dose-related; immunologic. Severe cutaneous reactions, including SJS/TEN and DRESS, are delayed type IV hypersensitivity reactions involving a T-cell mediated drug-specific immune response (Ref).

Onset: Varied; type IV reactions are delayed hypersensitivity reactions that typically occur days to weeks after drug exposure, but may occur more rapidly (usually within 1 to 4 days) upon re-exposure (Ref).

Risk factors:

• Concurrent therapy with lamotrigine may increase the risk of SJS/TEN and DRESS (Ref).

• Previous hypersensitivity to aromatic antiseizure medications: Cross-reactivity of valproate, a non-aromatic antiseizure medication, with aromatic antiseizure medications (eg, phenytoin and carbamazepine), is not well described (Ref). However, there are isolated reports of patients who develop DRESS following an aromatic antiseizure medications, as well as with valproate (Ref).

Pancreatitis

Cases of pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic pancreatitis with rapid progression from initial symptoms to death. Recurrence after rechallenge with valproate has also been documented (Ref).

Mechanism: Non-dose-related; idiosyncratic (Ref). Direct toxicity has been proposed (Ref).

Onset: Varied; in clinical trials, pancreatitis that was possibly or probably related to valproate occurred between 48 and 88 days after initiation (Ref). In postmarketing reports, cases occurred in the first year of therapy, but cases have been reported beyond 1 year. In one series, the average onset was 32 months of therapy (Ref).

Risk factors:

• Most cases have been reported in children with epilepsy or in adults with kidney impairment (Ref)

Suicidal ideation/tendencies

Antiseizure medications have been associated with suicidal ideation and suicidal tendencies. However, the FDA meta-analysis has been criticized due to several important limitations (Ref). The risk of suicide is increased in epilepsy (Ref), but the occurrence of suicidal ideation/tendencies in epilepsy is multifactorial. While some AEDs (but not all) have been associated with treatment-emergent psychiatric effects such as anxiety and depression, other factors such as postictal suicidal behavior and pertinent patient history must also be evaluated to provide an accurate assessment of risk for any individual drug (Ref).

Onset: Varied; peak incidence of suicidality across AEDs (not specific to individual agents) has been noted to occur between 1 and 12 weeks of therapy (Ref). A review of clinical trials noted that risk extended from 1 week to 24 weeks of therapy, corresponding to the duration of most trials.

Risk factors:

History of depression (Ref)

Use in conditions other than epilepsy, depression, or bipolar disorder (Ref)

In patients with bipolar disorder, risk for repeat suicide attempt was increased in patients with alcohol/substance abuse disorder, rapid cycling, and earlier age at onset of first manic episode (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported with oral administration, unless otherwise noted.

>10%:

Dermatologic: Alopecia (6% to 24%)

Gastrointestinal: Abdominal pain (oral: 7% to 23%; IV: 1%), anorexia (4% to 12%), diarrhea (oral: 7% to 23%; IV: <1%), dyspepsia (7% to 23%), nausea (oral: 15% to 48%; IV: 3% to 6%), vomiting (oral: 7% to 27%; IV: 1%)

Hematologic & oncologic: Thrombocytopenia (1% to 27%; dose related)

Infection: Infection (12% to 20%)

Nervous system: Dizziness (oral: 12% to 25%; IV: 5% to 7%) (table 1), drowsiness (oral: 7% to 30%; IV: 2% to 11%) (table 2), headache (oral: 31%; IV: 3% to 4%), insomnia (9% to 15%), nervousness (oral: 7% to 11%; IV: <1%), pain (oral: 11%; IV: 1%)

Valproic Acid and Derivatives: Adverse Reaction: Dizziness

Drug (Valproic Acid and Derivatives)

Placebo

Dosage Form

Indication

Number of Patients (Valproic Acid and Derivatives)

Number of Patients (Placebo)

12%

4%

Delayed-release oral

Acute mania

89

97

12%

7%

Extended-release oral

Acute mania

338

263

25%

13%

Delayed-release oral

Complex partial seizures

77

70

18%

N/A

Oral (high dose)

Complex partial seizures

131

N/A

13%

N/A

Oral (low dose)

Complex partial seizures

134

N/A

Valproic Acid and Derivatives: Adverse Reaction: Drowsiness

Drug (Valproic Acid and Derivatives)

Placebo

Dosage Form

Indication

Number of Patients (Valproic Acid and Derivatives)

Number of Patients (Placebo)

26%

14%

Extended-release oral

Acute mania

338

263

19%

12%

Delayed-release oral

Acute mania

89

97

30%

N/A

Oral (high dose)

Complex partial seizures

131

N/A

27%

11%

Delayed-release oral

Complex partial seizures

77

70

18%

N/A

Oral (low dose)

Complex partial seizures

134

N/A

17%

5%

Delayed-release oral

Migraine

202

81

7%

2%

Extended-release oral

Migraine

122

115

Neuromuscular & skeletal: Asthenia (oral: 6% to 27%; IV: 7%), tremor (oral: 9% to 57%; IV: <1%) (table 3)

Valproic Acid and Derivatives: Adverse Reaction: Tremor

Drug (Valproic Acid and Derivatives)

Placebo

Dosage Form

Indication

Number of Patients (Valproic Acid and Derivatives)

Number of Patients (Placebo)

57%

N/A

Oral (high dose)

Complex partial seizures

131

N/A

25%

6%

Delayed-release oral

Complex partial seizures

77

70

19%

N/A

Oral (low dose)

Complex partial seizures

134

N/A

9%

0%

Delayed-release oral

Migraine

202

81

Ophthalmic: Diplopia (16%), visual disturbance (amblyopia, blurred vision: 4% to 12%)

Respiratory: Flu-like symptoms (12%)

Miscellaneous: Accidental injury (6% to 11%)

1% to 10%:

Cardiovascular: Cardiac arrhythmia (>1%), chest pain (2%), edema (1% to 5%), facial edema (1% to 5%), hypertension (1% to 5%), hypotension (1% to 5%), orthostatic hypotension (1% to 5%), palpitations (1% to 5%), peripheral edema (3% to 8%), tachycardia (1% to 5%), vasodilation (oral: 1% to 5%; IV: <1%)

Dermatologic: Diaphoresis (oral: >1%; IV: <1%), ecchymoses (1% to 5%), erythema nodosum (>1%), furunculosis (1% to 5%), maculopapular rash (1% to 5%), pruritus (1% to 5%), seborrhea (1% to 5%), skin rash (6%), vesiculobullous dermatitis (>1%), xeroderma (1% to 5%)

Endocrine & metabolic: Amenorrhea (1% to 5%), weight gain (4% to 9%), weight loss (6%)

Gastrointestinal: Constipation (1% to 5%), dysgeusia (2%), dysphagia (>1%), eructation (1% to 5%), fecal incontinence (1% to 5%), flatulence (1% to 5%), gastroenteritis (1% to 5%), gingival hemorrhage (>1%), glossitis (1% to 5%), hematemesis (1% to 5%), hiccups (>1%), increased appetite (6%), oral mucosa ulcer (>1%), pancreatitis (1% to 5%; may be hemorrhagic pancreatitis) (Ozaydin 2008; Werlin 2006), periodontal abscess (1% to 5%), stomatitis (1% to 5%), xerostomia (1% to 5%)

Genitourinary: Cystitis (1% to 5%), dysmenorrhea (1% to 5%), dysuria (1% to 5%), urinary frequency (1% to 5%), urinary incontinence (1% to 5%), urinary tract infection (>1%), vaginal hemorrhage (1% to 5%), vaginitis (1% to 5%)

Hematologic & oncologic: Anemia (>1%), hypoproteinemia (>1%), leukopenia (>1%), petechia (1% to 5%), prolonged bleeding time (>1%)

Hepatic: Increased serum alanine aminotransferase (1% to 5%), increased serum aspartate aminotransferase (1% to 5%)

Infection: Fungal infection (>1%), viral infection (1% to 5%)

Local: Injection site reaction (IV: 2%), pain at injection site (IV: 3%)

Nervous system: Abnormal dreams (1% to 5%), abnormal gait (1% to 5%), abnormality in thinking (6%), agitation (1% to 5%), amnesia (4% to 7%), anxiety (1% to 5%), ataxia (8%), catatonia (1% to 5%), chills (1% to 5%), confusion (1% to 5%), depression (1% to 5%), dysarthria (1% to 5%), emotional lability (6%), hallucination (1% to 5%), hyperreflexia (1% to 5%), hypertonia (1% to 5%), malaise (1% to 5%), myasthenia (1% to 5%), paresthesia (oral, IV: ≤7%), personality disorder (1% to 5%), psychosis (>1%), sleep disorder (>1%), speech disturbance (1% to 5%), tardive dyskinesia (1% to 5%), twitching (1% to 5%), vertigo (1% to 5%)

Neuromuscular & skeletal: Arthralgia (1% to 5%), back pain (8%), discoid lupus erythematosus (1% to 5%), hypokinesia (1% to 5%), lower limb cramp (1% to 5%), myalgia (1% to 5%), neck pain (1% to 5%), neck stiffness (1% to 5%), osteoarthritis (1% to 5%)

Ophthalmic: Conjunctivitis (1% to 5%), dry eye syndrome (1% to 5%), eye pain (1% to 5%), nystagmus disorder (1% to 8%), photophobia (>1%)

Otic: Deafness (1% to 5%), otitis media (1% to 5%), tinnitus (1% to 7%)

Respiratory: Bronchitis (5%), cough (1% to 5%), dyspnea (1% to 5%), epistaxis (1% to 5%), pharyngitis (oral: 2% to 8%; IV: <1%), pneumonia (1% to 5%), rhinitis (1% to 5%), sinusitis (1% to 5%)

Miscellaneous: Fever (6%)

<1% (any indication):

Local: Inflammation at injection site (IV)

Nervous system: Euphoria (IV), hypoesthesia (IV)

Frequency not defined (any indication or formulation): Nervous system: Suicidal ideation, suicidal tendencies

Postmarketing (any indication or formulation):

Cardiovascular: Bradycardia, hemorrhagic stroke (Buoli 2018), hypersensitivity angiitis (Lasic 2012)

Dermatologic: Changes of hair (color, texture) (Kakunje 2018), erythema multiforme (Gau 2008), erythroderma (Rener-Primec 2014), nail bed changes (Güler 2017), nail disease (Solak 2017), psoriasiform eruption (Kwan 2014), skin photosensitivity, Stevens-Johnson syndrome (Gau 2008; Hashim 2004), toxic epidermal necrolysis (Gau 2008; Hashim 2004)

Endocrine & metabolic: Abnormal thyroid function test (Connacher 1987), acute intermittent porphyria (Herrick 1989), decreased plasma carnitine concentrations (Al-sharefi 2015), female hyperandrogenism (Morrell 2008), galactorrhea not associated with childbirth, hirsutism (Sidhu 2018), hyperammonemia (elevations identified in up to 50% of patients, but asymptomatic in most) (Segura-Bruna 2006), hyperammonemic encephalopathy (up to 2.5% of patients, particularly high risk in patients with urea cycle disorders) (Lewis 2017), hyperglycinemia, hyponatremia (Yamamoto 2019), increased testosterone level (DeVries 2007; Sidhu 2018), infrequent uterine bleeding (Joffe 2006), SIADH (Bavbek 2008)

Gastrointestinal: Parotid gland enlargement (Derin 2017)

Genitourinary: Asthenospermia (Yerby 1999), azoospermia, breast hypertrophy, decreased ejaculate volume, Fanconi-like syndrome (risk increased in children or in non-ambulatory, tube-fed, and/or developmentally delayed patients) (Knights 2016; Ono 2019), irregular menses, male infertility (Yerby 1999), oligospermia (Ocek 2018), polycystic ovary syndrome (may be more common in females with bipolar disorder) (Okanovvic 2016; Rasgon 2005), spermatozoa disorder (abnormal morphology) (Yerby 1999)

Hematologic & oncologic: Acquired blood coagulation disorder (coagulation factor deficiencies, von Willebrand’s disease), agranulocytosis, aplastic anemia, bone marrow depression, decreased platelet aggregation, hypofibrinogenemia, lymphocytosis, macrocytosis (with or without anemia), neutropenia (Acharya 2000), pancytopenia, pure red cell aplasia (Acharya 2000)

Hepatic: Hepatic failure (Mindikoglu 2011), hepatotoxicity (Chalasani 2021)

Hypersensitivity: Anaphylaxis, hypersensitivity reaction (Bota 2011, Toker 2015), multi-organ hypersensitivity reaction (Conilleau 1999, Dreesman 2010)

Immunologic: Drug reaction with eosinophilia and systemic symptoms (Gupta 2019)

Nervous system: Aggressive behavior, behavioral changes (including apathy, behavioral deterioration, and irritability), cerebral atrophy (reversible or irreversible), cognitive dysfunction (Pigoni 2020), delirium (Gareri 2009; may manifest as acute encephalopathy in the absence of elevated ammonia levels), dementia (some cases reversible) (Papazian 1995), developmental delay (learning disorder), disturbance in attention, emotional disturbance, hostility, hypothermia, parkinsonism (Balzabal-CarvaLLo 2019), psychomotor agitation, Reye's syndrome (specifically Reye's-like syndrome) (Hilmas 2000, Sugimoto 1983), seizure (Tsuyusaki 2012)

Neuromuscular & skeletal: Bone fracture (Vestergaard 2004), decreased bone mineral density (Fan 2019), osteopenia, osteoporosis (effect on fracture risk inconsistent/controversial; however, multiple biochemical changes documented) (Pitetzis 2017; Verrotti 2010), ostealgia

Ophthalmic: Acute angle-closure glaucoma (associated with DRESS) (Sanoria 2019)

Otic: Hearing loss (Yeap 2014)

Pulmonary: Interstitial pneumonitis (Kim 2014)

Renal: Interstitial nephritis (Yoshikawa 2002)

Contraindications

Hypersensitivity to valproic acid, divalproex, derivatives, or any component of the formulation; hepatic disease or significant impairment; urea cycle disorders; prevention of migraine in pregnant women and women of childbearing potential who are not using effective contraception; known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase gamma (POLG; eg, Alpers-Huttenlocher syndrome [AHS]) or children <2 years of age suspected of having a POLG-related disorder

Canadian labeling: Additional contraindications (not in US labeling): Treatment of epilepsy in pregnant women, unless no suitable alternative; treatment of epilepsy in women of childbearing potential, unless requirements of Pregnancy Prevention Program fulfilled (see Canadian labeling for more information); known porphyria

Epival: Additional contraindication: Treatment of bipolar disorder in pregnant women, unless no suitable alternative; treatment of bipolar disorder in women of childbearing potential, unless requirements of Pregnancy Prevention Program fulfilled (see Canadian labeling for more information)

Warnings/Precautions

Disease-related concerns:

• Acute head trauma: Not recommended for post-traumatic seizure prophylaxis in patients with acute head trauma; study results for this indication suggested increased mortality with IV valproate sodium use compared to IV phenytoin.

• Dementia: Not recommended for treatment of dementia-associated agitation or aggression; evidence suggests lack of efficacy for this indication, as well as, an increased risk of adverse effects (Baillon 2018; NICE 2018).

• Hepatic impairment: Contraindicated for use in hepatic disease.

Special populations:

• Elderly: Use with caution as elderly patients may be more sensitive to sedating effects and dehydration; in some elderly patients with somnolence, concomitant decreases in nutritional intake and weight loss were observed. Reduce initial dosages in elderly patients and closely monitor fluid status, nutritional intake, somnolence, and other adverse events.

Other warnings/precautions:

• Gastrointestinal: Medication residue in stool has been reported (rarely) with oral divalproex sodium formulations; some reports have occurred in patients with shortened GI transit times (eg, diarrhea) or anatomic GI disorders (eg, ileostomy, colostomy). In patients reporting medication residue in stool, it is recommended to monitor valproate level and clinical condition.

• Viral replication: In vitro studies have suggested valproate stimulates the replication of HIV and CMV viruses under experimental conditions. The clinical consequence of this is unknown, but should be considered when monitoring affected patients.

• Withdrawal: Antiseizure medications should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Warnings: Additional Pediatric Considerations

Although carnitine is indicated for the management of valproic acid overdose and hepatotoxicity (and strongly recommended for select patients at high risk of valproic acid-associated hepatotoxicity), the role of routine prophylactic carnitine supplementation is unclear (Freeman 1994; Raskind 2000). A case of a fatal hepatotoxic reaction has been reported in a child receiving valproic acid despite carnitine supplementation (Murphy 1993).

Medication residue in stool has been reported (rarely) with oral Depakote (divalproex sodium) formulations; some reports have occurred in patients with shortened GI transit times (eg, diarrhea) or anatomic GI disorders (eg, ileostomy, colostomy). In patients reporting medication residue in stool, it is recommended to monitor valproate level and clinical condition.

Metabolism/Transport Effects

Substrate of CYP2A6 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2E1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Apixaban: Valproate Products may diminish the therapeutic effect of Apixaban. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Barbiturates: Valproate Products may increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Bupivacaine: Valproate Products may enhance the adverse/toxic effect of Bupivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabidiol: Valproate Products may enhance the hepatotoxic effect of Cannabidiol. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

CarBAMazepine: Valproate Products may increase serum concentrations of the active metabolite(s) of CarBAMazepine. Parent carbamazepine concentrations may be increased, decreased, or unchanged. CarBAMazepine may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Carbapenems: May decrease the serum concentration of Valproate Products. Management: Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure medication. Risk D: Consider therapy modification

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

ChlorproMAZINE: May increase the serum concentration of Valproate Products. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the serum concentration of Valproic Acid and Derivatives. Management: Separate administration of valproic acid and cholestyramine by at least 3 hours whenever possible in order to minimize this interaction. The impact of concurrent cholestyramine on delayed- or extended-release valproic acid is uncertain. Risk D: Consider therapy modification

CloBAZam: Valproate Products may enhance the CNS depressant effect of CloBAZam. CloBAZam may increase the serum concentration of Valproate Products. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Cosyntropin: May enhance the hepatotoxic effect of Valproate Products. Management: Avoid concomitant use of Synacthen Depot (dosage form available in Canada) with valproic acid. Risk X: Avoid combination

Dabigatran Etexilate: Valproate Products may diminish the therapeutic effect of Dabigatran Etexilate. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dolutegravir: Valproate Products may decrease the serum concentration of Dolutegravir. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Estrogen Derivatives (Contraceptive): May decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Ethosuximide: May decrease the serum concentration of Valproate Products. Valproate Products may increase the serum concentration of Ethosuximide. Risk C: Monitor therapy

Felbamate: May increase the serum concentration of Valproate Products. Management: Initiate felbamate at typical doses (1,200 mg/day in 3 or 4 divided doses for adults and children 14 years of age or older; 15 mg/kg/day in 3 or 4 divided doses in children 2 to 14 years of age) while reducing the valproate product dose by 20%. Risk D: Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fosphenytoin-Phenytoin: Valproate Products may decrease the protein binding of Fosphenytoin-Phenytoin. This appears to lead to an initial increase in the percentage of unbound (free) phenytoin and to a decrease in total phenytoin concentrations. Whether concentrations of free phenytoin are increased is unclear. With long-term concurrent use, total phenytoin concentrations may increase. Fosphenytoin-Phenytoin may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Fotemustine: Valproate Products may enhance the adverse/toxic effect of Fotemustine. Risk C: Monitor therapy

Ginkgo Biloba: May decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

GuanFACINE: May increase the serum concentration of Valproate Products. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

LamoTRIgine: Valproate Products may enhance the adverse/toxic effect of LamoTRIgine. Valproate Products may increase the serum concentration of LamoTRIgine. Management: Lamotrigine dose reductions are needed when combined with valproate. See full interaction monograph for details. Increase monitoring for lamotrigine toxicity (eg, rash, hematologic toxicities) when these agents are combined. Risk D: Consider therapy modification

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lesinurad: Valproate Products may increase the serum concentration of Lesinurad. Risk X: Avoid combination

LevETIRAcetam: May enhance the CNS depressant effect of Valproate Products. Risk C: Monitor therapy

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

LORazepam: Valproate Products may increase the serum concentration of LORazepam. Management: Reduce lorazepam dose 50% during coadministration with valproate products. Monitor for increased lorazepam effects, particularly CNS depression. Patients taking lorazepam extended-release capsules should be switched to lorazepam tablets. Risk D: Consider therapy modification

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mefloquine: May diminish the therapeutic effect of Antiseizure Agents. Mefloquine may decrease the serum concentration of Antiseizure Agents. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If antiseizure drugs are being used for another indication, monitor antiseizure drug concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification

Methotrexate: May decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Methylfolate: May decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Mianserin: May diminish the therapeutic effect of Antiseizure Agents. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Minoxidil (Systemic): Valproate Products may increase the serum concentration of Minoxidil (Systemic). Risk C: Monitor therapy

OLANZapine: Valproate Products may decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orlistat: May decrease the serum concentration of Antiseizure Agents. Risk C: Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

OXcarbazepine: Valproate Products may decrease the serum concentration of OXcarbazepine. Risk C: Monitor therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: Valproate Products may increase the serum concentration of Oxybate Salt Products. Management: Decrease the dose of the oxybate salt product by at least 20% when initiating therapy with valproate products. When initiating oxybate salt products in patients taking valproate products, use a lower starting dose of the oxybate salt. Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paliperidone: Valproate Products may increase the serum concentration of Paliperidone. Risk C: Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Perampanel: Valproate Products may enhance the CNS depressant effect of Perampanel. Perampanel may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pivmecillinam: Valproate Products may enhance the adverse/toxic effect of Pivmecillinam. Specifically, the risk for carnitine deficiency may be increased. Risk X: Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Primidone: Valproate Products may increase the serum concentration of Primidone. More specifically, the serum concentration of phenobarbital, primidone's primary active metabolite, may be increased. Primidone may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Propofol: Valproate Products may enhance the therapeutic effect of Propofol. Risk C: Monitor therapy

Protease Inhibitors: May decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

RifAMPin: May decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

RisperiDONE: Valproate Products may enhance the adverse/toxic effect of RisperiDONE. Generalized edema has developed. Risk C: Monitor therapy

Rivaroxaban: Valproate Products may diminish the therapeutic effect of Rivaroxaban. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: Valproate Products may increase the serum concentration of Rufinamide. Management: Initiate rufinamide at a dose less than 10 mg/kg/day (children) or 400 mg/day (adults) in patients receiving valproic acid. In patients receiving rufinamide, initiate valproic acid at a low dose and titrate based on clinical response. Risk D: Consider therapy modification

Salicylates: May increase the serum concentration of Valproate Products. Risk C: Monitor therapy

Sapropterin: Valproate Products may decrease the serum concentration of Sapropterin. Specifically, valproate products may decrease tissue concentrations of tetrahydrobiopterin. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Temozolomide: Valproate Products may enhance the adverse/toxic effect of Temozolomide. Valproate Products may increase the serum concentration of Temozolomide. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Topiramate: May enhance the adverse/toxic effect of Valproate Products. Risk C: Monitor therapy

Tricyclic Antidepressants: Valproate Products may increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Urea Cycle Disorder Agents: Valproate Products may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Valproate Products may increase plasma ammonia concentrations and thereby increase the doses of Urea Cycle Disorder Agents needed to maintain concentrations in the target range. Risk C: Monitor therapy

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Vorinostat: Valproate Products may enhance the thrombocytopenic effect of Vorinostat. This may increase the risk of gastrointestinal bleeding. Risk C: Monitor therapy

Warfarin: Valproate Products may decrease the protein binding of Warfarin. Risk C: Monitor therapy

Zidovudine: Valproate Products may increase the serum concentration of Zidovudine. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Food Interactions

Food may delay but does not affect the extent of absorption. Management: May administer with food if GI upset occurs.

Reproductive Considerations

Valproate is contraindicated for prophylaxis of migraine headaches in patients of childbearing potential who are not using effective contraception.

Valproate should not be used to treat patients with epilepsy or bipolar disorder who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.

Evaluate pregnancy status in patients who could become pregnant (Larsen 2015; Toledo 2021). Patients with epilepsy prescribed valproate should be switched to other agents prior to menarche (Toledo 2021). Counsel patients at the onset of puberty and regularly during therapy regarding risks and benefits of valproate if pregnancy should occur during treatment. Valproate should not be administered to a patient of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. If valproate therapy is required in patients who could become pregnant, highly effective individualized contraception should be used. When use of valproate is required in patients with epilepsy who could become pregnant, the minimum effective dose should be used, and slow-release formulations should be prescribed (to avoid high peak concentrations) (Toledo 2021).

Algorithms are available for the management of patients who are planning a pregnancy or could have an unexpected pregnancy while taking valproic acid for bipolar disorder. Nonpregnant patients who are stable on monotherapy and are planning a pregnancy should undergo a slow taper (>4 weeks); alternative treatment and a faster taper should be introduced in unstable patients during this time. Additional details are available for patients planning a pregnancy who are on multiple medications (Anmella 2019).

When pregnancy is being planned in patients with epilepsy, consider tapering off of therapy prior to conception if appropriate (Anmella 2019; Harden 2009a); abrupt discontinuation of therapy may cause status epilepticus and lead to maternal and fetal hypoxia. Pregnancies should be planned 1 year prior to conception, ≥ 1 month after the last valproate dose during a seizure-free period. Contraception should continue for 3 months after discontinuing valproate and transitioning to a new antiepileptic medication (Toledo 2021).

Counsel patients planning to become pregnant regarding benefits and risk of valproate use during pregnancy. Folic acid decreases the risk of neural tube defects in the general population; supplementation with folic acid should be used prior to conception and during pregnancy in all patients, including those taking valproate.

Infertility, irregular menses, secondary amenorrhea, polycystic ovary syndrome, aspermia, azoospermia, decreased sperm count and motility, and abnormal sperm morphology have been reported following valproate use.

Pregnancy Considerations

Valproate crosses the placenta (Harden 2009b).

Valproate can cause major congenital malformations, particularly neural tube defects (eg, spina bifida). In addition, valproate can cause decreased IQ scores and neurodevelopmental disorders following in utero exposure. Neural tube defects, craniofacial defects (eg, oral clefts, craniosynostosis), cardiovascular malformations, hypospadias, and limb malformations (eg, clubfoot, polydactyly) have been reported. Information from the North American Antiepileptic Drug Pregnancy Registry notes the rate of major malformations to be 9% to 11% following an average exposure to valproate monotherapy 1,000 mg/day; this is an increase in congenital malformations when compared with monotherapy with other antiseizure drugs (AED). Based on data from the CDC National Birth Defects Prevention Network, the risk of spinal bifida is approximately 1% to 2% following valproate exposure (general population risk estimated to be 0.06% to 0.07%).

Nonteratogenic adverse effects have also been reported. Decreased IQ scores have been noted in children exposed to valproate in utero when compared to children exposed to other antiseizure medications or no antiseizure medications; the risk of autism spectrum disorders and attention deficit/hyperactivity disorder may also be increased. Hearing loss or impairment may occur following in utero exposure. Fatal hepatic failure and hypoglycemia in infants have been noted in case reports following in utero exposure to valproate.

The pharmacokinetic properties of valproate in pregnancy are highly variable. If use is needed, monitoring of total and unbound serum concentrations should be done prior to and during pregnancy (Johannessen 2018). Clotting factor abnormalities (hypofibrinogenemia, thrombocytopenia, or decrease in other coagulation factors) may develop in the mother following valproate use during pregnancy; close monitoring of coagulation factors is recommended.

Due to the risks of adverse fetal events, valproate is contraindicated for prophylaxis of migraine headaches in pregnant patients. Valproate should not be used to treat pregnant patients with epilepsy or bipolar disorder unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. Current guidelines recommend complete avoidance of valproate for the treatment of epilepsy in pregnant patients whenever possible (Harden 2009a).

Data collection to monitor pregnancy and infant outcomes following exposure to valproate is ongoing. A pregnancy registry is available for patients who have been exposed to valproic acid. Patients may enroll themselves in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling (888) 233-2334. Additional information is available at www.aedpregnancyregistry.org.

Breastfeeding Considerations

Valproate is present in breast milk.

A study presented information from 30 lactating women with epilepsy on monotherapy (51%), combination therapy with one additional agent (46%), or triple therapy (3%). In all cases, breast milk was collected between 6 and 32 days postpartum (median 7 days) and sampling occurred prior to the morning dose. Using information from all women in the study, values for maternal dose (3.6 to 20.6 mg/kg), maternal serum (5.4 to 69 mg/L), breast milk (<1 to 16.7 mg/L), and infant serum (<1 to 17.5 mg/L) were presented. Breast milk concentrations were highly variable and did not correlate with maternal dose. In this study, valproate concentrations were below the limit of quantification in 67% of breast milk and 33% of infant serum samples. This study did not monitor adverse events in the infants (Kacirova 2019).

The risk of valproate-related hepatotoxicity is increased following therapeutic use in pediatric patients <2 years of age; theoretically, this risk is also present in infants exposed to valproate via breast milk. Reported adverse effects in breastfed infants include a possible case of thrombocytopenia and anemia (Stahl 1997).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Infants exposed to valproate via breast milk should be monitored for signs of liver damage, including jaundice and unusual bruising or bleeding. Valproate is considered compatible with breastfeeding (Ito 2000; Larsen 2015; Toledo 2021; WHO 2002); monitoring of the infant for side effects (eg, jaundice) is recommended (WHO 2002).

Monitoring Parameters

Liver enzymes (at baseline and frequently during therapy especially during the first 6 months), CBC with platelets (baseline and periodic intervals), PT/PTT (especially prior to surgery), serum ammonia (with symptoms of unexplained lethargy and vomiting, hypothermia, or mental status change), serum valproate levels; signs and symptoms of hepatotoxicity (eg, malaise, weakness, facial edema, anorexia, jaundice, and vomiting; especially in patients >2 years of age who are clinically suspected of having a hereditary mitochondrial disease); signs and symptoms of pancreatitis (eg, abdominal pain, nausea, vomiting, and/or anorexia); suicidality (eg, suicidal thoughts, depression, behavioral changes); mental alertness; signs and symptoms of motor and cognitive function decline; evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation; signs and symptoms of drug reaction with eosinophilia and systemic symptoms (eg, possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems); menstrual history to assess for polycystic ovary syndrome (at 3 to 6 month intervals for the first year, then annually) (CANMAT [Yatham 2018]).

Evaluate pregnancy status in patients who could become pregnant (Larsen 2015; Toledo 2021).

Reference Range

Note: In general, trough concentrations should be used to assess adequacy of therapy; peak concentrations may also be drawn if clinically necessary (eg, concentration-related toxicity). Within 3 to 4 days of initiation or dose adjustment, trough concentrations should be drawn just before the next dose (CANMAT/ISBD [Yatham 2018]). When extended release tablets are administered at bedtime, levels drawn at least 18 hours post-dose have been suggested to provide an acceptable estimate of trough concentrations when levels timed closer to the next dose are inconvenient (eg, during outpatient monitoring) (Reed 2006). Additional patient-specific factors must be taken into consideration when interpreting drug levels, including indication, age, clinical response, pregnancy status, adherence, comorbidities, adverse effects, and concomitant medications (Patsalos 2018).

Valproic acid, total:

Therapeutic:

Epilepsy: 50 to 100 mcg/mL (SI: 350 to 700 micromole/L); although seizure control may improve at levels >100 mcg/mL (SI: 700 micromole/L), toxicity may occur at levels of 100 to 150 mcg/mL (SI: 700 to 1,040 micromole/L)

Mania: Adults: 50 to 125 mcg/mL (SI: 350 to 875 micromole/L); lower levels up to 90 mcg/mL (624 micromole/L) have been suggested in the elderly (Chen 1999).

Valproic acid, free: Adults:

Therapeutic: 5 to 15 mcg/mL (Smetana 2016)

Mechanism of Action

Causes increased availability of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, to brain neurons or may enhance the action of GABA or mimic its action at postsynaptic receptor sites. Also blocks voltage-dependent sodium channels, which results in suppression of high-frequency repetitive neuronal firing (Bourin 2009). Divalproex sodium is a compound of sodium valproate and valproic acid; divalproex dissociates to valproate in the GI tract.

Pharmacokinetics

Distribution: Distributes into CSF at concentrations similar to unbound concentration in plasma (ie, ~10% of total plasma concentration)

Vd: Total valproate: 11 L/1.73 m2; Free valproate 92 L/1.73 m2

Protein binding (concentration dependent): 80% to 90%; free fraction: ~10% at 40 mcg/mL and ~18.5% at 130 mcg/mL; protein binding decreased in neonates, the elderly and patients with hepatic or renal impairment

Metabolism: Extensively hepatic via glucuronide conjugation (30% to 50% of administered dose) and 40% via mitochondrial beta-oxidation; other oxidative metabolic pathways occur to a lesser extent.

Bioavailability: Extended release: ~90% relative to IV dose and ~89% relative to delayed release formulation. In pediatric patients 10 to 17 years of age, once-daily administration of the ER formulation produced valproate plasma concentration-time profiles similar to adults.

Half-life elimination (increased in neonates, elderly, and patients with liver impairment):

Newborns (exposed to VPA in utero): 30 to 60 hours

Neonates first week of life: 40 to 45 hours

Neonates <10 days: 10 to 67 hours

Children >2 months: 7 to 13 hours

Children and Adolescents 2 to 14 years: 9 hours (range: 3.5 to 20 hours) (Cloyd 1993)

Adults: 9 to 19 hours

Time to peak, serum:

Oral:

Divalproex sodium:

Delayed release: tablet and sprinkle capsules: ~4 hours

Extended release: 4 to 17 hours

Immediate release enteric-coated tablet [Canadian product]: 4 hours

Valproic acid delayed release capsule: 2 hours

Rectal (off-label route): 1 to 3 hours (Graves 1987)

Excretion: Urine (30% to 50% as glucuronide conjugate, <3% as unchanged drug); faster clearance in children who receive other antiseizure drugs and those who are younger; age and polytherapy explain 80% of interpatient variability in total clearance; children >10 years of age have pharmacokinetic parameters similar to adults

Note: ER formulation has 10% to 20% less fluctuation in serum concentration than delayed release formulation. ER formulation is not bioequivalent to delayed release formulation.

Pharmacokinetics: Additional Considerations

Renal function impairment: A 27% reduction in clearance of unbound valproate is seen in patients with CrCl <10 mL/minute. Hemodialysis reduces valproate concentrations by 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding is reduced. Monitoring of free valproate concentrations may be of clinical value; total valproate concentrations may be misleading.

Hepatic function impairment: Clearance is decreased with liver impairment. Hepatic disease is also associated with decreased albumin concentrations and 2- to 2.6-fold increase in the unbound fraction. Free concentrations of valproate may be elevated while total concentrations appear normal.

Pricing: US

Capsule, delayed release (Stavzor Oral)

125 mg (100): $153.30

250 mg (100): $301.09

500 mg (100): $555.19

Capsule, sprinkles (Depakote Sprinkles Oral)

125 mg (100): $137.53

Capsule, sprinkles (Divalproex Sodium Oral)

125 mg (100): $89.61

Capsules (Depakene Oral)

250 mg (100): $404.33

Capsules (Valproic Acid Oral)

250 mg (100): $82.51

Solution (Depacon Intravenous)

100 mg/mL (5 mL): $25.76

Solution (Valproate Sodium Intravenous)

100 mg/mL (5 mL): $8.03

Syrup (Depakene Oral)

250 mg/5 mL (480 mL): $413.27

Tablet, 24-hour (Depakote ER Oral)

250 mg (100): $257.70

500 mg (100): $453.28

Tablet, 24-hour (Divalproex Sodium ER Oral)

250 mg (100): $167.91

500 mg (100): $295.36

Tablet, EC (Depakote Oral)

125 mg (100): $144.25

250 mg (100): $283.36

500 mg (100): $522.54

Tablet, EC (Divalproex Sodium Oral)

125 mg (100): $89.72

250 mg (100): $176.23

500 mg (100): $324.97

Brand Names: International
  • Absenor (SE);
  • Aleptiz (PH);
  • Apilepsin (HR);
  • Convulex (AT, BE, BG, CH, CZ, DE, EE, GB, HN, HU, IE, LU, PL, RU, SG, TR, TW);
  • Delepsine (DK);
  • Depacon (KP, PH);
  • Depakene (AR, CN, CO, ID, JP, PE, PH, PY, UY);
  • Depakin (IT, PK, RU, TR);
  • Depakine (AE, AT, BE, BG, BH, CH, CY, EE, EG, ES, FR, GR, HN, HU, IQ, IR, JO, KW, LB, LU, LY, OM, PL, PT, QA, RU, SA, SY, TH, VE, YE);
  • Depakine Chrono (KP, LU, TH, TW);
  • Depakote (BZ, SR);
  • Deprakine (DK, FI, NO);
  • Desorate (TH);
  • Epilim (AU, BF, BJ, CI, ET, GB, GH, GM, GN, HK, IE, KE, KP, LR, MA, ML, MR, MU, MW, MY, NE, NG, NZ, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW);
  • Epilim Chrono 500 (BB, BM, BS, GY, HK, JM, MY, NL, PR, TT);
  • Episenta (GB);
  • Epival (AE, BH, CR, CY, DO, EG, GT, IQ, IR, JO, KW, LB, LY, MX, NI, OM, PA, PH, QA, SA, SV, SY, YE);
  • Ergenyl (SE);
  • Everiden (HU);
  • Lepavent (TW);
  • Leptilan (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TW, TZ, UG, ZA, ZM, ZW);
  • Neuractin (CO);
  • Oltril (TH);
  • Orfiril (CZ, DE, FI, HU);
  • Orfiril Retard (SG);
  • Petilin (AE, BF, BH, BJ, CI, CY, EG, ET, GH, GM, GN, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, QA, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZA, ZM, ZW);
  • Valcote (CO, EC);
  • Valeptol SR (KP);
  • Valpakine (BR, EC);
  • Valparin (TH);
  • Valporal (IL);
  • Valprax (PE);
  • Valpro (AU, HK);
  • Valpron (VE);
  • Valsup (CO);
  • Valtec-CR (IN);
  • Vematina (MX)


For country abbreviations used in Lexicomp (show table)

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