Medically reviewed by Drugs.com. Last updated on Feb 23, 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.
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
Brand Names: U.S.
- Depakote ER
- Depakote Sprinkles
- 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. 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.
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
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)
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 (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.
Off Label Uses
Bipolar major depression (alternative agent)
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 [Davis 2005], [Ghaemi 2007], [Muzina 2011].
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 [CANMAT/ISBD [Yatham 2018]].
Maintenance treatment of bipolar disorder
Data from a limited number of clinical trials suggest that valproate 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 valproate is 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, valproate is recommended for maintenance treatment to prevent a mixed episode following a depressed or manic episode based on limited positive evidence [WFSBP [Grunze 2018]].
Data from multiple studies, including randomized controlled trials, support the use of valproate sodium 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, 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 [Trinka 2014].
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.
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)
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.
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 preparations: To continue therapy IV in patients temporarily unable to receive oral therapy, total daily IV dose should be equivalent to the total daily oral dose (expressed as valproic acid) and divided every 6 hours. Trough levels may fall below the equivalent oral regimen when administered less frequently than every 6 hours; in these cases, closely monitor trough plasma concentrations.
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.
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.
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
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.
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:
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
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)
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).
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).
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).
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.
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 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.
• 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.
• 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.
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)
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.
• 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.
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