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Valproic Acid and Derivatives

Pronunciation

Pronunciation

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

Index Terms

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

Dosage Forms

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.

  • Depacon
  • Depakene
  • Depakote
  • Depakote ER
  • Depakote Sprinkles
  • Stavzor [DSC]

Pharmacologic Category

  • Anticonvulsant, Miscellaneous
  • Antimanic Agent
  • Histone Deacetylase Inhibitor

Pharmacology

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.

Distribution

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

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

Metabolism

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

Excretion

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

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)

Half-Life Elimination

Increased in neonates, elderly, and patients with liver impairment

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

Neonates first week of life: 40 to 45 hours

Neonates <10 days: 10 to 67 hours

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

Protein Binding

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

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%. Protein binding is reduced, monitoring only 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

Epilepsy: Oral, IV: Monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures; monotherapy and adjunctive therapy of simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures

Mania: Depakote, Depakote ER, Stavzor, Epival [Canadian product]: Mania associated with bipolar disorder

Migraine: Depakote, Depakote ER, Stavzor: Migraine prophylaxis

Limitation of use: Do not administer to a woman of childbearing potential unless essential for the management of her condition.

Off Label Uses

Painful diabetic neuropathy

Data from a limited number of clinical trials suggest that valproate may be beneficial in decreasing pain in painful diabetic neuropathy [Kochar 2002], [Kochar 2004]. Additional data may be necessary to further define the role of valproate in this condition.

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.

Postherpetic neuralgia

Data from a limited number of patients studied suggest that valproate may be beneficial in decreasing pain in postherpetic neuralgia. Additional data may be necessary to further define the role of valproate acid in this condition.

Based on the European Federation of Neurological Societies guidelines on the management of neuropathic pain, valproate acid is generally not recommended for the management of postherpetic neuralgia due to limited evidence.

Status epilepticus (adults)

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], [Limbdi 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 2015]]. 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].

Traumatic brain injury related seizure prophylaxis

Data from a limited number of patients studied suggest that valproate may be beneficial for the prevention of seizures that occur within 7 days following TBI; however, it may not prevent late seizures that occur more than 1 week after injury, and it may also increase the risk of mortality [Tempkin 1999]. In addition, data from a limited number of patients studied suggests that valproate does not negatively affect cognition following TBI [Dikmen 2000]. Additional data may be necessary to further define the role of valproate in this condition.

Based on the Brain Trauma Foundation, American Association of Neurological Surgeons and Congress of Neurological Surgeons guidelines for anti-seizure prophylaxis, valproate is not recommmended for the prevention of late seizures (at least 7 days post-TBI) due to questionable efficacy and potential for increased mortality[Bratton 2007].

Based on recommendations from the Neurobehavioral Guidelines working group, valproate is recommended over phenytoin for seizure prophylaxis in patients with cognitive impairment after TBI [Warden 2006].

Contraindications

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

Dosing: Adult

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

Seizures: Note: Administer doses >250 mg/day in divided doses. Extended-release formulation is not available in Canada.

Oral:

Simple and complex absence seizure: Initial: 15 mg/kg/day; increase by 5 to 10 mg/kg/day at weekly intervals until therapeutic levels are achieved; maximum: 60 mg/kg/day.

Complex partial seizure: Initial: 10 to 15 mg/kg/day; increase by 5 to 10 mg/kg/day at weekly intervals until therapeutic levels are achieved; maximum: 60 mg/kg/day.

Note: Regular release and delayed release formulations are usually given in 2 to 4 divided doses per day; extended release formulation (Depakote ER) is usually given once daily. In patients previously maintained on regular release valproic acid therapy (Depakene) who convert to delayed release valproate tablets or capsules (Depakote, Stavzor, Epival [Canadian product]), the same daily dose and frequency as the regular release should be used; once therapy is stabilized, the frequency of Depakote, Stavzor, or Epival may be adjusted to 2 to 3 times 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 therapy is initiated or 1 to 2 weeks following valproate initiation.

IV: Total daily IV dose should be equivalent to the total daily dose of the oral valproate product; administer dose as a 60-minute infusion (≤20 mg/minute) with the same frequency as oral products; switch patient to oral products as soon as possible. Alternatively, rapid infusions of 1.5 to 6 mg/kg/minute have been used in clinical trials to quickly achieve therapeutic concentrations, and were generally well tolerated (Ramsay 2003; Venkataraman 1999; Wheless 2004). One study reported undiluted valproic acid administered at ≤10 mg/kg/minute (dose of ≤30 mg/kg) was well tolerated (Limdi 2007).

Mania: Oral: Note: Extended-release formulation is not available in Canada.

Depakote tablet, Stavzor, Epival [Canadian product]: Initial: 750 mg/day in divided doses; dose should be adjusted as rapidly as possible to desired clinical effect; maximum recommended dosage: 60 mg/kg/day

Depakote ER: Initial: 25 mg/kg/day given once daily; dose should be adjusted as rapidly as possible to desired clinical effect; maximum recommended dose: 60 mg/kg/day.

Migraine prophylaxis: Oral:

Depakote tablet, Stavzor: 250 mg twice daily; adjust dose based on patient response, up to 1,000 mg/day

Depakote ER: 500 mg once daily for 7 days, then increase to 1,000 mg once daily; adjust dose based on patient response; usual dosage range: 500 to 1,000 mg/day

Painful diabetic neuropathy (off-label use): Oral: Initial: 500 mg/day; increase to 1,000 mg/day after 1 week; doses as high as 1,200 mg/day have been studied (Kochar 2002; Kochar 2004). Additional data may be necessary to further define the role of valproate in this condition.

Postherpetic neuralgia (off-label use): Oral: Usual dose: 1,000 mg daily (Kochar 2005). Additional data may be necessary to further define the role of valproate in this condition.

Status epilepticus (off-label use): IV: Loading dose: 20 to 40 mg/kg administered at rate of 3 to 6 mg/kg/minute; if necessary, may give an additional dose of 20 to 40 mg/kg administered at rate of 3 to 6 mg/kg/minute; if necessary, may give an additional dose of 20 mg/kg 10 minutes after the loading infusion (NCS [Brophy, 2012]).

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). Additional data may be necessary to further define the role of valproate in this condition.

Dosing: Geriatric

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. Upward titration should be done slowly and with close monitoring for adverse events (eg, sedation, dehydration, decreased nutritional intake). Safety and efficacy for use in patients >65 years have not been studied for migraine prophylaxis.

Dosing: Pediatric

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

Seizures: Note: Administer doses >250 mg daily in divided doses.

Oral:

Simple and complex absence seizures: Refer to adult dosing. Larger maintenance doses may be required in younger children.

Complex partial seizures: Children ≥10 years: Refer to adult dosing. Larger maintenance doses may be required in younger children.

Note: Depakote ER is not recommended for use in children <10 years of age. Extended-release formulation is not available in Canada.

Conversion to Depakote ER from a stable dose of Depakote: Refer to adult dosing.

Conversion to monotherapy from adjunctive therapy: Refer to adult dosing.

IV: Refer to adult dosing.

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 and Adolescents (Stavzor): Oral: Refer to adult dosing.

Status epilepticus (off-label use): Infants, Children, and Adolescents: IV: 20 to 40 mg/kg 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 (NCS [Brophy, 2012]) or 40 mg/kg as a single dose (maximum dose: 3,000 mg) (AES [Glauser 2016]).

Dosing: Renal Impairment

Mild to severe impairment: No dosage adjustment necessary; however, due to decreased protein binding in renal impairment, monitoring only total valproate concentrations may be misleading.

Hemodialysis: No dosage adjustment necessary; however, due to decreased protein binding in renal impairment, monitoring only 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.

Reconstitution

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)

Administration

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: 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 1.5-6 mg/kg/minute have been used in clinical trials to quickly achieve therapeutic concentrations, and were generally well tolerated (Ramsay, 2003; Wheless, 2004). One study reported undiluted valproic acid administered at ≤10 mg/kg/minute (dose of ≤30 mg/kg) was well tolerated (Limdi, 2007).

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

Storage

Oral capsules:

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).

Oral tablets:

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.

Drug Interactions

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

Barbiturates: Valproate Products may increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Valproate Products. 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

Contraceptives (Estrogens): May decrease the serum concentration of Valproate Products. Monitor therapy

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

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

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

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

Test Interactions

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

Adverse Reactions

As reported with oral administration, unless otherwise noted.

>10%:

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

Dermatologic: Alopecia (>1% to 24%)

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

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

Infection: Infection (≤20%)

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

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

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

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

1% to 10%:

Cardiovascular: Peripheral edema (>1% to 8%), edema (>1% to 5%), facial edema (>1% to 5%), hypertension (>1% to 5%), hypotension (1% to 5%), orthostatic hypotension (1% to 5%), palpitations (>1% to 5%), vasodilatation (oral: >1% to 5%; intravenous: <1%), tachycardia (>1% to <5%), chest pain (2%)

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

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

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

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

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

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

Hepatic: Increased serum ALT (>1% to <5%), increased serum AST (>1% to <5%)

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

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

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

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

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

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

Miscellaneous: Fever (>1% to 6%)

<1% (Limited to important or life-threatening): 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, disturbance in attention, DRESS syndrome, 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, 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

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first 6 months of treatment. Serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Monitor patients closely for appearance of these symptoms. Perform serum liver tests prior to therapy and at frequent intervals thereafter, especially during the first 6 months.

Children younger than 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When these products are used in this patient group, use with extreme caution and as a sole agent. Weigh the benefits of therapy against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Patients with mitochondrial disease:

There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase gamma (POLG) gene (eg, Alpers-Huttenlocher syndrome). Valproate is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children younger than 2 years who are clinically suspected of having a mitochondrial disorder. In patients older than 2 years who are clinically suspected of having a hereditary mitochondrial disease, only use after other anticonvulsants have failed. Closely monitor this older group of patients during treatment for the development of acute liver injury with regular clinical assessments and serum liver testing. Perform POLG mutation screening in accordance with current clinical practice.

Fetal risk:

Valproate can cause major congenital malformations, particularly neural tube defects (eg, spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Only use valproate to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable. Do not administer valproate to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (eg, migraine). Women should use effective contraception while using valproate.

An information sheet describing the teratogenic potential of valproate is available for patients.

Pancreatitis:

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

Warnings/Precautions

Concerns related to adverse effects:

• 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.

• 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. In addition to platelets, valproate may be associated with a decrease in other cell lines and myelodysplasia.

Disease-related concerns:

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

• Sedatives: CNS effects may be potentiated when used with other sedative drugs or ethanol.

Special populations:

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

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

• Pregnancy: [US Boxed Warning]: 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.

Other warnings/precautions:

• 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.

Monitoring Parameters

Liver enzymes (at baseline and frequently during therapy especially during the first 6 months), CBC with platelets (baseline and periodic intervals), PT/PTT (especially prior to surgery), serum ammonia (with symptoms of lethargy, mental status change), serum valproate levels; suicidality (eg, suicidal thoughts, depression, behavioral changes); motor and cognitive function (for signs or symptoms of brain atrophy)

Pregnancy Risk Factor

X (migraine prophylaxis)/D (all other indications)

Pregnancy Considerations

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.

Patient Education

• 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.

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

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