Introduction ⬇
AHFS Class:
- GABA-mediated Anticonvulsants 28:12.28
Generic Name(s):
Valproic acid, valproate sodium, and divalproex sodium are carboxylic acid-derivative anticonvulsants that also are used to treat acute manic episodes or for prophylaxis of migraine headache as well as certain other psychiatric disorders.
Uses ⬆ ⬇
Seizure Disorders 
Valproic acid, valproate sodium, and divalproex sodium are used for the management of various seizure disorders, including complex partial seizures, absence seizures, and other seizure types.179,182,183,184,185,195,224 Because there are only minor differences in the pharmacokinetics of the formulations and because all forms of the drug circulate in plasma as valproic acid, the term “valproic acid” will mainly be used in the following discussion.
Valproic acid is used alone or with other anticonvulsants (e.g., ethosuximide) in the prophylactic management of simple and complex absence (petit mal) seizures. The drug also may be used in conjunction with other anticonvulsants in the management of multiple seizure types that include absence seizures. Valproic acid is considered a drug of choice for absence or atypical absence seizures.
Valproic acid is used alone or with other anticonvulsants (e.g., carbamazepine, phenytoin) in the prophylactic management of complex partial seizures that occur either by themselves or in association with other seizure types. Some clinicians state that valproic acid may be considered a drug of choice for the management of complex partial seizures. Two randomized, placebo-controlled trials, one of valproic acid as monotherapy and one of valproic acid as adjunctive therapy, demonstrated that the drug decreased the frequency of seizures in patients inadequately controlled by other therapies (e.g., carbamazepine, phenytoin, phenobarbital).
Valproic acid has been used and is considered by some clinicians as a drug of choice for management of other generalized seizures, including primary generalized tonic-clonic seizures†, myoclonic seizures†, or atonic seizures†, especially for those patients with more than one type of generalized seizure. In addition, some clinicians state that valproic acid may be used as a drug of choice for the management of simple partial seizures†. Valproic acid also has been administered rectally† or by intragastric drip† with some success in the management of status epilepticus refractory to IV diazepam†. A parenteral formulation of valproic acid has been studied and has been effective when administered IV† in the management of status epilepticus.
Prevention of Posttraumatic Seizures
Valproate sodium has been used for the prevention of posttraumatic seizures in patients with acute head injuries†.185,195 In a randomized, double-blind study comparing the efficacy of IV valproate sodium (administered for 1 week followed by oral valproic acid for 1 or 6 months) with that of IV phenytoin (administered for 1 week followed by placebo) for this use, the mortality rate was found to be higher in patients treated with valproate sodium followed by valproic acid compared with those receiving phenytoin (13 versus 8.5%, respectively).185 Many of these patients were critically ill with multiple and/or severe injuries and a causal relationship to valproic acid has not been established.185,195 However, pending further study, the manufacturer and some clinicians state that it is prudent to not use IV valproate sodium in patients with acute head trauma for posttraumatic seizure prophylaxis.185,195
Dravet Syndrome
Valproate has been used in the treatment of seizures associated with Dravet syndrome† (also known as severe myoclonic epilepsy of infancy), a rare and severe type of epilepsy characterized by early onset of multiple refractory seizure types, frequent episodes of status epilepticus, and developmental delay with cognitive and psychomotor impairment.310,311,312,314 Although evidence from controlled studies is limited,311,314,315 experts generally recommend initial treatment with either clobazam or valproic acid, followed by a combination of both drugs; however, adequate seizure control is rarely achieved with these drugs alone, and most patients will require additional anticonvulsant agents.310,311,312,314 For additional information on Dravet syndrome, see Dravet Syndrome under Uses: Epilepsy Syndromes, in the Anticonvulsants General Statement 28:12.
Bipolar Disorder
Divalproex sodium and valproic acid are used in the treatment of acute manic or mixed episodes associated with bipolar disorder;182,183 valproate sodium† also has been used. Because there are only minor differences in the pharmacokinetics of the formulations and because all forms of the drug circulate in plasma as valproic acid, the term “valproic acid” will mainly be used in the following discussion.
Valproic acid has been used as monotherapy or as part of combination therapy (e.g., with lithium, antipsychotic agents [e.g., olanzapine], antidepressants, carbamazepine) in the treatment of acute manic episodes. The 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. For mixed episodes, valproic acid may be preferred over lithium. Valproic acid or lithium also is recommended for the initial acute treatment of rapid cycling.
A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility.
Efficacy of divalproex sodium (given as Depakote® or Depakote® ER tablets) in the treatment of manic episodes has been established in several short-term, placebo-controlled, parallel-group trials in patients who were hospitalized for acute mania; response to therapy was assessed using objective rating scales such as the Young Mania Rating Scale (YMRS), an augmented Brief Psychiatric Rating Scale (BPRS-A), the Mania Rating Scale (MRS), and the Global Assessment Scale (GAS). In these studies, valproic acid was found to be substantially superior to placebo in all of the outcome measures assessed.182,183 One study specifically enrolled patients who were intolerant of or unresponsive to previous lithium therapy.183 Up to 40% of patients fail to respond to or are intolerant of lithium therapy for manic episodes; such patients may demonstrate a response to valproic acid, although response to valproic acid appears to be independent of prior response to lithium therapy. Valproic acid therapy appears to be about as effective as lithium for the treatment of manic episodes. In one placebo-controlled trial, 48% of patients receiving valproic acid demonstrated a response to the drug as measured by changes in the Manic Syndrome subscale of the MRS; 49% of patients receiving lithium responded to therapy, while 25% of patients receiving placebo responded. Antimanic response to valproic acid typically occurs within 1-2 weeks of initiating therapy. Valproic acid therapy also appears to be effective in specific types of mania, including rapid-cycling mania and dysphoric mania, which have been reported to be poorly responsive to lithium.
Although the manufacturers state that safety and efficacy of long-term (i.e., longer than 3 weeks) valproic acid therapy have not been established in the treatment of manic episodes,182,183 valproic acid also has been used, alone or in combination therapy, for long-term or maintenance antimanic therapy†, and APA currently considers the best empiric evidence to support the use of valproic acid or lithium for maintenance therapy. Antimanic efficacy has been maintained from several months to more than 10 years, and such long-term therapy appears to decrease the frequency and severity of bipolar episodes over extended periods of time; however, further study is required to establish the efficacy of valproic acid as maintenance therapy of manic episodes. Valproic acid does not appear to be as effective for the management of the depressive component of bipolar disorder†; although some evidence suggests that long-term valproic acid therapy may be moderately effective in the prophylaxis of depressive episodes, its acute effects on depression appear to be limited. 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.
Migraine
Prophylaxis of Chronic Attacks
Divalproex sodium and valproic acid are used in the prophylaxis of migraine headache;182,183 sodium valproate† also has been used. Because there are only minor differences in the pharmacokinetics of the formulations, and because all forms of the drug circulate in plasma as valproic acid, the term “valproic acid” will mainly be used in the following discussion.
Valproic acid should not be used in pregnant women for the prevention of migraine headaches; in such patients, the risks of the drug (e.g., major congenital malformations and cognitive impairment in prenatally exposed children) outweigh any possible benefits (see Pregnancy under Cautions: Pregnancy, Fertility, and Lactation).182,183,205 Valproic acid also should not be used in women of childbearing potential unless the drug is clearly shown to be essential in the management of their medical condition; this is especially important when the drug is being contemplated or used for the management of a condition not ordinarily associated with permanent injury or risk of death such as migraine headaches.182,183,205
The US Headache Consortium states that there is good evidence from multiple well-designed clinical trials that valproic acid and divalproex sodium have medium to high efficacy for the prophylaxis of migraine headache. Divalproex sodium (given as Depakote® tablets) was demonstrated to be effective in the prophylaxis of migraine headache in 2 randomized, double-blind, placebo-controlled trials in patients with at least a 6-month history of migraine, with or without associated aura. Patients also had to experience at least 2 migraines per month in the 3 months prior to enrollment in the studies; patients were excluded if they had cluster headaches. Although women of childbearing potential were excluded from one study because of the teratogenic properties of valproic acid, they were included in the other, provided that they were practicing an effective form of contraception. In both studies, after a 4-week single-blind placebo baseline period, patients were randomized to receive either valproic acid or placebo during a 12-week treatment period consisting of a 4-week titration period and an 8-week maintenance period. Assessment of treatment outcome was based on 4-week migraine headache rates during the 12-week treatment period. In the first study, dosage titration was guided by the use of actual or sham trough total serum valproate concentrations for patients receiving valproic acid or placebo, respectively. The mean dosage of valproic acid was 1087 mg daily (range: 500-2500 mg daily), with dosages of more than 500 mg being given in 3 divided doses daily. Patients receiving valproic acid experienced a substantial decrease in the mean 4-week migraine headache rate compared with those receiving placebo (3.5 versus 5.7, respectively). In the second study, patients were randomized to receive (after titration from an initial dosage of 250 mg daily) 500, 1000, or 1500 mg of valproic acid daily or placebo, administered as 2 daily doses. Efficacy of valproic acid in the second study was to be determined by comparing the 4-week migraine headache rate in the combined groups of patients receiving 1000 and 1500 mg of valproic acid to that of patients receiving placebo. However, the manufacturer reports that the mean 4-week migraine headache rates in patients receiving valproic acid 500, 1000, or 1500 mg daily were 3.3, 3, or 3.3, respectively, compared to a rate of 4.5 in patients receiving placebo, and that the rate in the combined groups of patients receiving 1000 or 1500 mg daily was substantially lower than that of the placebo group.
In addition, divalproex sodium (given once daily as Depakote® ER extended-release tablets) was demonstrated to be effective in the prophylaxis of migraine headache in a 12-week, multicenter, double-blind, placebo-controlled clinical trial in patients with a history of migraine headaches with or without associated aura.182 In this study, patients receiving extended-release divalproex sodium tablets (initiated at 500 mg once daily for 1 week, then increased to 1 g once daily if tolerated) experienced a substantial mean reduction in 4-week migraine headache rate compared with those receiving placebo (reduction of 1.2 from a baseline mean of 4.4 versus a reduction of 0.6 from a baseline mean of 4.2, respectively).182
Other studies also have shown valproic acid to be effective in the prophylaxis of migraine. In one comparative, single-blind, placebo-controlled, crossover study, valproic acid was shown to be as effective in migraine prophylaxis as propranolol.
Acute Attacks
IV† valproate sodium has been used for the acute† management of migraine headache;157,160,161,162,163,164,166 however, the role of the drug relative to other acute therapies (selective serotonin type 1-like receptor agonists [“triptans”], ergot alkaloids, antiemetics, nonsteroidal anti-inflammatory agents [NSAIAs], butalbital-containing analgesics, opiate analgesics)156,170,172 requires further elucidation.166,173 Results of several studies, including open-label,159,161,164,166,168,169 comparative,158,159,166 randomized,157,159,166 prospective,159,161,164,166 retrospective,162,166 and/or double-blind,160,166 studies and at least one placebo-controlled study,157,166 as well as case reports,163,166 indicate that IV valproate sodium may alleviate acute migraine attacks in patients with or without aura and generally appears to be well tolerated. Efficacy generally was evaluated in terms of a reduction in headache severity as rated by the patient (i.e., a reduction in pain from severe or moderately severe to mild or absent usually using a 3- or 4-point scale)157,158,159,166 or by a visual analog pain score (VAS).158,160,166 Limited data indicate that 300-mg to 1-g IV valproate sodium doses (some of which were repeated at the same initial dose or less) were associated with relief of migraine headache, usually within 1 to several hours.157,159,160,161,162,163,164,166,168,169
IV valproate sodium also has been used in the management of chronic daily headache† in a limited number of patients175 some of whom have had an inadequate response to dihydroergotamine or when dihydroergotamine was contraindicated.165,166
Further study and experience are needed to more clearly define the role of IV valproate sodium in the management of acute migraine attacks and other headaches.161,164,165,166
There is no evidence that orally administered valproic acid or divalproex sodium is useful in the acute† treatment of migraine headaches.182,183
For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses, in Sumatriptan 28:32.28.
Schizophrenia
Valproic acid or divalproex sodium has been used as an adjunct to antipsychotic agents 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 The American Psychiatric Association (APA)146 and some clinicians148 state that anticonvulsant agents such as valproic acid or divalproex sodium may be useful adjuncts in schizophrenic patients with prominent mood lability or with agitated, aggressive, hostile, or violent behavior.146,148 In general, for such adjunctive therapy, valproic acid or divalproex sodium is administered in the same dosage and with the same resulting therapeutic plasma concentrations as that in the management of seizure disorders.146,147,148 The APA states that, with the exception of patients with schizophrenia whose illness has strong affective components, valproic acid or divalproex sodium alone has not been shown to be substantially effective in the long-term treatment of schizophrenia.146 For additional information on the management of schizophrenia, see Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.
While some evidence suggested potential benefit of valproic acid in relieving tardive dyskinesia in patients receiving long-term antipsychotic drug therapy†, recent systematic review of randomized controlled trials with nonbenzodiazepine γ-aminobutyric acid (GABA) agonists such as valproic acid found the evidence for such benefit unconvincing, and indicated that any possible benefit may be outweighed by adverse effects.
Other Uses
Some experts recommend use of valproic acid for the treatment of aggressive outbursts in children with ADHD. For a more detailed discussion on the management of ADHD, see Uses: Attention Deficit Hyperactivity Disorder, in Methylphenidate 28:20.04.
Valproic acid used alone or in conjunction with GABA was ineffective in the treatment of chorea† (including Huntington's chorea). Valproic acid has been effective in a limited number of patients with organic brain syndrome†.
Dosage and Administration ⬆ ⬇
Administration
Valproate sodium can be administered orally or by IV infusion and valproic acid and divalproex sodium are administered orally. Valproic acid also has been administered rectally† by enema or in wax-based suppositories.
Patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Cautions: Nervous System Effects and Cautions: Precautions and Contraindications.)
A medication guide explaining the risks and benefits of valproic acid therapy should be distributed to patients receiving valproic acid, valproate sodium, or divalproex sodium.188
Oral Administration
Valproic acid, valproate sodium, and divalproex sodium are administered orally. Valproic acid capsules should be swallowed whole, not chewed, in order to prevent local irritation to the mouth and throat. If GI irritation occurs, the drug may be administered with food or the dosage may be gradually increased from an initially low dosage.179,182,183,184 Patients who are unable to tolerate the GI effects of valproic acid or valproate sodium may tolerate divalproex sodium.
Delayed-release tablets of divalproex sodium (e.g., Depakote®) should be swallowed intact, and not crushed or chewed.183
When switching to divalproex sodium delayed-release tablets (e.g., Depakote®) in patients receiving conventional valproic acid (e.g., Depakene®), the same daily dosage and schedule should be used.183 After stabilization with the delayed-release formulation, the daily dosage may be divided and administered 2 or 3 times daily in selected patients.183
Extended-release tablets of divalproex sodium (e.g., Depakote® ER) are administered once daily; patients should be advised that the extended-release tablets must be swallowed intact and not chewed or crushed.182
If a patient misses a dose of valproic acid or divalproex sodium, the dose should be taken as soon as possible, unless it is almost time for the next dose.182,183,184 However, if the patient skips a dose, a double dose should not be taken to make up for the missed dose.182,183,184
Valproate sodium oral solution should not be administered in carbonated drinks because valproic acid will be liberated and may cause local irritation to the mouth and throat as well as an unpleasant taste.
The commercially available capsules containing coated particles of divalproex sodium (e.g., Depakote® Sprinkle Capsules) may be swallowed intact or the entire contents of the capsule(s) may be sprinkled on a small amount (about 5 mL) of soft food (e.g., applesauce, pudding) and swallowed (not chewed) immediately.179 The mixture of coated particles and food should not be stored for future use.179 Patients receiving divalproex sodium capsules containing coated particles may notice coated particles in their stool because these particles do not completely dissolve and may be passed in the stool.179 (See Cautions: Precautions and Contraindications.)
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 with these dosage forms may vary (e.g., higher peak valproic acid concentrations generally are achieved with the delayed-release tablets). These differences are unlikely to be clinically important; however, increased monitoring of plasma valproic acid concentrations is recommended if one dosage form is substituted for the other.
IV Administration
Valproate sodium injection is intended for IV use only.185
For IV use, the manufacturer states that the appropriate dose of valproate sodium injection should be diluted with at least 50 mL of a compatible IV solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection, lactated Ringer's injection). Diluted IV solutions of the drug should be infused IV over 60 minutes; the manufacturer recommends that the rate not exceed 20 mg/minute.185
Rapid IV infusion of valproate sodium has been associated with an increased risk of adverse effects and is not currently included in the manufacturer's labeling. However, rates exceeding 20 mg/minute or infusion periods less than 60 minutes have been studied in a limited number of patients with seizure disorders and in patients with acute migraine headaches, and such administration generally appeared to be well tolerated.166,173 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 of the drug; the study was not designed to assess the efficacy of the regimen. The drug also appeared to be well tolerated in studies evaluating efficacy in the management of acute migraine attacks† when valproate sodium doses of 300 mg to 1 g were infused IV at rates ranging from 17-250 mg/minute173 or occasionally by direct rapid (“bolus”) IV injection (100-mg doses).159,160,161,162,164,165,166,169,173
Use of rapid infusions in patients receiving the IV preparation as a parenteral replacement for oral valproic acid has not been established.
Valproate sodium injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Dosage
Dosage of valproate sodium and divalproex sodium is expressed in terms of valproic acid. Dosage must be carefully and slowly adjusted according to individual requirements and response.
Seizure Disorders
IV Dosage
IV valproate sodium therapy may be employed in patients in whom oral therapy is temporarily not feasible, but therapy should be switched to oral administration as soon as clinically possible. IV administration of the drug can be used for monotherapy or as adjunctive therapy in the management of seizure disorders. The manufacturer states that the usual total daily dosages of valproic acid are equivalent for IV or oral administration, and the doses and frequency of administration employed with oral therapy in seizures disorders are expected to be the same with IV therapy, although plasma concentration monitoring and dosage adjustment may be necessary. The use of IV therapy for longer than 14 days has not been studied to date. The manufacturer also states that the 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. Patients receiving dosages near the maximum recommended dosage of 60 mg/kg daily should be monitored closely, particularly when enzyme-inducing drugs are not used concomitantly.
Oral Dosage
Various valproic acid dosage regimens have been used in published studies. A correlation between plasma valproic acid concentration and therapeutic effect has not been established; however, an anticonvulsant therapeutic range of 50-100 mcg/mL of total (bound and unbound) valproic acid has been suggested.183,184,185
For the management of complex partial seizures, the manufacturers state that the usual initial dosage of valproic acid as monotherapy or as adjunctive therapy, when being added to a current therapeutic regimen, for adults and children 10 years of age and older is 10-15 mg/kg daily. For the management of simple or complex absence seizures, the manufacturers state that the usual initial dosage of valproic acid is 15 mg/kg daily. Dosage may be increased by 5-10 mg/kg daily at weekly intervals until seizures are controlled or adverse effects prevent further increases in dosage. The manufacturers state that the maximum recommended dosage is 60 mg/kg daily. These dosage recommendations also apply when anticonvulsant therapy is being initiated with divalproex sodium as delayed- or extended-release formulations. If the total daily dose exceeds 250 mg, the drug (with the exception of the extended-release tablet formulation [e.g., Depakote® ER]) should be administered in divided doses.179,183,184
When converting a patient from a current anticonvulsant to valproic acid therapy for the treatment of complex partial seizures, valproic acid therapy should be initiated at usual starting dosages. The dosage of the current anticonvulsant may be decreased by 25% every 2 weeks, either starting concomitantly with the 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. The speed and duration of withdrawal of the current anticonvulsant can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. When divalproex sodium delayed-release tablets are administered, a twice-daily dosing regimen is suggested whenever feasible and appears to adequately maintain plasma valproic acid concentrations in most patients receiving the drug. The frequency of adverse effects (particularly hepatic effects) may be dose related. The benefit of improved seizure control which may accompany higher dosages should therefore be weighed carefully against the risk of adverse effects.
When converting a patient whose seizure disorder is controlled with delayed-release divalproex sodium tablets (e.g., Depakote®) to the extended-release tablets (e.g., Depakote® ER), the drug should be administered once daily using a total daily dosage 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, clinicians may consider increasing the delayed-release total daily dosage to the next higher dosage before converting to the appropriate extended-release dosage.182
For the treatment of seizures associated with Dravet syndrome†, initial valproic acid dosages of 10-15 mg/kg daily (given in 2-3 divided doses) and target dosages of 25-60 mg/kg daily have been used, based on clinical response, tolerability, and blood concentrations.311,314
For the management of status epilepticus refractory to IV diazepam†, 400-600 mg of valproic acid has been administered rectally† by enema or in wax base suppositories at 6-hour intervals.
Bipolar Disorder
The recommended initial dosage of valproic acid or divalproex sodium in the acute treatment of manic or mixed episodes is 750 mg daily in divided doses when given as delayed-release tablets (e.g., Depakote®)183 or 25 mg/kg once daily when given as extended-release tablets (e.g., Depakote® ER).182 The dosage of valproic acid or divalproex sodium should be increased as quickly as possible to achieve the lowest therapeutic dosage producing the desired clinical effect or desired serum concentration; however, the manufacturers recommend that the dosage not exceed 60 mg/kg daily.182,183 In placebo-controlled studies of patients receiving divalproex sodium as the delayed-release tablet for the treatment of acute mania, the trough serum valproic acid concentration that produced the desired clinical effect ranged from 50-125 mcg/mL;183 maximum serum concentrations generally were achieved within 14 days after initiating therapy.183 In a placebo-controlled study of patients receiving divalproex sodium as the extended-release tablet for the treatment of manic or mixed-type episodes, dosage was adjusted to achieve trough serum valproic acid concentrations of 85-125 mcg/mL.182
The manufacturers state that although it is agreed that pharmacologic treatment beyond an initial response in patients with manic episodes is desirable, both for the maintenance of initial response and for prevention of new manic episodes, the safety and efficacy of long-term (i.e., longer than 3 weeks) valproic acid and divalproex sodium therapy for manic episodes have not been established in controlled clinical trials.182,183 Clinicians who elect to use such therapy for extended periods (i.e., longer than 3 weeks) should continually reevaluate the usefulness of valproic acid therapy in the individual patient.182,183 Safety of valproic acid for longer-term therapy is supported by data from record reviews involving approximately 360 patients treated with valproic acid for longer than 3 months.183
Dosing guidelines for maintenance therapy† with valproic acid are less evidence-based than those for acute therapy, and dosages lower than those employed for acute therapy occasionally have been used. A 1-year study with divalproex sodium found an association between higher serum concentrations and increased appetite and decreased platelet and leukocyte counts.
Migraine
Prophylaxis of Chronic Attacks
In the prophylaxis of migraine headache, the recommended initial dosage of divalproex sodium or valproic acid is 250 mg twice daily given as delayed-release tablets (e.g., Depakote®)183 or 500 mg once daily given as extended-release divalproex sodium tablets (e.g., Depakote® ER).182 Some patients may benefit from dosages of up to 1 g daily; in clinical trials, there was no evidence of additional benefit with higher dosages .183 After 1 week at the initial dosage of 500 mg daily in patients receiving the extended-release tablets (e.g., Depakote® ER), dosage may be increased to 1 g once daily.182 Although maintenance dosages other than 1 g once daily have not been evaluated in patients with migraine headache, the effective dosage range for these patients is 500 mg to 1 g daily.182 It should be considered that divalproex sodium extended-release tablets and divalproex sodium delayed-release tablets are not bioequivalent.182 If a patient requires smaller dosage adjustment than that available using the extended-release tablets, the delayed-release tablets should be used instead.182
Acute Attacks
For the acute management of migraine headache† in adults and adolescents, the optimum IV dosage, frequency, and rate of administration have not been established.166,173 In most reports, IV166 valproate sodium was given in doses of 300 mg to 1 g 157,158,159,161,164 diluted in a compatible IV infusion (e.g., 5% dextrose injection, 0.9% sodium chloride injection) solution (usually about 100-250 mL) and infused IV at rates ranging from 17-100 mg/minute.159,161,162,163,164 In some patients, the dose was administered more rapidly (e.g., 500 mg over 2 minutes,173 100 mg by direct [“bolus”] IV injection).160,169 A repeat dose (equal to the initial dose or less) was given to some patients within a few hours, if reduction of pain was not sufficient.162,163,164,165,166 In one study, 500-mg doses of valproate sodium were administered every 8 hours for 2 days.158,166 Some patients have received166,168,169 direct IV injections of 100-mg doses repeated at 5-minute intervals169 or infusions of a single 500-mg dose (diluted in 5 mL of 0.9% sodium chloride injection) into a free-flowing IV line of 0.9% sodium chloride injection.168
When IV valproate sodium has been used in the management of chronic daily headache, an initial dose of 15 mg/kg was administered over 30 minutes followed by a dose of 5 mg/kg (infused over 15 minutes) given every 8 hours.165,166
Dosage in Geriatric Patients
Because of a decrease in clearance of free (unbound) valproic acid and the possibility of increased sensitivity to adverse effects (e.g., somnolence) in geriatric patients, the initial dosage should be reduced.182,183,184 Subsequent dosage should be increased more slowly in geriatric patients.179,182,183,184,185 In addition, the manufacturer recommends regular monitoring of fluid and nutritional intake, dehydration, somnolence, and other adverse effects in these individuals.179,182,183,184,185 Dosage reduction or discontinuance of valproic acid should be considered in geriatric patients with decreased food or fluid intake and in those with excessive somnolence.179,182,183,184,185 The ultimate therapeutic dosage in these patients should be determined on the basis of tolerability and clinical response.182,183,184
Cautions ⬆ ⬇
The adverse effect profile of parenteral valproate sodium can be expected to include all of the effects associated with oral administration of the drug. In addition, IV infusion of valproate sodium may cause local effects at the injection site and effects associated with the rate of infusion. (See Cautions: Local and Infusion-related Effects.)
GI Effects
Nausea, vomiting, abdominal pain, anorexia, diarrhea, and dyspepsia may occur in patients receiving valproic acid. The most frequent adverse effects of valproic acid following initiation of therapy with the drug are nausea, vomiting, and indigestion. These adverse effects usually are transient, rarely require discontinuance of therapy, and can be minimized by administering the drug with meals or by beginning therapy with low dosages and increasing the dosage very gradually. While divalproex sodium shares the toxic GI potential of valproic acid, the frequency of adverse GI effects appears to be lower and the effects possibly less severe with divalproex sodium than with valproic acid; patients who are unable to tolerate the GI effects of valproic acid or valproate sodium may tolerate divalproex sodium, but GI intolerance to divalproex sodium can also occur. Both anorexia with some weight loss and increased appetite with weight gain have been reported in patients receiving valproic acid. Eructation, fecal incontinence, gastroenteritis, glossitis, flatulence, hematemesis, periodontal abscess, tooth disorder, dry mouth, stomatitis, and constipation were reported in 1-5% of patients receiving valproic acid in clinical trials. Dysphagia, gum hemorrhage, and mouth ulceration also have occurred in greater than 1% of patients receiving the drug.
Medication residue in the stool has been reported rarely with divalproex sodium (e.g., Depakote®, Depakote® ER) formulations; in some reports, the residue occurred in the presence of diarrhea.179,182,183 Some of the patients in the reported cases had anatomic (e.g., ileostomy, colostomy) or functional GI disorders that decrease GI transit times.179,182,183 (See Cautions: Precautions and Contraindications.)
Pancreatitis
Cases of life-threatening pancreatitis have been reported in children and adults shortly after initial use or after several years of therapy with valproic acid.179,182,183,184,185 Pancreatitis may be hemorrhagic with a rapid progression from initial symptoms to death.179,182,183,184,185 Development of manifestations suggestive of pancreatitis (e.g., abdominal pain, nausea, vomiting, and/or anorexia) requires prompt medical evaluation.179,182,183,184,185 (See Cautions: Precautions and Contraindications.) It should be considered that patients receiving valproic acid are at greater risk of developing pancreatitis than that expected in the general population; in addition, pancreatitis recurred on rechallenge with the drug in several patients. 179,182,183,184,185 In clinical trials involving 2416 patients, 2 cases of pancreatitis without alternative etiology were reported, representing 1044 patient-years experience.179,182,183,184,185
Nervous System Effects
Sedation and drowsiness may occur with valproic acid therapy, especially in patients receiving other anticonvulsants. (See Drug Interactions: CNS Depressants, Antidepressants, and Anticonvulsants.) Somnolence, asthenia, dizziness, and tremor generally are the most frequently reported adverse nervous system effects in patients receiving valproic acid in clinical trials. Ataxia, emotional lability, abnormal thinking, amnesia, and depression have been reported in up to 5-8% of patients receiving the drug. Some patients have reported increased alertness, insomnia, and nervousness during valproic acid therapy. Coma has been reported rarely in patients receiving valproic acid as monotherapy or in combination with phenobarbital.
Between 1-5% of patients receiving valproic acid in clinical trials experienced anxiety, confusion, headache, myasthenia, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder, hallucinations, euphoria, agitation, catatonia, dysarthria, speech disorder, hypokinesia, increased reflexes, tardive dyskinesia, or vertigo. Asterixis, hypoesthesia, parkinsonism, hostility, emotional upset, and psychosis/acute psychosis also have occurred rarely. Hyperactivity, aggressiveness, and other behavioral disturbances have been reported in a few children receiving valproic acid.
Patients have rarely developed encephalopathy with or without fever, without evidence of hepatic dysfunction or abnormal valproic acid plasma concentrations, shortly after the introduction of valproic acid therapy. Although this condition can be reversible upon discontinuance of the drug, there have been fatalities in patients with hyperammonemic encephalopathy, often in patients with underlying urea cycle disorder. (See Cautions: Endocrine and Metabolic Effects and see also Cautions: Precautions and Contraindications.)
Reversible and irreversible cerebral or cerebellar atrophy (or pseudoatrophy), temporally associated with the use of valproic acid and often accompanied by cognitive decline, has been reported during postmarketing experience.182,183,215,216,217,218,219,220 In some cases, patients recovered with permanent sequelae.182,183 (See Cautions: Precautions and Contraindications.)
Suicidality Risk
An analysis of 199 randomized, placebo-controlled studies involving 11 anticonvulsants in patients with epilepsy, psychiatric disorders, and other conditions found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).179,183,184 This increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks.179,183,184 Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality when compared with placebo, but the relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.179,183,184 (See Cautions: Precautions and Contraindications.)
Hepatic Effects
Minor elevations in serum concentrations of aminotransferases (transaminases) and lactate dehydrogenase occur frequently in patients receiving valproic acid and appear to be dose related. In clinical trials, increased ALT (SGPT) and increased AST (SGOT) concentrations occurred in 1-5% of patients receiving valproic acid. Occasionally, increases in serum bilirubin concentration and abnormal changes in other hepatic function test results occur; these results may reflect potentially serious hepatotoxicity. (See Cautions: Precautions and Contraindications.)
Hepatic failure resulting in death has occurred in patients receiving valproic acid, usually during the first 6 months of therapy.182,183,184,185,221,222,223 Patients receiving multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particularly high risk of valproic acid-induced hepatotoxicity.182,183,184,185,221 Clinical experience indicates that children younger than 2 years of age, especially those with the previously mentioned conditions, have a considerably increased risk of developing fatal hepatotoxicity.182,183,184,185 (See Cautions: Precautions and Contraindications.) In patients older than 2 years of age, clinical experience in epilepsy indicates that the frequency of fatal hepatotoxicity decreases considerably in progressively older patient groups.182,183,184,185
An increased risk of valproic acid-induced acute liver failure and resultant deaths have been observed in patients with hereditary neurometabolic syndromes caused by mutations in the mitochondrial DNA polymerase gamma ( POLG ) gene (e.g., Alpers-Huttenlocher syndrome) compared with those without these conditions.182,183,221,222,223 Most of the cases were reported in children and adolescents.182,183,221,223 (See Cautions: Precautions and Contraindications.)
Severe or fatal hepatotoxicity induced by valproic acid may be preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting.182,183,184,185 In epileptic patients, loss of seizure control also may precede the development of hepatotoxicity.182,183,184,185 (See Cautions: Precautions and Contraindications.)
Endocrine and Metabolic Effects
Hyperammonemic encephalopathy, including some fatalities, has been reported in patients with urea cycle disorders (UCD), particularly ornithine transcarbamylase deficiency, following initiation of valproic acid therapy.182,183,184,185 Hyperammonemia may occur in patients receiving valproic acid and may occur in the absence of abnormal hepatic function test results.182,183,184,185 Development of symptoms of unexplained hyperammonemic encephalopathy (e.g., lethargy, vomiting, changes in mental status) requires prompt medical evaluation.182,183,184,185 (See Cautions: Precautions and Contraindications.)
Plasma ammonia concentrations have not been systematically evaluated following IV administration of valproate sodium; however, hyperammonemia with encephalopathy has been reported in at least 2 patients who received IV infusions of the drug.185
Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with or without encephalopathy in patients who have previously tolerated either drug alone.182,183,184,185 (See Drug Interactions: CNS Depressants, Antidepressants, and Anticonvulsants.) Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at increased risk of hyperammonemia with or without encephalopathy.182,183,184,185
Hypothermia (defined as an unintentional drop in body core temperature to less than 35°C) has been reported in association with valproic acid therapy, both in conjunction with and in the absence of hyperammonemia.182,183,184,185 Hypothermia may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and substantial alterations in other major organ systems such as the cardiovascular and respiratory systems.182,183,184,185 Hypothermia also may occur in patients receiving concurrent topiramate and valproic acid therapy after initiating topiramate therapy or following an increase in the daily dosage of topiramate.182,183,184,185
Hyponatremia and inappropriate antidiuretic hormone (ADH) secretion also have been reported. Hyperglycinemia has been reported in patients receiving valproic acid and was associated with a fatal outcome in one patient with preexisting nonketotic hyperglycinemia. Between 1-5% of patients receiving valproic acid in clinical trials experienced dysmenorrhea, amenorrhea, vaginitis, metrorrhagia, or vaginal hemorrhage. Breast enlargement, galactorrhea, irregular menses, polycystic ovaries, hyperandrogenism, weight gain, Fanconi's syndrome (principally reported in children), and parotid gland swelling have occurred in some patients receiving valproic acid. Abnormal thyroid function test results and decreased carnitine concentrations also have been reported; however, the clinical importance of these abnormalities has not been elucidated.
Hematologic Effects
Valproic acid inhibits the secondary phase of platelet aggregation and may prolong bleeding time. In one study of valproic acid monotherapy for seizures, 27% of patients receiving approximately 50 mg/kg per day had at least one platelet count of 75,000/mm3 or less.182,183,184,185 Approximately half of the patients discontinued therapy, with their platelet counts returning to normal; the remaining patients experienced normalization of their platelet counts with continued valproic acid therapy.182,183,184,185 In this study, the probability of thrombocytopenia appeared to increase significantly at total trough valproate plasma concentrations of 110 mcg/mL or greater (females) or 135 mcg/mL or greater (males).182,183,184,185 (See Cautions: Precautions and Contraindications.)
Ecchymosis, petechiae, bruising, hematoma formation, epistaxis, frank hemorrhage, lymphocytosis, leukopenia, eosinophilia, macrocytosis, acute intermittent porphyria, decreased fibrinogen concentrations, anemia (including macrocytic anemia, with or without folate deficiency), bone marrow suppression, pancytopenia, and aplastic anemia have been reported in patients receiving valproic acid therapy.
Dermatologic and Sensitivity Reactions
Between 1-5% of patients receiving valproic acid in clinical trials experienced seborrhea, dry skin, pruritus, furunculosis, rash (including maculopapular), or discoid lupus erythematosus. Transient alopecia, cutaneous vasculitis, generalized pruritus, anaphylaxis, photosensitivity, Stevens-Johnson syndrome, erythema nodosum, and erythema multiforme have been reported in patients receiving valproic acid therapy. Rare cases of toxic epidermal necrolysis have been reported, including a fatal case in a 6-month-old infant receiving valproic acid therapy; however, the infant was receiving other drugs concomitantly. An additional case of fatal toxic epidermal necrosis was reported in a 35-year-old patient with acquired immunodeficiency syndrome (AIDS) who was taking several concomitant drugs and who had a history of multiple cutaneous drug reactions.
Multi-organ hypersensitivity reactions have been reported rarely in close temporal association (median time to detection: 21 days; range: 1-40 days) to initiation of valproic acid therapy in adult and pediatric patients.182,183,184,185 Many of these cases resulted in hospitalization and at least one death has been reported.182,183,184,185
Although signs and symptoms are diverse, patients with multi-organ hypersensitivity 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 Because multi-organ hypersensitivity reactions are variable in their expression, signs and symptoms associated with other organ systems also may occur.182,183,184,185 Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, experience with drugs associated with multi-organ hypersensitivity indicates that this may be a possibility.182,183,184,185 (See Cautions: Precautions and Contraindications.)
Local and Infusion-related Effects
In addition to the usual adverse effects associated with oral therapy, IV infusion of valproate sodium can produce local effects at the site of injection as well as adverse effects associated with the rate of IV infusion. In clinical trials involving healthy adults as well as patients with seizure disorders at total IV dosages of 120-6000 mg daily, adverse local effects at the site of infusion were reported in up to 2.6% of patients and included pain (2.6%), injection site reaction (2.4%), and inflammation (0.6%). In these trials, about 2% of patients discontinued parenteral therapy with the drug because of adverse effects, principally because of nausea and vomiting and elevated amylase. Other reasons for discontinuing parenteral valproate sodium therapy included hallucinations, pneumonia, headache, injection site reaction, and abnormal gait.
Dizziness and injection site pain were reported more frequently when valproate sodium was infused IV at a rate of 100 mg/minute relative to slower rates that ranged up to 33 mg/minute. At an IV infusion rate of 200 mg/minute, dizziness and taste perversion occurred more frequently than at an IV infusion rate of 100 mg/minute. In clinical trials, the maximum IV infusion rate studied was 200 mg/minute.
Ocular and Otic Effects
Diplopia, amblyopia, nystagmus, and tinnitus have been reported in up to 7-16% of patients receiving valproic acid in clinical trials. Other adverse ocular and otic effects reported in patients receiving valproic acid include abnormal vision, otitis media, conjunctivitis, dry eyes, ocular pain, ocular disorder, photophobia, otic pain, and otic disorder. Reversible and irreversible hearing loss (including deafness) has been reported; however, a casual relationship has not been established.
Other Adverse Effects
Infection has been reported in up to 20% of patients receiving valproic acid in clinical trials. Back pain, fever, flu syndrome, bronchitis, rhinitis, pharyngitis, dyspnea, and peripheral edema have been reported in up to 5-12% of patients receiving the drug in clinical trials. Increased cough, chest pain, tachycardia, hypertension, palpitation, arrhythmia, bradycardia, hypotension, postural hypotension, taste perversion, hiccups, facial edema, pneumonia, sinusitis, dysuria, urinary incontinence, cystitis, urinary frequency, arthralgia, myalgia, arthrosis, leg cramps, twitching, malaise, chills, fever with chills, sweating, vasodilation, cyst, neck pain, neck rigidity, and accidental injury also may occur. Adverse effects reported rarely in patients receiving valproic acid include muscular weakness, interstitial nephritis, enuresis, urinary tract infection, bone pain, lupus erythematosus, and fatigue. A case of reversible skeletal muscle weakness and ventilatory failure also has been reported in a geriatric patient receiving valproic acid therapy.
Precautions and Contraindications
Since divalproex sodium is a prodrug of valproate, it shares the toxic potentials of valproic acid, and the usual cautions, precautions, and contraindications of valproic acid therapy should be observed with divalproex sodium therapy.
Patients should be warned that valproic acid may impair ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery or driving a motor vehicle).
Because of an increased risk of suicidality (suicidal behavior or ideation) with anticonvulsants (see Suicidality Risk under Cautions: Nervous System Effects), all patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior.179 Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality so that they are aware and able to notify their clinician of any unusual behavioral changes.179,181,183,184 Patients, family members, and caregivers should pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences.179 In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (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).179 If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately.179,181,183,184 Clinicians who prescribe valproic acid or any other anticonvulsant should balance the risk for suicidality with the risk of untreated illness.179,181,183,184 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior.179,181,183,184 If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.179,181,183,184
Results of in vitro studies indicate that valproate appears to stimulate replication of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) under certain experimental conditions.179,182,183,184,185 The clinical importance of these in vitro findings, including any relevance to patients receiving maximally suppressive antiretroviral therapy, is not known.179,182,183,184,185 (See Pharmacology: Antiviral Effects.) It has been suggested that these in vitro effects should be considered when interpreting test results concerning the clinical condition of HIV-infected patients (e.g., plasma HIV RNA levels) or patients with CMV infection receiving valproic acid.179,182,183,184,185
Since valproic acid may cause serious and potentially fatal hepatotoxicity, patients receiving the drug should be closely monitored for possible nonspecific symptoms of hepatic dysfunction (e.g., malaise, weakness, lethargy, facial edema, anorexia, vomiting, loss of seizure control).182,183,184,185 In addition, hepatic function tests should be performed before and at frequent intervals during therapy, especially during the first 6 months.182,183,184,185 (See Cautions: Hepatic Effects.) Since results of hepatic function tests may not be abnormal in all instances, clinicians must also consider the results of careful interim medical history and physical examination of the patient.182,183,184,185 Valproic acid therapy should be discontinued immediately in the presence of suspected or apparent substantial hepatic dysfunction.182,183,184,185 In some patients, hepatic dysfunction has progressed despite discontinuance of the drug.182,183,184,185 Since elevations in hepatic enzyme concentrations may be dose related, the benefit of improved seizure control which may accompany higher doses of the drug must be weighed against the potential risks. Valproic acid should be used with caution in patients with a history of hepatic disease. 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 of hepatotoxicity.182,183,184,185 Because children younger than 2 years of age, especially those with the previously listed conditions, have a considerably increased risk of developing fatal hepatotoxicity compared with older patient groups, valproic acid should be used in these patients only with extreme caution and as a single agent; the benefits of therapy must be weighed against the potential risks.182,183,184,185 In patients older than 2 years of age, experience in epilepsy indicates that the frequency of fatal hepatotoxicity decreases considerably in progressively older patient groups.182,183,184,185 Valproic acid should not be used in patients with hepatic disease or substantial hepatic dysfunction.182,183,184,185
Valproic acid is contraindicated in patients known to have a mitochondrial disorder caused by mutations in the POLG gene (e.g., Alpers-Huttenlocher syndrome) and in children younger than 2 years of age in whom there is a clinical suspicion of such a disorder.179,182,183,185 In patients older than 2 years of age with suspected hereditary mitochondrial disease, valproic acid should be used only if other anticonvulsant therapies have failed; such patients should be closely monitored during valproic acid therapy for the development of acute liver injury with regular clinical assessments and liver function test monitoring.179,182,183,185 POLG -related disorders should be suspected in any patient with a family history and/or symptoms suggestive of such a disorder (e.g., unexplained encephalopathy, refractory epilepsy [focal, myoclonic], status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia, complicated migraine with occipital aura).179,182,183,185,221,223 POLG screening should be performed, if necessary, in accordance with current clinical practice.179,182,183,185,222,223 The A467T and W748S mutations are present in approximately two-thirds of patients with autosomal recessive POLG -related disorders.179,182,183,185,221,223 Valproic acid therapy should be discontinued immediately in the presence of suspected or apparent substantial hepatic dysfunction.179,182,183,185 In some patients, hepatic dysfunction has progressed despite discontinuance of the drug.179,182,183,185,221 (See Cautions: Hepatic Effects.)
Because the use of valproic acid has been associated with life-threatening pancreatitis in children and adults (see Cautions: Pancreatitis), patients and guardians should be instructed that if symptoms of pancreatitis (e.g., abdominal pain, nausea, vomiting, anorexia) develop, prompt medical evaluation is needed.179,182,183,184,185 If pancreatitis is diagnosed, valproic acid usually should be discontinued and alternative therapy for the underlying medical condition should be initiated as clinically indicated.179,182,183,184,185
Because the use of valproic acid has been associated with hyperammonemic encephalopathy, patients should be advised that if symptoms of this disorder (e.g., lethargy, vomiting, changes in mental status) develop, they should notify their clinician promptly.179,182,183,184,185 (See Cautions: Endocrine and Metabolic Effects.) If such symptoms are present, plasma ammonia concentrations should be determined, and, if these concentrations are increased, valproic acid therapy should be discontinued.179,182,183,184,185 Appropriate treatment of hyperammonemia should be initiated and the patient should be evaluated for urea cycle disorders.179,182,183,184,185 Asymptomatic elevation of ammonia concentrations is more common than symptomatic hyperammonemia.182,183,184,185 In patients with asymptomatic elevations, plasma ammonia concentrations should be closely monitored and, if elevations persist, discontinuance of valproic acid therapy should be considered.179,182,183,184,185 Prior to the initiation of valproic acid therapy, an evaluation for urea cycle disorders should be considered 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 urea cycle disorders or unexplained infant deaths (particularly males); and patients with other signs or symptoms of urea cycle disorders.179,182,183,184,185
Discontinuance of valproic acid therapy should be considered in patients who develop hypothermia, which can be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and substantial alterations in other major organ systems such as the cardiovascular and respiratory systems.182,183,184,185 Since hypothermia also may be a symptom of hyperammonemia, clinical management and assessment of the condition should include determination of blood ammonia concentrations.182,183,184,185
In a randomized, double-blind study comparing the efficacy of IV valproate sodium (administered for one week followed by oral valproic acid for 1 or 6 months) with that of IV phenytoin (administered for 1 week followed by placebo) for the prevention of posttraumatic seizures in patients with acute head injuries†, the mortality rate was found to be higher in patients treated with valproate sodium followed by valproic acid compared with those receiving phenytoin (13 versus 8.5%, respectively).185 Many of these patients were critically ill with multiple and/or severe injuries and a causal relationship to the drug has not been established.185,195 However, pending further information, the manufacturer and some clinicians state that it is prudent to not use IV valproate sodium in patients with acute head trauma for posttraumatic seizure prophylaxis.185,195
Anticonvulsant drugs (including valproic acid) should not be discontinued abruptly in patients, including in pregnant women, receiving the drugs to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.182,183,184 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)
Since valproic acid may cause thrombocytopenia and inhibit platelet aggregation, platelet counts and coagulation studies should be determined before and periodically during therapy with the drug and before planned (i.e., elective) surgery is performed in patients receiving the drug.182,183,184,185 Some clinicians have recommended thromboelastography as a more reliable method to assess the effects of valproic acid on coagulation. If clinical evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation occurs during valproic acid therapy, dosage should be reduced or the drug withdrawn pending further evaluation.182,183,184,185
Because the use of valproic acid has been associated with multi-organ hypersensitivity reactions (see Cautions: Dermatologic and Sensitivity Reactions), patients should be advised that a fever associated with other organ system involvement (e.g., rash, lymphadenopathy) may be drug-related and should be reported immediately to the clinician.182,183,184,185 If a multi-organ hypersensitivity reaction is suspected, valproic acid should be discontinued and alternative treatment initiated.182,183,184,185
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 Drug Interactions.)
Because of the possibility of cerebral and cerebellar atrophy associated with the use of valproic acid, patients should be routinely monitored for motor and cognitive impairments during therapy; if any manifestations of brain atrophy develop or are suspected, continued use of the drug should be evaluated.182,183 (See Cautions: Nervous System Effects.)
Patients receiving divalproex sodium formulations (e.g., Depakote®, Depakote® ER, Depakote® Sprinkle Capsules) should be instructed to notify their clinician if they notice any medication residue in their stool.179,182,183 It is recommended that plasma valproic acid concentrations and clinical status be monitored in such patients; if clinically indicated, alternative therapy may be considered.179,182,183
Valproic acid is contraindicated in patients with hepatic disease or substantial hepatic dysfunction.179,182,183,184,185 Valproic acid also is contraindicated in patients with known mitochondrial disorders caused by POLG mutations and in children younger than 2 years of age suspected of having a POLG -related disorder.182,183 (See Cautions: Hepatic Effects.)
Valproic acid is contraindicated in patients with known hypersensitivity to the drug.182,183,184,185 Valproic acid also is contraindicated in patients with known urea cycle disorders.182,183,184,185 (See Cautions: Endocrine and Metabolic Effects.) In addition, use of valproic acid is contraindicated for prophylaxis of migraine headaches in pregnant women.182,183 (See Cautions: Pregnancy, Fertility, and Lactation.)
Pediatric Precautions
Experience with oral valproic acid therapy in the management of seizures indicates that children younger than 2 years of age are at an increased risk of developing fatal hepatotoxicity.182,183,184,185 The drug should be used with extreme caution and as single-agent therapy in such children, and the benefits of valproic acid therapy weighed against the risks.182,183,184,185 Experience in epilepsy indicates that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups (i.e., older than 2 years of age).182,183,184,185 (See Cautions: Hepatic Effects and see also Cautions: Precautions and Contraindications.)
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
The safety and efficacy of valproic acid in the treatment of complex partial seizures have not been established in pediatric patients younger than 10 years of age.179 Available data from placebo-controlled clinical trials failed to demonstrate efficacy of extended-release divalproex sodium tablets for the treatment of mania in pediatric patients 10-17 years of age and for the prevention of migraine headaches in adolescent patients 12-17 years of age.182,183 Safety and tolerability of divalproex sodium in pediatric patients appear to be similar to those observed in adults.182,183
The safety of valproate sodium injection has not been studied in pediatric patients younger than 2 years of age.185 If a decision is made to use the injection in this age group, the manufacturer states that it should be used with extreme caution and only as monotherapy, and the potential benefits should be weighed against the possible risks.185 No unusual adverse effects were observed in clinical trials employing IV valproate sodium for the management of seizure disorders in 35 pediatric patients 2-17 years of age.185
Geriatric Precautions
No geriatric patients older than 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 of almost 600 patients treated with valproic acid for manic episodes, approximately 12% of patients were older than 65 years of age.182,183,184,185 A higher percentage of these patients reported accidental injury, infection, pain, somnolence, or tremor during valproic acid therapy compared with younger patients.182,183,184,185 Discontinuance of valproic acid therapy occasionally was associated with somnolence or tremor.182,183,184,185 The manufacturer states that it is unclear whether these events indicate additional risks of drug therapy or whether they result from preexisting medical conditions or concomitant medication use in these geriatric patients.182,183,184,185
Results of a double-blind, multicenter study of geriatric patients (mean age: 83 years) with dementia who were receiving valproic acid (dosages increased by 125 mg daily up to a target daily dosage of 20 mg/kg) indicate that the incidence of somnolence was higher in patients receiving valproic acid than in those receiving placebo and discontinuance of therapy because of somnolence was higher in those receiving valproic acid than in those receiving placebo.179,182,183,184,185 In about 50% of patients with somnolence, a reduced nutritional intake and weight loss also were observed.179,182,183,184,185 The incidence of dehydration also appeared to be higher in geriatric patients receiving valproic acid than in those receiving placebo.179,182,183,184,185 In the patients who experienced the mentioned adverse effects, a trend for lower baseline albumin concentration, lower valproic acid clearance, and higher BUN was observed. 179,182,183,184,185 Therefore, it is recommended that initial dosage of valproic acid be reduced and subsequent dosages be increased more slowly in geriatric patients.179,182,183,184,185 In addition, the manufacturers recommend regular monitoring of fluid and nutritional intake, dehydration, somnolence, and other adverse effects in these individuals.179,182,183,184,185 Dosage reduction or discontinuance of valproic acid should be considered in geriatric patients with decreased food or fluid intake and in those with excessive somnolence.179,182,183,184,185
The safety and efficacy of valproic acid for the prevention of migraine headaches in geriatric patients older than 65 years of age have not been established.182,183
No unique safety concerns were identified in geriatric patients older than 65 years of age receiving IV valproate sodium in clinical trials.185
Mutagenicity and Carcinogenicity
Studies of valproic acid that used bacterial and mammalian test systems have shown no evidence to date of a mutagenic potential for the drug.
In rats and mice receiving valproic acid dosages of 80 and 170 mg/kg daily for 2 years, an increased incidence of subcutaneous fibrosarcomas occurred in male rats at the higher dosage level and a dose-related trend for an increased incidence of benign pulmonary adenomas was observed in male mice. The importance of these findings to humans is not known.
Pregnancy, Fertility, and Lactation
Pregnancy
Use of valproic acid during pregnancy is associated with an increased risk of neural tube defects (NTDs; e.g., spina bifida) and other major congenital malformations (e.g., craniofacial defects, cardiovascular malformations, malformations involving various body systems).182,183,184,185,188,189,190,191,192,193,194 In utero exposure to valproic acid also can cause decreased intelligence quotient (IQ) scores and other adverse cognitive effects in children.196,197,198,199,200,201,202,203,204,205,206,207,208,212
Adverse fetal effects similar to those observed in humans have been observed in developmental toxicity studies in animals.182,183,184,190 Administration of valproic acid to mice, rats, rabbits, and monkeys during the period of organogenesis resulted in an increased incidence of fetal structural malformations (e.g., skeletal, cardiac, urogenital), intrauterine growth retardation, and embryofetal death.182,183,184,185,190 Such effects were observed at clinically relevant dosages of valproic acid.182,183,184,185 In addition, fetal NTDs were observed in mice following valproic acid administration during critical periods of organogenesis; this teratogenic response correlated with maximum maternal drug concentrations.182,183,184,185 Behavioral abnormalities (e.g., cognitive, locomotor, and social interaction deficits) and brain histopathologic changes also have been observed in mice and rats following prenatal exposure to clinically relevant dosages of valproic acid.182,183
Valproic acid can cause major congenital malformations in humans, particularly NTDs, and this risk appears to be greatest during the first trimester of pregnancy.182,183,184,185,188,189,190 Recent data indicate that the risk of major congenital malformations is substantially greater with use of valproic acid than with use of other anticonvulsant agents during pregnancy.182,183,184,185,188,189,190,191,192,193,194 To monitor maternal-fetal outcomes of pregnant women exposed to anticonvulsant agents, including valproic acid, the North American Antiepileptic Drug (NAAED) pregnancy registry has been established.182,183,184,185,188,189,191 Data obtained from the NAAED registry indicate that the rate of major malformations in infants exposed in utero to valproic acid as monotherapy is about fourfold higher than the rate of major malformations in infants exposed to monotherapy with another anticonvulsant agent.182,183,184,185,188,189,191 Among 149 women in the registry who received valproic acid (average daily dosage of 1 g) for epilepsy during the first trimester of pregnancy, 16 infants were born with a birth defect, including NTDs (3 cases), craniofacial defects, cardiovascular defects, and other malformations involving various body systems.182,183,184,185,188,189,191 The rate of major malformations in infants exposed to valproic acid was 10.7% compared with a rate of 2.9% among infants born to a control group of women in the registry who received another anticonvulsant drug during the first trimester of pregnancy.182,183,184,185,188,189,191 The strongest association between maternal use of valproic acid and congenital anomalies is with the development of NTDs (e.g., spina bifida).182,183,184,185 Use of valproic acid during pregnancy is associated with an approximate 1-2% fetal risk of congenital spinal bifida (based on data from the US Centers for Disease Control and Prevention [CDC]); according to data from the CDC's National Birth Defects Prevention Network, the estimated risk of spina bifida in the general population is about 0.06-0.07%.182,183,184,185 Evidence suggests that prophylactic use of folic acid prior to conception and during pregnancy decreases the incidence of congenital NTDs in the general population, and folic acid supplementation prior to conception and during pregnancy should be routinely recommended in women receiving valproic acid.182,183,184,185,188,189,190,191,192 It is not known whether folic acid supplementation specifically reduces the risk of NTDs or decreased IQ in the offspring of women receiving valproic acid therapy.182,183,184,185,190,192
In utero exposure to valproic acid also appears to be associated with an increased risk of adverse cognitive effects in children.182,196,197,198,199,200,201,202,203,204,205,206,207,208,212 Several epidemiologic studies have shown that children born to women who received valproic acid during pregnancy score lower on IQ tests and other cognitive function tests measuring a variety of mental and developmental abilities than those exposed in utero to other anticonvulsant agents or to no anticonvulsant therapy.182,196,197,198,199,200,201,202,203,205,206,207,208 In one large, prospective, observational cohort study (the Neurodevelopmental Effects of Antiepileptic Drugs [NEAD] study), children who had been exposed to valproic acid in utero had significantly lower IQ scores at 6 years of age than those exposed in utero to lamotrigine, phenytoin, or carbamazepine monotherapy.182,196,197,205,206 After adjustment for potentially confounding factors, IQ scores were on average 8-11 points lower in valproic acid-exposed children compared with those exposed to the other anticonvulsant drugs.196,197,205,206 These findings of reduced IQ were consistent with those reported in 2 interim analyses that were conducted when the children were 2-3 and 4.5 years of age, although overall IQ scores tended to improve with age.197,206,207 Fetal exposure to valproic acid also was associated with impairments in a range of other cognitive domains (e.g., memory, verbal and nonverbal abilities, executive functions, cognitive fluency and originality); in general, the effects of the drug were dose dependent, with higher dosages associated with worse cognitive outcomes.197,206,207,208 Other observational studies also have demonstrated poorer cognitive outcomes, including delayed mental development, increased special education needs, and reduced verbal IQ, in cohorts of children exposed in utero to valproic acid compared with other anticonvulsant agents.196,197,198,199,200,201,202,203 Despite the methodologic limitations of these studies (e.g., lack of randomization, small sample size), the weight of available evidence currently supports a correlation between prenatal valproic acid exposure and an increased risk of cognitive deficits, including decreased IQ, in children.182,183,196,197,198,199,200,201,202,203,205,206,207,213 The long-term effects of prenatal valproic acid exposure on cognitive development have not been established.196 It is also not known whether these effects occur when fetal exposure is limited with respect to duration or timing (e.g., to the first trimester) during pregnancy.182,196,205 Therefore, the risk for development of adverse cognitive effects in valproic acid-exposed children should be considered at any time during pregnancy.205 In the NEAD study, a positive association was found between periconceptional use of folic acid and IQ scores; however, this finding should be interpreted with caution because the study was not specifically designed to evaluate this outcome.182,205,206 Folic acid supplementation prior to conception and during pregnancy should be routinely recommended in all women of childbearing age receiving valproic acid to decrease the risk of birth defects.182,205,206
There also is a possible association between in utero valproic acid exposure and developmental delay, autism, or autism spectrum disorders.179,182,183,190,191,192,194,209,210 Results of a population-based cohort study using national register data from Denmark found that maternal use of valproic acid during pregnancy was associated with an increased risk of autism spectrum disorders and childhood autism in the offspring.209,210 The study identified a cohort of children (total of 655,615) born during a 10-year period and followed these children from birth until death, emigration, diagnosis of autism spectrum disorder or childhood autism, or study end.209 Among 508 children who were identified as having been exposed to valproic acid in utero, the absolute risk of autism spectrum disorder was 4.42% (adjusted hazard ratio of 2.9) and the absolute risk of childhood autism was 2.5% (adjusted hazard ratio of 5.2); the estimated absolute risk of these disorders in the entire population of children studied was 1.53 and 0.48%, respectively, after 14 years of follow-up.209,210
Valproic acid is contraindicated in pregnant women for the prevention of migraine headaches.182,183,205 The drug should not be used in pregnant women with epilepsy or bipolar disorder unless other treatments have failed to provide adequate symptom relief or are otherwise unacceptable; in these cases, the benefits of valproic acid may continue to outweigh its risks.182,205 It should be kept in mind that untreated or inadequately treated epilepsy or bipolar disorder during pregnancy increases the risk of complications in both the pregnant woman and her developing fetus.188,196,212,213
Because of the risk of major congenital malformations and other adverse pregnancy outcomes (e.g., decreased IQ in offspring) which may occur very early in pregnancy, use of valproic acid should be avoided whenever possible in women of childbearing potential.205,206,213 Alternative therapies to valproic acid should be considered, especially if the drug is being used for the treatment of migraines or other conditions not usually considered life-threatening, in women of childbearing potential.182,183,184,185,188,196,205,210 If valproic acid is necessary in a woman of childbearing potential, some experts suggest that the lowest possible dosage be employed.207,213 Effective contraception should be used in such women during valproic acid therapy.182,183 If pregnancy occurs during therapy, the clinician should be notified immediately; valproic acid should not be discontinued abruptly in a pregnant woman with epilepsy because of the risk of precipitating seizures.182 In individual cases when the severity and frequency of the seizure disorder are such that discontinuance of therapy does not pose a serious threat to the patient, discontinuance of the drug may be considered prior to and during pregnancy; however, even minor seizures can pose some hazard to the developing embryo or fetus.182,183,184,185
In women who are contemplating pregnancy, alternative therapies to valproic acid should be considered; clinicians should review and revise the treatment plan with the patient well before conception.182,205,212 Women who become pregnant while receiving valproic acid should be encouraged to enroll in the NAAED pregnancy registry by calling 888-233-2334; information on the NAAED registry also is available on the website [Web].182,183,184,188,196 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 all women who become pregnant while receiving valproic acid.182,183,184,185,188,191
Patients receiving valproic acid may develop clotting abnormalities.182,183,184,185 A pregnant patient taking multiple anticonvulsant agents, including valproic acid, developed hypofibrinogenemia; the patient then gave birth to an infant with afibrinogenemia, who subsequently died of hemorrhage.182,183,184,185 If valproic acid is to be used during pregnancy, clotting parameters should be monitored closely.182,183,184,185
Cerebral atrophy has been reported in children following prenatal exposure to valproic acid.182,183 In addition, fatal cases of hepatic failure in infants exposed to valproic acid in utero have been reported.182,183,184,185 (See Cautions: Hepatic Effects and see also Cautions: Precautions and Contraindications.)
Fertility
The effect of valproic acid on the development of the testes and on sperm production and fertility in humans is not known. Chronic toxicity studies in rats and dogs demonstrated reduced spermatogenesis and testicular atrophy. Further animal studies are ongoing.
Lactation
Valproic acid is distributed into milk; caution is advised when administering the drug to nursing women.182,183,184,185
Drug Interactions ⬆ ⬇
Drugs Affecting Hepatic Microsomal Enzymes
Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate the levels of glucuronyltransferases, may increase valproic acid clearance.182 Carbamazepine, phenobarbital (or primidone), or phenytoin can double the clearance of valproic acid.182 Therefore, patients receiving valproic acid monotherapy generally will have longer elimination half-lives and higher plasma concentrations than patients who are concurrently receiving more than one anticonvulsant.182 (See Drug Interactions: CNS Depressants, Antidepressants, and Anticonvulsants.)
Drugs that inhibit cytochrome P450 (CYP450) isoenzymes, including some antidepressants, are unlikely to substantially affect valproic acid clearance because CYP450-mediated oxidation is a relatively minor secondary metabolic pathway compared with glucuronidation and β-oxidation.182 (See Drug Interactions: CNS Depressants, Antidepressants, and Anticonvulsants.)
Because of possible alterations in clearance of valproate, increased monitoring of plasma valproic acid concentrations and concomitant drug concentrations is recommended whenever enzyme-inducing drugs are introduced or withdrawn in valproic acid-treated patients.182
CNS Depressants, Antidepressants, and Anticonvulsants
Additive CNS depression may occur when valproic acid is administered concomitantly with other CNS depressants including other anticonvulsants (particularly phenobarbital and primidone) and alcohol. If valproic acid is used in conjunction with other CNS depressant drugs including alcohol, caution should be used to avoid overdosage.
Valproic acid displaces diazepam from its albumin binding sites and also inhibits its metabolism. In a study in a limited number of healthy individuals, coadministration of valproic acid (1.5 g daily) increased the free fraction of diazepam (10 mg) by 90%; plasma clearance and volume of distribution of free diazepam were decreased by 25% and 20%, respectively. The elimination half-life of diazepam was unaffected by concomitant valproic acid administration.
Concomitant use of amitriptyline (a single 50-mg oral dose) and valproic acid (500 mg twice daily) resulted in a 21% decrease in the plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline (the pharmacologically active metabolite of amitriptyline).179,182,183 In addition, increased amitriptyline concentrations have been reported rarely in patients receiving amitriptyline concomitantly with valproic acid; concomitant use has rarely been associated with toxicity.179,182,183 The manufacturers state that monitoring of amitriptyline concentrations should be considered for patients receiving valproic acid concomitantly with amitriptyline/nortriptyline.179,182,183
Because valproic acid may potentiate the effects of monoamine oxidase inhibitors and other antidepressants, dosage reduction of these drugs may be necessary if valproic acid is administered to patients receiving antidepressants.
Valproic acid inhibits the metabolism of ethosuximide. Administration of a single 500-mg dose of ethosuximide to a limited number of healthy individuals receiving valproic acid (800-1600 mg daily) resulted in a 25% increase in ethosuximide elimination half-life and a 15% decrease in total ethosuximide clearance when compared with ethosuximide administration alone. Patients receiving concomitant valproic acid and ethosuximide therapy, especially if receiving other concomitant anticonvulsant therapy, should have their serum drug concentrations monitored carefully.
Concomitant administration of valproic acid with felbamate (1.2 g daily) in a limited number of patients with epilepsy resulted in a 35% increase in mean peak serum valproic acid concentration, from 86 to 115 mcg/mL when compared with administration of valproic acid alone. Increasing the felbamate dose to 2.4 g daily resulted in another 16% increase in mean peak valproic acid concentration to 133 mcg/mL. A decrease in valproic acid dosage may be required when initiating concomitant felbamate therapy.
Valproic acid inhibits lamotrigine metabolism. In a steady-state study in healthy individuals, the elimination half-life of lamotrigine increased from 26 to 70 hours when concomitant valproic acid was administered. Serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) also have been reported following concomitant use of lamotrigine and valproic acid.182,183,184,185 Lamotrigine dosage should be decreased when valproic acid therapy is initiated. For detailed information on dosing lamotrigine during concurrent valproic acid therapy, see Dosage and Administration: Dosage, in Lamotrigine 28:12.92.
Concomitant administration of valproic acid and phenobarbital (or primidone which is metabolized to phenobarbital) can result in increased phenobarbital plasma concentrations and excessive somnolence. This combination can produce CNS depression (possibly severe) even without substantial increases in serum concentrations of either drug. A few patients have become comatose during therapy with valproic acid and phenobarbital. In a study of concomitant valproic acid (250 mg twice daily for 14 days) and single-dose phenobarbital (60 mg) administration in a limited number of healthy individuals, a 50% increase in phenobarbital half-life, a 30% decrease in phenobarbital clearance, and a 50% increase in unchanged phenobarbital excreted in the urine were observed. If valproic acid is used with a barbiturate, the patient should be closely observed for possible neurologic toxicity, plasma concentrations of the barbiturate should be monitored if possible, and the dosage of the barbiturate decreased if necessary.
Serum concentrations of carbamazepine have been reported to decrease by 17% and concentrations of the metabolite carbamazepine-10,11-epoxide have been reported to increase by 45% during concomitant therapy with valproic acid; such interaction may result in carbamazepine CNS toxicity (e.g., acute psychotic reaction). In addition, carbamazepine has been reported to decrease plasma valproic acid concentrations by altering its clearance during concomitant therapy, which may be clinically important. Discontinuance of carbamazepine following concomitant carbamazepine/valproic acid therapy has been reported to result in increased valproic acid concentrations. If concomitant therapy is being undertaken, or if a patient currently is receiving concomitant carbamazepine/valproic acid therapy and one agent is to be discontinued, careful therapeutic drug monitoring should be considered.
Concomitant administration of valproic acid and clonazepam has produced absence status; therefore, some clinicians recommend that concomitant use of these drugs be avoided.
Concomitant administration of valproic acid and lorazepam in healthy males decreased plasma lorazepam clearance by 17%; however, this pharmacokinetic interaction is unlikely to be clinically important.182,183,184,185
Concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with or without encephalopathy in patients who have previously tolerated either drug alone.182,183,184,185 In most cases, manifestations resolved with discontinuance of either drug.182,183,184,185 It is not known if topiramate monotherapy is associated with hyperammonemia.182,183,184,185 Although not studied, the interaction between valproic acid and topiramate may exacerbate existing defects or unmask deficiencies in susceptible patients.182,183,184,185 (See Cautions: Endocrine and Metabolic Effects and see also Cautions: Precautions and Contraindications.)
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 intoxication. Therefore, it is 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 required. Since valproic acid also may interact with other anticonvulsants, it is advisable to monitor plasma concentrations of concomitantly administered anticonvulsants during initial valproic acid therapy.
Concomitant use of valproate and cannabidiol may increase the risk of hepatic enzyme elevations.300 Dosage reduction or discontinuance of cannabidiol and/or valproate should be considered if hepatic enzyme elevations occur.300 In healthy individuals, cannabidiol did not have any effect on systemic exposure of valproate.300
Anti-infective Agents
Acyclovir
In a child receiving both phenytoin and valproic acid, short-term oral therapy with acyclovir apparently reduced the plasma concentrations of both anticonvulsant agents to subtherapeutic levels; an increase in seizure frequency and a worsening in the EEG were observed. Although further study is needed to confirm the effects of acyclovir on the pharmacokinetics of anticonvulsant agents, such concomitant therapy should be undertaken with caution.
Antiretroviral Agents
Concomitant use of valproic acid (250 or 500 mg every 8 hours) and oral zidovudine (100 mg every 8 hours) for 4 days in a limited number of adults with human immunodeficiency virus (HIV) infection resulted in an 80% increase in the area under the concentration-time curve (AUC) of zidovudine.149 The effect of concomitant zidovudine on the pharmacokinetics of valproic acid was not evaluated.149 Although the clinical importance of this interaction between zidovudine and valproic acid is not known, patients receiving both drugs should be monitored more closely for zidovudine-related adverse effects.149 Severe anemia has been reported following initiation of valproic acid therapy (500 mg twice daily) in an HIV-infected adult who was receiving an antiretroviral regimen that contained zidovudine, lamivudine, and abacavir; the patient had stable hematologic status at the time valproic acid was started.152 The manufacturer of zidovudine states that a reduction in zidovudine dosage may be considered if a patient experiences substantial anemia or other severe adverse effect while receiving zidovudine concomitantly with valproic acid.149
Hepatotoxicity was reported in an HIV-infected adult receiving valproic acid concomitantly with an antiretroviral regimen containing ritonavir, saquinavir, stavudine, and nevirapine.154 It has been suggested that this may have occurred as the result of a pharmacokinetic interaction between valproic acid and ritonavir and/or nevirapine.154
Concomitant use of efavirenz and valproic acid in HIV-infected adults does not appear to affect the pharmacokinetics of either drug.153
Concomitant use of the fixed combination of lopinavir and ritonavir with valproic acid may result in slightly increased lopinavir concentrations, but does not affect valproic acid concentrations.153 It has been suggested that this pharmacokinetic interaction is not clinically important.153
Carbapenem Antibiotics
Carbapenem antibiotics (e.g., ertapenem, imipenem, meropenem) may reduce plasma valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control.179,182,183,184,185,186,187 The mechanism of this interaction is not fully understood, but may involve a combination of factors affecting the absorption, distribution, and metabolism of valproic acid.182,183,184,185,186
Concomitant use of valproic acid with a carbapenem antibiotic should generally be avoided, if possible.186,187 If concomitant therapy is necessary, plasma valproic acid concentrations should be monitored frequently after the carbapenem antibiotic is initiated or discontinued;182,183,184,185 more frequent monitoring during concurrent therapy also is recommended by some clinicians.186 Alternative anti-infective or anticonvulsant therapy should be considered if plasma valproic acid concentrations decrease substantially or seizure control deteriorates.182,183,184,185,187
Rifampin
A study of administration of a single dose of valproic acid (7 mg/kg) given 36 hours after short-term rifampin administration (600 mg daily for 5 days) revealed a 40% increase in the clearance of valproic acid. Valproic acid dosage adjustment may be required when rifampin therapy is initiated.
Other Drugs
Since valproic acid may affect bleeding time (see Cautions: Hematologic Effects), it should be administered with caution in patients receiving drugs which affect coagulation such as aspirin or warfarin. In addition, valproic acid potentially may displace warfarin from its plasma albumin binding sites. Although the clinical relevance of this interaction is unknown, coagulation tests should be monitored if concomitant valproic acid and anticoagulant therapy is undertaken.
In a study of a limited number of pediatric patients receiving valproic acid and antipyretic aspirin therapy (11-16 mg/kg), a decrease in valproic acid protein binding and metabolism was observed. Free valproic acid concentration increased fourfold, compared with valproic acid therapy alone. The oxidative metabolic pathway of valproic acid was inhibited, resulting in a decrease in excretion of valproic acid metabolites, from 25% to 8.3% of total metabolites excreted. Concomitant aspirin and valproic acid therapy should be instituted with caution.
In vitro studies demonstrated that addition of tolbutamide to plasma samples of patients receiving valproic acid therapy resulted in an increase in the unbound tolbutamide fraction from 20% to 50%. The clinical importance of this displacement is unknown.
Limited pharmacokinetic studies reveal either no interaction or a clinically unimportant interaction following concomitant administration of valproic acid with the following drugs: antacids, chlorpromazine, haloperidol, H2-receptor antagonists (i.e., ranitidine, cimetidine), acetaminophen, clozapine, lithium, or oral contraceptives.182,183,184,185
Other Information ⬆ ⬇
Laboratory Test Interferences
Tests for Urinary Ketones
A ketone metabolite in the urine of patients receiving valproic acid may produce false-positive results for urine ketones.
Tests for Thyroid Function
Valproic acid reportedly alters thyroid function test results, but the clinical importance of this effect is not known.
Acute Toxicity
Manifestations
Overdosage of valproic acid may produce somnolence, heart block, or deep coma. One adult who ingested 36 g of valproic acid (as valproate sodium) in addition to 1 g of phenobarbital and 300 mg of phenytoin experienced deep coma 4 hours after ingestion of the drugs. The patient recovered following supportive therapy. Fatalities have been reported following valproic acid overdosa however, patients have recovered from serum valproic acid concentrations as high as 2.12 mg/mL.
Treatment
Treatment of valproic acid intoxication consists of general supportive therapy, particularly maintenance of adequate urinary output. Because the drug is rapidly absorbed, gastric lavage may be of limited value; since absorption of divalproex sodium delayed-release tablets is delayed, the value of gastric lavage or emesis will vary with time since ingestion if this form of the drug has been ingested. In overdose situations, the free or unbound serum valproic acid concentration is high. Hemodialysis or tandem hemodialysis with hemoperfusion may result in significant removal of drug. Naloxone has been reported to reverse the CNS depressant effects of valproic acid overdosa however, naloxone should be used with caution since it could also theoretically reverse the anticonvulsant effects of valproic acid.
Pharmacology
Anticonvulsant Effects
The mechanism of the anticonvulsant effects of valproic acid is not known. Effects of the drug may be related, at least in part, to increased brain concentrations of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Animal studies have shown that valproic acid inhibits GABA transferase and succinic aldehyde dehydrogenase, enzymes which are important for GABA catabolism. Results of one study indicate the drug inhibits neuronal activity by increasing potassium conductance. In animals, valproic acid protects against seizures induced by electrical stimulation as well as those induced by pentylenetetrazol.
Antiviral Effects
Valproic acid inhibits histone deacetylase 1 (HDAC1) (an enzyme that maintains latency of human immunodeficiency virus [HIV] in resting CD4+ T-cells) and induces HIV expression from resting CD4+ T-cells ex vivo.150,151 It has been suggested that this effect may be useful in depleting latent infection in resting CD4+ T-cells in HIV-infected patients.150 Although highly active antiretroviral therapy (HAART) suppresses plasma HIV-1 RNA levels and restores immune function, the presence of replication-competent provirus in resting CD4+ T-cells and persistent HIV replication prevents HAART from eradicating HIV infection.150 Efficacy of valproic acid in depleting HIV from resting CD4+ T-cells has been evaluated in a small proof-of-concept pilot study in 4 HIV-infected adults (plasma HIV-1 RNA levels less than 50 copies/mL for at least 2 years) receiving HAART.150,151 Enfuvirtide was added to the HAART regimens (to prevent the spread of virus in the presence of valproic acid) and, after 4-6 weeks of this intensified regimen, valproic acid (500-750 mg twice daily) was added.150 After 16-18 weeks of combined valproic acid and enfuvirtide-intensified HAART, there was a substantial decline in the frequency of replication-competent HIV in circulating resting CD4+ T-cells.150 These preliminary findings suggest that use of valproic acid with HAART and enfuvirtide may represent a new therapeutic approach that possibly represents a step toward the elimination of HIV infection in resting CD4+ T-cells and eventual cure of HIV infection.150,151 However, it is unclear whether latently infected CD4+ T-cells are the only reservoir for HIV, and larger, controlled studies are needed to investigate the possible benefits of valproic acid in HIV-infected patients.155
Pharmacokinetics
Absorption
Oral Administration
Following oral administration, valproate sodium is rapidly converted to valproic acid in the stomach. Valproic acid is rapidly and almost completely absorbed from the GI tract. Absorption of the drug 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. Following oral administration of divalproex sodium extended-release tablets, divalproex sodium dissociates into valproic acid in the GI tract.182 Following oral administration of divalproex sodium delayed-release tablets and passage of the tablets into the upper small intestine, divalproex sodium dissociates into valproic acid, which is then absorbed; because of the enteric coating, absorption is delayed compared with that following oral administration of valproic acid capsules or valproate sodium solution.
The bioavailability of valproate from divalproex sodium delayed-release tablets and capsules containing coated particles has been shown to be equivalent to that of valproic acid capsules. The absolute bioavailability of divalproex sodium extended-release tablets following oral administration of a single dose after a meal is about 90%.182 The manufacturer states that divalproex sodium extended-release tablets and delayed-release tablets are not bioequivalent.182 Results of 5 multiple-dose studies in healthy individuals and in patients with epilepsy indicate that divalproex sodium extended-release tablets (administered either in the fasting or nonfasting state) have an average bioavailability of 89% relative to an equal, total daily dose of divalproex sodium delayed-release tablets given 2-4 times daily.182 Administration of divalproex sodium with food would be expected to slow absorption but not affect the extent of absorption.
Peak plasma concentrations of valproic acid are usually attained 1-4 hours following a single oral dose of the acid or the sodium salt, 3-5 hours following a single oral dose of divalproex sodium, and 7-14 hours following oral administration of multiple doses of divalproex sodium extended-release tablets. There is wide interindividual variation in plasma concentrations of the drug with a specific dose. Results of a multiple-dose study indicate that following oral administration of divalproex sodium extended-release tablets once daily average plasma concentrations of the drug are 10-20% lower than those achieved with twice-daily administration of divalproex sodium delayed-release tablets.182 Plasma concentrations of valproic acid required for therapeutic or toxic effects have not been definitely established. Some reports indicate that therapeutic plasma concentrations may be 50-100 mcg/mL of total (bound and unbound) valproic acid and that concentrations in this range are maintained in most adults receiving 1.2-1.5 g of valproic acid daily. However, the possibility that some patients may be controlled with lower or higher plasma concentrations and that the free fraction of valproic acid increases with increasing dosage should be considered. (See Pharmacokinetics: Distribution.) The onset of therapeutic effects is several days to more than one week following initiation of valproic acid therapy.
The relationship between dose and total valproic acid concentration is nonlinear; concentration does not increase proportionally with dose, because of saturable protein binding. The pharmacokinetics of unbound drug are linear.
Parenteral Administration
Equivalent valproic acid dosages as the IV injection (available as valproate sodium), administered over 1 hour, or various conventional or delayed-release oral formulations (available as valproate sodium or divalproex sodium) are expected to result in equivalent peak and trough plasma concentrations and total systemic exposure to the valproic acid. Although the rate of valproic acid absorption may vary with the specific formulation, any such differences should be of minor clinical importance under steady-state conditions achieved with chronic therapy for seizure disorders.
When oral divalproex sodium delayed-release tablets or IV valproate sodium (as a 1-hour infusion) was administered at a dosage of 250 mg of valproic acid every 6 hours for 4 days in healthy males, the resulting area under the plasma concentration-time curves (AUCs) and peak and trough plasma concentrations of the drug were equivalent at steady state as well as after the initial dose. However, the time to reach peak plasma concentrations was delayed with the tablets, occurring at approximately 4 hours after an oral dose versus at the end of the 1-hour infusion with the IV dose. Because the pharmacokinetics of unbound valproic acid are linear, bioequivalence between IV valproate sodium and oral delayed-release divalproex sodium can be expected up to maximum dosages of 60 mg/kg daily. The AUCs and peak plasma concentrations also were equivalent in healthy males receiving single 500-mg doses as the IV injection (infused over 1 hour) or valproate sodium oral solution. In addition, patients maintained on valproic acid dosages of 750-4250 mg daily (given in divided doses every 6 hours) as oral delayed-release divalproex sodium tablets alone or while stabilized on another anticonvulsant (e.g., carbamazepine, phenytoin, or phenobarbital) exhibited comparable plasma concentrations when switched from oral divalproex sodium to IV valproate sodium (as 1-hour infusions).
When valproate sodium (at a dosage of 1 g of valproic acid) was administered IV over 5, 10, 30, and 60 minutes in healthy individuals, peak plasma concentrations of the drug averaged 145 mcg/mL after the 5-minute infusion compared with 115 mcg/mL after the 60-minute infusion. However, plasma concentrations measured at 90-120 minutes after initiation of the valproate sodium infusions were similar for the 4 rates of infusion.
Distribution
Valproic acid is rapidly distributed; distribution appears to be restricted to plasma and rapidly exchangeable extracellular water. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m2, respectively. Valproic acid has been detected in CSF (approximately 10% of serum concentrations), saliva (about 1% of plasma concentrations), and milk (about 1-10% of plasma concentrations). The drug crosses the placenta.
Plasma protein binding of valproic acid is concentration dependent; the free fraction of drug increases from 10% at a concentration of 40 mcg/mL to 18.5% at a concentration of 130 mcg/mL. Protein binding of valproic acid is decreased in geriatric patients, in patients with renal impairment or hepatic disease, or in the presence of other protein-bound drugs. Conversely, valproic acid may displace other drugs from protein binding sites. Because of decreased protein binding of the drug in special patient populations (i.e., patients with renal or hepatic disease), monitoring of total drug concentrations may be misleading, owing to the increased free fraction of valproic acid.
Elimination
Valproic acid is eliminated by first-order kinetics and reportedly has an elimination half-life of 5-20 hours (average 10.6 hours). Elimination half-lives in the lower portion of the range are usually observed in patients receiving other anticonvulsants concomitantly. Half-lives of up to 30 hours have been reported following overdosage of valproate sodium.
Mean plasma clearance of total or free valproic acid is 0.56 or 4.6 L/hour per 1.73 m2, respectively. Drug clearance may be decreased in special patient populations (e.g., patients with renal failure, geriatric patients). Because hemodialysis typically reduces plasma valproic acid concentration by about 20%, generally there is no dosage adjustment required in patients with renal failure (i.e., creatinine clearance less than 10 mL/min). Geriatric patients should receive lower initial dosages of the drug. (See Dosage and Administration: Dosage.)
Pediatric patients (i.e., age range 3 months to 10 years) have 50% higher clearance of the drug expressed by weight (i.e., mL/minute per kg); over the age of 10 years, pharmacokinetic parameters of valproic acid approximate those in adults. Neonates (i.e., younger than 2 months) have a markedly decreased clearance of valproic acid compared with older children and adults, possibly because of delayed development of metabolic enzyme systems and an increased volume of distribution. In one study, the elimination half-life in children younger than 10 days old ranged from 10-67 hours, compared with 7-13 hours in children older than 2 months.
Valproic acid is metabolized principally in the liver by beta (over 40%) and omega oxidation (up to 15-20%). Valproic acid metabolites are excreted in urine; 30-50% of an administered dose is excreted as glucuronide conjugates. Less than 3% of an administered dose is excreted in urine unchanged. The major metabolite in urine is 2-propyl-3-ketopentanoic acid; minor urinary metabolites are 2-propylglutaric acid, 2-propyl-5-hydroxypentanoic acid, 2-propyl-3-hydroxypentanoic acid, and 2-propyl-4-hydroxypentanoic acid. Small amounts of the drug are also excreted in feces and in expired air. Results of studies in rats suggest the drug may undergo enterohepatic circulation.
Liver disease impairs the ability to eliminate valproic acid. In one study, the clearance of free valproic acid was decreased by 50% in a limited number of patients with cirrhosis and by 16% in a limited number of patients with acute hepatitis, compared with healthy individuals. Half-life of valproic acid was increased from 12 to 18 hours.
Chemistry and Stability
Chemistry
Valproic acid, valproate sodium, and divalproex sodium are carboxylic acid-derivative anticonvulsants. Valproic acid is structurally unrelated to other commercially available anticonvulsants; it lacks nitrogen and/or an aromatic moiety found in most anticonvulsants. Divalproex sodium is a stable coordination compound consisting of valproic acid and valproate sodium in a 1:1 molar ratio and is formed during partial neutralization of valproic acid with sodium hydroxide. Divalproex sodium is a prodrug of valproate, dissociating into valproate in the GI tract.
Valproic Acid
Valproic acid occurs as a colorless to pale yellow, slightly viscous, clear liquid with a characteristic odor and is slightly soluble in water and freely soluble in alcohol. Valproic acid has a pKa of 4.8.
Valproate Sodium
Valproate sodium occurs as a white, crystalline, very hygroscopic powder with a saline taste and is very soluble in water and in alcohol.
Valproate sodium injection is a sterile solution of the drug in water for injection. The injection occurs as a clear, colorless solution; sodium hydroxide and/or hydrochloric acid may be added to adjust the pH to 7.6.
Divalproex Sodium
Divalproex sodium occurs as a white powder with a characteristic odor and is insoluble in water and very soluble in alcohol.
Stability
Valproic Acid
USP recommends that valproic acid capsules be stored in tight containers at 15-30°C; however, the manufacturer of Depakene® recommends that the capsules be stored in tight containers at 15-25°C.
Valproate Sodium
Valproate sodium oral solution has a pH of 7-8. Valproate sodium oral solution should be stored in tight containers at a temperature less than 30°C; freezing should be avoided.
Valproate sodium injection should be stored at a controlled room temperature of 15-30°C. Because the injection does not contain a preservative, unused portions of the solution should be discarded. When stored in glass or PVC containers at 15-30°C, valproate sodium 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.
Divalproex Sodium
Divalproex sodium delayed-release tablets should be stored at a temperature less than 30°C; divalproex sodium capsules containing coated particles should be stored at a temperature less than 25°C.179,183 Divalproex sodium extended-release tablets should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.182
Additional Information
For further information on uses and dosage and administration of valproic acid, see the Anticonvulsants General Statement 28:12. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Valproate Sodium
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Oral | Solution | 250 mg (of valproic acid) per 5 mL* | Valproate Sodium Oral Solution | |
Parenteral | Injection, for IV use | 100 mg (of valproic acid) per mL* | 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 | 250 mg* | 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 Capsules | 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 | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
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