Divalproex Sodium

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

Special Alerts:

[Posted 06/30/2011] ISSUE: FDA notified healthcare professionals that children born to mothers who take the anti-seizure medication valproate sodium (Depacon) or related products [valproic acid (Depakene and Stavzor) and divalproex sodium (Depakote, Depakote CP, and Depakote ER)] during pregnancy have an increased risk of lower cognitive test scores than children exposed to other anti-seizure medications during pregnancy. This conclusion is based on the results of epidemiologic studies that show that children born to mothers who took valproate sodium or related products throughout their pregnancy tend to score lower on cognitive tests (IQ and other tests) than children born to mothers who took other anti-seizure medications during pregnancy. See the Drug Safety Communication for a data summary and additional information.

BACKGROUND: Valproate products are FDA-approved drugs to treat seizures, and manic or mixed episodes associated with bipolar disorder (manic-depressive disorder), and to prevent migraine headaches. They are also used off-label (for unapproved uses) for other conditions, particularly for other psychiatric conditions.

RECOMMENDATION: Healthcare professionals should inform women of childbearing age of the increased risk for adverse effects on cognitive development with prenatal valproate exposure, and should continue to counsel women of childbearing potential taking valproate about the increased risk of major malformations, including neural tube defects, when valproate is used during pregnancy. In addition, healthcare professionals should weigh the benefits and risks of valproate when prescribing this drug to women of childbearing age, particularly when treating a condition not usually associated with permanent injury or death. Alternative medications that have a lower risk of adverse birth outcomes should be considered. Patients should not stop taking valproate without talking to a healthcare professional. For more information visit the FDA website at: and .

• Hepatotoxicity


• 
  

  Potentially fatal hepatic failure can occur.^{182 183 184 185}

  
  


• 
  

  Usually occurs during the initial 6 months of therapy.^{182 183 184 185}

  
  


• 
  

  Children <2 years of age are at considerably increased risk of developing fatal hepatotoxicity, especially those receiving multiple anticonvulsants and those with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease.^{182 183 184 185}

  
  


• 
  

  Use with extreme caution in such children and only as single-agent therapy; weigh carefully benefits versus risks.^{182 183 184 185}

  
  


• 
  

  Above this age group, experience in epilepsy indicates that the risk of fatal hepatotoxicity decreases considerably in progressively older patient groups.^{182 183 184 185}

  
  


• 
  

  Serious fatal hepatotoxicity may be preceded by 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 its development.^{182 183 184 185}

  
  


• 
  

  Monitor patients closely for development of any such changes.^{182 183 184 185}

  
  


• 
  

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

  
  

• Fetal/Neonatal Morbidity and Mortality


• 
  

  Can produce teratogenic effects (e.g., neural tube defects such as spinal bifida).^{182 183 184 185 188 189 190 191 192 193 194}

  
  


• 
  

  Use in women of childbearing potential requires that potential benefits of therapy be weighed against the risk of fetal injury.^{182 183 184 185} This is particularly important when contemplating treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine).^{182 183 184 185} (See Pregnancy under Cautions.)

  
  


• 
  

  An information sheet (medication guide) describing the teratogenic potential of valproic acid is available for patients.^{183 188} (See Advice to Patients.)

  
  

• Pancreatitis


• 
  

  Life-threatening pancreatitis has occurred both in children and adults.^{179 182 183 184 185}

  
  


• 
  

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

  
  


• 
  

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

  
  


• 
  

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

  
  


• 
  

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

  
  

Introduction

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

Uses for Divalproex Sodium

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Absence (Petit Mal) Seizures

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

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

Complex Partial Seizures

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

Generalized Seizures

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

Simple Partial Seizures

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

Status Epilepticus

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

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

Bipolar Disorder

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

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

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

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

Migraine

Prophylaxis of migraine headache, with or without associated aura.^{170 b}

Because valproic acid poses a hazard to the fetus (see Boxed Warning and also see Pregnancy under Cautions), it should be considered for use in women of childbearing potential only after this risk has been discussed thoroughly with the patient, and weighed against the potential benefits of treatment.^{182 183 184 185 b} Consider alternative therapies in such patients.¹⁸⁸

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

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

Schizophrenia

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

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

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

Divalproex Sodium Dosage and Administration

General

Anticonvulsants, including valproic acid, should not be discontinued abruptly in patients receiving the drug(s) for seizure disorders; withdraw gradually to minimize the potential for increased seizure frequency.^{182 183 184}

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

Distribute medication guide explaining risks and benefits of therapy to patients receiving valproic acid.¹⁸⁸

Administration

Valproate sodium can be administered orally or by IV infusion; valproic acid and divalproex sodium are administered orally.^{182 183 184 185 b}

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

Oral Administration

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

Valproic acid capsules should be swallowed whole, not chewed, in order to prevent local irritation to the mouth and throat.^{184 b} If GI irritation occurs, may administer valproic acid with food or gradually increase dosage from an initial low dosage.^{179 182 183 184 b}

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

Extended-release tablets of divalproex sodium are administered once daily; advise patients that the tablets must be swallowed intact and not chewed or crushed.¹²⁷

Do not administer valproate sodium oral solution in carbonated beverages.^b

The commercially available capsules containing coated particles of divalproex sodium (Depakote) may be swallowed intact or the entire contents of capsule(s) may be sprinkled on a small amount (about 5 mL) of semisolid food (e.g., applesauce, pudding) immediately prior to administration.^b

The mixture containing coated particles from the capsules should not be chewed or stored for future use.^b

Although the extent of GI absorption of valproic acid from capsules containing coated particles or delayed-release tablets of divalproex sodium is equivalent, peak and trough plasma concentrations achieved may vary (e.g., higher peak valproic acid concentrations generally are achieved with the delayed-release tablets); increased monitoring of plasma valproic acid concentrations is recommended if one dosage form is substituted for the other.^b Divalproex sodium extended-release tablets are not bioequivalent to the delayed-release tablets.¹²⁷

IV Administration

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

Valproate sodium injection is intended for IV use only.^{185 b}

Dilution

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

Rate of Administration

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

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

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

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

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

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

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

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

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

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

To minimize adverse GI effects, give dosages >250 mg daily in 2 or more divided doses.^b

When 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.^b

When extended-release tablets are administered, a once-daily dosing regimen is used.¹⁸²

If a patient misses a dose of extended-release tablets, take the dose as soon as possible, unless it is almost time for the next dose.¹²⁷ If the patient skips a dose, do not take a double dose of extended-release tablets to make up for the missed dose.¹²⁷

When switching to divalproex sodium delayed-release tablets in patients receiving valproic acid, the same daily dose and schedule should be used.^b

After stabilization with divalproex sodium therapy, the daily dose may be divided and administered 2 or 3 times daily in selected patients.^b

Pediatric Patients

Consider increased risk of fatal hepatotoxicity in children <2 years of age.^{182 183 184 185} (See Hepatotoxicity in Boxed Warning.)

Neonates: Ability to eliminate valproic acid is markedly reduced.¹⁸³ (See Neonates under Dosage and Administration.)

Children 3 months to 10 years of age: Consider the possibility that the 50% increased clearance (on a proportionate weight basis) relative to older children and adults may affect dosage.¹⁸³

Children >10 years of age and adolescents: Pharmacokinetic parameters approximate those of adults.¹⁸³

Seizure Disorders

Complex Partial Seizures (Monotherapy and Adjunctive Therapy)

Oral (conventional, delayed-, and extended-release preparations)

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

Initial dosage: 10–15 mg/kg daily.^{179 182 183 184 b}

Increase valproic acid dosage by 5–10 mg/kg daily at weekly intervals, usually up to the maximum recommended dosage of 60 mg/kg daily, according to response and tolerability.^{179 182 183 184 b}

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

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

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

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.^b

IV

IV therapy may be employed in patients in whom oral therapy temporarily is not feasible, but therapy should be switched to oral administration as soon as clinically possible.^{185 b}

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

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

Daily dosages >250 mg should be administered in divided doses.¹⁸⁵

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

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

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

Simple or Complex Absence Seizures

Oral (conventional, delayed-, and extended-release preparations)

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

Initial dosage: 15 mg/kg daily.^{179 182 183 184 b}

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

IV

IV therapy may be employed in patients in whom oral therapy temporarily is not feasible, but therapy should be switched to oral administration as soon as clinically possible.^{185 b}

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

Daily dosages >250 mg should be administered in divided doses.¹⁸⁵

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

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

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

Adults

Seizure Disorders

Complex Partial Seizures

Oral (conventional, delayed-, and extended-release preparations)

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

Initial dosage: 10–15 mg/kg daily.^{183 184 b}

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

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

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

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

IV

IV therapy may be employed in patients in whom oral therapy temporarily is not feasible, but therapy should be switched to oral administration as soon as clinically possible.^{185 b}

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

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

Daily dosages >250 mg should be administered in divided doses.¹⁸⁵

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

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

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

Simple or Complex Absence Seizures

Oral (conventional, delayed-, and extended-release preparations)

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

Initial dosage: 15 mg/kg daily.^{183 184 b}

Increase dosage by 5–10 mg/kg daily at weekly intervals, usually up to 60 mg/kg daily according to response and tolerability.^{183 184 b}

IV

IV therapy may be employed in patients in whom oral therapy temporarily is not feasible, but therapy should be switched to oral administration as soon as clinically possible.^{185 b}

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

Daily dosages >250 mg should be administered in divided doses.¹⁸⁵

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

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

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

Seizure Disorders

Conversion from Delayed-release (Depakote) to Extended-release (Depakote ER) Tablets

Oral

When converting a patient whose seizure disorder is controlled with delayed-release tablets (Depakote) to the extended-release tablets (Depakote ER), give the drug once daily using a total daily dose that is 8–20% higher than the corresponding delayed-release dosage that the patient was receiving.^{182 b}

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

Refractory Status Epilepticus

Rectally†

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

Bipolar Disorder

Manic or Mixed Episodes

Oral

Initially, 750 mg daily in divided doses as delayed-release tablets (Depakote) or 25 mg/kg once daily as extended-release tablets (Depakote ER) for acute episodes.^{182 183 b}

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

Usually dosed to clinical response with trough plasma concentrations of 50–125 mcg/mL.^{182 183}

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

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

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

Migraine Prophylaxis

With or without Aura

Oral

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

Maintenance: After 1 week at the initial dosage of extended-release tablets, may increase dosage to 1 g daily.¹⁸² May increase dosage of delayed-release tablets up to 1 g daily.¹⁸³ No evidence of additional benefit with higher dosages.^{183 b}

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

Schizophrenia†

Oral

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

Prescribing Limits

Pediatric Patients

Seizure Disorders

Oral

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

Adults

Seizure Disorders

Oral

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

Bipolar Disorder

Manic or Mixed Episodes

Oral

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

Migraine Prophylaxis

With or without Aura

Oral

Maximum recommended dosage is 1 g daily.^{182 183 b}

Special Populations

Hepatic Impairment

Decreased clearance.^{183 185}

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

Should not be used in patients with hepatic disease or significant hepatic dysfunction.^{182 183 184 185} (See Contraindications under Cautions.)

Renal Impairment

Slightly decreased (by 27%) clearance of unbound (active) drug in patients with renal failure.^{183 184} Hemodialysis usually reduces valproic acid concentrations by about 20%.^{183 184}

Dosage adjustment does not appear necessary.^{183 184}

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

Neonates

Markedly decreased ability to eliminate the drug in patients ≤2 months of age.¹⁸³

Consider increased risk of fatal hepatotoxicity in children <2 years of age.^{182 183} (See Hepatotoxicity in Boxed Warning.)

Geriatric Patients

Starting dosage should be reduced because of a decrease in clearance of unbound valproic acid; subsequent dosage should be increased more slowly in geriatric patients.^{182 183 184 185}

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

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

Gender

No dosage adjustment necessary based solely on gender.¹⁸³

Race

Potential effects not studied.¹⁸³

Cautions for Divalproex Sodium

Contraindications

• 
  

  Should not be administered to patients with hepatic disease or significant hepatic dysfunction.^{182 183 184 185}

  
  


• 
  

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

  
  


• 
  

  Known urea cycle disorders.^{182 183 184 185} (See Urea Cycle Disorders [UCD] under Cautions.)

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Hepatotoxicity

May cause serious and potentially fatal hepatotoxicity.^{182 183 184 185} (See Hepatotoxicity in Boxed Warning.)

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

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

Pancreatitis

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

Urea Cycle Disorders (UCD)

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

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

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

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

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

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

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

Fetal/Neonatal Morbidity and Mortality

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Can produce teratogenic effects (e.g., neural tube defects such as spinal bifida).^{182 183 184 185}