Valproic Acid

Class: Anticonvulsants, Miscellaneous
Note: This monograph also contains information on Divalproex Sodium, Valproate Sodium
VA Class: CN105
CAS Number: 1069-66-5
Brands: Depacon, Depakene, Depakote, Stavzor

Warning(s)

  • Hepatotoxicity
  • Potentially fatal hepatic failure can occur.179 182 183 184 185 221 222 223

  • Usually occurs during the initial 6 months of therapy.179 182 183 184 185 221 222 223

  • Children <2 years of age are at considerably increased risk of developing fatal hepatotoxicity, especially those receiving multiple anticonvulsants and those with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease.179 182 183 184 185 Use with extreme caution in this age group and only as single-agent therapy; carefully weigh benefits versus risks.179 182 183 184 185 Incidence of fatal hepatotoxicity appears to decrease progressively with increasing age.179 182 183 184 185 223

  • Serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting.179 182 183 184 185 221

  • In epileptic patients, loss of seizure control also may precede development of hepatotoxicity.179 182 183 184 185

  • Monitor patients closely for development of any such changes.179 182 183 184 185

  • Perform liver function tests prior to and at frequent intervals during therapy, especially during the first 6 months.179 182 183 184 185 (See Hepatotoxicity under Cautions.)

  • Increased risk of acute liver failure (sometimes resulting in death) in patients with hereditary mitochondrial disorders caused by mutations in the polymerase gamma (POLG) gene (e.g., Alpers-Huttenlocher syndrome);179 182 183 185 221 222 223 contraindicated in patients known to have such disorders and in children <2 years of age in whom there is a clinical suspicion of a mitochondrial disorder.179 182 183 185 In children >2 years of age with suspected hereditary mitochondrial disease, use only if other anticonvulsant therapies have failed; closely monitor such patients with regular clinical assessments and liver function tests.179 182 183 185 Perform POLG mutation screening according to current clinical practice.179 182 183 185 222 223

  • Fetal Risk
  • Risk of major congenital malformations, particularly neural tube defects (NTDs).182 183 184 185 188 189 190 191 192 193 194

  • Risk of decreased IQ scores following in utero exposure.182 196 197 198 199 200 201 202 203 204 205 206 207 212

  • Contraindicated in pregnant women for migraine prophylaxis.182 205 In pregnant women with epilepsy or bipolar disorder, use only if other therapies fail or are otherwise unacceptable.182 205

  • Do not use in women of childbearing potential unless the drug is essential to their medical condition.182 183 184 185 This is particularly important when contemplating treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine headaches).182 183 184 185 (See Pregnancy under Cautions.)

  • A medication guide describing the risks of valproic acid is available for patients.182 183 188 (See Advice to Patients.)

  • Pancreatitis
  • Life-threatening pancreatitis has occurred both in children and adults.179 182 183 184 185

  • Some cases described as hemorrhagic with rapid progression from initial symptoms to death.179 182 183 184 185

  • Can occur shortly after initial use as well as after several years of use.179 182 183 184 185

  • Warn patients and caregivers that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation.179 182 183 184 185

  • Usually discontinue the drug and initiate alternative therapy if pancreatitis is diagnosed.179 182 183 184 185

Introduction

Valproic acid (the active moiety), valproate sodium, and divalproex sodium are carboxylic acid-derivative anticonvulsants; also antimanic, other psychotherapeutic, and antimigraine agents.182 183 184 185 b

Uses for Valproic Acid

Valproic acid (ionized form: valproate) is the active moiety for valproate sodium and divalproex sodium.b

Absence (Petit Mal) Seizures

Alone or with other anticonvulsants (e.g., ethosuximide) as first-line therapy in the prophylactic management of simple and complex absence (petit mal) seizures.179 182 183 184 185 224 b

In conjunction with other anticonvulsants in the management of multiple seizure types that include absence seizures.b

Complex Partial Seizures

Alone or with other anticonvulsants (e.g., carbamazepine, phenytoin) as first-line therapy in the prophylactic management of complex partial seizures that occur either by themselves or in association with other seizure types.179 182 183 184 185 b

Generalized Seizures

First-line therapy for generalized seizures, including primary generalized tonic-clonic, primary generalized tonic-clonic absence, myoclonic, or atonic seizures, especially when more than one type of generalized seizure is present.b

Simple Partial Seizures

First-line therapy for the management of simple partial seizures.b

Status Epilepticus

Has been administered rectally or by intragastric drip with some success in the management of status epilepticus refractory to IV diazepam.b

A parenteral formulation of valproic acid has been studied and has been effective when administered IV in the management of status epilepticus.b

Bipolar Disorder

Alone or as a component of combination therapy (e.g., with lithium, antipsychotic agents [e.g., olanzapine], antidepressants, carbamazepine) for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features.182 183 214

American Psychiatric Association (APA) currently recommends combined therapy with valproic acid plus an antipsychotic agent or with lithium plus an antipsychotic agent as first-line drug therapy for the acute treatment of more severe manic or mixed episodes and monotherapy with one of these drugs for less severe episodes.b

Valproic acid or lithium also is recommended for the initial acute treatment of rapid cycling.b

Some clinicians recommend that valproic acid therapy be used in patients with bipolar disorder or schizoaffective disorder, bipolar type, who have responded inadequately to or have been unable to tolerate treatment with lithium salts or other therapy (e.g., carbamazepine), particularly if the patient displays residual manic symptoms, or in the presence of rapid-cycling, dysphoric mania or hypomania, associated neurologic abnormalities, or organic brain disorder.b

Migraine

Prophylaxis of migraine headache.170 182 183 214 b

Because valproic acid poses a hazard to the fetus (see Fetal Risk in Boxed Warning and also see Pregnancy under Cautions), do not use in pregnant women for migraine prophylaxis; in such patients, the risks of the drug outweigh any possible benefits.182 183 184 185 205 Use in women of childbearing potential only if the drug is essential.182 183 184 185 188 190 196 205

The US Headache Consortium states that valproic acid has medium to high efficacy for the prophylaxis of migraine headache.170 b

Has also been used IV for the acute management (i.e., abortive therapy) of migraine headache;157 158 160 161 162 163 164 166 however, role of drug relative to other acute therapies requires further elucidation.156 166 170 172 173

Schizophrenia

As an adjunct to antipsychotic drugs in the symptomatic management of schizophrenia in patients who fail to respond sufficiently to an adequate trial of an antipsychotic agent alone.146 147 148

APA146 and some clinicians148 state that anticonvulsant agents such as valproic acid and divalproex sodium may be useful adjuncts in schizophrenic patients with prominent mood lability or in those with agitated, aggressive, hostile, or violent behavior.146 148

APA states that, with the exception of patients with schizophrenia whose illness has strong affective components, monotherapy with valproic acid or divalproex sodium has not been shown to be substantially effective in the long-term treatment of schizophrenia.146

Valproic Acid Dosage and Administration

General

Do not abruptly discontinue anticonvulsants, including valproic acid, in patients with seizure disorders; withdraw gradually to minimize the potential for increased seizure frequency.182 183 184

Closely monitor patients for marked changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.176 177 178 180 183 184 (See Suicidality Risk under Cautions.)

Distribute medication guide explaining risks and benefits of therapy to patients receiving oral formulations of the drug.188

Administration

Administer valproate sodium orally or by IV infusion; administer valproic acid and divalproex sodium orally.182 183 184 185 b

Valproic acid also has been administered rectally by enema or in wax-based suppositories, but a rectal dosage form is not commercially available in the US.b

Oral Administration

Valproic acid, valproate sodium, and divalproex sodium are administered orally.182 183 184 b

If GI irritation occurs, may administer with food or gradually increase dosage from an initial low dosage.179 182 183 184 b

Patients unable to tolerate the GI effects of valproic acid or valproate sodium may tolerate divalproex sodium.b

If a dose is missed, take as soon as possible unless it is almost time for the next dose.182 183 184 Do not double a dose to make up for a missed dose.182 183 184

Divalproex sodium extended-release tablets are not bioequivalent to the delayed-release tablets.182

Although the extent of GI absorption of valproic acid from capsules containing coated particles or delayed-release tablets of divalproex sodium is equivalent, peak and trough plasma concentrations achieved may vary (e.g., peak valproic acid concentrations generally are higher with the delayed-release tablets); increased monitoring of plasma valproic acid concentrations is recommended if one dosage form is substituted for the other.b

Formulation-specific Administration Instructions

Administer divalproex sodium extended-release tablets (e.g., Depakote ER) once daily; for other oral formulations, administer in divided doses if total daily dosage >250 mg.179 182 183 184 214

Valproic acid capsules: Swallow capsules whole, not chewed, in order to prevent mouth and throat irritation.184 b

Valproate sodium oral solution: Do not administer in carbonated beverages.b

Valproic acid delayed-release capsules (Stavzor): Swallow capsules whole; do not crush, chew, or break.214

Divalproex sodium delayed-release (e.g., Depakote) or extended-release (e.g., Depakote ER) tablets: Swallow tablets intact; do not chew or crush.182 183

Capsules containing coated particles of divalproex sodium (e.g., Depakote Sprinkle Capsules): Swallow capsules intact or sprinkle entire contents of capsule(s) on a small amount (about 5 mL) of soft food (e.g., applesauce, pudding) and swallow (not chew) immediately.179 Do not store the mixture for future use.179

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Valproate sodium injection is intended for IV use only.185

Dilution

For IV use, dilute the appropriate dose of valproate sodium injection with at least 50 mL of a compatible IV solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection, lactated Ringer’s injection).185 b (See Solution Compatibility under Stability.)

Rate of Administration

Infuse diluted IV solutions over 60 minutes; the manufacturer recommends that the rate not exceed 20 mg/minute.185

Rapid IV infusion has been associated with an increased risk of adverse effects.b

Experience from clinical studies of rates >20 mg/minute or infusion periods <60 minutes is limited.b

In a study of the safety of initial 5- to 10-minute IV infusions of valproate sodium (1.5–3 mg/kg per minute of valproic acid), patients generally tolerated such rapid infusions; however, the study was not designed to assess the efficacy of the regimen.185 b

Use of rapid infusions as a parenteral replacement for oral valproic acid has not been established.b

Dosage

Dosage of valproate sodium and divalproex sodium is expressed in terms of valproic acid.b

Must adjust dosage carefully and slowly according to individual requirements and response.b

An anticonvulsant therapeutic range of 50–100 mcg/mL has been suggested; seizure control occasionally may occur with lower or higher concentrations, but >150 mcg/mL usually is toxic.b

For acute manic or mixed episodes in bipolar disorder, usually dosed to clinical response with trough plasma concentrations of 50–125 mcg/mL.182 183

Frequency of adverse effects (particularly elevated liver enzyme concentrations and thrombocytopenia) may be dose related; carefully weigh the benefit of improved therapeutic effect that may accompany higher dosages against the risk of adverse effects.182 183 b (See Thrombocytopenia under Cautions.)

When switching to divalproex sodium delayed-release tablets or valproic acid delayed-release capsules in patients receiving conventional valproic acid, use same daily dosage and schedule.183 214 After stabilization with the delayed-release formulation, may divide daily dosage and administer 2 or 3 times daily in selected patients.183 214

Pediatric Patients

Seizure Disorders
Complex Partial Seizures (Monotherapy and Adjunctive Therapy)
Oral (conventional, delayed-, and extended-release preparations)

Dosages apply to conventional (capsules and solution), delayed-release (capsules and tablets), and extended-release (tablets) dosage forms of valproic acid (active moiety), valproate sodium, and divalproex sodium.179 182 183 184 214

Children ≥10 years of age: Initially, 10–15 mg/kg daily.179 182 183 184 214

Increase dosage by 5–10 mg/kg daily at weekly intervals, according to response and tolerability, up to maximum recommended dosage of 60 mg/kg daily.179 182 183 184 214

When used adjunctively, may continue concurrent anticonvulsant therapy, adjusting dosages according to response and tolerability.182 183 184 (See Interactions.)

Alternatively, may attempt to decrease dosage of the current anticonvulsant by 25% every 2 weeks, either starting concomitantly with initiation of valproic acid therapy or delayed by 1–2 weeks if there is a concern that seizures are likely to occur with a reduction.b

Speed and duration of withdrawal of the current anticonvulsant can be highly variable; monitor patients closely during this period for increased seizure frequency.b

When converting a patient from a current anticonvulsant to valproic acid therapy for the treatment of complex partial seizures, initiate valproic acid therapy at usual starting dosages.b

IV

May employ IV therapy in patients in whom oral therapy temporarily is not feasible, but switch to oral administration as soon as clinically possible.185 b

IV administration can be used for monotherapy or as adjunctive therapy in the management of seizure disorders.185 b

The usual total daily dosages are equivalent for IV or oral administration, and the doses and frequency of administration employed with oral therapy in seizure disorders are expected to be the same with IV therapy, although plasma concentration monitoring and dosage adjustment may be necessary.185 b

Administer daily dosages >250 mg in divided doses.185

Use of IV therapy for >14 days not established.185 b

Use of IV valproate sodium for initial monotherapy has not been systematically studied; however, usual dosages and titration employed with oral therapy can be employed with parenteral therapy.185 b

Monitor patients receiving dosages near the usual maximum recommended dosage of 60 mg/kg daily closely, particularly when enzyme-inducing drugs are not used concomitantly.b

Simple or Complex Absence Seizures
Oral (conventional, delayed-, and extended-release preparations)

Dosages apply to conventional (capsules and solution), delayed-release (capsules and tablets), and extended-release (tablets) dosage forms of valproic acid (active moiety), valproate sodium, and divalproex sodium.179 182 183 184 214

Initially, 15 mg/kg daily.179 182 183 184 214

Increase dosage by 5–10 mg/kg daily at weekly intervals, according to response and tolerability, up to maximum recommended dosage of 60 mg/kg daily.179 182 183 184 214

IV

May employ IV therapy in patients in whom oral therapy temporarily is not feasible, but switch to oral administration as soon as clinically possible.185 b

The usual total daily dosages are equivalent for IV or oral administration, and the doses and frequency of administration employed with oral therapy in seizure disorders are expected to be the same with IV therapy, although plasma concentration monitoring and dosage adjustment may be necessary.185 b

Administer daily dosages >250 mg in divided doses.185

Use of IV therapy for >14 days has not been studied to date.185 b

Use of IV valproate sodium for initial monotherapy has not been systematically studied; however, usual dosages and titration employed with oral therapy can be employed with parenteral therapy.185 b

Monitor patients receiving dosages near the usual maximum recommended dosage of 60 mg/kg daily closely, particularly when enzyme-inducing drugs are not used concomitantly.185 b

Adults

Seizure Disorders
Complex Partial Seizures
Oral (conventional, delayed-, and extended-release preparations)

Dosages apply to conventional (capsules and solution), delayed-release (capsules and tablets), and extended-release (tablets) dosage forms of valproic acid (active moiety), valproate sodium, and divalproex sodium.182 183 184 214

Initially, 10–15 mg/kg daily.183 184 214

Increase dosage by 5–10 mg/kg daily at weekly intervals until seizures are controlled or adverse effects prevent further dosage increases, usually up to 60 mg/kg daily according to response and tolerability.b

When used adjunctively, may continue concurrent anticonvulsant therapy, adjusting dosages according to response and tolerability.182 183 184 (See Interactions.)

Alternatively, may attempt to decrease dosage of the current anticonvulsant by 25% every 2 weeks, either starting concomitantly with initiation of valproic acid therapy or delayed by 1–2 weeks if there is a concern that seizures are likely to occur with a reduction.b

Speed and duration of withdrawal of the current anticonvulsant can be highly variable; monitor patients closely during this period for increased seizure frequency.b

IV

May employ IV therapy in patients in whom oral therapy temporarily is not feasible, but switch to oral administration as soon as clinically possible.185 b

IV administration can be used for monotherapy or as adjunctive therapy in the management of seizure disorders.b

The usual total daily dosages are equivalent for IV or oral administration, and the doses and frequency of administration employed with oral therapy in seizure disorders are expected to be the same with IV therapy, although plasma concentration monitoring and dosage adjustment may be necessary.185 b

Administer daily dosages >250 mg in divided doses.185

Use of IV therapy for >14 days not established.185 b

Use of IV valproate sodium for initial monotherapy has not been systematically studied; however, usual dosages and titration employed with oral therapy can be employed with parenteral therapy.b

Monitor patients receiving dosages near the usual maximum recommended dosage of 60 mg/kg daily closely, particularly when enzyme-inducing drugs are not used concomitantly.b

Simple or Complex Absence Seizures
Oral (conventional, delayed-, and extended-release preparations)

Dosages apply to conventional (capsules and solution), delayed-release (capsules and tablets), and extended-release (tablets) dosage forms of valproic acid (active moiety), valproate sodium, and divalproex sodium.182 183 184 214

Initially, 15 mg/kg daily.183 184 b

Increase dosage by 5–10 mg/kg daily at weekly intervals, according to response and tolerability, up to maximum recommended dosage of 60 mg/kg daily.183 184 214

IV

May employ IV therapy in patients in whom oral therapy temporarily is not feasible, but switch to oral administration as soon as clinically possible.185 b

The usual total daily dosages are equivalent for IV or oral administration, and the doses and frequency of administration employed with oral therapy in seizure disorders are expected to be the same with IV therapy, although plasma concentration monitoring and dosage adjustment may be necessary.185 b

Administer daily dosages >250 mg in divided doses.185

Use of IV therapy for >14 days not established.185 b

Use of IV valproate sodium for initial monotherapy has not been systematically studied; however, usual dosages and titration employed with oral therapy can be employed with parenteral therapy.b

Monitor patients receiving dosages near the usual maximum recommended dosage of 60 mg/kg daily closely, particularly when enzyme-inducing drugs are not used concomitantly.b

Seizure Disorders
Conversion from Divalproex Sodium Delayed-release (e.g., Depakote) to Extended-release (e.g., Depakote ER) Tablets
Oral

When converting a patient whose seizure disorder is controlled with divalproex sodium delayed-release tablets to the extended-release tablets, give the drug once daily using a total daily dose that is 8–20% higher than the corresponding delayed-release dosage that the patient was receiving.182

For patients whose delayed-release daily dosage cannot be directly converted to a corresponding commercially available extended-release dosage, consider increasing the delayed-release total daily dosage to the next higher dosage before converting to the appropriate extended-release total daily dosage at the clinician’s discretion.182

Refractory Status Epilepticus
Rectally

400–600 mg of valproic acid has been administered by enema or in wax-based suppositories at 6-hour intervals.b

Bipolar Disorder
Manic or Mixed Episodes
Oral

Initially, 750 mg daily in divided doses as delayed-release tablets (e.g., Depakote) or delayed-release capsules (Stavzor) or 25 mg/kg once daily as extended-release tablets (e.g., Depakote ER) for acute episodes.182 183 214

For acute episodes, increase dosage as quickly as possible to achieve the lowest therapeutic dosage producing the desired clinical effect or desired plasma concentration; however, the manufacturers recommend that the dosage not exceed 60 mg/kg daily.182 183 214 b

In clinical studies, dosed to clinical response with trough plasma concentrations of 50–125 mcg/mL.182 183

Efficacy beyond 3 weeks not systematically evaluated; if continued, periodically reevaluate long-term usefulness and risk for the individual patient.182 183 214

Safety for longer-term antimanic therapy is supported by data from record reviews involving approximately 360 patients treated for >3 months.183 214

Dosing guidelines for maintenance therapy are less evidence-based than those for acute therapy, and dosages lower than those employed for acute therapy occasionally have been used.b

Migraine
Prophylaxis of Chronic Attacks
Oral

Initially, 250 mg twice daily as delayed-release tablets (e.g., Depakote)183 or delayed-release capsules (Stavzor)214 or 500 mg once daily as extended-release tablets (e.g., Depakote ER).182

Maintenance: After 1 week at the initial dosage of extended-release tablets, may increase dosage to 1 g daily.182 Some patients may benefit from dosages up to 1 g daily.183 214 No evidence of additional benefit with higher dosages.183 214

If a patient requires smaller dosage adjustment than that available using the extended-release tablets, use the delayed-release tablets instead.182

Schizophrenia
Oral

In general, for adjunctive therapy, administer in the same dosages, and with the same resulting therapeutic plasma concentrations, as those for the management of seizure disorders.146 147 148

Prescribing Limits

Pediatric Patients

Seizure Disorders
Oral

Usual maximum recommended dosage is 60 mg/kg daily;182 183 b if therapeutic response not achieved, monitor plasma concentrations.182 183

Adults

Seizure Disorders
Oral

Usual maximum recommended dosage is 60 mg/kg daily;182 183 b if therapeutic response not achieved, monitor plasma concentrations.182 183

Bipolar Disorder
Manic or Mixed Episodes
Oral

Maximum recommended dosage is 60 mg/kg daily.182 183 b

Migraine
Prophylaxis of Chronic Attacks
Oral

Maximum recommended dosage is 1 g daily.182 183 214

Special Populations

Hepatic Impairment

Because of substantially decreased protein binding, monitoring total (bound + unbound) drug concentrations may be misleading.183 185

Renal Impairment

Dosage adjustment does not appear necessary.183 184

Because of substantially decreased protein binding, monitoring total (bound + unbound) drug concentrations may be misleading.183 184

Geriatric Patients

Reduce initial dosage because of a decrease in clearance of unbound valproic acid and possibility of greater sensitivity to adverse effects (e.g., somnolence); increase subsequent dosage more slowly.182 183 184 185

Consider dosage reduction or discontinuance in geriatric patients with reduced food or fluid intake and in those with excessive somnolence.182 183 184 185 (See Somnolence in Geriatric Patients under Cautions and also see Geriatric Use under Cautions.)

Determine ultimate therapeutic dosage on the basis of tolerability and clinical response.b

Gender

No dosage adjustment necessary based solely on gender.183

Cautions for Valproic Acid

Contraindications

  • Hepatic disease or substantial hepatic dysfunction.182 183 184 185

  • Patients with mitochondrial disorders caused by POLG mutations and children <2 years of age suspected of having a POLG-related disorder.179 182 183 185

  • Known hypersensitivity to valproic acid, valproate sodium, divalproex sodium, or any ingredient in the respective formulation.182 183 184 185 b

  • Urea cycle disorders.182 183 184 185 (See Urea Cycle Disorders [UCD] under Cautions.)

  • Use for prophylaxis of migraine headache in pregnant women.182 183 (See Pregnancy under Cautions.)

Warnings/Precautions

Warnings

Hepatotoxicity

May cause serious and potentially fatal hepatotoxicity.182 183 184 185 221 222 223 (See Hepatotoxicity in Boxed Warning.)

Children and patients receiving multiple anticonvulsants or those with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease may be at particular risk.182 183 184 185 221

Higher incidence of acute liver failure and resultant deaths reported in patients with hereditary neurometabolic syndromes caused by POLG mutations than in those without such disorders; most cases identified in children and adolescents.182 221 222 223

Use with caution in patients with a history of hepatic disease.182

Immediately discontinue valproic acid if substantial hepatic dysfunction, suspected or apparent, is present.182 183 184 185 In some cases, hepatic dysfunction has progressed despite discontinuance of the drug.182 183 184 185

Pancreatitis

May cause life-threatening pancreatitis.182 183 184 185 (See Pancreatitis in Boxed Warning.)

Urea Cycle Disorders (UCD)

Potentially fatal hyperammonemic encephalopathy can occur following initiation of therapy in patients with UCD, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency.182 183 184 185 (See Contraindications under Cautions.)

Plasma ammonia concentrations not systematically studied following IV administration; however, hyperammonemia with encephalopathy reported in at least 2 patients who received IV infusions of valproate sodium.185

Advise patients to contact a clinician promptly if symptoms of this disorder (e.g., lethargy, vomiting, changes in mental status) develop.182 183 184 185

If such symptoms are present, determine plasma ammonia concentrations, and, if increased, discontinue therapy.182 183 184 185

Initiate appropriate treatment for hyperammonemia and evaluate the patient for an underlying UCD.182 183 184 185

Prior to the initiation of therapy, consider evaluating for UCD in patients with: a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine concentrations; patients with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN concentration, or protein avoidance; patients with a family history of UCD or unexplained infant deaths (particularly males); or those with other signs or symptoms of UCD.182 183 184 185

Asymptomatic elevation of ammonia concentrations is more common than symptomatic hyperammonemia.182 183 184 185 In patients with asymptomatic elevations, closely monitor plasma ammonia concentrations and, if elevations persist, consider discontinuance of the drug.182 183 184 185

Fetal Risk

Can produce NTDs and other structural malformations (e.g., craniofacial defects, cardiovascular malformations, anomalies involving various body systems) following in utero exposure.182 183 184 185 188 189 190 191 192 193 194 In addition, decreased IQ and other cognitive impairments observed in children exposed in utero.205 206 207 208 212 (See Fetal Risk in Boxed Warning.)

In animal studies, adverse fetal effects, including structural malformations (e.g., skeletal, cardiac, urogenital), neural tube closure defects, intrauterine growth retardation, neurobehavioral abnormalities, and death, observed.182 183 184 190

Do not use in pregnant women for prevention of migraine headaches; use only in pregnant women with epilepsy or bipolar disorder if absolutely necessary.182 183 184 185 188 196 205 (See Pregnancy under Cautions.)

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).176 177 178 179 180 183 184 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.176 177 178 179 183 184 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.176 178 179 183 184

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.177 178 179 180 183 184 Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.176

Balance risk of suicidality with the risk of untreated illness.176 179 183 184 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.179 183 184 If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.179 183 184 (See Advice to Patients.)

Brain Atrophy

Cerebral and cerebellar atrophy (or pseudoatrophy) reported during postmarketing experience; may be irreversible or reversible.182 183 215 216 217 218 219 220 Some patients recovered with permanent sequelae.182 183

Monitor patients routinely for motor and cognitive impairments during therapy; if any manifestations of brain atrophy develop or are suspected, evaluate whether therapy should be continued.182 183

Cerebral atrophy also reported in children exposed in utero to valproic acid.182 183 (See Pregnancy under Cautions.)

Interaction with Carbapenem Antibiotics

Carbapenem antibiotics (e.g., ertapenem, imipenem, meropenem) may reduce plasma valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control.179 182 184 185 186 187 (See Specific Drugs and Laboratory Tests under Interactions.)

Somnolence in Geriatric Patients

Somnolence reported, particularly in geriatric patients.182 183 184 185 (See Advice to Patients.)

In geriatric patients with dementia, somnolence occurred in a significantly higher proportion of patients receiving valproic acid compared with those receiving placebo.182 183 184 185 Dehydration also occurred in more valproic acid-treated patients, although the difference was not clinically significant.182 183 184 185 In some patients (approximately half) with somnolence, associated reduced nutritional intake and weight loss occurred.182 183 184 185 (See Geriatric Use under Cautions.)

In geriatric patients, increase dosage more slowly and monitor patients regularly for fluid and nutritional intake, dehydration, somnolence, and other adverse effects.182 183 184 185 (See Geriatric Patients under Dosage and Administration.)

Thrombocytopenia

Frequency of valproic acid-associated adverse effects, particularly elevated liver enzyme concentrations and thrombocytopenia, may be dose-related.182 183 b

The probability of thrombocytopenia appears to increase substantially at total plasma valproic acid concentrations ≥110 mcg/mL (females) or ≥135 mcg/mL (males).182 183 184 185

Weigh the therapeutic benefit of relatively high dosages with the possibility of dose-related thrombocytopenia and other adverse effects.182 183

Monitor platelet counts and coagulation tests before initiating valproic acid therapy and periodically during therapy.182 183 b Such monitoring is also recommended prior to planned (i.e., elective) surgery.182 183 b

Consider thromboelastography as a more reliable method to assess the effects of valproic acid on coagulation.b

If clinical evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation occurs during therapy, reduce dosage or withdraw the drug pending further evaluation.182 183 184 185

Hypothermia

Hypothermia (unintentional drop in body core temperature to <35°C) reported in association with valproic acid therapy both in conjunction with and in the absence of hyperammonemia (see Hyperammonemia under Cautions).182 183 184 185 May also occur in patients receiving concurrent topiramate and valproic acid after starting topiramate therapy or increasing the daily topiramate dosage.182 183 184 185 (See Hyperammonemia and Encephalopathy associated with Concurrent Topiramate under Cautions.)

Consider discontinuing valproic acid therapy in patients who develop manifestations of hypothermia, including lethargy, confusion, coma, and significant alterations in other major organ systems (e.g., cardiovascular and respiratory systems).182 183 184 185 Include examination of blood ammonia concentrations in clinical assessment and management of hypothermia.182 183 184 185 (See Urea Cycle Disorders [UCD] under Cautions.)

Hyperammonemia

Hyperammonemia reported; may be present despite normal liver function tests.182 183 184 185 In patients who develop unexplained lethargy and vomiting or changes in mental status, consider hyperammonemic encephalopathy and measure blood ammonia concentrations.182 183 184 185 Also consider hyperammonemia in patients who present with hypothermia.182 183 184 185

If ammonia concentrations are increased, discontinue valproic acid therapy and initiate appropriate treatment interventions.182 183 184 185 Also evaluate hyperammonemic patients for possible underlying UCD.182 183 184 185 (See Urea Cycle Disorders [UCD] under Cautions.)

Asymptomatic elevations of ammonia concentrations are more common and, when present, require close monitoring of plasma ammonia concentrations.182 183 184 185

Hyperammonemia and Encephalopathy Associated with Concurrent Topiramate

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have previously tolerated either drug alone.182 183 184 185 Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function accompanied by lethargy or vomiting.182 183 184 185 Hypothermia also may be a manifestation of hyperammonemia.182 183 184 185

In most cases, signs and symptoms abated upon discontinuance of either drug.182 183 184 185 It is not known if topiramate monotherapy is associated with hyperammonemia.182 183 184 185 Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at increased risk for hyperammonemia with or without encephalopathy.182 183 184 185

In patients who develop unexplained lethargy, vomiting, or changes in mental status, consider hyperammonemic encephalopathy and measure blood ammonia concentration.182 183 184 185 (See Urea Cycle Disorders [UCD] under Cautions, see Hyperammonemia under Cautions, and see Specific Drugs and Laboratory Tests under Interactions.)

Posttraumatic Seizures

Fatality rate was higher for valproic acid (IV valproate sodium then oral valproic acid) versus IV phenytoin in patients with acute head injuries receiving the drugs for prevention of posttraumatic seizures; causal relationship not established.185 195

Prudent to not use IV valproate sodium in acute head trauma for posttraumatic seizure prophylaxis pending further study.185 195

Sensitivity Reactions

Multi-organ Hypersensitivity Reactions

Multi-organ hypersensitivity reactions reported rarely in close temporal association to initiation of valproic acid therapy in adult and pediatric patients (median time to detection: 21 days; range: 1–40 days).182 183 184 185 Many reported cases resulted in hospitalization and at least one death.182 183 184 185

Patients typically, although not exclusively, present with fever and rash associated with other organ system involvement.182 183 184 185 Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematologic abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia, and asthenia.182 183 184 185 This disorder is variable in its expression, and signs and symptoms associated with other organ systems also may occur.182 183 184 185

If a multi-organ hypersensitivity reaction is suspected, discontinue valproic acid and initiate alternative treatment.182 183 184 185 Although the existence of cross sensitivity with other drugs that produce this disorder is unclear, experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.182 183 184 185

Other Hypersensitivity Reactions

Anaphylaxis, photosensitivity, generalized pruritus, Stevens-Johnson syndrome, erythema nodosum, and erythema multiforme reported.b

Rare cases of toxic epidermal necrolysis, including a fatal case in a 6-month-old infant receiving valproic acid therapy; however, infant was receiving other drugs concomitantly.b

General Precautions

Discontinuance of Therapy

Do not discontinue anticonvulsant drugs abruptly in patients, including pregnant women, receiving the drugs to prevent major seizures; strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.182 183 184 b (See Pregnancy under Cautions.)

Therapeutic Drug Monitoring

Since valproic acid may interact with concurrently administered drugs that are capable of hepatic enzyme induction, periodic determinations of plasma concentrations of valproic acid and concomitant drugs are recommended during the early course of therapy.182 183 184 185 (See Interactions.)

Effect on HIV and Cytomegalovirus (CMV) Replication

Appears to stimulate replication of HIV and CMV under certain experimental conditions; however, clinical importance not known.179 182 183 184 185

Relevance to patients receiving maximally suppressive antiretroviral therapy also is not known.179 182 183 184 185

Consider these effects when interpreting test results concerning the clinical condition of patients with HIV (plasma HIV RNA levels [viral load]) or CMV infection.179 182 183 184 185

Medication Residue in Stool

Medication residue in stool reported rarely with divalproex sodium formulations (e.g., Depakote, Depakote ER, Depakote Sprinkle Capsules); some cases occurred in the presence of diarrhea.179 182 183 Some patients had anatomic (e.g., ileostomy, colostomy) or functional GI disorders that decrease GI transit times.179 182 183 Monitor plasma valproic acid concentrations and clinical status in such patients; consider alternative therapy if clinically necessary.179 182 183

Specific Populations

Pregnancy

Category D (epilepsy, bipolar disorder); category X (migraine prophylaxis).182 183 184 185 196 205 (See Fetal Risk in Boxed Warning.)

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients); NAAED registry information also available on the website .182 183 184 185 196

Risk of major congenital malformations, particularly NTDs; risk appears to be greatest during the first trimester of pregnancy.182 183 184 185 188 189 190 Rate of major malformations in infants exposed in utero to valproic acid is fourfold higher than that observed in infants exposed to other anticonvulsants.182 183 184 185 188 189 191

CDC estimates the fetal risk of spina bifida in valproic acid-treated pregnant women to be approximately 1–2%; estimated risk of spina bifida in the general population is 0.06–0.07%.182 183 184 185 190

Folic acid supplementation in pregnant women may decrease risk of congenital NTDs.182 183 184 185 188 189 190 191 192 Not known whether risk of NTDs in offspring of women receiving valproic acid is specifically reduced by folic acid supplementation.182 183 184 185 190 192 Folic acid supplementation prior to conception and during pregnancy should be routinely recommended in women.182 183 184 185 188 190 191 192

In utero exposure to valproic acid also appears to increase risk of adverse cognitive effects in children.182 196 197 198 199 200 201 202 203 204 205 206 207 212 Reduced IQ scores and other cognitive deficits (e.g., decreased memory, verbal and nonverbal abilities, cognitive fluency and originality, or executive functions; delayed mental development; increased special education needs) observed in several observational studies in children exposed in utero to valproic acid compared with those with no exposure.196 197 198 199 200 201 202 203 205 206 207 208 210 Dose-dependent effect observed, with higher dosages associated with worse cognitive outcomes.197 206 207 Long-term effects of such exposure not known; also not known whether risk occurs when fetal exposure is limited with respect to duration or timing (e.g., first trimester) during pregnancy.196 205

Possible association between in utero valproic acid exposure and developmental delay, autism, and/or autism spectrum disorders.179 183 190 191 192 194 209 210

Potentially fatal neonatal clotting abnormalities and hepatic failure have occurred rarely with maternal exposure to the drug.182 183 184 185

Do not use in pregnant women for prevention of migraine headaches; use in pregnant women with epilepsy or bipolar disorder only if other treatments have failed to provide adequate symptom relief or are otherwise unacceptable.182 205

Use in women of childbearing potential only if the drug is clearly shown to be essential in the management of their medical condition; use effective contraception.182 183 184 185 188 190 196 b Consider alternative therapies in women contemplating pregnancy.182 205 212

Tests to detect neural tube and other malformations using current accepted procedures should be considered a part of routine prenatal care and be offered to pregnant women receiving valproic acid.182 183 184 185 b

If used during pregnancy, monitor clotting parameters closely.182 183 184 185 b

Do not discontinue anticonvulsants in pregnant women in whom the drugs are administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.b

Lactation

Distributes into milk.183 184 185 b Caution advised.182 183

Pediatric Use

Experience with oral valproic acid in the management of seizures indicates that children <2 years of age are at an increased risk of developing fatal hepatotoxicity.182 183 184 185 (See Hepatotoxicity in Boxed Warning.)

Use with extreme caution and only as single-agent therapy in such children, and weigh the benefits of therapy against the risks.182 183 184 185

The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups (i.e., >2 years of age).182 183 184 185

Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance dosages to attain targeted total and unbound valproic acid concentrations for the management of seizures.182 183 184 185 The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations alone.182 183 184 185

Interpretation of valproic acid concentration in children should include consideration of factors that affect hepatic metabolism and protein binding.182 183 184 185

Safety and efficacy of valproic acid for complex partial seizures not established in pediatric patients <10 years of age.179 214

Efficacy of extended-release tablets (e.g., Depakote ER) for mania or migraine prophylaxis in pediatric patients not demonstrated in placebo-controlled studies.182 183 214

Safety and tolerability of divalproex sodium in pediatric patients appear similar to those in adults.182 183 214

Safety of the injection has not been studied in pediatric patients <2 years of age.185 b If a decision is made to use the injection in this age group, use with extreme caution and only as monotherapy, and weigh potential benefits against possible risks.185 b

Geriatric Use

No geriatric patients >65 years of age were enrolled in controlled trials of oral valproic acid for the treatment of manic episodes associated with bipolar disorder.182 183 184 185 In a case review study, a higher percentage of patients >65 years of age reported accidental injury, infection, pain, somnolence, and tremor compared with younger patients.182 183 184 185

Increased risk of somnolence in geriatric patients.179 182 183 184 185 (See Somnolence in Geriatric Patients under Cautions.)

Safety and efficacy of valproic acid for the prevention of migraine headaches in geriatric patients >65 years of age not established.182 183

No unique safety concerns were identified in geriatric patients >65 years of age receiving IV valproate sodium in clinical trials.185

Dosage adjustments are necessary in geriatric patients.179 182 183 184 185 (See Geriatric Patients under Dosage and Administration.)

Regularly monitor geriatric patients for fluid and nutritional intake, dehydration, somnolence, and other adverse effects.182 183 184 185

Hepatic Impairment

Liver disease impairs the capacity to eliminate valproic acid.184 185 b (See Elimination: Special Populations, under Pharmacokinetics.)

Substantially increased unbound (active) drug fraction because of decreased albumin.183 184 185 Because of decreased protein binding, monitoring total (bound + unbound) drug concentrations may be misleading.183 185 (See Distribution: Special Populations, under Pharmacokinetics.)

Contraindicated in patients with hepatic disease or substantial hepatic dysfunction.182 183 184 185 Use with caution in patients with a history of hepatic disease.182 183 184 185 (See Hepatotoxicity in Boxed Warning and also see Hepatotoxicity under Cautions.)

Common Adverse Effects

The most frequent adverse effects following initiation of therapy are nausea, vomiting, and indigestion.b

Eructation, fecal incontinence, gastroenteritis, glossitis, flatulence, hematemesis, periodontal abscess, tooth disorder, dry mouth, stomatitis, and constipation may occur.b

Somnolence, asthenia, dizziness, and tremor generally are the most frequently reported adverse nervous system effects.185 b

In addition, IV infusion may cause local effects at the injection site and effects associated with the rate of infusion.185

Interactions for Valproic Acid

CYP microsomal-mediated oxidation is a relatively minor metabolic pathway.183

Drugs Affecting Hepatic Enzymes

Drugs affecting expression of hepatic enzymes, particularly glucuronyltransferases, may increase valproic acid clearance.183

Phenobarbital or primidone, phenytoin, or carbamazepine can double valproic acid clearance.183

Increase monitoring of valproic acid and concomitantly used drug concentrations whenever enzyme-inducing drugs are introduced or withdrawn.183

Inhibitors of CYP isoenzymes are unlikely to have a clinically important effect on valproic acid clearance.183

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Acetaminophen

Limited pharmacokinetic studies reveal little to no interaction following concomitant administrationb

Acyclovir

May reduce plasma anticonvulsant concentrations to subtherapeutic levels; an increase in seizure frequency and a worsening in the EEG may be observedb

Use concomitantly with cautionb

Alcohol

Additive CNS depression may occurb

Use concomitantly with cautionb

Amitriptyline

Decreased plasma clearance of amitriptyline and nortriptyline (the pharmacologically active metabolite of amitriptyline)179 182

Consider monitoring concentrations and reducing dosage of amitriptyline during concomitant use179 182

Antacids

Limited pharmacokinetic studies reveal little to no interaction during concomitant administration182 b

Anticoagulants, oral (warfarin)

May increase unbound fraction of warfarin183

Clinical relevance unknown; monitor coagulation tests during concomitant useb

Anticonvulsants (phenobarbital, phenytoin, and primidone)

Additive, potentially severe CNS depression may occur (particularly with phenobarbital and primidone)b

Concomitant administration of valproic acid and phenobarbital (or primidone which is metabolized to phenobarbital) can result in increased plasma phenobarbital concentrations and excessive somnolenceb

May displace phenytoin from protein binding and inhibit its metabolism183

Observe closely for possible neurotoxicity if phenobarbital or primidone is used concomitantly183

Combination can produce CNS depression (possibly severe) even without substantial increases in serum concentrations of either drugb

Observe for breakthrough seizures during concomitant phenytoin use; adjust dosage accordingly

Since valproic acid also may interact with other anticonvulsants, it is advisable to monitor plasma concentrations of concomitantly administered anticonvulsants during initial valproic acid therapyb

Aspirin

Aspirin can increase unbound (active) valproic acid fourfold182 183 185

Possible combined effects on plateletsb

Use concomitantly with caution182 183 185

Carbamazepine

Decreased serum carbamazepine concentrations and increased carbamazepine-10,11-epoxide metabolite concentrationsb

May decrease plasma valproic acid concentration by altering its clearance, which may be clinically importantb

Discontinuance of carbamazepine following concomitant carbamazepine/valproic acid therapy has been reported to result in increased valproic acid concentrationsb

Use concomitantly with caution; observe for possible carbamazepine CNS toxicity (e.g., acute psychotic reaction)b

Closely monitor valproic acid concentrations whenever carbamazepine is initiated or discontinuedb

Carbapenem antibiotics (e.g., ertapenem, imipenem, meropenem)

May cause a clinically important and marked decrease in plasma valproic acid concentrations, which may result in loss of seizure control179 182 183 184 185 186 187

Avoid combined therapy, if possible186 187

If concurrent therapy is necessary, frequently monitor valproic acid concentrations after carbapenem is initiated or discontinued;182 183 184 185 186 more frequent monitoring during concurrent therapy also is recommended by some clinicians186

Consider alternative anti-infective or anticonvulsant therapy if valproic acid concentrations decrease substantially or seizure control deteriorates182 183 184 185 187

Chlorpromazine

May increase trough plasma valproic acid concentrations (e.g., by 15%)182 183

Clonazepam

Concomitant use may precipitate absence status in patients with a history of absence-type seizures182 183 b

Consider avoiding concomitant useb

Clozapine

Interaction unlikelyb

CNS depressants

Possible additive CNS depression182 183 184 185 b

Use concomitantly with caution182 183 184 185 b

Diazepam

Displaces diazepam from its albumin binding sites and also inhibits its metabolism; increases free fraction of diazepam182 183 184 185 b

Possible additive CNS depression182 183 184 185 b

Use concomitantly with caution182 183 184 185 b

Ethosuximide

Inhibits the metabolism of ethosuximide182 b

Monitor plasma concentrations of valproic acid and ethosuximide closely during concomitant use, especially if receiving other concomitant anticonvulsant therapy182 b

Felbamate

May increase mean peak plasma valproic acid concentration182 185 b

A decrease in valproic acid dosage may be required when initiating concomitant felbamate therapy182 185 b

Haloperidol

No clinically important effect on trough valproic acid concentrations182 b

H2-receptor antagonists (cimetidine, ranitidine)

Valproic acid clearance unaffected182 183

Lamotrigine

Valproic acid inhibits lamotrigine metabolism; the elimination half-life of lamotrigine is increased (by 165%) during concurrent administration182 183 184 185 b

Serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) also reported during concurrent administration182 183 184 185

Reduce lamotrigine dosage during concurrent administration182 183 184 185

Lithium

Lithium steady-state pharmacokinetics unaffected183

Lorazepam

May decrease lorazepam clearance (e.g., by 17%); unlikely to be clinically important182 183 184 185

MAO inhibitors and other antidepressants

Valproic acid may potentiate the effects of MAO inhibitors and other antidepressants.

Dosage reduction of these drugs may be necessary if valproic acid is administered to patients receiving antidepressantsb

Nortriptyline

During concurrent administration of valproic acid and amitriptyline, decreased plasma clearance of amitriptyline and nortriptyline (the pharmacologically active metabolite of amitriptyline) reported182

Consider monitoring nortriptyline concentrations and reducing dosage of nortriptyline during concomitant use182

Oral contraceptives

Pharmacokinetic interaction unlikely183 b

Phenytoin

Valproic acid has been associated both with decreased plasma phenytoin concentrations and increased seizure frequency and with increased plasma concentrations of free phenytoin and phenytoin intoxicationb

Important to monitor plasma phenytoin concentrations whenever valproic acid is added to or withdrawn from the patient’s therapy and adjust the dosage of phenytoin as requiredb

Rifampin

May increase valproic acid clearance (e.g., by 40%)182 183 b

Valproic acid dosage adjustment may be required during concurrent rifampin therapy182 183 b

Test, for urinary ketones

A ketone metabolite in the urine of patients receiving valproic acid may produce false-positive results for urine ketones185 b

Test, for thyroid function

Valproic acid reportedly alters thyroid function test results, but clinical importance is not known185 b

Tolbutamide

In vitro, addition of tolbutamide to plasma samples of patients receiving valproic acid resulted in an increase in the unbound tolbutamide fraction from 20% to 50%b

Clinical relevance unknown183 b

Topiramate

Concurrent administration of valproic acid and topiramate associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone182 183 184 185

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting; hypothermia may also be a manifestation of hyperammonemia182 183 184 185

Measure blood ammonia concentrations in patients who develop possible symptoms of hyperammonemia (unexplained lethargy, vomiting, or changes in mental status) or hypothermia;182 183 184 185 promptly treat hyperammonemia, if present, and discontinue valproic acid; consider valproic acid discontinuance in patients with hypothermia182 183 184 185 (see Cautions)

Zidovudine

Valproic acid inhibits glucuronidation of zidovudine and increases its oral bioavailability;b such concomitant administration may alter the efficacy and toxicity profile of zidovudineb

Valproic Acid Pharmacokinetics

Absorption

Bioavailability

Valproic acid: Rapidly and almost completely absorbed from the GI tract.b

Equivalent oral doses of valproic acid and divalproex sodium preparations (but not extended-release tablets) deliver equivalent amounts of valproate ion systemically following oral administration.182 183 184

Divalproex sodium extended-release tablets have decreased oral bioavailability relative to delayed-release tablets, averaging about 89% relative to delayed-release tablets.182

Oral, valproate sodium: Rapidly converted to valproic acid in the stomach.184 b

Oral, divalproex sodium delayed-release tablets: Upon passage of the tablets into the upper small intestine, divalproex sodium dissociates into valproic acid.b

Oral, divalproex sodium extended-release tablets: Divalproex sodium dissociates into valproic acid in the GI tract.182

Peak concentration usually attained 1–4 hours following a single oral dose of valproic acid or valproate sodium, 3–5 hours following a single oral dose of divalproex sodium, or 6–14 hours after oral administration of multiple doses of divalproex sodium extended-release tablets.b

Divalproex sodium delayed-release tablets and valproic acid delayed-release capsules demonstrate similar plasma concentration-time profiles following single-dose administration under fasting conditions.214

Equivalent valproic acid dosages as the IV injection, administered over 1 hour, or various conventional or delayed-release oral formulations are expected to result in equivalent peak and trough plasma concentrations and total systemic exposure to valproic acid.b

Food

Absorption of valproic acid is delayed but not decreased by administration with meals; administration of the drug with milk products does not affect the rate or degree of absorption.b

Administration of divalproex sodium with food is expected to slow absorption but not affect the extent of absorption.b

Absolute bioavailability of divalproex sodium extended-release tablets after a meal is about 90%.182

Plasma Concentrations

An anticonvulsant therapeutic range of 50–100 mcg/mL of total (bound and unbound) valproic acid has been suggested; seizure control occasionally may occur with lower or higher concentrations, but >150 mcg/mL usually is toxic.183 184 185 b

For acute manic episodes in bipolar disorder, usually dosed to clinical response with trough plasma concentrations of 50–125 mcg/mL.182 183

Distribution

Extent

Valproic acid is rapidly distributed; distribution appears to be restricted to plasma and rapidly exchangeable extracellular water.b

Detected in CSF.b

Detected in saliva.b

Crosses the placenta.190 b

Distributes into milk.182 183 184 185 b

Plasma Protein Binding

Plasma protein binding of valproic acid is concentration dependent; the free fraction of drug increases from 10% to 18.5% as the plasma concentration increases.b

Special Populations

Hepatic impairment: Increased unbound (active) drug fraction (2–2.6-fold increase) because of decreased albumin.183 184 185

Renal impairment: Substantially decreased protein binding.183 184

Elimination

Metabolism

Valproic acid is metabolized principally in the liver by beta and omega oxidation.b

Elimination Route

Valproic acid metabolites are excreted in urine; <3% of an administered dose is excreted in urine unchanged.b

Small amounts also are excreted in feces and in expired air.b

Half-life

Valproic acid: 5–20 hours.b

Special Populations

Neonates: Markedly decreased clearance compared with older children and adults; elimination half-life in neonates <10 days of age ranged from 10–67 hours.b

Children 3 months to 10 years of age: 50% increased clearance (on a proportionate weight basis) relative to older children and adults.183

Geriatric patients: Clearance may be decreased.182 183 184 185 b

Hepatic impairment: Impairs the ability to eliminate valproic acid; half-life is increased from 12 to 18 hours in hepatic disease.184 185 b Clearance of free valproic acid was decreased by 50% in cirrhosis and by 16% in acute hepatitis.183 184 185

Renal impairment: Clearance of unbound (active) drug is decreased by 27% in patients with renal failure.183 184 Hemodialysis usually reduces valproic acid concentrations by about 20%.184

Stability

Storage

Oral

Capsules

Valproic acid: Tight containers at 15–30°C.b Depakene: Tight containers at 15–25°C.184 b Stavzor: 25°C; may be exposed to 15–30°C.214

Divalproex sodium capsules containing coated particles (Depakote Sprinkle): <25°C.179 b

Tablets

Divalproex sodium delayed-release tablets: Tight, light-resistant containers at a temperature <30°C.b

Divalproex sodium extended-release tablets: 25°C, but may be exposed to temperatures ranging from 15–30°C.182

Solution

Valproate sodium: Tight containers at <30°C; avoid freezing.184 b

Parenteral

Injection

15–30°C.185 b

Discard unused portions of the solution.185 b

When stored in glass or PVC containers at 15–30°C, injection that has been further diluted with at least 50 mL of 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer’s injection is stable for at least 24 hours.185 b

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility185 HID

Compatible

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug CompatibilityHID
Y-Site CompatibilityHID

Compatible

Cefepime HCI

Ceftazidime

Actions

  • Mechanism of action not known.b

  • Effects may be related, at least in part, to increased brain concentrations of the inhibitory neurotransmitter, GABA.b

  • May inhibit neuronal activity by increasing potassium conductance.b

Advice to Patients

  • Importance of providing copy of written patient information (medication guide) each time valproic acid is dispensed; importance of patient reading this information prior to taking the drug.182 183 184 185 188

  • Risk of suicidality (anticonvulsants, including valproic acid, may increase risk of suicidal thoughts or actions in about 1 in 500 people).176 177 178 180 183 184 Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).176 177 178 183 184

  • Warn patients and caregivers that serious or fatal hepatotoxicity may be preceded by symptoms such as malaise, weakness, lethargy, facial edema, anorexia, nausea, vomiting, abdominal pain, diarrhea, and/or jaundice and to contact a clinician promptly if such symptoms occur.182 183 185 (See Hepatotoxicity in Boxed Warning.)

  • Advise pregnant women and women of childbearing potential that the drug can cause major birth defects such as NTDs (e.g., spina bifida) and decreased IQ in children exposed in utero.182 183 184 185 188 196 Advise such women of alternative therapeutic options.182 188 196 Advise women of childbearing potential to use effective contraceptive methods during valproic acid therapy.182 183 188 196

  • Importance of women immediately informing clinicians if they are or plan to become pregnant or plan to breast-feed.182 188 196 b Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries.182 184 188 196 (See Pregnancy under Cautions.)

  • Warn patients and caregivers that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and therefore require prompt medical evaluation.182 183 184 185 (See Pancreatitis in Boxed Warning.)

  • Importance of advising patients to notify a clinician promptly if symptoms of hyperammonemic encephalopathy (e.g., lethargy, vomiting, changes in mental status) develop.182 183 184 185 (See Urea Cycle Disorders [UCD] under Cautions.)

  • In patients receiving divalproex sodium formulations (e.g., Depakote, Depakote ER, Depakote Sprinkle Capsules), importance of instructing patients to notify their clinician if they notice any medication residue in their stool.179 182 183

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects are known.182 183 184 185

  • Importance of informing patients, including pregnant women, not to suddenly stop taking valproic acid without first talking to their clinician since stopping the drug suddenly can cause serious problems, including seizures.182 183 184 185 188

  • Risk of multi-organ hypersensitivity reaction.182 Importance of advising patients that a fever associated with other organ system involvement (such as rash or lymphadenopathy) may be drug-related and should be reported to the clinician immediately.182

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.182 183 184 185 188

  • Importance of informing patients of other important precautionary information.182 183 184 185 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Valproate Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

250 mg (of valproic acid) per 5 mL*

Depakene

AbbVie

Valproate Sodium Oral Solution

Parenteral

Injection, for IV use

100 mg (of valproic acid) per mL*

Depacon

AbbVie

Valproate Sodium Injection

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Valproic Acid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, delayed-release

125 mg

Stavzor

Noven Therapeutics

250 mg

Stavzor

Noven Therapeutics

500 mg

Stavzor

Noven Therapeutics

Capsules, liquid-filled

250 mg*

Depakene

AbbVie

Valproic Acid Capsules

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Divalproex Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules (containing coated particles)

equivalent to valproic acid 125 mg*

Depakote Sprinkle

AbbVie

Divalproex Sodium Capsules (Sprinkle)

Tablets, delayed-release

equivalent to valproic acid 125 mg*

Depakote

AbbVie

Divalproex Sodium Delayed-Release Tablets

equivalent to valproic acid 250 mg*

Depakote

AbbVie

Divalproex Sodium Delayed-Release Tablets

equivalent to valproic acid 500 mg*

Depakote

AbbVie

Divalproex Sodium Delayed-Release Tablets

Tablets, extended-release

equivalent to valproic acid 250 mg*

Depakote ER

AbbVie

Divalproex Sodium Extended-Release Tablets

equivalent to valproic acid 500 mg*

Depakote ER

AbbVie

Divalproex Sodium Extended-Release Tablets

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Depakene 250MG Capsules (ABBOTT): 30/$89.99 or 90/$255.97

Depakene 250MG/5ML Syrup (ABBOTT): 150/$104.99 or 450/$303.97

Depakote 125MG Enteric-coated Tablets (ABBOTT): 60/$70.99 or 180/$200.97

Depakote 250MG Enteric-coated Tablets (ABBOTT): 60/$136.99 or 180/$385.98

Depakote 500MG Enteric-coated Tablets (ABBOTT): 60/$256.00 or 180/$749.93

Depakote ER 250MG 24-hr Tablets (ABBOTT): 30/$67.99 or 90/$180.96

Depakote ER 500MG 24-hr Tablets (ABBOTT): 30/$111.99 or 90/$307.97

Depakote Sprinkles 125MG Sprinkle Capsules (ABBOTT): 60/$71.99 or 180/$199.96

Divalproex Sodium 125MG Enteric-coated Tablets (UPSHER-SMITH): 100/$24.99 or 300/$59.97

Divalproex Sodium 125MG Sprinkle Capsules (ZYDUS PHARMACEUTICALS (USA)): 30/$25.99 or 90/$65.97

Divalproex Sodium 250MG 24-hr Tablets (MYLAN): 100/$139.99 or 300/$389.99

Divalproex Sodium 250MG Enteric-coated Tablets (UPSHER-SMITH): 100/$29.99 or 300/$69.96

Divalproex Sodium 500MG 24-hr Tablets (MYLAN): 100/$59.99 or 300/$179.96

Divalproex Sodium 500MG Enteric-coated Tablets (UPSHER-SMITH): 100/$49.99 or 300/$129.96

Valproic Acid 250MG Capsules (TEVA PHARMACEUTICALS USA): 30/$19.99 or 90/$35.97

Valproic Acid 250MG/5ML Syrup (QUALITEST): 150/$21.99 or 450/$55.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 12, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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