Neurology

Ropakin 400 (Valproate Sodium)


Pharmacologic Category

Anticonvulsant, Miscellaneous; Antimanic Agent; Histone Deacetylase Inhibitor

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: Pediatric

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: 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: Renal Impairment

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

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

Dosing: Hepatic Impairment

Mild to moderate impairment: Not recommended for use in hepatic disease; clearance is decreased with liver impairment. Hepatic disease is also associated with decreased albumin concentrations and 2- to 2.6-fold increase in the unbound fraction. Free concentrations of valproate may be elevated while total concentrations appear normal, therefore, monitoring only total valproate concentrations may be misleading.

Severe impairment: Use is contraindicated.

Dosage Form

lyophilized powder 400mg

Administration

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

Use

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

Use: Off-Label

Painful diabetic neuropathy; Postherpetic neuralgia; Status epilepticus (adults); Status epilepticus (infants/children/adolescents); Traumatic brain injury-related agitation and aggression; Traumatic brain injury-related seizure prophylaxis

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%)

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

Warnings/Precautions

Concerns related to adverse effects:

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

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

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

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

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

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

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

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

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

Disease-related concerns:

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

Hepatic impairment: Contraindicated with significant impairment.

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

Concurrent drug therapy issues:

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

Special populations:

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

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

Pregnancy: [US Boxed Warning]: 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.

Drug Interactions

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

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

CarBAMazepine: Valproate Products may increase serum concentrations of the active metabolite(s) of CarBAMazepine. Parent carbamazepine concentrations may be increased, decreased, or unchanged. CarBAMazepine may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

Carbapenems: May decrease the serum concentration of Valproate Products. Management: Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure medication. Risk D: Consider therapy modification

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

Cholestyramine Resin: May decrease the serum concentration of Valproic Acid and Derivatives. Management: Separate administration of valproic acid and cholestyramine by at least 3 hours whenever possible in order to minimize the potential for a significant interaction. Risk D: Consider therapy modification

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

Estrogen Derivatives (Contraceptive): May decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

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

Felbamate: May increase the serum concentration of Valproate Products. Risk D: Consider therapy modification

Fosphenytoin-Phenytoin: Valproate Products may decrease the protein binding of Fosphenytoin-Phenytoin. This appears to lead to an initial increase in the percentage of unbound (free) phenytoin and to a decrease in total phenytoin concentrations. Whether concentrations of free phenytoin are increased is unclear. With long-term concurrent use, total phenytoin concentrations may increase. Fosphenytoin-Phenytoin may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

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

LamoTRIgine: Valproate Products may enhance the adverse/toxic effect of LamoTRIgine. Valproate Products may increase the serum concentration of LamoTRIgine. Risk D: Consider therapy modification

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

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

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

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

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

Minoxidil (Systemic): Valproate Products may increase the serum concentration of Minoxidil (Systemic). Risk C: Monitor therapy

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

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

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

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

Primidone: Valproate Products may decrease the metabolism of Primidone. More specifically, the metabolism of phenobarbital, primidone’s primary active metabolite, may be decreased. Primidone may increase the serum concentration of Valproate Products. Risk C: Monitor therapy

Propofol: Valproate Products may enhance the therapeutic effect of Propofol. Risk C: Monitor therapy

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

RifAMPin: May decrease the serum concentration of Valproate Products. Risk D: Consider therapy modification

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

Rufinamide: Valproate Products may increase the serum concentration of Rufinamide. Management: Initiate rufinamide at a dose less than 10 mg/kg/day (children) or 400 mg/day (adults) in patients receiving valproic acid. In patients receiving rufinamide, initiate valproic acid at a low dose and titrate based on clinical response. Risk D: Consider therapy modification

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

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

Temozolomide: Valproate Products may enhance the adverse/toxic effect of Temozolomide. Valproate Products may increase the serum concentration of Temozolomide. Risk C: Monitor therapy

Topiramate: May enhance the adverse/toxic effect of Valproate Products. Risk C: Monitor therapy

Tricyclic Antidepressants: Valproate Products may increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Urea Cycle Disorder Agents: Valproate Products may diminish the therapeutic effect of Urea Cycle Disorder Agents. More specifically, Valproate Products may increase plasma ammonia concentrations and thereby increase the doses of Urea Cycle Disorder Agents needed to maintain concentrations in the target range. Risk C: Monitor therapy

Vorinostat: Valproate Products may enhance the thrombocytopenic effect of Vorinostat. This may increase the risk of gastrointestinal bleeding. Risk C: Monitor therapy

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

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

Pregnancy Risk Factor

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

Breast-Feeding Considerations

Valproate is present in breast milk. Breast milk concentrations of valproic acid have been reported as 1% to 10% of maternal concentration. The weight-adjusted dose to the infant has been calculated to be ~4% (Hagg 2000). The manufacturer recommends that caution be used if administered to breastfeeding women.

Monitoring Parameters

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

Reference Range Note: In general, trough concentrations should be used to assess adequacy of therapy; peak concentrations may also be drawn if clinically necessary (eg, concentration-related toxicity). Within 2 to 4 days of initiation or dose adjustment, trough concentrations should be drawn just before the next dose (extended-release preparations) or before the morning dose (for immediate-release preparations). Patients with epilepsy should not delay taking their dose for >2 to 3 hours. Additional patient-specific factors must be taken into consideration when interpreting drug levels, including indication, age, clinical response, pregnancy status, adherence, comorbidities, adverse effects, and concomitant medications (Patsalos, 2008; Reed, 2006).

Valproic acid, total:

Therapeutic:

Epilepsy: 50 to 100 mcg/mL (SI: 350 to 700 micromole/L); although seizure control may improve at levels >100 mcg/mL (SI: 700 micromole/L), toxicity may occur at levels of 100 to 150 mcg/mL (SI: 700 to 1,040 micromole/L)

Mania: 50 to 125 mcg/mL (SI: 350 to 875 micromole/L)

Toxic: Despite the usual upper reference range of 100 to 125 mcg/mL, clinical toxicity can occur at lower concentrations.

Epilepsy: Although seizure control may improve at levels >100 mcg/mL (SI: 700 micromole/L), toxicity may occur at levels of 100 to 150 mcg/mL (SI: 700 ro 1,050 micromole/L)

Mania: Clinical response seen with trough levels between 50 to 125 mcg/mL (SI: 350 to 875 micromole/L); risk of toxicity increases at levels >125 mcg/mL (SI: 875 micromole/L)

Valproic acid, free:

Therapeutic: 5 to 15 mcg/mL (Smetana 2015)

Mechanism of Action

Causes increased availability of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, to brain neurons or may enhance the action of GABA or mimic its action at postsynaptic receptor sites. Divalproex sodium is a compound of sodium valproate and valproic acid; divalproex dissociates to valproate in the GI tract.

Pharmacodynamics/Kinetics

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

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

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

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

Bioavailability: Depakote ER: ~90% relative to IV dose and ~89% relative to delayed release formulation. In pediatric patients 10 to 17 years of age, once-daily administration of Depakote-ER produced valproate plasma concentration-time profiles similar to adults.

Half-life elimination (increased in neonates, elderly, and patients with liver impairment):

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

Neonates first week of life: 40 to 45 hours

Neonates <10 days: 10 to 67 hours

Children >2 months: 7 to 13 hours

Children and Adolescents 2 to 14 years: 9 hours (range: 3.5 to 20 hours) (Cloyd 1993)

Adults: 9 to 19 hours

Time to peak, serum:

Oral: 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)

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

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