Sodium Valproate

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 24-hour extended release (ER) (dosed once daily) formulations and an IV injection. The 24-hour 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:

Acute manic or mixed episodes (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 2019).

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 (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 2018).

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 prophylaxis: Oral: Initial: 500 mg once daily (24-hour extended release) or in 2 divided doses (delayed release); 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 (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 (Gaspard 2018).

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 2019). In patients discontinuing therapy for treatment of bipolar disorder, close monitoring for several weeks to months for reemergence of mania/hypomania is recommended (Post 2019).

Dosing conversions: Note: The 24-hour ER formulation is not available in Canada:

Conversion from immediate release to DR or 24-hour 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 24-hour ER, increase the total daily dose of 24-hour ER by 8 to 20% and dose once daily.

Conversion from DR to 24-hour ER: For patients on a stable dose of DR, increase the total daily dose of 24-hour ER by 8% to 20% to maintain similar serum concentrations, and dose once daily.

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.

Dosing: Geriatric

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 24-hour extended release (ER) (dosed once daily) formulations and an IV injection. The 24-hour 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 24-hour ER formulation is not available in Canada:

Conversion from immediate release to DR or 24-hour ER: Refer to adult dosing.

Conversion from DR to 24-hour ER: Refer to adult dosing.

Conversion to IV valproate preparations: Refer to adult dosing.

Dosing: Renal Impairment: Adult

Mild to severe impairment: No dosage adjustment necessary; however, due to decreased protein binding in renal impairment, monitoring of free valproate concentrations may be of clinical value. Total valproate concentrations may be misleading.

Hemodialysis: No dosage adjustment necessary; however, due to decreased protein binding in renal impairment, monitoring of free valproate concentrations may be of clinical value. Total valproate concentrations may be misleading. Dose supplementation is generally not needed, but may be required with high-flux dialyzers (Asconapé 2014).

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

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 anticonvulsant (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. 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 antiepileptic 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; refractory: Limited data available: Infants, Children, and Adolescents:

IV:

Loading dose: Initial: 20 to 40 mg/kg; some experts recommend an additional 20 mg/kg after 10 to 15 minutes if needed (Brophy 2012); there is limited experience with loading doses >40 mg/kg in infants.

In one retrospective study, an initial loading dose of 25 mg/kg was effective in stopping seizure activity within 20 minutes after the end of the infusion in all 18 patients treated for status epilepticus (Yu 2003). A separate retrospective trial found a higher efficacy rate in pediatric patients who received an initial loading dose of 30 to 40 mg/kg (73.3%, n=15) compared to 20 to 30 mg/kg (46.2%, n=26) or >40 mg/kg (40%, n=10) (Uberall 2000). In an open-label, randomized comparative trial, an initial loading dose of 30 mg/kg was administered (n=20; age range: 7 months to 10 years of age; mean age: 3 years); a repeat bolus of 10 mg/kg could be administered if seizures were not controlled within 10 minutes; mean required dose: 37.5 ± 4.4 mg/kg; median required dose: 40 mg/kg (Mehta 2007). In one prospective, randomized comparative trial, valproic acid (n=30; median age: 5 years; range: 3 to 16 years) was compared to phenobarbital (n=30; median age: 4 years; range: 3 to 11 years) for treatment of convulsive status epilepticus or prolonged convulsive seizures in patients who had failed diazepam; the primary outcome measure was response at 20 minutes after initiation of the dose; results showed in the valproic acid group, 27 patients (90%) had attained seizure control compared to 23 patients (77%) that received phenobarbital (Malamiri 2012).

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).

Rectal: Dilute oral syrup 1:1 with water for use as a retention enema (Snead 1985):

Loading dose: 15 to 20 mg/kg once.

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

Dosing: Renal 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.

Use: Labeled Indications

Bipolar disorder: Treatment of manic episodes (delayed release) or acute manic or mixed episodes with or without psychotic features (24-hour 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 women, women who plan to become pregnant, or women of childbearing potential for the treatment of epilepsy or bipolar disorder unless essential for the management of her condition.

Use: Off-Label: Adult

Bipolar major depression (alternative agent)Level of Evidence [C, G]

Data from a limited number of patients studied suggest that valproate may be beneficial as monotherapy for the treatment of depressive episodes in patients with bipolar disorder ^Ref.

Based on the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines for the management of patients with bipolar disorder, valproate is recommended as monotherapy or as an adjunct to antidepressants in patients who have not responded to first-line options ^Ref.

Maintenance treatment of bipolar disorderLevel of Evidence [C, G]

Data from a limited number of clinical trials suggest that valproate may delay future mood episodes following a manic episode in bipolar disorder ^Ref.

Based on the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines for the management of patients with bipolar disorder and the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders, medications that are effective in acute mania are recommended for continuation during maintenance treatment, and valproate is recommended for maintenance treatment of bipolar disorder based on limited positive evidence ^Ref. Based on the WFSBP guidelines for the acute and long-term treatment of mixed states in bipolar disorder, valproate is recommended for maintenance treatment to prevent a mixed episode following a depressed or manic episode based on limited positive evidence ^Ref.

Status epilepticusLevel of Evidence [B, G]

Data from multiple studies, including randomized controlled trials, support the use of valproate sodium for the treatment of urgent or refractory status epilepticus ^Ref. In a systematic review of clinical trials in status epilepticus, valproate sodium was determined to be a safe therapeutic option in patients with established status epilepticus who previously failed conventional first-line treatment with benzodiazepines ^Ref.

Based on the Neurocritical Care Society guidelines for the evaluation and management of status epilepticus and the American Epilepsy Society Guidelines for the treatment of convulsive status epilepticus in children and adults, the use of intravenous valproate sodium is an effective and recommended treatment option for urgent control of status epilepticus in adults; however, benzodiazepines continue to be the agents of choice for initial therapy.

Level of Evidence Definitions

Level of Evidence Scale

Use: Unsupported: Adult

Tardive dyskinesia

Use of valproic acid in the treatment of neuroleptic-induced tardive dyskinesia has been evaluated in older controlled trials demonstrating conflicting results. There is no current evidence to support this use ^Ref. Access Full Off-Label Monograph

Clinical Practice Guidelines

Bipolar Disorder:

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD), “Guidelines for the Management of Patients with Bipolar Disorder - Update 2018,” March 2018

World Federation of Societies of Biological Psychiatry (WFSBP), “Guidelines for the Biological Treatment of Bipolar Disorders: Acute and Long-Term Treatment of Mixed States in Bipolar Disorder,” November 2017

WFSBP, “Guidelines for the Biological Treatment of Bipolar Disorders: Update 2009 on the Treatment of Acute Mania,” 2009

WFSBP, “Guidelines for the Biological Treatment of Bipolar Disorders: Update 2010 on the Treatment of Acute Bipolar Depression,” 2010

WFSBP, “Guidelines for the Biological Treatment of Bipolar Disorders: Update 2012 on the long-term treatment of bipolar disorder,” 2013

Drug-Induced Liver Injury:

American College of Gastroenterology (ACG), “2014 ACG Guideline for Idiosyncratic Drug-induced Liver Injury,” July 2014

Migraine Prophylaxis:

AAN, "Evidence-Based Guideline Update: Pharmacologic Treatment for Episodic Migraine Prevention in Adults,” April 2012

Seizure disorders:

American Academy of Neurology and American Epilepsy Society, “Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy,” 2018

Status Epilepticus:

American Epilepsy Society Guidelines, “Treatment of Convulsive Status Epilepticus in Children and Adults,” January 2016

Neurocritical Care Society (NCS), “Guidelines for the Evaluation and Management of Status Epilepticus,” April 2012

Administration: IV

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: 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, 24-hour 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).

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 (Brophy 2012).

Rapid IV loading doses: Infants and Children: Dilute dose prior to administration; administer at 1.5 to 3 mg/kg/minute (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).

Storage/Stability

Oral capsules:

Immediate release: Store at 15°C to 25°C (59°F to 77°F).

Delayed release: Store at 25°C (77° F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Oral sprinkle capsules: Delayed release: Store below 25°C (77°F).

Oral solution: Immediate release: Store below 30°C (86°F).

Oral tablets:

Delayed release: Store below 30°C (86°F).

24-hour extended release: Store tablets at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Immediate release [Canadian product]: Store at 15°C and 25°C (59°F and 77°F). Protect from light.

IV: Store at controlled room temperature 15°C to 30°C (59°F to 86°F). Stable in D5W, NS, and LR for at least 24 hours when stored in glass or PVC.

Preparation for Administration: Adult

Parenteral: IV: Manufacturer's labeling recommends diluting dose in 50 mL of D5W, NS, or LR.

Rectal: Dilute oral solution or syrup 1:1 with an equal volume of water prior to administration (Graves 1987)

Preparation for Administration: Pediatric

Parenteral:

IV:

Intermittent doses:

Migraines: Adolescents: In trials, doses were diluted in NS to a final volume of 60 mL (Reiter 2005).

Seizure disorders: Manufacturer's labeling recommends diluting dose in 50 mL of D5W, NS, or LR for patients ≥10 years of age. In pediatric clinical trials doses were usually diluted 1:1 with NS or D5W (Mehta 2007; Uberall 2000).

Continuous infusion: In migraine trials, valproic acid was diluted in NS or D5W to a final concentration of ≤4 mg/mL (Taylor 2007).

Rectal: Dilute oral solution or syrup 1:1 with an equal volume of water prior to administration (Graves 1987).

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat seizures.

• It is used to prevent migraine headaches.

• It is used to treat bipolar problems.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache

• Nausea

• Vomiting

• Dizziness

• Fatigue

• Constipation

• Diarrhea

• Abdominal pain

• Trouble sleeping

• Lack of appetite

• Increased hunger

• Weight gain

• Weight loss

• Anxiety

• Flu-like signs

• Hair loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.

• High ammonia level like abnormal heartbeat, abnormal breathing, confusion, pale skin, slow heartbeat, seizures, vomiting, or twitching.

• Chest pain

• Swelling of arms or legs

• Vision changes

• Trouble with memory

• Severe loss of strength and energy

• Change in balance

• Abnormal gait

• Bruising

• Bleeding

• Purple or red spots on skin

• Unable to pass urine

• Change in amount of urine passed

• Swollen glands

• Agitation

• Panic attacks

• Irritability

• Mood changes

• Behavioral changes

• Muscle pain

• Muscle weakness

• Joint pain

• Joint swelling

• Tremors

• Seizures

• Involuntary eye movements

• Noise or ringing in the ears

• Cold sensation

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

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/2019/021168s040lbl.pdf#page=47

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

Concerns related to adverse effects:

• Blood disorders: May cause dose-related thrombocytopenia, inhibition of platelet aggregation, and bleeding. In some cases, platelet counts may be normalized with continued treatment; however, reduce dose or discontinue drug if patient develops evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation. Evaluate platelet counts prior to initiating therapy and periodically thereafter. Probability of thrombocytopenia increases with total valproate levels ≥110 mcg/mL in females or ≥135 mcg/mL in males. In addition to platelets, valproate may be associated with a decrease in other cell lines and myelodysplasia.

• Brain atrophy: Reversible and irreversible cerebral and cerebellar atrophy have been reported; motor and cognitive function should be routinely monitored to assess for signs and symptoms of brain atrophy.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hepatic failure: [US Boxed Warning]: Hepatic failure resulting in fatalities has occurred in patients, usually in the initial 6 months of therapy; children <2 years of age are at considerable risk. Risk is also increased in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase gamma (POLG) gene (eg, Alpers-Huttenlocher syndrome [AHS]). Other risk factors include organic brain disease, mental retardation with severe seizure disorders, congenital metabolic disorders, and patients on multiple anticonvulsants. Monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; discontinue immediately with signs/symptom of significant or suspected impairment. Liver function tests should be performed at baseline and at regular intervals after initiation of therapy, especially within the first 6 months. Hepatic dysfunction may progress despite discontinuing treatment. Should only be used as monotherapy and with extreme caution in children <2 years of age and/or patients at high risk for hepatotoxicity.

• Hyperammonemia/encephalopathy: Hyperammonemia and/or encephalopathy, sometimes fatal, has been reported following the initiation of valproate therapy and may be present with normal transaminase levels. Ammonia levels should be measured in patients who develop unexplained lethargy and vomiting, or changes in mental status or in patients who present with hypothermia. Discontinue therapy if ammonia levels are increased and evaluate for possible urea cycle disorder (UCD). Hyperammonemic encephalopathy has been reported in patients with UCD, particularly ornithine transcarbamylase deficiency. Use is contraindicated in patients with known UCD. Evaluation of UCD should be considered for the following patients prior to the start of therapy: History of unexplained encephalopathy or coma; encephalopathy associated with protein load; pregnancy or postpartum encephalopathy; unexplained mental retardation; history of elevated plasma ammonia or glutamine; history of cyclical vomiting and lethargy; episodic extreme irritability, ataxia; low BUN or protein avoidance; family history of UCD or unexplained infant deaths (particularly male); or signs or symptoms of UCD (hyperammonemia, encephalopathy, respiratory alkalosis). Hyperammonemia and/or encephalopathy may also occur with concomitant topiramate therapy in patients who previously tolerated monotherapy with either medication.

• Hypothermia: Hypothermia (unintentional drop in core body temperature to <35°C/95°F) has been reported with valproate therapy; hypothermia may or may not be associated with hyperammonemia; may also occur with concomitant topiramate therapy following topiramate initiation or dosage increase.

• Multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]): Potentially serious, sometimes fatal multiorgan hypersensitivity reactions have rarely been reported with some antiepileptic drugs including valproate therapy in adults and children; monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; discontinuation and conversion to alternate therapy may be required.

• Pancreatitis: [US Boxed Warning]: Cases of life-threatening pancreatitis, occurring at the start of therapy or following years of use, have been reported in adults and children. Some cases have been hemorrhagic with rapid progression of initial symptoms to death. Promptly evaluate symptoms of abdominal pain, nausea, vomiting, and/or anorexia; should generally be discontinued if pancreatitis is diagnosed.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

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.

• Hepatic impairment: Contraindicated with significant impairment.

• Mitochondrial disease: [US Boxed Warning]: Risk of valproate-induced acute liver failure and death is increased in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial polymerase gamma (POLG) gene (eg, Alpers Huttenlocher syndrome [AHS]). Use is contraindicated in patients with known mitochondrial disorders caused by POLG mutations and children <2 years of age suspected of having a POLG-related disorder. Use in children ≥2 years of age suspected of having a POLG-related disorder only after other anticonvulsants have failed and with close monitoring for the development of acute liver injury. POLG mutation testing should be performed in accordance with current clinical practice.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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 and closely monitor fluid status, nutritional intake, somnolence, and other adverse events.

• Pediatric: Children <2 years of age are at increased risk for fatal hepatotoxicity; if valproate therapy is used in this age group, use with extreme caution and only as monotherapy.

• Pregnancy: [US Boxed Warning]: 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 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. Counsel women planning a pregnancy and females at the onset of puberty regarding benefits and risk of valproate use during pregnancy and consider alternative treatment options, when appropriate.

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: Anticonvulsants 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.

Geriatric Considerations

Although there is little data in elderly for the use of valproate in the treatment of seizures, there are a number of studies which demonstrate its benefit in the treatment of agitation and dementia and other psychiatric disorders. It is important that the clinician understand that serum concentrations do not correlate with behavior response; likewise, it is imperative to monitor LFTs and CBC during the first 6 months of therapy. See Warnings/Precautions, Monitoring Parameters, and Additional Information.

Elimination is decreased in elderly. Studies of older adults with dementia show a high incidence of somnolence (which is usually transient); cognitive side effects generally minimal. In some patients, this was associated with weight loss. Starting doses should be lower and increased slowly, with careful monitoring of nutritional intake and dehydration. Safety and efficacy for use in patients >65 years of age have not been studied for migraine prophylaxis.

Warnings: Additional Pediatric Considerations

Neonates, infants, and children <2 years of age are at considerably increased risk for hepatotoxicity/hepatic failure, especially those on anticonvulsant polytherapy, with congenital metabolic disorders, with severe seizure disorders and mental retardation, or with organic brain disease; monitor patients closely for appearance of malaise, loss of seizure control, weakness, facial edema, anorexia, jaundice, and vomiting; monitor liver enzymes prior to therapy and at frequent intervals, especially during the first 6 months; discontinue valproic acid and derivatives if hepatotoxicity occurs; hepatic dysfunction may progress despite discontinuing treatment. Although carnitine is clearly 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). A valproic acid-associated Reye's-like syndrome has also been reported (Hilmas 2000).

Rare multiorgan hypersensitivity reactions have been reported pediatric patients in association with initiation of valproic acid and derivatives; at least one death has been reported; patient may present with fever and rash in association with symptoms of organ system dysfunction (eg, lymphadenopathy, hepatitis, abnormalities in liver function tests, hematologic abnormalities [eosinophilia, neutropenia, thrombocytopenia], pruritus, oliguria, nephritis, arthralgia, asthenia); valproic acid and derivatives should be discontinued in patients suspected of having multiorgan hypersensitivity reactions. 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.

Pregnancy Considerations

Valproate crosses the placenta (Harden 2009b).

[US Boxed Warning]: 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 antiepileptic 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 antiepileptic medications or no antiepileptic medications; the risk of autism spectrum disorders 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.

[US Boxed Warning]: Due to the risks of adverse fetal events, valproate is 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. Current guidelines recommend complete avoidance of valproate for the treatment of epilepsy in pregnant women whenever possible (Harden 2009a), especially when used for conditions not associated with permanent injury or risk of death.

Algorithms are available for the management of females of reproductive potential who are taking valproic acid for bipolar disorder. Non-pregnant women who are stable on mono-therapy 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 women planning a pregnancy who are on multiple medications or those experiencing an unexpected pregnancy (Anmella 2019).

Effective contraception should be used during treatment. When pregnancy is being planned, 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. Counsel women planning a pregnancy and girls at the onset of puberty 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 women, including those taking valproate.

A pregnancy registry is available for women 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.

Breast-Feeding 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; WHO 2002); monitoring of the infant for side effects (eg, jaundice) is recommended (WHO 2002).

Briggs' Drugs in Pregnancy & Lactation

• Valproic Acid

Adverse Reactions

As reported with oral administration, unless otherwise noted.

>10%:

Central nervous system: Headache (oral: 31%; intravenous: 3% to 4%), drowsiness (oral: 7% to 30%; intravenous: 2% to 11%), dizziness (oral: 12% to 25%; intravenous: 5% to 7%), insomnia (>1% to 15%), pain (oral: 11%; intravenous: 1%), nervousness (oral: 7% to 11%; intravenous: <1%)

Dermatologic: Alopecia (>1% to 24%)

Gastrointestinal: Nausea (oral: 15% to 48%; intravenous: 3% to 6%), vomiting (oral: 7% to 27%; intravenous: 1%), abdominal pain (oral: 7% to 23%; intravenous: 1%), diarrhea (oral: 7% to 23%; intravenous: <1%), dyspepsia (7% to 23%), anorexia (>1% to 12%)

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

Infection: Infection (≤20%)

Neuromuscular & skeletal: Tremor (≤57%), asthenia (6% to 27%; intravenous: 7%)

Ophthalmic: Diplopia (>1% to 16%), visual disturbance (amblyopia, blurred vision ≤1% to 12%)

Respiratory: Flu-like symptoms (>1% to 12%)

Miscellaneous: Accidental injury (>1% to 11%)

1% to 10%:

Cardiovascular: Peripheral edema (>1% to 8%), 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%), vasodilation (oral: >1% to 5%; intravenous: <1%), tachycardia (>1% to <5%), chest pain (2%)

Central nervous system: Ataxia (>1% to 8%), amnesia (>1% to 7%), paresthesia (≤7%), abnormality in thinking (>1% to 6%), emotional lability (>1% to 6%), abnormal dreams (>1% to 5%), abnormal gait (>1% to 5%), confusion (>1% to 5%), depression (>1% to 5%), hallucination (>1% to 5%), hypertonia (>1% to 5%), speech disturbance (>1% to 5%), tardive dyskinesia (>1% to 5%), agitation (1% to 5%), catatonia (1% to 5%), chills (1% to 5%), hyperreflexia (1% to 5%), vertigo (1% to 5%), anxiety (>1% to <5%), malaise (>1% to <5%), myasthenia (>1% to <5%), personality disorder (>1% to <5%), twitching (>1% to <5%), sleep disorder (>1%)

Dermatologic: Skin rash (>1% to 6%), maculopapular rash (>1% to 5%), pruritus (>1% to 5%), xeroderma (>1% to 5%), diaphoresis (oral: >1%; intravenous: <1%), erythema nodosum (>1%), vesiculobullous dermatitis (>1%), furunculosis (1% to 5%), seborrhea (1% to 5%)

Endocrine & metabolic: Weight gain (>1% to 9%), weight loss (6%), amenorrhea (>1% to <5%), menstrual disease (>1%)

Gastrointestinal: Increased appetite (>1% to 6%), constipation (>1% to 5%), flatulence (>1% to 5%), periodontal abscess (>1% to 5%), fecal incontinence (1% to 5%), gastroenteritis (1% to 5%), glossitis (1% to 5%), stomatitis (1% to 5%), xerostomia (1% to 5%), eructation (>1% to <5%), hematemesis (>1% to <5%), pancreatitis (>1% to <5%), dysgeusia (2%), dysphagia (>1%), gingival hemorrhage (>1%), hiccups (>1%), oral mucosa ulcer (>1%)

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

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

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

Infection: Viral infection (>1% to 5%), fungal infection (>1%)

Local: Pain at injection site (intravenous: 3%), injection site reaction (intravenous: 2%)

Neuromuscular & skeletal: Back pain (>1% to 8%), arthralgia (>1% to 5%), discoid lupus erythematosus (>1% to 5%), lower limb cramps (>1% to 5%), hypokinesia (1% to 5%), neck pain (1% to 5%), neck stiffness (1% to 5%), osteoarthritis (1% to 5%), dysarthria (>1% to <5%), myalgia (>1% to <5%)

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

Otic: Tinnitus (1% to 7%), deafness (>1% to 5%), otitis media (>1% to <5%)

Respiratory: Pharyngitis (oral: 2% to 8%; intravenous: <1%), bronchitis (5%), rhinitis (>1% to 5%), dyspnea (1% to 5%), cough (>1% to <5%), epistaxis (>1% to <5%), pneumonia (>1% to <5%), sinusitis (>1% to <5%)

Miscellaneous: Fever (>1% to 6%)

<1%, postmarketing, and/or case reports: Abnormal behavior, abnormal thyroid function tests, acute intermittent porphyria, aggressive behavior, agranulocytosis, anaphylaxis, anemia, aplastic anemia, asthenospermia, azoospermia, bone fracture, bone marrow depression, bradycardia, brain disease (rare), breast hypertrophy, cerebral atrophy (reversible or irreversible), change in prothrombin time, changes of hair (color, texture), coma (rare), decreased bone mineral density, decreased plasma carnitine concentrations, decreased platelet aggregation, decreased spermatozoa motility, dementia, developmental delay (learning disorder), disturbance in attention, drug reaction with eosinophilia and systemic symptoms, emotional disturbance, eosinophilia, erythema multiforme, euphoria, Fanconi-like syndrome (rare, in children), female hyperandrogenism, galactorrhea not associated with childbirth, hemorrhage, hepatic failure, hepatotoxicity, hirsutism, hostility, hyperactive behavior, hyperammonemia, hyperammonemic encephalopathy (in patients with UCD), hyperglycinemia, hypersensitivity angiitis, hypersensitivity reaction, hypoesthesia, hypofibrinogenemia, hyponatremia, hypothermia, increased testosterone level, injection site inflammation, leukopenia, lymphocytosis, macrocytosis, male infertility, myelatelia, nail bed changes, nail disease, oligospermia, ostealgia, osteopenia, osteoporosis, pancytopenia, parkinsonism (Easterford 2004), parotid gland enlargement, polycystic ovary syndrome (rare), psychomotor disturbance, psychosis, seizure (paradoxical), severe hypersensitivity reaction (with multiorgan dysfunction), SIADH, skin photosensitivity, sleep disturbance, spermatozoa disorder (abnormal morphology), Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies, toxic epidermal necrolysis (rare), urinary incontinence, urinary tract infection

Allergy and Idiosyncratic Reactions

• Valproic Acid and Derivative Allergy

Toxicology

• Valproic Acid and Derivatives

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 Open Interactions

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

Cannabidiol: Valproate Products may enhance the hepatotoxic effect of Cannabidiol. 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

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 the potential for a significant interaction. Risk D: Consider therapy modification

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

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. 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

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

LamoTRIgine: Valproate Products may enhance the adverse/toxic effect of LamoTRIgine. Valproate Products may increase the serum concentration of LamoTRIgine. Management: Lamotrigine labeling recommends an approximate 50% decrease in lamotrigine dose when used with valproic acid or other valproate products. See full monograph or lamotrigine labeling for more specific recommendations. Monitor lamotrigine response closely. Risk D: Consider therapy modification

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

LORazepam: Valproate Products may increase the serum concentration of LORazepam. Risk D: Consider therapy modification

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

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification

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

Mianserin: May diminish the therapeutic effect of Anticonvulsants. 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

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

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

Paliperidone: Valproate Products may increase the serum concentration of Paliperidone. 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

Primidone: Valproate Products may decrease the metabolism of Primidone. More specifically, the metabolism of phenobarbital, primidone's primary active metabolite, may be decreased. Primidone may increase 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 D: Consider therapy modification

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

Sodium Oxybate: Valproate Products may increase the serum concentration of Sodium Oxybate. Management: Consider a sodium oxybate dose reduction of at least 20% if combined with valproic acid. 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

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

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

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

Food Interactions

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

Test Interactions

May cause a false-positive result for urine ketones (valproate partially eliminated as a keto-metabolite in the urine); may alter thyroid function tests

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 lethargy, mental status change), serum valproate levels; suicidality (eg, suicidal thoughts, depression, behavioral changes); motor and cognitive function (for signs or symptoms of brain atrophy); menstrual history to assess for polycystic ovary syndrome (at 3 to 6 month intervals for the first year, then annually) (CANMAT [Yatham 2018]).

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 24-hour 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: 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:

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

Advanced Practitioners Physical Assessment/Monitoring

Obtain liver function tests (at initiation and then frequently during therapy especially first 6 months), CBC with platelets (at initiation and then periodically), PT/PTT, and serum ammonia (with changes in mental status). Obtain serum valproate levels as clinically indicated. Assess for signs of depression, behavioral changes, and suicidal ideation. Assess motor and cognitive function. Monitor therapeutic effectiveness (type of seizure activity, and duration). Assess for signs of liver toxicity and pancreatitis. Check pregnancy status and educate patients of childbearing age on the importance of not becoming pregnant and using reliable birth control while on this medicine.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Educate patients of childbearing age on the importance of not becoming pregnant and using reliable birth control while on this medicine. Instruct patient to track seizure activity, type, and duration to help monitor effectiveness. Monitor for and educate patient to report signs and symptoms of hepatic failure (malaise, weakness, facial edema, anorexia, jaundice, and vomiting), signs and symptoms of pancreatitis (abdominal pain, nausea, vomiting, and/or anorexia), and signs and symptoms of depression including suicidal ideation.

Dosage Forms Considerations

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

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 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

Dosage Forms: Canada

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] [contains fd&c yellow #6 (sunset yellow), methylparaben, propylparaben]

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 fd&c red #40]

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

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

Generic: 125 mg, 250 mg, 500 mg

Anatomic Therapeutic Chemical (ATC) Classification

• N03AG01

Generic Available (US)

Yes

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

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.

Pharmacodynamics/Kinetics

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

V_d: 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: 24-hour extended release (ER): ~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 24-hour 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, 24 hour: 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 antiepileptic 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: 24-hour ER formulation has 10% to 20% less fluctuation in serum concentration than delayed release (DR) formulation. 24-hour ER formulation is not bioequivalent to DR formulation.

Pharmacodynamics/Kinetics: 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.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Infrequent occurrences of facial edema, orthostatic hypotension, speech disturbance, tardive dyskinesia, periodontal abscess, glossitis, stomatitis, xerostomia, gingival hemorrhage, oral mucosa ulcer, dysgeusia, and fungal infections have been reported. Rare occurrences of erythema multiforme and parotid gland enlargement have also been reported.

Effects on Bleeding

Has been associated with dose-related thrombocytopenia. Normal coagulation may generally be expected unless thrombocytopenia is present and severe.

Related Information

• Adverse Effects of Anticonvulsants
• Agents Approved for Bipolar Disorder
• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Narrow Therapeutic Index Drugs
• Oral Medications That Should Not Be Crushed or Altered
• Safe Handling of Hazardous Drugs

Index Terms

2-Propylpentanoic Acid; 2-Propylvaleric Acid; Dipropylacetic Acid; Divalproex Sodium; DPA; Valproate Semisodium; Valproate Sodium; Valproic Acid; Valproic Acid Derivative

FDA Approval Date

February 28, 1978

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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)

Last Updated 2/28/20