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Sodium Valproate

Sodium Valproate
21.Jan.2021-Expires: 7 days - Do not archive

DESCRIPTION

SUBSTANCE NAME

Sodium Valproate
 

SUBSTANCE CLASS

Antiepileptic
 
Carboxylic Acid Derivative
 
Antipsychotic
 

INTERVENTION CRITERIA

Intervention Level

Acute

Child and Adult

Medical assessment and observation at an emergency department is recommended for:
- Ingestions greater than 50 mg/kg
- Symptomatic cases
- Exposures with intent to self-harm
 
Decontamination, if appropriate, and medical observation at an emergency department is recommended for:
- Ingestions greater than 100 mg/kg
 

Acute On Chronic

Medical assessment and observation at an emergency department is recommended for:
- Ingestions 50 mg/kg greater than the patients usual single therapeutic dose
- Symptomatic cases
- Exposures with intent to self-harm
 
Decontamination, if appropriate, and medical observation at an emergency department is recommended for:
- Ingestions 100 mg/kg greater than the patients usual single therapeutic dose is ingested
 

Chronic

Medical assessment and observation is recommended for:
 - Any symptomatic chronic ingestion
 

Observation Period

Observation at Home

If the patient does not require medical observation they can be monitored at home for 12 hours in the care of a reliable observer.
 
The patient should be medically assessed if any symptoms develop, including:
Vomiting
Lethargy/drowsiness
Confusion
Agitation
Tremor
Ataxia
Racing heart
 

Medical Observation

If the patient’s ingested dose is above the intervention criteria:
- Observe for development of symptoms for a minimum period of 6 hours when a standard-release preparation has been ingested
- Observe for development of symptoms for a minimum period of 12 hours when an enteric-coated or sustained-release preparation has been ingested
 
If the patient remains asymptomatic throughout the observation period, and any necessary decontamination and investigations have been carried out, they may be:
Discharged into the care of a reliable observer, or
Referred for psychological assessment if the overdose or exposure was with intent of self-harm
 
If the patient is symptomatic on presentation, or develops symptoms during the initial observation period, they should be observed until there has been resolution of signs of valproate toxicity and serum concentrations have fallen into the therapeutic range.
 

Investigations

Concentrations

Valproic acid serum concentrations should be measured following ingestion of immediate- and sustained release-preparations when the suspected dose is > 100 mg/kg.
 
Serum concentrations should be taken on presentation and repeated at 2 to 3 hourly intervals initially and 4 to 6 hourly intervals later (to help identify the time of peak concentration and to ensure that a downward trend is observed)[1][2][3]
In particular, patients ingesting enteric coated formulations of valproic acid, or large numbers of tablets/capsules, may have slowed absorption or form concretions in the GI tract. Absorption may be delayed and prolonged. Hence, serial serum valproic acid estimations may be useful to ascertain on-going absorption and guide the need for further GI decontamination and extracorporeal elimination.[3]
 
Click here to link to toxic serum concentrations
 

Monitoring

Monitor:
Level of consciousness
Heart rate
Blood pressure
ECG
Respiratory rate
Blood gas analysis
Seizure activity
Urea and electrolytes
Serum ammonia
Serum lactate
Full blood count
Liver function tests
Blood glucose
 

Admission Criteria

Admission to an intensive care environment is recommended when:
- 400 mg/kg or more is ingested
- Serum concentration is greater than 6,250 umol/L (900 mg/L) valproic acid
- Following symptoms occur 
Coma or respiratory depression requiring mechanical ventilation
Recurrent seizures
- Following conditions are present
Severe electrolyte disturbances (e.g. marked hypernatremia)
Hyperammonemia
Metabolic acidosis
Encephalopathy
Hepatotoxicity
 

TREATMENT

TREATMENT SUMMARY

Severe toxicity is unlikely in the majority of overdoses.[4] Emergency stabilization may occasionally be required following exposure to massive amounts of valproate, when treatment of cardio-respiratory arrest, seizures, or metabolic acidosis may be necessary. Decontamination with activated charcoal may be warranted for ingestions over 100 mg/kg. Whole bowel irrigation may be a useful adjunct in the treatment of overdoses of enteric coated formulations or patients with rising concentrations despite activated charcoal.
 
There are no proven antidotes for valproate capable of immediately reversing its toxic effects, however, L-carnitine may be considered an adjunct to standard management.[5][6][7][8] Multiple dose activated charcoal[9][10] and hemodialysis may be useful in severe toxicity.[11][12] Valproic acid concentrations should be regularly monitored.[3]
 
Further treatment is primarily symptomatic and supportive. CNS depression is a common manifestation of toxicity requiring treatment. Treatment of encephalopathy, seizures, hypotension, electrolyte disturbances, thrombocytopenia, metabolic acidosis, and delayed cerebral edema may sometimes be required following large to massive overdoses. Ammonia concentrations should be checked if encephalopathy is suspected. Hepatotoxicity and pancreatitis are uncommon with overdose, but can occur even with regular therapeutic doses and may be fatal.[13][14][15]
 
Patients with chronic valproate toxicity will require referral to a neurologist for dosage adjustment and monitoring of their on-going therapy.
 
Emergency Stabilization
Ensure adequate cardiorespiratory function
Cardiac arrest
Seizure
Metabolic acidosis
Emergency monitoring
Decontamination
Ingestion
Single dose activated charcoal
Whole bowel irrigation
Exclude bezoar
Antidote(s)
None recommended
L-Carnitine
Enhanced Elimination
Multiple dose activated charcoal
Hemodialysis
Supportive Care
Monitoring
Neurologic
CNS depression
Encephalopathy
Cerebral edema
Seizure
Hepatic
Hepatotoxicity
Metabolic
Metabolic acidosis
Fluid and electrolytes
Electrolyte abnormalities
Respiratory
Respiratory depression
Cardiovascular
Hypotension
Hematologic
Thrombocytopenia
 

EMERGENCY STABILIZATION

Ensure Adequate Cardiopulmonary Function

Endotracheal intubation may be required for airway protection and adequate ventilation of the obtunded patient following overdose. Ensure that the patient is well perfused and hemodynamically stable.
 
Immediately establish secure intravenous access.
 

Seizure

Seizures are possible but uncommon with valproate overdose.
 
Administer a benzodiazepine as first-line treatment to patients with seizure activity.[16]
 
Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, supplemental dextrose should be administered IV.
 
If seizure activity continues or if there is need for maintenance dosing proceed to further supportive care of toxic seizure.
 

Metabolic Acidosis

Follow standard protocols for the management of metabolic acidosis.

Emergency Monitoring

Level of consciousness
Heart rate
Blood pressure
ECG
Respiratory rate
Blood gas analysis
Seizure activity
Urea and electrolytes
Serum ammonia
Serum lactate
Full blood count
Liver function tests
Blood glucose
 

DECONTAMINATION

Ingestion

Single Dose Activated Charcoal

Decontamination with activated charcoal is recommended for ingestions over 100 mg/kg.
 
CNS depression is a likely consequence of significant overdose. Gastrointestinal decontamination should be undertaken with appropriate airway protection in those who are CNS depressed.[4]
 
Administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a solid formulation (e.g. tablet or capsule) up to 4 hours previously.
 
Single dose activated charcoal[17]
CHILD
1 to 2 g/kg orally
ADULT
50 to 100 g orally
 

Nasogastric Administration

Nasogastric instillation of activated charcoal is not recommended unless the ingestion is considered potentially severely toxic. If endotracheal intubation is otherwise required, activated charcoal can be administered following intubation, however, intubation should not be performed solely for the purpose of then administering charcoal.
 

Whole Bowel Irrigation

Whole bowel irrigation may be a useful adjunct in the treatment of overdoses of enteric coated formulations or patients with rising concentrations despite activated charcoal.
 
Whole Bowel Irrigation Procedure
 
When performed optimally, whole bowel irrigation is a labor intensive task that is more likely to be successful with 1:1 nursing care and can take 4 to 6 hours to complete. Use of a nasogastric (NG) tube is recommended over oral administration as it can be difficult for patients to drink the appropriate amount of irrigation fluid over several hours.
 
Before commencing ensure the airway is adequately protected, the NG tube is confirmed to be in the stomach, and there is no ileus or intestinal obstruction. The patient should be in an upright position with easy access to a commode (or use a rectal tube).[18][19]
 
The only irrigant recommended is an iso-osmotic polyethylene glycol electrolyte solution (e.g Macrogol 3350, PEG 3350) approved for GI cleansing and administered at the following rates until the rectal effluent is clear.[18][19]
 
CHILD
< 9 months:
There is limited evidence for use in this age group, consultation with a medical toxicologist is advised
9 months to 6 years:
500 mL/hour (or 25 mL/kg/hour) via NG tube
6 to 12 years:
1,000 mL/hour (or 25 mL/kg/hour) via NG tube
ADOLESCENT or ADULT
1,500 to 2,000 mL/hour via NG tube
 
To achieve desired infusion rates it may be helpful to start at a slower rate and increase as tolerated over the first 10 to 15 minutes. Enteral feeding pumps may not be able to achieve target rates for adults even on the “flush” setting (if considering use of an enteral feeding pump check the device manual to see what rates can be achieved). A gravity infusion, i.e. hanging the irrigant solution bag to gravity, will typically be able to achieve a rate up to 2,000 mL/hour via NG tube.
 
Monitor the patient for abdominal distension or vomiting during the procedure. Pre-treatment with antiemetics can be considered. If vomiting occurs, and ileus or obstruction are not suspected, decrease the infusion rate by 50% for 30 to 60 minutes then attempt to increase back to the full rate.[18]
 
After completion of the procedure the patient should be expected to have additional liquid bowel movements for a period of time.[18]
 

Exclude Bezoar

While bezoar formation is unlikely following most cases of valproate overdose, the possibility should be considered with the ingestion of enteric-coated or modified-release formulations or in situations where high numbers of tablets/capsule are ingested. Valproate tablets are not radiopaque and are unlikely to be seen on plain x-ray imaging.
 
Suspect a bezoar or tablet concretion where serum valproate concentration remains persistently elevated or plateaued despite apparently adequate GI decontamination.
 
Pharmacobezoars (drug concretions) may occur following an ingested overdose of various drugs and, particularly, modified release (e.g. sustained release) or enteric-coated preparations. Such masses may significantly extend or increase the duration of toxicity.[20]
 
Investigation for the presence of a tablet mass in the upper GI tract may be of benefit in the patient with life-threatening toxicity.
 
Bezoars may be detected by:
- Gastroscopy (can only view stomach and duodenum and impractical if charcoal has been administered as the bezoar may be hidden)
- Abdominal CT scanning with oral contrast
- Plain X-ray examination (but only for radio-opaque concretions)
- Ultrasound examination
 
If found, the risk and practicality of removal should be weighed against use of supportive care with or without the addition of whole bowel irrigation.
 
If the bezoar is located in the stomach or duodenum, removal may be attempted endoscopically. Bezoars in the small intestine are inherently difficult to localize and can be impossible to remove without laparotomy.
 

ANTIDOTE(S)

There Are No Antidotes For This Substance

No clinically established antidotes capable of immediately reversing toxic effects exist for the treatment of valproic acid overdose. However, L-carnitine and naloxone have both been used in a number of cases with varying results.
 

L-Carnitine

Evidence supporting clinical efficacy and safety of L-carnitine in acute valproic acid poisoning is limited.[5] The primary route of metabolism of valproic acid by beta-oxidation is inhibited by hypocarnitemia,[21] a state which is commonly observed in chronic, supratherapeutic valproic acid poisoning. Hypocarnitemia may favor the production of toxic metabolites, and contribute to the development of hyperammonemia.[11] Administration of L-carnitine is thought to normalize metabolism and has well established clinical benefit in reversing hyperammonemia in these patients.[22] It is recommended prophylactically in “at-risk” patients on valproic acid therapy.[8][23][24]
 
In acute poisoning there is some, albeit scant, evidence that valproic acid metabolism is similarly inhibited and that administration of L-carnitine similarly normalizes metabolism.[5][21][25] There are also anecdotal reports of reversal of hyperammonemia in acute poisoning.[6][8][26][27] L-carnitine does not appear to have any direct effect on neurological toxicity.[25]
 
L-carnitine may be considered in acute valproic acid poisoning as an adjunct to standard management where hyperammonemia or decreased level of consciousness is present.[5][7][8]
 

Indications

L-carnitine administration is indicated in patients with:[5][7][8][25][28][29]
Decreased level of consciousness
Hyperammonemia
Some authors also recommend considering L-carnitine administration if severe toxicity is present or likely:
Ingestions > 100 mg/kg valproic acid[5]
Serum valproic acid concentrations > 3,128 umol/L (> 450 mg/L)[5][7][30]
Hepatotoxicity[24][25]
 

Dose and Administration

The recommended L-carnitine dose for acute valproic acid poisoning is higher than that used for chronic, supratherapeutic poisoning or mild hypocarnitemia.[5][6][7][21][24][26][28] L-carnitine infusion may be required for up to 3 to 4 days.[5][26]
 
L-Carnitine Dosage in Acute Valproic Acid Poisoning
 
CHILD and ADULT[5][7]
IV
Loading dose:
100 mg/kg
Doses given as an infusion over 30 minutes
Maximum dose 3 g (up to 6 g has been given)
Maintenance dose:
50 mg/kg every 8 hours or 15 mg/kg every 4 hours
Doses given as an infusion over 30 minutes
Maximum single dose 3 g
End Point:
Ammonia concentrations decreasing, patient demonstrates clinical improvement, or significant adverse effects occur
 

Precautions

Seizures have occurred in patients taking L-carnitine therapeutically; caution is recommended in patients with underlying seizure disorder. Adequate hydration and a good renal output must be maintained as there is potential for accumulation of toxic metabolites of L-carnitine (trimethylamine and trimethylamine-N-oxide) in patients with renal impairment.[31][32]
 

Contra-indications

L-carnitine does not have any absolute contraindications other than known previous hypersensitivity.[31][32]
 

Adverse Effects

Seizures are reported, both in patients with or without a prior history of convulsive disorder.[31][32] Tachydysrhythmias, hypertension, and hypotension are also noted.[5] Gastrointestinal upset[32] and an unpleasant, fishy body odor may occur.[25][28] No allergic reactions or adverse effects were observed when L-carnitine was administered in 215 acute valproic acid poisoning cases.[29]
 

Naloxone

Naloxone has been used anecdotally in a small number of cases to reverse valproate-induced CNS depression.[33][34][35][36][37][38][39] This appears to have been more effective with minimally elevated serum concentrations,[39][40][41] with other reports showing no effect with much higher concentrations.[42][43][44] Any effect may be due to reversal of valproate blockade of GABA cellular uptake or reversal of valproate-induced release of endogenous opioids.[39][40][45]
 

ENHANCED ELIMINATION

Multiple Dose Activated Charcoal

Multiple dose activated charcoal may decrease enterohepatic circulation of the drug, and enhance its elimination. A small number of case reports has shown that this therapy may reduce serum valproate half-life.[9][10] As a result, it may be useful with large overdoses (> 500 mg/kg) and very high, or continuously rising, serum valproate concentrations. However, clinical experience with this method in valproate overdose is limited, and there are no controlled studies that determine if its use improves outcome or shortens the duration of toxicity.[9][34][46]
 
Care should be taken to monitor for signs of ileus while performing this therapy. Charcoal administration should be ceased if abdominal distension, loss of bowel sounds, vomiting, or increased nasogastric aspirates are observed.
 
Multiple dose activated charcoal dose
CHILD
0.5 to 1 g/kg bolus/every 2 to 4 hours
ADULT
25 to 50 g bolus/every 2 to 4 hours
 
Administer orally or via nasogastric tube and continue until signs of clinical and biochemical improvement.[47] Charcoal should not be administered to a patient with ileus or bowel obstruction.
 

Hemodialysis

Although valproate exhibits high plasma protein binding at therapeutic blood concentrations, saturation of the binding at the higher concentrations found in overdose results in increased concentrations of unbound drug. In this situation valproate elimination may be enhanced by hemodialysis.[11][48] Hemodialysis has resulted in clinical improvement and/or enhanced elimination in the treatment of valproate overdose.[49][50][51][52][53][54][55][56]
 
Hemodialysis is recommended in any of the following situations:[11]
Serum concentration is > 1,300 mg/L (9,000 umol/L)
Evidence of shock or cerebral edema
 
Hemodialysis is suggested in any of the following situations:[11]
Serum concentration is > 900 mg/L (6,250 umol/L)
Coma or respiratory depression requiring mechanical ventilation
Acute hyperammonemia
Blood pH is < 7.1
 
Intermittent hemodialysis is preferred as it achieves the highest possible clearance rate but intermittent hemoperfusion or continuous renal replacement therapy are acceptable alternatives if hemodialysis is not available.[11]
 
Hemodialysis should continue until sustained clinical improvement is observed or the serum valproic acid concentration is between 50 and 100 mg/L (350 to 700 umol/L).[11] A rebound in valproate concentrations may occur following discontinuation of hemodialysis.
 

Other Forms of Enhanced Elimination

Hemoperfusion[2][57] hemofiltration[55][57] and combinations of these techniques with hemodialysis[43][58][59] have been used to enhance elimination in the treatment of valproate overdose. These methods have not been systematically compared with supportive care alone, with respect to outcome. If hemodialysis is not available hemoperfusion or continuous renal replacement therapy are acceptable alternatives.[11]
 

SUPPORTIVE CARE

Monitoring

Level of consciousness
Heart rate
Blood pressure
ECG
Respiratory rate
Blood gas analysis
Seizure activity
Urea and electrolytes
Sodium
Calcium
Magnesium
Phosphate
Bicarbonate
Blood urea nitrogen
Full blood count including platelets
Serum ammonia
Serum lactate
Liver function tests
Blood glucose
Amylase or lipase (if concern for pancreatitis)
EEG
Intracranial pressure (if severe toxicity)
 
Serum valproic acid concentrations should be performed in all overdoses over 100 mg/kg. Normal therapeutic concentrations lie in the range 350 to 690 umol/L (50 to 100 mg/L).[60]Initial serum concentrations may be misleading, especially with the ingestion of enteric-coated formulations or high numbers of tablets/capsules.[3]
 
Valproic acid concentrations should be repeated every 2 to 3 hours initially and every 4 to 6 hours later. Declining concentrations should be documented before discharge is considered.[3]
 

Neurologic

CNS Depression

CNS depression, ranging from drowsiness to coma, is the most frequent symptom after valproate overdose.[4] In small overdoses drowsiness may be the only feature,[4][61] while massive overdose may result in coma.[8][62][63] The exact mechanism is unclear but may be due to increasing brain GABA concentrations.[64] Primary consideration is given to establishing and maintaining an effective airway and ventilatory support.
 
Closely monitor level of consciousness.
 
Manage depressed level of consciousness following standard treatment protocols.
 

Encephalopathy

Valproate-induced hyperammonemic encephalopathy is characterized by acute onset of impaired consciousness, focal neurologic symptoms, and increased seizure frequency. Severe hyperammonemic encephalopathy may develop following large overdoses.[6][27][65] This condition has also developed in patients taking therapeutic doses chronically including sometimes in combination with other antiepileptics; it may also be present in the setting of valproic acid concentrations within or near the therapeutic range.[23][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80]
 
Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, or those with carnitine deficiency may develop hyperammonemic encephalopathy following initiation of valproate therapy at normal doses. Such individuals would be expected to be at increased risk of such complications following overdose.[66]
 
Monitor:
Level of consciousness
Mental status
Neurological status
Seizure frequency
Urea and electrolytes
Liver function
Serum ammonia
EEG
 
Manage hyperammonemic encephalopathy following standard treatment protocols.
 

Cerebral Edema

Cerebral edema is relatively uncommon following valproate intoxication. The condition may be related to hyperammonemia, which increases intracellular osmolarity thereby promoting an influx of water leading to cerebral edema.[81] Onset is usually delayed. It may develop two to three days into the course of severe valproate poisoning.[82][83] Management is supportive including correcting metabolic and electrolyte abnormalities and preventing fluid overload.[82]
 
Closely monitor patient for development of raised intracranial pressure which may indicate the onset of cerebral edema. Cerebral CT scan is indicated in this instance.
 
Manage cerebral edema following standard treatment protocols.
 

Seizures

Seizures rarely occur after ingestion. It may be difficult to determine which are due to valproate toxicity and which reflect an underlying seizure disorder.[62][63][65]
 
Observe the patient closely for onset of seizure activity.
 

Hepatic

Hepatotoxicity

Increases in serum aminotransferases and ammonia are relatively common in patients taking valproate drugs therapeutically.[13][67][84] These changes have also been observed in overdose although they do not necessarily indicate severe toxicity.[63][65][85][86][87]
 
Hepatotoxicity, and rarely hepatic failure, have been reported with overdose[83][88][89][90] and may also occur with therapeutic use.[14][15][23][91] It is thought to be due to mitochondrial dysfunction or to a disturbance in fatty acid metabolism.[87] Young children with multiple medical problems, on multiple antiepileptic agents are at highest risk of fatal hepatotoxicity.[14][15][91][92]
 
Hepatic monitoring should include:
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
International normalized ratio (INR)
Serum bilirubin
Blood or plasma glucose
Serum lactate
 
Manage acute hepatotoxicity following standard treatment protocols.
 

Metabolic

Metabolic Acidosis

Metabolic acidosis may occur following valproate overdose. It is more commonly associated with massive valproate overdose and serum concentrations greater than 850 mg/L (5,908 umol/L).[46][81][83][88][89][93]
 
Monitor:
Blood gases
Plasma lactate
 
Manage metabolic acidosis following standard treatment protocols.
 

Fluid and Electrolytes

Electrolyte Abnormalities

Prolonged and severe electrolyte disturbances, including hypocalcemia and hypernatremia may occur following massive valproate overdoses.[63][94][95] Hypocalcemia is generally caused by calcium binding to valproate metabolites, which act as anions.[96] Hypernatremia may indirectly indicate a large ingestion of the sodium salt of valproate.[89] Electrolyte replacement, whether oral or parenteral, should be guided by symptomatology and electrolyte concentrations (repeated when indicated).
 
Monitor serum electrolytes.
 
Manage serum electrolyte abnormalities following standard treatment protocols.
 

Respiratory

Respiratory Depression

Marked respiratory depression requiring intubation and prolonged artificial ventilation may occur following severe valproate overdose. In most cases, patients will recover without chronic sequelae. Respiratory failure has been observed in cases of fatal valproate poisoning.[2][94][97]
 
Monitor:
Respiratory rate
Pulse oximetry
Blood gas analysis
 
Manage respiratory depression following standard treatment protocols.
 

Cardiovascular

Hypotension

Hypotension may occur in a minority of cases, usually following massive valproate overdose.[42][49][53][65][83] Treatment with fluid resuscitation, vasopressors, and inotropic support is recommended,[4] however, severe hypotension may be resistant to treatment.[65] It carries a poor prognosis.[42][88]
 
Monitor:
Heart rate/rhythm
Blood pressure
ECG
Level of consciousness
End-organ perfusion
 
Manage hypotension following standard treatment protocols.
 

Hematologic

Thrombocytopenia

Clinically significant thrombocytopenia may occur following overdoses of large amounts of valproate.[42][85][93][98][86][65] The exact mechanism is unknown but may involve a dose-dependant direct toxic effect on bone marrow production of platelets and/or the formation of autoantibodies against platelets leading to platelet destruction.[99] Platelet transfusions have been required.[88]
 
Monitor:
White blood cell count
Platelet count
 
Manage thrombocytopenia following standard treatment protocols.
 

DISCHARGE CRITERIA

A prolonged period of observation should be documented before discharge is considered, especially when enteric-coated preparations or high numbers of tablets/capsules are ingested. Discharge should not be considered until serum valproate concentrations are within the therapeutic range, serial concentrations are declining, and clinical evidence of toxicity has resolved. Patients should be instructed to return should symptoms develop or recur.
 

FOLLOW UP

Medical follow-up is unlikely to be required, as long as recovery from any complications is complete. Psychiatric intervention may be necessary depending on the circumstances of the exposure.
 

PROGNOSIS

Following appropriate supportive care the prognosis is good.
 

SIGNS AND SYMPTOMS

Sodium valproate is rapidly metabolized to valproic acid in vivo.
 
Common clinical symptoms of valproic acid toxicity vary in severity, depending on the ingested dose, from mild confusion and drowsiness to deep coma and rarely, death.
 
With ingestions less than 200 mg/kg, effects are generally mild or the patient may remain asymptomatic.[4][62][100] Ingestions from 200 to 400 mg/kg are likely to develop varying degress of decreased consciousness (lethargy, sedation, ataxia). Additionally, gastrointestinal disturbances, tachycardia, hyperammonemia, hypothermia, and rarely hepatic or renal toxicity may develop. Significant CNS depression is likely, with multi-organ involvement as the dose increases.[46][83][101]
 
Massive overdoses (typically > 800 mg/kg) can result in serious CNS and respiratory depression, hypotension, and metabolic acidosis. Severe hyperammonemic encephalopathy, cerebral edema, and clinically significant thrombocytopenia may develop; hypernatremia, hypocalcemia, and other electrolyte disturbances may be severe and prolonged.[27][85][93]Delayed cerebral edema may occur though it is not common.[86][102] Death is rare, and usually results from cardiac or respiratory arrest.[103]
 
Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, are at increased risk of developing hyperammonemic encephalopathy.[104][105] Pancreatitis and other adverse effects seen with therapeutic doses may occasionally occur with overdose.[88]
 

Onset/Duration of Symptoms

Symptoms would usually be expected to develop within 1 to 6 hours of ingestion with most standard preparations.[36][81][86][103][106][107][108][109] Delayed toxicity may occur with ingestion of sustained release or enteric-coated formulations,[2][93][110] or with the prodrug valpromide,[1] with CNS depression developing as late as 8 hours post-ingestion. Ingestion of high numbers of tablets/capsules may also be associated with delayed or prolonged absorption. Metabolic disturbances usually present early, and may be severe and prolonged. The development of cerebral edema is generally delayed, presenting 2 to 3 days or more post-ingestion, and is associated with a higher mortality.[81][82]
 
Depending on the severity, the duration of intoxication can range from 24 hours to 7 days or longer.[46][49][103][107][109][111]
 

Severity of Poisoning

Mild Valproate ToxicityModerate Valproate ToxicitySevere Valproate Toxicity
Mild drowsiness
Confusion
Nausea
Vomiting
Tachycardia
Moderate to severe drowsiness
Agitation
Hyperammonemia
Hypocalcemia
Hypernatremia
Thrombocytopenia
Hypotension
Miosis
Unconsciousness / coma
Respiratory depression
Metabolic acidosis
Elevated creatnine kinase
Hepatotoxicity
Seizure
Encephalopathy
Cerebral edema
Cardiac or respiratory arrest
 

ACUTE EFFECTS (ORGAN SYSTEM)

Neurologic

Hepatic

Elevated alkaline phosphatase[83]
Elevated gamma glutamyl transpeptidase[102]
Decreased bilirubin[65]
Steatosis[94][120]
 

Metabolic

Cardiovascular

Bradycardia[122]
QT prolongation[61][98]
Supraventricular tachycardia[85]
Atrial fibrillation[122]
Cardiac arrest[103][118][120]
 

Respiratory

Respiratory depression[34][88][89][103][118]
Shallow respirations[42][107][110]
Irregular respiration[63][110]
Crackles[83]
Respiratory alkalosis[53][87]
Decreased pO2[6][42][109][113]
Decreased oxygen saturation[107]
Bronchopneumonia[94][120]
Aspiration[27][89]
Respiratory distress syndrome[42]
Respiratory paralysis[81][94][120]
Pulmonary edema[42][115]
Apnea/respiratory arrest[39][46][103][106][118][122]
 

Fluid and Electrolytes

Hyperphosphatemia[63][82]
Hyperkalemia[63][88]
Hypokalemia[53][120]
Hyperchloremia[58]
Hyponatremia[63]
Hypomagnesemia[65] 
Hyperosmolality[87]
Hyperosmolarity[94][120]
 

Hematologic

Leukocytosis[6][98][109]
Bone marrow suppression[58][125]
Neutropenia[4]
Prolonged activated partial thromboplastin time (aPTT)[63][82][87]
Prolonged prothrombin time[87][109]
Decreased serum fibrinogen[63][98]
Decreased hematocrit[98]
Methemoglobinemia[107]
 

Gastrointestinal

Nausea[119]
Abdominal pain[119]
Hyperamylasemia[88][107][113]
Hyperlipasemia[65][88][125][103]
Pancreatitis[88][103]
Hypoactive/absent bowel sounds[114]
 

Renal

Elevated creatinine[82][88][98]
Elevated BUN[39][82][98]
Hematuria[98]
Nephropathy[9]
Diabetes insipidus[27]
Anuria/renal failure[42][49][63][89][98]
 

Musculoskeletal

Diminished muscle stretch reflexes[111]
Muscle spasms[82]
 

Ocular

Mydriasis[63][81][118]
Pupils sluggishly reactive to light[6][36][109][118]
Pupils unresponsive to light[27]
Unequal pupils[108]
Nystagmus[119]
Optic nerve atrophy[85]
 

Dermatologic

Cyanosis[46][120]
Pale[63]
Bullous skin lesions[125]
 

Other

Stevens-Johnson syndrome (rare adverse drug reaction)[127]
Toxic epidermal necrolysis (rare adverse drug reaction)[127]
 

ACUTE EFFECTS (ROUTE OF EXPOSURE)

Injection

As some valproate drugs are available in a formulation for injection, intravenous overdose is possible. However, the lack of reports in the literature suggests that this is not a common route of exposure.
 

TOXICITY

HUMAN

Acute

Medical observation in children and adults is recommended for ingestions greater than 50 mg/kg,[100] and, if there are no contraindications, decontamination with activated charcoal is recommended for ingestions greater than 100 mg/kg.
 

Child

Serious toxicity has been reported in children. Fatality has occurred following an accidental overdose of 75 mg/kg over a 12 hour period in a 26-day old infant.[118] However, in most cases ingested doses between 200 and 625 mg/kg have caused moderate to severe toxicity.[36][46][61][83][109][111] An ingested dose of 750 mg/kg proved fatal in a 20 month old child after 46 hours.[120]
 
Case Studies
Sodium valproate, valproate pivoxil, valproate semisodium, and valpromide are rapidly metabolized to valproic acid in vivo.
 
300 mg Valproic Acid (75 mg/kg) administered over 12 hours (ingested)
26 day female: Twelve hours after ingestion mildly elevated blood pressure of 95/55 mmHg with confusion, slurred weeping, and obtundation. Developed depressed respiration, sluggishly reactive pupils, and depressed gag reflex with absence of Moro reflex. Serum concentration of ammonia was 279 ug/dL and valproate was 268.8 mg/L (1,868 umol/L). Developed fixed dilated pupils and extensor posturing bilaterally 36 hours after ingestion. Death from cardiorespiratory arrest due to severe brain edema 42 hours after ingestion
Decontamination and supportive care, including activated charcoal, lactulose, nasal oxygen, and fluid therapy. Naloxone 0.01 mg/kg IV. Later given mannitol and hyperventilation [118]
Fatal after 42 hours[118]
9.8 g Valproic Acid (196 mg/kg) (ingested)
9 year female: 4 hours post-ingestion BP of 112/62 mmHg, heart rate of 105 bpm, respiratory rate of 28 bpm, and body temperature of 36.3 degrees C. Patient was stuporous (GCS 6) with equal pupils and a sluggish light reflex. pH was 7.27, increased white blood cell count and prothrombin time, and increased ammonia of 111 ug/dL
Decontamination and supportive care, including activated charcoal, intubation and ventilation. Two rounds of hemoperfusion with activated charcoal along with L-carnitine 200 mg/kg per day IV in 4 doses[109]
Recovered. Discharged after 9 days[109]
2.25 g Sodium Valproate (203 mg/kg) (ingested)
19 month male: Lethargy and irritability 45 minutes post-ingestion. Three hours later unconscious, miosis, and poorly reactive. Serum concentration of 185 mg/L(1286 umol/L) sodium valproate
Decontamination and supportive care, including activated charcoal, naloxone (0.01 mg/kg) IV 3 hours after ingestion. A second dose of naloxone was required[36]
Recovered[36]
310 mg/kg Valproate (ingested)
6 day male: Four hours after administration developed hypoactivity, poor response to stimuli, somnolence and elevated concentrations of ammonia. Later developed lethargy, severe hypotonia, diminished muscle stretch reflexes, and miosis. Five days following exposure an MRI scan showed a focal T1 prolonged signal in both globi pallidi
Decontamination and supportive care, including gastric lavage, blood exchange transfusion, carnitine (100 mg/kg/day), phenylbutyrate (1 g/day) and benzoate (1 g/day)[111]
Recovered. Discharged after 13 days[111]
4 g Sodium Valproate (330 mg/kg) (ingested)
2 year female: Tachycardia and GCS of 13 decreasing to 8. Valproate concentration was 611 mg/L (4,277 umol/L) 8 hours post-ingestion. QTc was 500 ms. After 19 hours of hemofiltration, valproate concentration had decreased to 97 mg/L (679 umol/L)
Supportive care, including intubation and continuous veno-venous hemofiltration[61]
Recovered[61]
4.5 g Valproic Acid (375 mg/kg) (ingested)
26 month male (Enteric coated tablets): No clinical symptoms or signs 1.5 hours following ingestion. At 4 hours became obtunded, limp, cyanotic, and apneic with a HR of 180 and a systolic BP of 70 mmHg. Nine hours after admission serum valproic acid concentration was 486 mg/L (3,370 umol/L). Child developed metabolic acidosis with pH of 7.256 and elevated lactate concentration of 7.7 mmol/L
Decontamination and supportive care, including activated charcoal and three doses of IV naloxone (0.017 mg/kg each). Transferred to ICU and continuous nasogastric infusion of charcoal with sorbitol was begun (0.25 g/kg/hour). Metoclopramide 1.25 mg/kg IV was also administered[46]
Recovered after 24 hours[46]
7.5 g Valproic Acid (625 mg/kg) (ingested)
26 month female: 2 hours post ingestion developed lethargy with HR of 130 and systolic BP of 62 mmHg. Serum pH was 7.07. Serum valproic acid concentration was 961 mg/L (6,679 umol/L) 2.5 hours after ingestion. Within 4 hours of admission, increased serum ammonia concentration and decreased calcium concentrations of 5.8 mg/dL. Hyperventilation and hypoglycemia developed. At 48 hours CT scan of the head demonstrated cerebral edema and serum valproic acid concentration was 278 mg/L (1,932 umol/L). Cerebral edema had resolved by day 5
Decontamination and supportive care, including ipecac administration at home by parents. Intubation and ventilation at hospital, administered mannitol (25 g), dopamine (1 to 8 ug/kg/min), supplemental calcium (10 mEq/L), bicarbonate (15 mEq/L), and glucose (25% in normal saline)[83]
Recovered[83]
15 g Sodium Valproate (750 mg/kg) (ingested)
20 month male: Within 45 mins of ingestion developed severe coma, areflexia, and respiratory paralysis. After 20 hours spontaneous breathing, reflexes, and consciousness returned. Then 14 hours later fever (39.5 degrees C), cyanosis, disturbance of consciousness, and symptoms of severe bronchopneumonia developed. Serum analysis showed elevated sodium and osmolarity, while potassium, calcium, pH, and leucocytes had decreased. Cardiac arrest ensued 46 hours following ingestion
Decontamination and supportive care, including ipecac syrup, gastric lavage followed by administration of sodium sulfate and activated charcoal. Artificial ventilation[120]
Fatal after 46 hours. Post mortem examination revealed cerebral edema, haemorrhagic bronchopneumonia, and steatosis of the hepatocytes[120]
 

Adult

Severe toxicity has been well-documented in case reports following ingestion of massive amounts of valproate, however, case reports of smaller ingestions are lacking. Case series also suggest that individual case reports may be giving an exaggerated view of valproate’s toxicity and that minor effects are more likely to develop in the majority of overdoses. These case series suggest that severe toxicity is unlikely at doses less than 200 mg/kg.[4][62] Fatalities are relatively uncommon, and doses of between 20 to 160 g (~300 to 2,300 mg/kg) have been survived with supportive care.[100]
 
> 200 mg/kg
Mild to moderate toxicity[4][34][62][100]
> 400 mg/kg
Severe toxicity, including coma[4][49][106][116]
> 1,000 mg/kg
Potentially lethal without treatment
 
Case Studies
Sodium valproate, valproate pivoxil, valproate semisodium, and valpromide are rapidly metabolized to valproic acid in vivo.
 
5 g Valproic Acid (66 mg/kg estimated) (ingested)
22 year male: Somnolent and depressed motor and respiratory activity. Pinpoint and nonreactive pupils. Initial valproic acid concentration was 180.4 mg/L (1,251 umol/L)
Decontamination and supportive care, including activated charcoal, IV normal saline, and 2 mg naloxone[34]
Recovered after 20 hours[34]
8 g Sodium Valproate (ingested)
22 year male: 15 hours after ingestion: coma (GCS 3/15), apnea, respiratory acidosis, bradycardia, hypotension, atrial fibrillation, severe hypothermia (27 degrees C, had been doused with cold water in an attempt to rouse him), hypernatremia, hypoglycemia, elevated creatine kinase. Valproate concentration of 1,255 mg/L (8,700 umol/L)
Supportive care, including intubation, ventilation, thiamine, glucose, naloxone, and rewarming[122]
Recovered by day 2[122]
20 g Valproic Acid (330 mg/kg) (ingested)
15 year female: On admission 5 hours after ingestion comatose (GCS 7) with areflexia, reflective bilateral mydriasis, and respiratory paralysis. Metabolic acidosis (pH 7.16), hyperglycemia (14 mmol/L), increased sodium (156 mmol/L), hyperlactatemia (8.3 mmol/L), hyperammonemia (228 umol/L), leucopenia, and cerebral edema. Peak valproate conentration of 1,550 mg/L (10,748 umol/L)
Decontamination and supportive care, including gastric lavage and activated charcoal[81]
Fatal after 4 days from cerebral edema[81]
30 g Valproic Acid (400 mg/kg estimated) (ingested)
35 year male: Lethargic 3 hours after ingestion. Four hours later unarousable, respiratory failure, and hemodynamically unstable. Serum concentration of 553 mg/L (3843 umol/L).
Decontamination and supportive care, including multiple-dose activated charcoal. Intubation, hemodialysis and hemoperfusion treatment for 4 hours. Continuous venovenous hemodiafiltration for 18 hours.[106]
Recovered after 1 day.[106]
30 g Valproic Acid (435 mg/kg) (ingested)
24 year male (medical history included compensated renal insufficiency): Eight hours after ingestion found unconscious. On arrival at hospital; patient was hemodynamically unstable with BP of 80/60 mmHg. Developed oliguria, hyperammonemia, thrombocytopenia, and aspiration pneumonia
Decontamination and supportive care, including gastric lavage, activated charcoal, and inotropic support (dopamine and norepinephrine (noradrenaline)), and high-flux hemodialysis[49]
Recovered. Discharged after 18 days[49]
50 g Valproic Acid (715 mg/kg) (ingested)
41 year male (Extended release tablets): Two hours after ingestion; lethargic, but hemodynamically stable. Plasma concentration 2 and 4 hours after ingestion was 789 and 1150 mg/L (5484 and 7993 umol/L), respectively.
Decontamination and supportive care, including gastric lavage, activated charcoal and a laxative. Hemodialysis was initiated 6 hours after ingestion and was performed over an 8 hour period. [116]
Recovered[116]
50 g Valproic Acid (ingested)
22 year male: Two hours after ingestion alert and stable. Obtunded at 7 hours, serum valproic acid concentration of 637.71 mg/L (4,432 umol/L) and serum ammonia concentration of 279 ug/mL. Ten hours after ingestion anisocoric pupils and diffuse cerebral edema suggestive of subarachnoid hemorrhage
Decontamination and supportive care, including activated charcoal, L-carnitine, and hemodialysis[108]
Recovered and discharged after 39 days with no detectable neurological deficit[108]
56.4 g Valproic Acid (795 mg/kg) (ingested)
34 year male (Enteric coated tablets): Found deceased
Treatment was not required[128]
Fatal[128]
60 g Sodium Valproate (ingested)
Adult male: Drowsy 6 hours after ingestion. Deep coma and respiratory arrest 9 hours after ingestion. At 10 hours valproic acid serum concentration of 1,361 mg/L (9,459 umol/L) and ammonia concentration of 541 ug/dL. Pancreatitis, circulatory failure, and cerebral edema developed on day 2. Multiorgan failure ensued on day 3 and cardiac arrest on day 8
Supportive care, including mechanical ventilation[103]
Fatal after 8 days.[103]
75 g Sodium Valproate (882 mg/kg) (ingested)
16 year female: On admission 8 hours after ingestion respiratory rate 25/min, GCS 6, metabolic acidosis with an anion gap of 22.3 mmol/L, and serum valproic acid concentration of 1,320 mg/L (9,174 umol/L). Developed hypoglycemia, hypocalcemia, hypernatremia, and hyperammonemia. Later developed thrombocytopenia
Supportive care, including 2 doses of IV naloxone (0.9 mg each) and 3 sessions of hemodialysis at 4, 13, and 25 hours after admission[93]
Recovered and discharged on day 4[93]
100 g Sodium Valproate (ingested)
24 year patient: Coma, areflexia, and supraventricular tachycardia 18 hours after ingestion. On day 2 developed a high fever. Developed increased creatine kinase (2360 U/L), AST (143 U/L), and LDH (1084 U/L) and a decrease in thrombocytes. Serum concentration of sodium valproate was 300 and 61 mg/L (2,085 and 424 umol/L) on day 2 and 4, respectively. EEG on day 8 showed diffuse slow-wave activity. After 10 days the patient was still in deep coma with high temperature and severe cerebral involvement with hypotonia and areflexia. Right side occulomotorius paresis and unequal pupils were found. On day 18 able to talk but still mentally reduced with focal paresis. After 2 month only severe reduction of the vision persisted, caused by atrophy of both optic nerves
Decontamination and supportive care, including gastric aspiration, artificial ventilation, cooling, sedation and ampicillin[85]
Recovered[85]
 

Chronic

Toxic effects are frequently associated with daily doses over 1,800 mg valproic acid and blood concentrations over 100 mg/L (695 umol/L).[123][129]
 
A 23 year old man died following initiation of valproic acid therapy at a dose of 750 mg three times daily. He received 11.25 g over five days.[115]
 
An 81 year old woman became increasingly somnolent, was unable to stand and fell repeatedly after receiving 6 g daily instead of 800 mg for three days. She recovered well following discontinuation of valproic acid.[117]
 
A 76 year old woman, who 3 months previously had her valproate dose increased from 500 mg to 750 twice daily, ingested her total daily dose in the morning. She presented with hypotension, myoclonic movements, drowsiness and a valproate concentration of 122 mg/L (848 umol/L). The patient showed rapid improvement of symptoms after IV bolus administration of 0.8 mg naloxone.[39]
 

ANIMAL

Acute

Sodium valproate, valproate pivoxil, valproate semisodium, and valpromide are rapidly metabolized to valproic acid in vivo.
 
Valproic acid:
LD50 Oral, Rat
670 mg/kg670 mg/kg/[130]
Sodium Valproate:
LD50 Oral, Mouse
1,700 mg/kg1,700 mg/kg/[130]

BIOLOGICAL LEVELS - TOXIC

SI Unit Conversion

To convert an valproate concentration expressed in mg/L into umol/L:
Multiply the mg/L by 6.9343
 
To convert an valproate concentration expressed in umol/L into mg/L:
Multiply the umol/L by 0.1442
 

Normal Plasma Level

Usual Therapeutic Concentration
50 to 100 mg/L (350 to 700 umol/L) valproic acid[60]
Note: Higher concentrations are used by some clinicians
 

Toxic Serum Level

Sodium valproate, valproate pivoxil, valproate semisodium, and valpromide are rapidly metabolized to valproic acid in vivo.
 
Serum concentration greater than 450 mg/L (3,120 umol/L) valproic acid may result in moderate or major toxic effects.[89][106]
 
Serum concentration greater than 850 mg/L (5,894 umol/L) valproic acid may result in major toxic effects, including, coma, respiratory depression, or metabolic acidosis.[88][89]
 
Serum concentration greater than 1,200 mg/L (8,321 umol/L) valproic acid may be fatal.[42][89]
 

REPRODUCTION

Sodium valproate is rapidly metabolized to valproic acid in vivo.
 

FERTILITY

Valproate-associated reproductive endocrine disorders are common among women treated with valproate. Studies found that menstrual disorders occurred in 45 to 59% of women taking valproate.[131][132] Young women seem to be vulnerable to the effects of valproate on ovarian function, as 80% of women treated with valproate before the age of 20 years had polycystic ovaries or hyperandrogenism.[131] These reproductive endocrine disorders may result in reduced fertility.
 
A study in males treated with valproate demonstrated significantly lower concentrations of free testosterone, lower sperm concentration, lower sperm count, lower sperm mobility, higher rates of immotile sperm, higher rates of abnormal forms, lower carnitine concentrations, and lower testicular volume compared to controls. It was postulated that that these findings would contribute to reduced fertility.[133] These findings are supported by previous observations that showed a higher frequency of morphologically abnormal sperm count, poor mobility of sperm, and smaller testicular volume in males taking valproate compared to controls.[134] 
 
Furthermore, increased serum androgen concentrations, without increased circulating LH or insulin concentrations, were found in 57% of 21 men taking valproate. The mean serum concentrations of androstenedione was also increased.[135]
 

PREGNANCY

Valproate crosses the placenta and is likely to affect the fetus. Taking this drug during pregnancy is not considered acceptable and it should not be used in female children, in female adolescents, or in women of child-bearing age, unless alternative treatments are not tolerated or are ineffective.[60] However, there are cases where the control of convulsions is impossible without valproate.[136]
 
Fetal valproate syndrome (FVS) is characterised by a pattern of minor and major malformations and neurodevelopmental problems together with a distinctive facial phenotype.[136][137][138][139] Common congenital malformations include defects of the neural tube, heart, limbs, genitourinary system, brain, and face.[138][140] Furthermore, developmental delays, growth retardation, and a decline in adaptive functioning,[136][141][142] as well as an increased risk of autism spectrum disorders and childhood autism have also been reported following in utero exposure to valproate.[143]
 
A dose-effect relationship between fetal malformations and valproate exposure during pregnancy has been demonstrated in that higher doses are associated with a significantly greater risk than lower doses.[144][145][146] Specifically, a maternal dose above 1,000 mg/day and blood concentrations above 70 mg/L are significantly associated with a higher incidence of fetal malformations.[145] Other studies suggest that malformations may occur regardless of the dose.[138][139] Reports estimate that between 6.7% to 11.1% of children exposed to valproate in utero develop major congenital malformations.[145][147]
 
The exact mechanism by which valproate is teratogenic is unknown. It has been hypothesized that histone deacetylase inhibition and/or valproate lowering the bioavailable folates by non-competitive inhibition of the folate receptors, could be disrupting the developmental processes during embryogenesis.[148]
 
Australian Classification:
D
 
For full details of these classification systems, Click here.
 

LACTATION

Valproate is excreted into human breast milk in low concentrations and is unlikely to affect the nursing infant.[149][150][151] Taking valproic acid is considered acceptable when breastfeeding when the benefits to the mother outweigh the risks to the infant.
 
In two mother-infant pairs, serum valproate concentrations were 1.5 and 6% of the maternal values.[149] In a series of 6 breastfeeding mother-infants pairs, infant serum concentrations were low, ranging from 0.9 to 2.3% of maternal serum concentrations.[150] A further case showed the breastfed child's serum concentration was 7.6% of the maternal serum concentration.[151]
 
While the majority of studies report no adverse effects in breast-feeding infants, one case report describes a 3 month old infant who developed thrombocytopenic purpura, anemia, and reticulocytosis following breast-feeding. The infant had a serum valproic acid concentration of 6.6 mg/L (46 umol/L), considered reflective of a dose equivalent to 6 to 13% of an adult therapeutic dose. The infant recovered once the mother stopped breast-feeding.[152]
 
The American Academy of Pediatrics considers valproic acid to be compatible with breast feeding.[153]
 

TOXIC MECHANISM

Sodium valproate is rapidly metabolized to valproic acid in vivo.
 
The toxic mechanism of valproic acid and its salts is not fully understood. Some features, such as CNS depression, which can also occur at therapeutic doses, may be expected to arise as an extension of the normal pharmacological actions of valproate. Those are thought to include potentiation of GABAergic functions by increasing both synthesis and release of GABA. This results in increasing brain GABA concentrations.[64] Valproate also seems to reduce the release of the epileptogenic amino acid gamma-hydroxybutyric acid and to attenuate neuronal excitation induced by NMDA-type glutamate receptors.[64] Other effects may arise as a result of metabolites of valproic acid or of metabolic changes, such as hyperammonemia.
 
Valproic acid is transported into the cell and also into the mitochondria via a carnitine transporter. It is primarily metabolized within the mitochondria by beta-oxidation to produce three major metabolites, including 2-en-VPA. It is also metabolized by omega-oxidation in the microsomes. Neurotoxicity and hyperammonemia have been associated with the production of 2-en-VPA, while hepatotoxicity has been associated with 4-en-VPA produced during omega-oxidation.[28]
 
Carnitine deficiency is common in those taking valproate therapeutically and is also found in overdose.[154][155] The main effect of carnitine deficiency is impaired translocation of long chain fatty acids across the inner mitochondrial membrane. This interrupts beta-oxidation, and increases omega-oxidation. Processes that protect the urea cycle, the tricarboxylic acid cycle and pathways of gluconeogenesis from toxic metabolites are also interrupted.[28]
 
Interruption of the urea cycle, by metabolites of omega-oxidation, disrupts metabolism of nitrogen loads and contributes to hyperammonemia. Renal ammonia production is also increased. Hyperammonemia may increase intracellular osmolarity, promoting influx of water into the cell, resulting in cerebral edema.[66][156]
 
Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, are prone to developing hyperammonemia due to a defect in the processing of waste nitrogen. They are at increased risk of developing hyperammonemic encephalopathy with valproate taken therapeutically or in overdose.[104][105] Patients with carnitine deficiency also appear to be at increased risk of this condition.[66]
 

THERAPEUTIC DRUG INFORMATION

INDICATIONS

This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information.
 
Generally, indicated for the management of:[60][157]
Partial and generalized seizure disorders
Bipolar disorder
 
Generally, indicated for the prophylaxis of:[157]
Migraine
 

THERAPEUTIC DOSE RANGE

This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information.
 

Child

Epilepsy[60]
Oral
Under 20 kg
Initially 20 mg/kg daily in two divided doses
May be increased in severe cases (but only in those whom plasma valproic acid concentrations can be monitored)
Above 40 mg/kg/day, clinical chemistry and hematological parameters should be monitored
Over 20 kg
Initially 400 mg/day (irrespective of weight) in two divided doses
Usual dose range is 20 to 30 mg/kg per day
Maximum of 35 mg/kg per day
 
IV
Usual dose range is 20 to 30 mg/kg per day
May be increased to 40 mg/kg or more in severe cases (but only in those for whom plasma valproic acid concentrations can be monitored)
Above 40 mg/kg/day, clinical chemistry and hematological parameters should be monitored
 

Adult

Epilepsy[60][157]
Oral
Initially 600 mg daily, increased by 200 mg daily at three-day intervals
Daily doses generally within the range 1,000 to 2,000 mg/day (20 to 30 mg/kg/day)
Maximum 30 to 60 mg/kg/day
IV
 
If already satisfactorily treated
Continue at current oral dosage but instead using continuous or repeated infusion
If not currently treated
400 to 800 mg (depending on body weight) up to 10 mg/kg by slow intravenous injection over 3 to 5 minutes, followed by continuous or repeated infusion as required
Maximum 2,500 mg daily
 
Bipolar Disorder[60][157]
Oral
Initial dose 600 to 750 mg in 2 to 3 divided doses
Increased as rapidly as possible to desired effect
Daily doses generally within the range 1,000 to 2,000 mg/day (20 to 30 mg/kg/day)
IV
 
If already satisfactorily treated
Continue at current oral dosage but instead using continuous or repeated infusion
If not currently treated
400 to 800 mg (depending on body weight) up to 10 mg/kg by slow intravenous injection over 3 to 5 minutes, followed by continuous or repeated infusion as required
Maximum 2,500 mg daily
 
Migraine Prophylaxis[157]
Oral
Initial dose 250 mg twice daily
Maximum 1,000 mg daily
 

PHARMACOLOGICAL ACTION

Sodium valproate is rapidly metabolized to valproic acid in vivo.
 
The mechanism of action of valproic acid and its salts is not fully established, though multiple effects are likely. The valproic acid group is structurally unrelated to other anticonvulsants.
 
Valproic acid and its salts increase central nervous system concentrations of the inhibitory neurotransmitter GABA. GABAergic activity is potentiated in specific brain regions thought to be involved in the control of seizure generation and propagation. Valproic acid does not appear to alter the uptake of GABA or to alter receptor binding, instead an indirect mechanism has been proposed involving inhibition of enzymes in the GABA shunt.[158]
 
Normally, in the GABA shunt alpha-ketoglutarate is converted to glutamate rather than continuing through to the tricarboxylic acid cycle (TCA). Glutamate is then metabolized to GABA, which is subsequently converted to succinate semialdehyde and then to succinate, which re-enters the TCA. Valproic acid inhibits succinate semialdehyde dehydrogenase, leading to an increase in succinate semialdehyde and by negative feedback to increased GABA concentrations. Valproic acid also weakly inhibits GABA-transaminase, which effect contributes to increased GABA concentrations. Activation of glutamic acid decarboxylase (GAD), the enzyme catalysing the synthesis of GABA from glutamate, may also be involved.[64][159][160][161]
 
Other possible effects of valproic acid and its salts include a reduction in neuronal excitation induced by NMDA-type glutamate receptors and a reduction in gamma-hydroxybutyrate (GHB) release. Other neurotransmitter systems may also be affected.[64][159]
 

KINETICS

Sodium valproate is rapidly metabolized to valproic acid in vivo.
 

ABSORPTION

Oral Absorption
Rapid and almost complete absorption[64][60][157][162][163][164]
Effect of Food
Absorption is delayed but not decreased[60][163]
Milk products do not affect the rate or degree of absorption[60]
Other Factors Affecting Absorption
Significant delays in overdose[2][165]
Bioavailability
86 to 100% (solution)[64][163]
68 to 100% (tablets)[64][163][166]
80 to 90% (enteric coated tablets)[163]
Onset of Action
Onset of therapeutic action is several days to more than one week[157]
Time to Peak Plasma Levels
30 minutes to 2 hours (solution)[163]
30 minutes to 4 hours (tablets)[60][162][164][166][167]
3 to 7.5 hours (enteric coated tablets)[60][163]
7 to 14 hours (slow release formulation)[157][168]
Up to 18 hours following overdose[2][89]
 

DISTRIBUTION

Distribution
  1. Rapid[60]
  2. Probably restricted to the circulation and rapidly exchangeable extracellular water[60]
Volume of Distribution
  1. 0.13 to 0.19 L/kg (adult)[64][163][164][166][167]
  2. 0.19 to 0.34 L/kg (children)[169][170][171]
  3. 0.17 to 0.72 L/kg (overdose)[162]
Plasma Protein Binding
  1. 80 to 95%[64][163][167][172]
  2. Decreases with:
  3. - Increasing drug concentration.[163][172][173][174] Following overdose plasma protein binding may be 15 to 70%[28][11]
  4. - In geriatric patients[167]
  5. - In those with renal or hepatic impairment[172][175]
  6. - In presence of other protein-bound drugs[60]
  7. Saturation of binding sites may occur with lowered serum albumin concentrations, causing free drug concentrations to rise rapidly[60]
Lipid Solubility
Crosses the blood brain barrier[176]
  1. CSF concentrations 5 to 25% of plasma concentrations[64][60][176]
Crosses the placenta[177][178]
  1. The concentration of valproic acid in cord serum is 1.5 to 1.7 times higher than the concentration in maternal serum[177][178]
Is excreted in breast milk
  1. Breast milk concentrations 1 to 10% of plasma concentrations[60][149][150][151][178]
 

METABOLISM

Metabolism
  1. Extensive hepatic[157]
Metabolites
  1. Glucuronide conjugate of parent drug (40 to 60% of dose)[60][179][180]
  2. 3-Ketovalproic acid[180]
  3. Minor:
  4. 3-Hydroxyvalproic acid[180]
  5. 4-Hydroxyvalproic acid[180]
  6. 5-Hydroxyvalproic acid[179][180][181]
  7. 2-Propylglutaric acid[179][180][181]
Major Metabolic Pathways
Parent:
  1. Glucuronidation: 40 to 60%[60]
  2. Beta-oxidation: 30 to 40%[60][157]
  3. Omega-oxidation: 15 to 20%[157]
 

ELIMINATION

Excretion
Urine
  1. 50 to 86% eliminated in the urine[179][180]
  2. 1 to 4% eliminated unchanged[60][157][180]
  3. Metabolites excreted in urine[181][180][182]
Feces
  1. Small amounts[157]
Expired in air
  1. Small amounts[157]
Half-life
Therapeutic
  1. 5 to 20 hours (adults)[60][157][163][164][166][167]
  2. 6 to 12 hours (children)[169][183]
  3. 17.2 to 47 hours (neonates)[171][178][184]
Overdose
  1. 8.8 to 30 or more hours[88][60][162]
Clearance Rate
  1. 7.7 to 8.3 mL/h/kg (adult following a single dose)[167][173]
  2. 4.8 to 6.7 mL/h/kg (adult following 500 to 1,500 mg/day)[173][174]
  3. 13.0 to 31.8 mL/h/kg (children)[169][170][171]
  4. 10.8 mL/h/kg (neonates)[171]
Other Factors Affecting Elimination
  1. Studies in rats suggest enterohepatic circulation[185]
  2. Elimination is prolonged by 50% in patients with liver disease[175]
 

IDENTIFICATION

PRODUCT INFORMATION

Generally, tablets and capsules range from 100 to 500 mg sodium valproate. Sustained release forms are available.

Formulations for injection usually contain 100 mg/mL. Oral solutions are available in 40 and 50 mg/mL preparations.

Each specific trade name will state an exact quantity of the active ingredient (if this information is available).

OTHER NAME(S)

Common Names

  1. Sodium valproate
  2. Valproate sodium
 

Chemical Name

Sodium Valproate:
2-Propylpentanoic acid; sodium salt
 

CODES

ATC CLASSIFICATION

Antiepileptics - Fatty Acid DerivativesAntiepileptics
N03A G01
Valproic Acid
N03A G
 

CAS NUMBER

Sodium Valproate:
    1069-66-5
 

MOLECULAR FORMULA

Sodium Valproate:
C8H15NaO2
 

PHYSICOCHEMICAL PROPERTIES

A white or almost white, crystalline, hygroscopic powder
 
Molecular Weight
166.2 166.2% degrees C[130]
pKa
4.8 4.8% degrees C[130]
Solubility
Water: freely soluble[130]
Ethanol: freely soluble[130]
 

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