Medically reviewed on Jan 30, 2019
(val PROE ik AS id & dah RIV ah tives)
- 2-Propylpentanoic Acid
- 2-Propylvaleric Acid
- Dipropylacetic Acid
- Divalproex Sodium
- Valproate Semisodium
- Valproate Sodium
- Valproic Acid
- Valproic Acid Derivative
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral, as valproic acid:
Depakene: 250 mg
Generic: 250 mg
Capsule Delayed Release, Oral, as valproic acid:
Stavzor: 125 mg [DSC], 250 mg [DSC], 500 mg [DSC] [contains fd&c yellow #6 (sunset yellow)]
Capsule Delayed Release Sprinkle, Oral, as divalproex sodium:
Depakote Sprinkles: 125 mg [contains brilliant blue fcf (fd&c blue #1)]
Generic: 125 mg
Solution, Intravenous, as valproate sodium:
Depacon: 100 mg/mL (5 mL)
Solution, Intravenous, as valproate sodium [preservative free]:
Generic: 100 mg/mL (5 mL)
Solution, Oral, as valproate sodium:
Depakene: 250 mg/5 mL (480 mL)
Generic: 250 mg/5 mL (5 mL, 10 mL, 473 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
Brand Names: U.S.
- Depakote ER
- Depakote Sprinkles
- Stavzor [DSC]
- Anticonvulsant, Miscellaneous
- Antimanic Agent
- Histone Deacetylase Inhibitor
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. Divalproex sodium is a compound of sodium valproate and valproic acid; divalproex dissociates to valproate in the GI tract.
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
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.
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
Time to Peak
Oral: Depakote tablet and sprinkle capsules: ~4 hours; Depakote ER: 4 to 17 hours; Stavzor: 2 hours; Epival [Canadian product]: 4 hours
Rectal (off-label route): 1 to 3 hours (Graves 1987)
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
Infants and 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 16 hours
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
Special Populations: 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.
Special Populations: 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.
Use: Labeled Indications
Bipolar disorder: Treatment of manic episodes (delayed release) or acute manic or mixed episodes with or without psychotic features (extended release) associated with bipolar disorder, as monotherapy or in combination with atypical antipsychotics (BAP [Goodwin 2016])
Focal onset (partial) and generalized onset seizures: Monotherapy and adjunctive therapy in the treatment of patients with focal-onset impaired awareness seizures (complex partial seizures); monotherapy and adjunctive therapy of aware or impaired awareness absence seizures (simple and complex absence seizures); adjunctive therapy in patients with multiple seizure types that include absence seizures
Migraine prophylaxis (excluding IV formulation): Prophylaxis of migraine headaches
Limitation of use: Do not administer to a woman of childbearing potential unless essential for the management of her condition.
Off Label Uses
Data in limited number of clinical trials suggest that valproic acid may delay future mood episodes following a manic episode in bipolar disorder [Cipriani 2013].
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 valproic acid and derivatives are recommended for maintenance treatment of bipolar disorder based on limited positive evidence [CANMAT/ISBD [Yatham 2018]], [WFSBP [Grunze 2013]]. Based on the WFSBP guidelines for the acute and long-term treatment of mixed states in bipolar disorder, valproic acid and derivatives are recommended for maintenance treatment to prevent a mixed episode following a depressed or manic episode based on limited positive evidence [WFSBP [Grunze 2018]].
Diabetic neuropathy (alternative agent)
Data from a limited number of clinical trials suggest that valproate may be beneficial in decreasing pain in diabetic neuropathy [Kochar 2002], [Kochar 2004].
Based on the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation guidelines for the treatment of painful diabetic neuropathy, it is probable that valproate is an effective treatment option and should be considered for this condition.
Data from a limited number of patients studied suggest that valproate may be beneficial in decreasing pain in postherpetic neuralgia.
Based on the European Federation of Neurological Societies guidelines on the management of neuropathic pain, valproic acid is generally not recommended for the management of postherpetic neuralgia due to limited evidence.
Status epilepticus (adults) (alternative agent)
Data from multiple studies including randomized controlled trials support the use of valproic acid for the treatment of urgent or refractory status epilepticus [Agarwal 2007], [Alvarez 2011], [Gilad 2008], [Limdi 2005], [Misra 2006], [Olsen 2007], [Peters 2005], [Sinha 2000], [Tripathi 2010]. In a systematic review of clinical trials in status epilepticus, valproic acid has been determined to be a safe therapeutic option in patients with established status epilepticus having failed conventional first-line treatment with benzodiazepines [Trinka 2014]. Additional trials may be necessary to further define the role of valproic acid in this condition.
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 valproic acid 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.
Status epilepticus (infants/children/adolescents)
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 valproic acid is an effective and recommended treatment option for urgent control of status epilepticus in infants, children, and adolescents. However, benzodiazepines continue to be the agents of choice for initial therapy.
Traumatic brain injury-related agitation and aggression
Data from a limited number of patients studied suggest that valproate may be beneficial for the treatment of agitation and aggressive symptoms in patients with acute and remote traumatic brain injury (TBI) [Chatham Showalter 2000], [Kim 2002]. Additional data may be necessary to further define the role of valproate in this condition.
Based on the French Society of Physical and Rehabilitation Medicine guidelines on the management of behavior disorders after TBI, valproate should be considered first-line for agitation, aggression, anger and irritability following TBI, particularly in the presence of mood swings [SOFMER [Plantier 2016]]. Based on the Neurobehavioral Guidelines Working Group guides for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury, valproate is recommended as an option for patients with aggressive or assaultive behavior following TBI [Warden 2006].
Hypersensitivity to valproic acid, divalproex, derivatives, or any component of the formulation; hepatic disease or significant impairment; urea cycle disorders; pregnant women for the prevention of migraine; 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): Known porphyria
Note: Valproic acid and derivatives are available as immediate-release, 12-hour delayed-release, and 24-hour extended-release oral formulations, and as an injectable. Extended-release oral formulation is not available in Canada.
Acute manic or mixed episodes (monotherapy or in combination with atypical antipsychotics) (BAP [Goodwin 2016]):
Fixed dose: Oral: 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). Usually, according to some experts, patients require 1,500 to 2,500 mg/day to achieve this goal (Stovall 2018). Maximum recommended dosage: 60 mg/kg/day.
Weight-based loading dose for rapid symptom control: Oral: 20 to 30 mg/kg/day (BAP [Goodwin 2016]; Bowden 2010; Hirschfeld 1999). After 2 to 3 days adjust dose to reach desired clinical effect and therapeutic serum concentration. In clinical trials 20 mg/kg/day doses were adjusted up in 500 mg increments and 30 mg/kg/day doses were adjusted down in 10 mg/kg/day increments (Bowden 2006; Hirschfeld 1999). Maximum recommended dosage: 60 mg/kg/day.
Maintenance (off-label): Oral: Continue dose achieved during acute episode; adjust dose based on response, tolerability and serum concentration (Gyulai 2003; McElroy 2008).
Diabetic neuropathy (alternative agent) (off-label use): Oral: Initial: 500 mg once daily; increase to 1,000 mg/day after 1 week; doses as high as 1,200 mg/day (in 3 divided doses) or 20 mg/kg/day have been studied (AAN [Bril 2011]; Agrawal 2009; Kochar 2002; Kochar 2004)
Focal onset (partial) and generalized onset seizures: Note: FDA approved for focal onset impaired awareness seizures (complex partial seizures) and aware or impaired awareness absence seizures as monotherapy or adjunctive therapy, and as adjunctive therapy for multiple seizure types. May be used off-label as monotherapy for other seizure types:
Oral: Initial: 10 to 15 mg/kg/day; increase by 5 to 10 mg/kg/day at weekly intervals until optimal clinical response and/or therapeutic levels are achieved; maximum: 60 mg/kg/day
Conversion to monotherapy from adjunctive therapy: Dosage reduction of the concomitant antiepileptic drug (AED) may begin when valproate therapy is initiated or 1 to 2 weeks following valproate initiation; decrease the concomitant AED by ~25% every 2 weeks.
IV (for non-status epilepticus): Total daily IV dose should be equivalent to the total daily oral valproate dose 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. Administer each dose as a 60-minute infusion (rate ≤20 mg/minute). Alternatively, rapid infusions of loading doses ranging from 15 to 30 mg/kg/dose at rates ranging from 1.5 to 10 mg/kg/minute have been used and were generally well tolerated in clinical trials to quickly achieve therapeutic concentrations (Boggs 2005; Limdi 2007; Ramsay 2003; Venkataraman 1999; Wheless 2004). Maximum recommended dose: 60 mg/kg/day. Note: IV formulation should be used only for those who temporarily cannot use oral formulations; switch patient to oral products as soon as possible.
Migraine prophylaxis: Oral: Initial: 500 mg once daily (extended release) or in 2 divided doses (delayed release) (manufacturer labeling); increase dose gradually based on response and tolerability in increments of 250 mg/day and intervals >3 days. Doses >1,000 mg/day have been associated with greater adverse effects and no additional benefit (Klapper 1997; Pringsheim 2010). However, some experts recommend doses up to 1,500 mg/day (Bajwa 2018; Linde 2013).
Postherpetic neuralgia (alternative agent) (off-label use): Oral: Usual dose: 1,000 mg/day (EFNS [Attal 2010]; Kochar 2005)
Status epilepticus (alternative agent) (off-label use): IV: Loading dose: 20 to 40 mg/kg administered at a rate up to 10 mg/kg/minute; if necessary, may give an additional dose of 20 mg/kg 10 minutes after the loading infusion (Limdi 2007; NCS [Brophy 2012]) or 40 mg/kg as a single dose (maximum dose: 3,000 mg) (AES [Glauser 2016]).
Traumatic brain injury related agitation and aggression (off-label use): Oral: Usual dosage range: 1,250 to 1,800 mg/day; adjust dose based on patient response; doses as high as 3,500 mg/day have been reported (Chatham Showalter 2000; Kim 2002)
Conversion from immediate release valproic acid to delayed release divalproex sodium or delayed release valproic acid: Initially use the same dose and frequency as the immediate release (usually dosed 3 to 4 times daily [Koch-Weser 1980]); once at steady state with improvement in symptoms, the frequency of the delayed release may be adjusted to 2 to 3 times daily
Conversion from delayed release to extended release divalproex sodium: For patients on a stable dose of delayed release divalproex sodium, increase the total daily dose of extended release divalproex sodium by 8% to 20% to maintain similar serum concentrations, and dose once daily.
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 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.
Conversion from immediate release valproic acid to delayed release divalproex sodium or delayed release valproic acid:Refer to adult dosing.
Conversion from delayed release to extended release divalproex sodium: Refer to adult dosing.
Focal onset (partial) and generalized onset seizures: Note: Administer doses >250 mg daily in divided doses.
Aware or impaired awareness absence seizures (simple and complex absence seizures): Refer to adult dosing. Larger maintenance doses may be required in younger children.
Focal-onset impaired awareness seizures (complex partial seizures): Children ≥10 years of age: Refer to adult dosing. Larger maintenance doses may be required in younger children.
Note: Extended release divalproex sodium is not recommended for use in children <10 years of age. Extended-release formulation is not available in Canada.
Conversion to monotherapy from adjunctive therapy: Refer to adult dosing.
IV: Children and Adolescents: Limited data available in some cases depending on seizure types and age (Piña-Garza 2013): 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 (off-label route): Dilute syrup 1:1 with water for use as a retention enema; acute and maintenance dose: 6 to 15 mg/kg/dose (Graves 1987)
Migraine prophylaxis: Children ≥12 years of age and Adolescents (Stavzor): Oral: Refer to adult dosing.
Status epilepticus (off-label use): Infants, Children, and Adolescents: IV: 20 to 40 mg/kg as a single dose administered at rate of 1.5 to 3 mg/kg/minute; if necessary, may give an additional dose of 20 mg/kg 10 minutes after the loading infusion; maximum dose: 3,000 mg (AES [Glauser 2016]; NCS [Brophy 2012])
Conversion from immediate release valproic acid to delayed release divalproex sodium or delayed release valproic acid:Refer to adult dosing.
Conversion from delayed release to extended release divalproex sodium: Refer to adult dosing.
Dosing: Renal Impairment
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
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.
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)
Oral: Oral valproate products may cause GI upset; taking with food or slowly increasing the dose may decrease GI upset should it occur.
Depakote ER: Swallow whole; do not crush or chew.
Depakote 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).
Depakene capsule, Stavzor: Swallow whole; do not chew.
Epival [Canadian product]: Swallow tablet whole; do not chew.
IV: For IV use only. Following dilution to final concentration, manufacturer's labeling recommends administering over 60 minutes at a rate ≤20 mg/minute. Alternatively, more rapid infusion rates of 1.5 to 10 mg/kg/minute have been used for loading doses in clinical trials to quickly achieve therapeutic concentrations, and were generally well tolerated (Boggs 2005; Limdi 2007; Ramsay 2003; Venkataraman 1999; Wheless 2004).
Neurocritical Care Society recommendations for status epilepticus (NCS [Brophy 2012]):
Adults: Maximum administration rate of 3 to 6 mg/kg/minute for the loading dose
Children and Adolescents: Maximum administration rate of 1.5 to 3 mg/kg/minute for the loading dose
Depakene: Store at 15°C to 25°C (59°F to 77°F).
Stavzor: Store at 25°C (77° F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Oral sprinkle capsules (Depakote): Store below 25°C (77°F).
Oral solution (Depakene): Store below 30°C (86°F).
Depakote: Store below 30°C (86°F).
Depakote ER: Store tablets at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Epival [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.
Barbiturates: Valproate Products may increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Valproate Products. Monitor therapy
Cannabidiol: Valproate Products may enhance the hepatotoxic effect of Cannabidiol. 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. 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. Consider therapy modification
ChlorproMAZINE: May increase the serum concentration of Valproate Products. 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. 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. Avoid combination
Estrogen Derivatives (Contraceptive): May decrease the serum concentration of Valproate Products. Monitor therapy
Ethosuximide: May decrease the serum concentration of Valproate Products. Valproate Products may increase the serum concentration of Ethosuximide. Monitor therapy
Felbamate: May increase the serum concentration of Valproate Products. 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. Monitor therapy
Fotemustine: Valproate Products may enhance the adverse/toxic effect of Fotemustine. Monitor therapy
GuanFACINE: May increase the serum concentration of Valproate Products. Monitor therapy
LamoTRIgine: Valproate Products may enhance the adverse/toxic effect of LamoTRIgine. Valproate Products may increase the serum concentration of LamoTRIgine. Consider therapy modification
Lesinurad: Valproate Products may increase the serum concentration of Lesinurad. Avoid combination
LORazepam: Valproate Products may increase the serum concentration of LORazepam. 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. Consider therapy modification
Methylfolate: May decrease the serum concentration of Valproate Products. Monitor therapy
Mianserin: May diminish the therapeutic effect of Anticonvulsants. Monitor therapy
Minoxidil (Systemic): Valproate Products may increase the serum concentration of Minoxidil (Systemic). Monitor therapy
OLANZapine: Valproate Products may decrease the serum concentration of OLANZapine. Monitor therapy
Orlistat: May decrease the serum concentration of Anticonvulsants. Monitor therapy
OXcarbazepine: Valproate Products may decrease the serum concentration of OXcarbazepine. Monitor therapy
Paliperidone: Valproate Products may increase the serum concentration of Paliperidone. Monitor therapy
Pivmecillinam: Valproate Products may enhance the adverse/toxic effect of Pivmecillinam. Specifically, the risk for carnitine deficiency may be increased. 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. Monitor therapy
Propofol: Valproate Products may enhance the therapeutic effect of Propofol. Monitor therapy
Protease Inhibitors: May decrease the serum concentration of Valproate Products. Monitor therapy
RifAMPin: May decrease the serum concentration of Valproate Products. Consider therapy modification
RisperiDONE: Valproate Products may enhance the adverse/toxic effect of RisperiDONE. Generalized edema has developed. 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. Consider therapy modification
Salicylates: May increase the serum concentration of Valproate Products. 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. Consider therapy modification
Temozolomide: Valproate Products may enhance the adverse/toxic effect of Temozolomide. Valproate Products may increase the serum concentration of Temozolomide. Monitor therapy
Topiramate: May enhance the adverse/toxic effect of Valproate Products. Monitor therapy
Tricyclic Antidepressants: Valproate Products may increase the serum concentration of Tricyclic Antidepressants. 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. Monitor therapy
Vorinostat: Valproate Products may enhance the thrombocytopenic effect of Vorinostat. This may increase the risk of gastrointestinal bleeding. Monitor therapy
Zidovudine: Valproate Products may increase the serum concentration of Zidovudine. Monitor therapy
May cause a false-positive result for urine ketones (valproate partially eliminated as a keto-metabolite in the urine); may alter thyroid function tests
As reported with oral administration, unless otherwise noted.
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
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.
• 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 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.
• 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]: May cause major congenital malformations such as neural tube defects (eg, spina bifida) and decreased IQ scores following in utero exposure. Use is contraindicated in pregnant women for the prevention of migraine. Use is not recommended in women of childbearing potential for any other condition unless valproate is essential to manage her condition and alternative therapies are not appropriate. Effective contraception should be used during therapy.
• Gastrointestinal: 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.
• 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.
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)
Pregnancy Risk Factor
X (migraine prophylaxis)/D (all other indications)
Adverse events have been observed in animal reproduction studies and in human pregnancies. [US Boxed Warning]: May cause major congenital malformations, such as neural tube defects (eg, spina bifida) and decreased IQ scores following in utero exposure. Use is contraindicated in pregnant women for the prevention of migraine. Use is not recommended in women of childbearing potential for any other condition unless valproate is essential to manage her condition and alternative therapies are not appropriate. Effective contraception should be used during therapy.
Valproic acid crosses the placenta (Harden 2009b). Neural tube defects, craniofacial defects, cardiovascular malformations, hypospadias, and limb malformations 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 valproic acid.
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.
Current guidelines recommend complete avoidance of valproic acid and derivatives 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. 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.
• 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, 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, enlarged lymph nodes, muscle pain, muscle weakness, joint pain, joint edema, tremors, seizures, behavioral changes, involuntary eye movements, tinnitus, severe fatigue, 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.
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