Valproic Acid and Derivatives (Lexi-Drugs)

ALERT: US Boxed Warning
  Hepatotoxicity:
  Patients with mitochondrial disease:
  Fetal risk:
  Pancreatitis:
Pronunciation

(val PROE ik AS id & dah RIV ah tives)

Brand Names: US

Depacon; Depakene; Depakote; Depakote ER; Depakote Sprinkles

Brand Names: Canada

APO-Divalproex; APO-Valproic; Depakene; DOM-Divalproex; DOM-Valproic Acid; DOM-Valproic Acid EC; Epival; MYL-Divalproex [DSC]; MYLAN-Divalproex; MYLAN-Valproic [DSC]; NOVO-Valproic [DSC]; PHL-Divalproex [DSC]; PHL-Valproic Acid EC [DSC]; PHL-Valproic Acid [DSC]; PMS-Divalproex; PMS-Valproic; PMS-Valproic Acid; RATIO-Valproic [DSC]; SANDOZ Valproic; TEVA-Divalproex

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) (off-label use): Based on limited data: Oral: Initial: 500 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 (Davis 2005; Ghaemi 2007; Muzina 2011).

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).

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 preparationsTo 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. Stavzor has been discontinued in the US for more than 1 year.

Migraine prophylaxis:

Divalproex sodium (eg, Depakote tablets):

Children ≥7 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]; Caruso 2000; Gunner 2008). Dosing based on an open-label trial of divalproate sodium (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). Other trials have also shown efficacy with similar daily dose range (500 to 1,000 mg/day): In a comparative trial with propranolol results showed both treatments reduced headache duration, severity, and frequency (ie, ≥50% reduction; divalproex sodium: 72%, propranolol: 69%) (Ashrafi 2005), and 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 (Serdaroglu 2002).

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

Stavzor: Children ≥12 years and Adolescents: 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 2009). 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)

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 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.

Absence seizures, 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 Depakote: May require an increase in the total daily dose between 8% and 20% to maintain similar serum concentrations

Conversion to monotherapy from adjunctive therapy: The concomitant antiepileptic drug (AED) can be decreased by ~25% every 2 weeks; dosage reduction of the concomitant AED may begin when valproate or derivative therapy is initiated or 1 to 2 weeks following valproate or derivative initiation

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).

Maintenance dose: 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).

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 valproate 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. 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,” February 2018

World Federation of Societies of Biological Psychiatry (WFSBP), “Guidelines for the Biological Treatment of Bipolar Disorders: Update 2010 on the Treatment of Acute Bipolar Depression,” 2010

World Federation of Societies of Biological Psychiatry (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, Stavzor: Swallow whole; do not break, crush, or chew.

Parenteral: IV:

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: 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).

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

Medication Patient Education with HCAHPS Considerations

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, vomiting, dizziness, fatigue, constipation, diarrhea, abdominal pain, insomnia, lack of appetite, increased hunger, weight gain, weight loss, anxiety, flu-like signs, or hair loss. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of a high ammonia level (abnormal heartbeat, abnormal breathing, confusion, pale skin, bradycardia, seizures, vomiting, or twitching), angina, swelling of arms or legs, vision changes, memory impairment, severe loss of strength and energy, change in balance, abnormal gait, bruising, bleeding, purple or red spots on skin, urinary retention, change in amount of urine passed, swollen glands, agitation, panic attacks, irritability, mood changes, behavioral changes, muscle pain, muscle weakness, joint pain, joint edema, tremors, seizures, involuntary eye movements, tinnitus, or cold sensation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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/2018/018723s060,019680s047lbl.pdf#page=97

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. Fatal hepatic failure and hypoglycemia in infants have been noted in case reports following in utero exposure to valproate.

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.

Effective contraception should be used during treatment. When pregnancy is being planned, consider tapering off of therapy prior to conception if appropriate; 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.

The relative infant dose (RID) of valproate is 2.7% to 5.4% when calculated using the highest average breast milk concentration located and compared to an infant therapeutic dose of 20 to 40 mg/kg/day.

In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).

The RID of valproate was calculated using a milk concentration of 50 mmol/L (7.2 mg/L), providing an estimated daily infant dose via breast milk of 1.08 mg/kg/day. This milk concentration represents the mean milk concentration at postpartum day 5 following maternal administration of valproate sodium 1,600 mg/day throughout pregnancy and the immediate postpartum period in one woman. Breast milk concentrations were between 5% and 10% of the maternal serum (Alexander 1979). Valproate can be detected in the plasma of breastfed infants (Hagg 2000).

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 thrombocytopenic purpura, anemia, and reticulocytosis (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. The World Health Organization (WHO) states that valproate is compatible with breastfeeding; monitoring of the infant for side effects (eg, jaundice) is recommended (WHO 2002).

Briggs’ Drugs in Pregnancy & Lactation
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%), weakness (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%), vasodilatation (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%), hyper-reflexia (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 ALT (>1% to <5%), increased serum AST (>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%), leg 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 (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 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, DRESS syndrome, drug-induced Parkinson disease, emotional disturbance, eosinophilia, erythema multiforme, euphoria, Fanconi-like syndrome (rare, in children), galactorrhea, hemorrhage, hepatic failure, hepatotoxicity, hirsutism, hostility, hyperactivity, hyperammonemia, hyperammonemic encephalopathy (in patients with UCD), hyperandrogenism, hyperglycinemia, hypersensitivity angiitis, hypersensitivity reaction, hypoesthesia, hypofibrinogenemia, hyponatremia, hypothermia, increased testosterone level, injection site inflammation, leukopenia, lymphocytosis, macrocytosis, male infertility, myelodysplasia, nail bed changes, nail disease, oligospermia, ostealgia, osteopenia, osteoporosis, pancytopenia, parotid gland enlargement, polycystic ovary syndrome (rare), psychomotor disturbance, psychosis, seizure (paradoxical), severe hypersensitivity (with multiorgan dysfunction), SIADH, skin photosensitivity, sleep disorder, spermatozoa disorder (abnormal morphology), Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies, toxic epidermal necrolysis (rare), urinary incontinence, urinary tract infection

Allergy and Idiosyncratic Reactions
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 

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. 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

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

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

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)

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). Patients with epilepsy should not delay taking their dose for >2 to 3 hours. 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 2008).

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.

Product Availability

Stavzor has been discontinued in the US for more than 1 year.

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.

Capsule, Oral, Immediate Release, as valproic acid:

Depakene: 250 mg

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)

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

Solution, Intravenous, as valproate sodium:

Depacon: 100 mg/mL (5 mL) [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 (240ml, 450ml, 480ml) [contains FD&C RED #40, METHYLPARABEN, PROPYLPARABEN]

Generic: 250 mg/5 mL (450ml, 480ml[DSC])

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)

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: 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: Periodontal abscess and taste perversion.

Effects on Bleeding

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

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
References

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Depacon (valproate sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; March 2017.

Depacon (valproate sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; October 2017.

Depacon (valproate sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; September 2016.

Depakene (valproic acid) [prescribing information]. North Chicago, IL: AbbVie Inc; March 2017.

Depakene (valproic acid) [prescribing information]. North Chicago, IL: AbbVie Inc; February 2019.

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Depakote (divalproex sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; September 2016.

Depakote Delayed-Release Tablets [prescribing information]. North Chicago, IL: AbbVie Inc; February 2019.

Depakote ER (divalproex sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; February 2019.

Depakote ER (divalproex sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; November 2016.

Depakote ER (divalproex sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; September 2016.

Depakote (divalproex sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; October 2017.

Depakote (divalproex sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; September 2016.

Depakote Sprinkle Capsules (divalproex sodium) [prescribing information]. North Chicago, IL: AbbVie Inc; February 2019.

Epival (divalproex sodium) [product monograph]. Etobicoke, Ontario, Canada: BGP Pharma ULC; February 2019.

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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)

Valproic Acid and Derivatives (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(val PROE ik AS id & dah RIV ah tives)

Brand Names: US

Depacon; Depakene; Depakote; Depakote ER; Depakote Sprinkles

Brand Names: Canada

Depakene; Epival

Warning
  • All products:
  • Liver problems have happened with this drug. Sometimes, these have been deadly. Most of the time, liver problems happened within the first 6 months after starting this drug. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes. In people who have seizures, loss of seizure control may happen. Have your blood work checked as you have been told by your doctor.
  • Children under 2 years are at greater risk of deadly liver problems. Those who take more than 1 seizure drug or who have a metabolic disorder, a very bad seizure disorder along with mental retardation, or certain brain problems are at highest risk. Talk with the doctor.
  • There is a greater risk of liver failure and death in patients who have a genetic liver problem caused by a mitochondrial disorder like Alpers–Huttenlocher syndrome. You may need to have a genetic test to check for this health problem. If you have or may have mitochondrial disorders do not take this drug before talking with your doctor.
  • This drug may cause severe birth defects if you take it while you are pregnant. It can also cause your child to have a lower IQ and brain problems. If you are pregnant or able to get pregnant, talk with your doctor to make sure this drug is right for you. Use birth control to prevent pregnancy while you take this drug. If you get pregnant while taking this drug, call your doctor right away.
  • Do not take this drug to prevent migraine headaches if you are pregnant or if you are not using birth control to prevent pregnancy.
  • This drug may cause very bad and sometimes deadly pancreas problems (pancreatitis). This may happen soon after use as well as many years after use. Signs of pancreatitis include belly pain, upset stomach, throwing up, or not feeling hungry. Call your doctor right away if you have any of these signs.
  • All oral products:
  • This drug comes with an extra patient fact sheet called a Medication Guide. Read it with care each time this drug is filled. If you have any questions about this drug, please talk with the doctor, pharmacist, or other health care provider.
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.
What do I need to tell my doctor BEFORE I take this drug?
  • If you have an allergy to this drug or any part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: Liver disease or a urea cycle disorder.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • All products:
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert or have clear eyesight until you see how this drug affects you.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
  • This drug may affect certain lab tests. Tell all of your health care providers and lab workers that you take this drug.
  • If you are not able to eat or drink like normal, talk with your doctor. This includes if you are sick, fasting, or you are having certain procedures or surgery.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • High blood levels of ammonia have happened with this drug. This can lead to certain brain problems. In some people, this has been deadly. Talk with the doctor.
  • Some people have had certain brain problems without high blood levels of ammonia. Sometimes, these brain problems have gone back to normal after this drug was stopped. However, sometimes they have not fully gone back to normal. Talk with the doctor.
  • A very bad and sometimes deadly reaction has happened with this drug. Most of the time, this reaction has signs like fever, rash, or swollen glands with problems in body organs like the liver, kidney, blood, heart, muscles and joints, or lungs. Talk with the doctor.
  • Patients who take this drug may be at a greater risk of having thoughts or actions of suicide. The risk may be greater in people who have had these thoughts or actions in the past. Call the doctor right away if signs like low mood (depression), nervousness, restlessness, grouchiness, panic attacks, or changes in mood or actions are new or worse. Call the doctor right away if any thoughts or actions of suicide occur.
  • This drug may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking this drug with your other drugs.
  • Some other drugs may affect how much of this drug is in your body. Talk with your doctor or pharmacist to see if any of your other drugs may interact with this drug.
  • If you are 65 or older, use this drug with care. You could have more side effects.
  • Use with care in children. Talk with the doctor.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
  • Valproic acid capsules:
  • Some brands of this drug have peanut oil in them. If you are allergic to peanuts, check with your pharmacist to see if your brand has peanut oil in it.
What are some side effects that I need to call my doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
  • Signs of high ammonia levels like a heartbeat that does not feel normal, breathing that is not normal, feeling confused, pale skin, slow heartbeat, seizures, sweating, throwing up, or twitching.
  • Chest pain.
  • Swelling in the arms or legs.
  • Change in eyesight.
  • Memory problems or loss.
  • Feeling very tired or weak.
  • Change in balance.
  • Trouble walking.
  • Any unexplained bruising or bleeding.
  • Purple spots or redness of the skin.
  • Not able to pass urine or change in how much urine is passed.
  • Swollen gland.
  • Muscle pain or weakness.
  • Joint pain or swelling.
  • Shakiness.
  • If seizures are worse or not the same after starting this drug.
  • Not able to control eye movements.
  • Ringing in ears.
  • Feeling cold.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
  • Headache.
  • Upset stomach or throwing up.
  • Dizziness.
  • Feeling sleepy.
  • Constipation.
  • Stomach pain or diarrhea.
  • Trouble sleeping.
  • Feeling more or less hungry.
  • Weight gain or loss.
  • Hair loss.
  • Feeling tired or weak.
  • Feeling nervous and excitable.
  • Flu-like signs.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • All oral products:
  • Take with or without food. Take with food if it causes an upset stomach.
  • To gain the most benefit, do not miss doses.
  • Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.
  • Do not stop taking this drug all of a sudden without calling your doctor. You may have a greater risk of seizures. If you need to stop this drug, you will want to slowly stop it as ordered by your doctor.
  • If you take cholestyramine, you may need to take it at some other time than this drug. Talk with your pharmacist.
  • Tablets and capsules:
  • Swallow whole. Do not chew, break, or crush.
  • Take with a full glass of water.
  • If you have trouble swallowing, talk with your doctor.
  • Long-acting tablets:
  • If you see parts of this drug in your stool, call your doctor.
  • Sprinkle capsule:
  • You may swallow whole or mix the contents of the capsule with certain foods like applesauce. Take the mixture right away. Do not store for later use.
  • If you see parts of this drug in your stool, call your doctor.
  • Liquid:
  • Measure liquid doses carefully. Use the measuring device that comes with this drug. If there is none, ask the pharmacist for a device to measure this drug.
  • Injection:
  • It is given as an infusion into a vein over a period of time.
What do I do if I miss a dose?
  • All oral products:
  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
  • Injection:
  • Call your doctor to find out what to do.
How do I store and/or throw out this drug?
  • All oral products:
  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Injection:
  • If you need to store this drug at home, talk with your doctor, nurse, or pharmacist about how to store it.
  • All products:
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Valproic Acid and Derivatives (Patient Education – Pediatric Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(val PROE ik AS id & dah RIV ah tives)

Brand Names: US

Depacon; Depakene; Depakote; Depakote ER; Depakote Sprinkles

Brand Names: Canada

Depakene; Epival

Warning
  • All products:
  • Liver problems have happened with this drug. Sometimes, these have been deadly. Most of the time, liver problems happened within the first 6 months after starting this drug. Call your child’s doctor right away if your child has signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes. In people who have seizures, loss of seizure control may happen. Have your child’s blood work checked as you have been told by your child’s doctor.
  • Children under 2 years are at greater risk of deadly liver problems. Those who take more than 1 seizure drug or who have a metabolic disorder, a very bad seizure disorder along with mental retardation, or certain brain problems are at highest risk. Talk with the doctor.
  • There is a greater risk of liver failure and death in patients who have a genetic liver problem caused by a mitochondrial disorder like Alpers–Huttenlocher syndrome. Your child may need to have a genetic test to check for this health problem. If your child has or may have mitochondrial disorders do not give this drug before talking with your child’s doctor.
  • This drug may cause very bad and sometimes deadly pancreas problems (pancreatitis). This could happen in children at any time during care. Signs of pancreatitis include belly pain, upset stomach, throwing up, or not feeling hungry. Call your child’s doctor right away if your child has any of these signs.
  • If your child is or may be sexually active:
  • If your child is pregnant or able to get pregnant, talk with the doctor to make sure this drug is right for your child. She must use birth control to prevent pregnancy while taking this drug.
  • If your child is or may be pregnant:
  • This drug may cause severe birth defects if your child takes it while pregnant. It can also cause the baby to have a lower IQ and brain problems. If your child gets pregnant while taking this drug, call your child’s doctor right away.
  • Do not give this drug to prevent migraine headaches if your child is pregnant or is not using birth control to prevent pregnancy.
  • All oral products:
  • This drug comes with an extra patient fact sheet called a Medication Guide. Read it with care each time this drug is filled. If you have any questions about this drug, please talk with the doctor, pharmacist, or other health care provider.
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 your child for other reasons. Talk with the doctor.
What do I need to tell the doctor BEFORE my child takes this drug?
  • If your child has an allergy to this drug or any part of this drug.
  • If your child is allergic to any drugs like this one or any other drugs, foods, or other substances. Tell the doctor about the allergy and what signs your child had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If your child has any of these health problems: Liver disease or a urea cycle disorder.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell the doctor and pharmacist about all of your child’s drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for your child to take this drug with all of his/her drugs and health problems. Do not start, stop, or change the dose of any drug your child takes without checking with the doctor.
What are some things I need to know or do while my child takes this drug?
  • All products:
  • Tell all of your child’s health care providers that your child is taking this drug. This includes your child’s doctors, nurses, pharmacists, and dentists.
  • Have your child avoid tasks or actions that call for alertness until you see how this drug affects your child. These are things like riding a bike, playing sports, or using items such as scissors, lawnmowers, electric scooters, toy cars, or motorized vehicles.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Alcohol may interact with this drug. Be sure your child does not drink alcohol.
  • Talk with the doctor before giving your child other drugs and natural products that may slow your child’s actions.
  • This drug may affect certain lab tests. Tell all of your child’s health care providers and lab workers that your child takes this drug.
  • If your child is not able to eat or drink like normal, talk with your child’s doctor. This includes if your child is sick, fasting, or having certain procedures or surgery.
  • Your child may bleed more easily. Make sure your child is careful and avoids injury. Be sure your child has a soft toothbrush.
  • High blood levels of ammonia have happened with this drug. This can lead to certain brain problems. In some people, this has been deadly. Talk with the doctor.
  • Some people have had certain brain problems without high blood levels of ammonia. Sometimes, these brain problems have gone back to normal after this drug was stopped. However, sometimes they have not fully gone back to normal. Talk with the doctor.
  • A very bad and sometimes deadly reaction has happened with this drug. Most of the time, this reaction has signs like fever, rash, or swollen glands with problems in body organs like the liver, kidney, blood, heart, muscles and joints, or lungs. Talk with the doctor.
  • Patients who take this drug may be at a greater risk of having thoughts or actions of suicide. The risk may be greater in people who have had these thoughts or actions in the past. Call the doctor right away if signs like low mood (depression), nervousness, restlessness, grouchiness, panic attacks, or changes in mood or actions are new or worse. Call the doctor right away if any thoughts or actions of suicide occur.
  • This drug may affect how much of some other drugs are in the body. If your child is taking other drugs, talk with the doctor. Your child may need to have blood work checked more closely while taking this drug with other drugs.
  • Some other drugs may affect how much of this drug is in your body. Talk with your doctor or pharmacist to see if any of your other drugs may interact with this drug.
  • Use with care in children. Talk with the doctor.
  • If your child is breast-feeding a baby:
  • Tell the doctor if your child is breast-feeding a baby. You will need to talk about any risks to the baby.
  • Valproic acid capsules:
  • Some brands of this drug have peanut oil in them. If your child is allergic to peanuts, check with your pharmacist to see if your child’s brand has peanut oil in it.
What are some side effects that I need to call my child’s doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your child’s doctor or get medical help right away if your child has any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
  • Signs of high ammonia levels like a heartbeat that does not feel normal, breathing that is not normal, feeling confused, pale skin, slow heartbeat, seizures, sweating, throwing up, or twitching.
  • Chest pain.
  • Swelling in the arms or legs.
  • Change in eyesight.
  • Memory problems or loss.
  • Change in balance.
  • Trouble walking.
  • If seizures are worse or not the same after starting this drug.
  • Feeling very tired or weak.
  • Any unexplained bruising or bleeding.
  • Purple spots or redness of the skin.
  • Not able to pass urine or change in how much urine is passed.
  • Swollen gland.
  • Muscle pain or weakness.
  • Joint pain or swelling.
  • Shakiness.
  • Not able to control eye movements.
  • Ringing in ears.
  • Feeling cold.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your child’s doctor or get medical help if any of these side effects or any other side effects bother your child or do not go away:
  • Headache.
  • Upset stomach or throwing up.
  • Dizziness.
  • Feeling sleepy.
  • Constipation.
  • Stomach pain or diarrhea.
  • Trouble sleeping.
  • Feeling more or less hungry.
  • Weight gain or loss.
  • Hair loss.
  • Feeling tired or weak.
  • Feeling nervous and excitable.
  • Flu-like signs.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your child’s doctor. Call your child’s doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best given?
  • Give this drug as ordered by your child’s doctor. Read all information given to you. Follow all instructions closely.
  • All oral products:
  • Give this drug with or without food. Give with food if it causes an upset stomach.
  • To gain the most benefit, do not miss giving your child doses.
  • Keep giving this drug to your child as you have been told by your child’s doctor or other health care provider, even if your child feels well.
  • Do not stop giving this drug to your child all of a sudden without calling the doctor. Your child may have a greater risk of seizures. If your child needs to stop this drug, you will want to slowly stop it as told by the doctor.
  • If your child takes cholestyramine, you may need to give it at some other time than this drug. Talk with the pharmacist.
  • Tablets and capsules:
  • Have your child swallow whole. Do not let your child chew, break, or crush.
  • Give this drug with a full glass of water.
  • If your child has trouble swallowing, talk with the doctor.
  • Long-acting tablets:
  • If you or your child see parts of this drug in your child’s stool, call the doctor.
  • Sprinkle capsule:
  • Your child may swallow whole or you may mix the contents of the capsule with certain foods like applesauce. Have your child take the mixture right away. Do not store for later use.
  • If you or your child see parts of this drug in your child’s stool, call the doctor.
  • Liquid:
  • Measure liquid doses carefully. Use the measuring device that comes with this drug. If there is none, ask the pharmacist for a device to measure this drug.
  • Injection:
  • It is given as an infusion into a vein over a period of time.
What do I do if my child misses a dose?
  • All oral products:
  • Give a missed dose as soon as you think about it.
  • If it is close to the time for your child’s next dose, skip the missed dose and go back to your child’s normal time.
  • Do not give 2 doses at the same time or extra doses.
  • Injection:
  • Call your child’s doctor to find out what to do.
How do I store and/or throw out this drug?
  • All oral products:
  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Injection:
  • If you need to store this drug at home, talk with your child’s doctor, nurse, or pharmacist about how to store it.
  • All products:
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your child’s symptoms or health problems do not get better or if they become worse, call your child’s doctor.
  • Do not share your child’s drug with others and do not give anyone else’s drug to your child.
  • Keep a list of all your child’s drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your child’s doctor.
  • Talk with your child’s doctor before giving your child any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your child’s doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.