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Sodium Valproate

Sodium Valproate
23.Mar.2019-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 400 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 400 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 exposure does not meet the intervention level and the patient is asymptomatic, they can be observed at home in the care of a reliable observer. The patient should be observed for 6 hours following ingestion of a standard preparation or for 24 hours if a sustained release formulation has been ingested.
 
The patient should be medically assessed if any symptoms develop, including:
Vomiting
Drowsiness
Confusion
Unconsciousness
Tremor
 

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:
- Discharge into the care of a reliable observer, or
- Refer for psychiatric assessment (if the overdose was intentional)
 
If the patient is symptomatic on presentation they should be observed until there has been resolution of signs of valproate toxicity and serum concentrations have fallen into the therapeutic range.
 

Investigations

Levels

Valproic acid serum concentrations should be measured following ingestion of immediate- and sustained release-preparations when the suspected dose is > 200 mg/kg.
 
Serum concentrations should be taken on presentation and repeated at 3 to 4 hour intervals (to identify the onset of peak concentrations and ensure that the serum concentrations are falling)[1][2][3]
In particular, patients ingesting enteric coated formulations of valproic acid may have slowed absorption or form concretions in the GI tract. Absorption may be delayed and prolonged. Hence, serial serum valproate estimations may be useful to ascertain ongoing absorption and guide the need for further GI decontamination and extracorporeal elimination.
 
Click here to link to toxic serum levels
 

Monitoring

Monitor:
Level of consciousness
Respiratory rate
Oxygen saturations
Heart rate
Blood pressure
ECG
Seizure activity
Blood gas analysis
Blood glucose
Urea and electrolytes
 

Admission Criteria

Hospital admission is recommended when:
- >400 mg/kg or more is ingested
- Serum concentration is greater than 5,908 umol/L (850 mg/L) valproic acid
- Following symptoms occur 
Any decreased level of consciousness
Respiratory depression
Hypotension
Hypoglycemia
Recurrent seizures
- Following conditions are present
Electrolyte disturbances (hypernatremia)
Metabolic acidosis
Encephalopathy
Hepatotoxicity
Pancreatitis
 

TREATMENT

TREATMENT SUMMARY

Severe toxicity is unlikely in the majority of overdoses. However, 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 is recommended for ingestions over 400 mg/kg sodium valproate.
 
There are no proven antidotes for valproic acid intoxication, although L-carnitine may be considered an adjunct to standard management.[4][5] Multiple dose activated charcoal and hemodialysis may be useful in severe toxicity.[6] Valproic acid concentrations should be monitored.
 
Acute treatment is primarily symptomatic and supportive, focussing mainly on CNS and respiratory depression. Treatment of encephalopathy, seizures, hypotension, electrolyte disturbances, thrombocytopenia, metabolic acidosis, bone marrow suppression, and hypothermia may sometimes be required following large to massive overdoses. Hepatotoxicity and pancreatitis are uncommon with overdose, but do occur with therapeutic doses and may be fatal. Delayed cerebral edema may occur. Ammonia concentrations should be checked if encephalopathy is suspected.
 
Patients with chronic valproate toxicity will require referral to their a neurologist for dosage adjustment and monitoring of their ongoing therapy.
 
Emergency Stabilization
Ensure adequate cardiorespiratory function
Cardiac arrest
Seizure
Metabolic acidosis
Emergency monitoring
Decontamination
Ingestion
Single dose activated charcoal
Exclude bezoar
Antidote(s)
None recommended
L-Carnitine
Enhanced Elimination
Multiple dose activated charcoal
Hemodialysis
Supportive Care
Monitoring
Neurologic
CNS depression
Seizure
Encephalopathy
Cerebral edema
Respiratory
Respiratory depression
Cardiovascular
Hypotension
Metabolic
Hypoglycemia
Metabolic acidosis
Fluid and electrolytes
Electrolyte abnormalities
Hematologic
Thrombocytopenia
Bone marrow suppression
Hepatic
Hepatotoxicity
Gastrointestinal
Pancreatitis
 

EMERGENCY STABILIZATION

Ensure Adequate Cardiopulmonary Function

Endotracheal intubation maybe 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 uncommon with valproate overdose.
 
Administer a benzodiazepine as first-line treatment to patients with seizure activity.[7]
 
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
Respiratory rate
Heart rate
ECG
Blood pressure
Seizure activity
Acid-base balance
 

DECONTAMINATION

Ingestion

Single Dose Activated Charcoal

Decontamination with activated charcoal is recommended for ingestions over 400 mg/kg sodium valproate.
 
CNS depression is a likely consequence of significant overdose. Gastrointestinal decontamination should be undertaken with appropriate airway protection.
 
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 2 hours previously.
 
Single dose activated charcoal[8]
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.
 

Exclude Bezoar

While bezoar formation is unlikely following valproate overdose, the possibility should be considered with the ingestion of enteric-coated or modified-release formulations.
 
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.[9]
 
Investigation for the presence of a tablet mass in the upper GI tract may be of benefit in the patient with life-threatening toxicity, but negative imaging studies do not exclude the presence of a bezoar.
 
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 impossible to remove without laparotomy.
 

ANTIDOTE(S)

There Are No Antidotes For This Substance

No clinically established antidotes exist for the treatment of valproic acid overdose. However, naloxone and L-carnitine have both been used in a number of cases with varying results.
 
Naloxone has been used successfully in a small number of cases to reverse valproate-induced CNS depression[10][11][12][13][14][15]This appears to have been more effective in patients with minimally elevated serum concentrations,[16][17]with other reports showing no effect in patients with much higher concentrations.[18][19][20]Any effect may be due to reversal of valproate blockade of GABA cellular uptake or reversal of valproate-induced release of endogenous opioids.[16][21]
 

L-Carnitine

Evidence supporting clinical efficacy and safety of L-carnitine in acute valproic acid poisoning is limited.[4] The primary route of metabolism of valproic acid by beta-oxidation is inhibited by hypocarnitemia,[22] a state which is commonly observed in chronic, supratherapeutic valproic acid poisoning. Administration of L-carnitine is thought to normalize metabolism[23]  and has well established clinical benefit in reversing hyperammonemia in these patients. It is strongly recommended prophylactically in “at-risk” patients on valproic acid therapy.[24][25]
 
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.[22][26][4] There are also anecdotal reports of reversal of hyperammonemia in acute poisoning.[27][28][29] L-carnitine does not appear to have any effect on neurological toxicity.[26]
 
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.[4][5]
 

Indications

L-carnitine administration is indicated in patients with:
Decreased level of consciousness[4][5]
Hyperammonemia[30][26][5][31]
Some authors also recommend considering L-carnitine administration if severe toxicity is present or likely:
Ingestions > 100 mg/kg valproic  acid[4]
Serum valproic acid concentrations > 3,128 umol/L (> 450 mg/L)[4][5][32]
Hepatotoxicity[25][26]
 

Dose and Administration

Note that the recommended L-carnitine dose for acute valproic acid poisoning is higher[4][5][27][28][22] than that used for chronic, supratherapeutic poisoning[30][25][5] or mild hypocarnitemia. Case reports indicate that L-carnitine infusion may be required for up to 3 to 4 days.[4][28]
 
L-Carnitine Dosage in Acute Valproic Acid Poisoning
 
CHILD and ADULT
IV
Loading dose:
100 mg/kg (bolus over 2 to 3 minutes or infusion over 15 to 30 minutes)[4][5]
Maximum dose 3 g[4](up to 6 g has been given)[5]
Maintenance dose:
50 mg/kg every 8 hours[4] or 15 mg/kg every 4 hours[5]
Doses given either as bolus over 2 to 3 minutes or infusion over 15 to 30 minutes[4][5]
End Point:
Ammonia levels decreasing, patient demonstrates clinical improvement, or significant adverse effects occur.[4][5]
 

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.[33][34]
 

Contra-indications

L-carnitine does not have any contraindications.[33][34]
 

Adverse Effects

Seizures are reported, both in patients with or without a prior history of convulsive disorder.[33][34] Tachydysrhythmias, hypertension, and hypotension are also noted.[4] Gastrointestinal upset[34] and an unpleasant, fishy body odor may occur.[26][30] No allergic reactions or adverse effects were observed when L-carnitine was administered in 215 acute valproic acid poisoning cases.[31]
 

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. As a result, it may be useful in patients with large overdoses and very high 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.[35][36][11]
 
Care should be taken to monitor the patient 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.[37] Charcoal should not be administered to a patient with ileus.
 

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.[6] Hemodialysis has resulted in clinical improvement and/or enhanced elimination in the treatment of valproate overdose.[38][39][40][41][42][43][44][45]
 
Hemodialysis is recommended in any of the following situations:[6]
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:[6]
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 but intermittent hemoperfusion or continuous renal replacement therapy are acceptable alternatives if hemodialysis is not available.[6]
 
Hemodialysis should continue until sustained clinical improvement is observed or the serum valproic acid concentration is below 100 mg/L (700 umol/L).[6]
 

Other Forms of Enhanced Elimination

Hemoperfusion[2][46] hemofiltration[46][44]and combinations of these techniques with hemodialysis[47][48][19]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.[6]
 

SUPPORTIVE CARE

Monitoring

Vital signs
Level of consciousness
Respiratory rate
Circulatory status
Acid base balance
Urea and electrolytes
Sodium
Calcium
Phosphate
Bicarbonate
Blood urea nitrogen
Blood glucose
Full blood count including platelets
Liver function tests
Serum ammonia (if persistent confusion, stupor or coma)
Pancreatic enzymes (if pancreatitis suspected)
 
Following intravenous overdose, also monitor ECG
 
Serum valproic acid concentrations should be performed in all valproate overdoses over 100 mg/kg. Normal therapeutic concentrations lie in the range 278 to 694 umol/L (40 to 100 mg/L).[49]Initial serum concentrations may be misleading, especially with the ingestion of enteric-coated formulations.[3]
 
Valproic acid concentrations should be repeated every three to four hours and closely monitored. Declining concentrations should be documented before discharge is considered.
 

Neurologic

CNS Depression

CNS depression, ranging from drowsiness to coma, is the most frequent symptom after valproate overdose. In small overdoses drowsiness may be the only feature, while massive overdose may result in coma. Sedation and ataxia may also occur in those taking valproate therapeutically.[50][51]
 
Closely monitor level of consciousness.
 
Manage depressed level of consciousness following standard treatment protocols.
 

Seizures

Seizures have occasionally been reported after ingestion of valproate drugs. However, it may be difficult to determine which are due to toxicity and which reflect an underlying seizure disorder.[52][53]
 
Observe the patient closely for onset of seizure activity.
 

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 of valproate drugs. This condition has also developed in patients taking therapeutic doses, either chronically or in combination with other antiepileptics.[54][55][56][24][57][58][59][60][61][62]
 
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.[54]
 
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 uncommon following valproate intoxication. Onset is usually delayed. It may develop two to three days into the course of severe valproate poisoning.[63][64]
 
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.
 

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.[65][66][2]
 
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 following valproate overdose. It has been observed following massive overdoses and may be resistant to treatment. It carries a poor prognosis.[51][67]
 
Monitor:
Heart rate/rhythm
Blood pressure
ECG
 
Manage hypotension following standard treatment protocols.
 

Metabolic

Hypoglycemia

Hypoglycemia is uncommon following valproate overdose, but may be prolonged and severe.[67]
 
Monitor serum glucose.
 
Manage hypoglycemia following standard treatment protocols.
 

Metabolic Acidosis

Metabolic acidosis may occur in a minority of patients following valproate overdose. It is commonly associated with massive valproate overdose and serum concentrations greater than 5,908 umol/L (850 mg/L).[51][67]
 
Monitor:
Blood gas analysis (pH, bicarbonate, pCO2, pO2)
Plasma lactate
Base deficit
 
Manage metabolic acidosis following standard treatment protocols.
 

Fluid and Electrolytes

Electrolyte Abnormalities

Prolonged and severe electrolyte disturbances, including hypocalcemia, hypernatremia and hypophosphatemia, may occur following massive valproate overdoses. Hypernatremia may indirectly indicate a large ingestion of the sodium salt of valproate.[67]
 
Monitor serum electrolytes.
 
Manage serum electrolyte abnormalities following standard treatment protocols.
 

Hematologic

Thrombocytopenia

Clinically significant thrombocytopenia may occur following overdoses of large amounts of valproate. Transfusions have been required.[51]
 
Monitor:
White blood cell count
Platelet count
 
Manage thrombocytopenia following standard treatment protocols.
 

Bone Marrow Suppression

Bone marrow suppression may present three to five days after a massive overdose, and usually resolves spontaneously a few days later.[51]However, severe bone marrow depression requiring transfusion has occurred with overdose and fatal bone marrow failure with therapeutic doses.[68]
 
Closely monitor serial full blood counts including platelets and white blood cells, and coagulation profiles. Observe for infection or bleeding.
 
Manage bone marrow suppression following standard treatment protocols.
 
If bone marrow suppression is severe, blood constituent replacement products may be necessary; a blood culture should also be considered. Treatment is best provided in an isolated and/or intensive care environment. Extra caution must be exercised with invasive IV or other lines. Granulocyte colony stimulating factor (G-CSF) may possibly accelerate recovery.
 

Hepatic

Hepatotoxicity

Increases in serum aminotransferases, bilirubin and ammonia are relatively common in patients taking valproate drugs therapeutically. These changes have also been observed in overdose and do not necessarily indicate severe toxicity.[49]
 
Hepatotoxicity, and rarely hepatic failure have been reported with overdose and may also occur with therapeutic use, most commonly in the first few months of treatment. Young children with multiple medical problems, on multiple antiepileptic agents are at highest risk of fatal hepatotoxicity.[69][70][71][72]
 
Hepatic monitoring should include:
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
International normalized ratio (INR)
Serum bilirubin
Plasma glucose
 
Manage acute hepatotoxicity following standard treatment protocols.
 

Gastrointestinal

Pancreatitis

Hemorrhagic pancreatitis with rapid progression from initial symptoms to death has occurred rarely with therapeutic use. This may occur shortly after initiation of treatment or following several years of use.[49]Pancreatitis has also been reported in overdose but is not common.[51][18]
 
Observe for:
Vomiting
Persistent, severe, abdominal pain (may radiate to the back)
 
Monitor:
Full blood count
Blood glucose
Urea and electrolytes
Serum amylase and lipase concentrations
 
Manage pancreatitis following standard treatment protocols.
 

DISCHARGE CRITERIA

Patients should not be considered for discharge until serum valproate concentrations are within the therapeutic range, serial concentrations are declining, and clinical evidence of toxicity has resolved. Alternatively, a prolonged period of observation should be documented before discharge is considered, especially when enteric-coated preparations are ingested. 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.
 
CNS depression, ranging from drowsiness to coma, is the most frequent sign after valproic acid overdose; with ingestions less than 200 mg/kg asymptomatic or displaying mild drowsiness and ataxia only. Ingestions from 200 to 400 mg/kg are likely to present varying levels of consciousness. Significant CNS depression is likely with multi-organ involvement as dose increases between 400 and 1,000 mg/kg. Massive overdoses (> 1,000 mg/kg) can result in serious CNS and respiratory depression, hypotension, metabolic acidosis, and bone marrow depression. Severe hyperammonemic encephalopathy, cerebral edema, and clinically significant thrombocytopenia may develop; hypernatremia, hypoglycemia, hypocalcemia and other electrolyte disturbances may be severe and prolonged.[73] Delayed cerebral edema may occur though is not common. Death is rare, and usually results from cardiac or respiratory arrest.
 
Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, are at increased risk of developing hyperammonemic encephalopathy. This may occur with therapeutic dosing.
 
Hepatotoxicity, pancreatitis and other adverse effects seen with therapeutic doses may occasionally occur with overdose.
 
There is a risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients starting carbamazepine therapy.[74]
 

Onset/Duration of Symptoms

Symptoms would usually be expected to develop within four hours of ingestion with most standard preparations of valproate. Delayed toxicity may occur with ingestion of sustained release or enteric-coated formulations, with CNS depression occurring as long as 8 to 13 hours post-ingestion.[75][76]
 
Metabolic disturbances usually present early, and may be severe and prolonged. The development of cerebral edema may also be delayed, presenting two to three days or more post-ingestion. Bone marrow suppression may present three to five days after a massive overdose, and usually resolves spontaneously a few days later.
 

Severity of Poisoning

Mild Valproate ToxicityModerate Valproate ToxicitySevere Valproate Toxicity
Mild drowsiness
Confusion
Nausea
Vomiting
Tachycardia
Increased drowsiness
Electrolyte disturbances
Hypoglycemia
Thrombocytopenia
Unconsciousness / coma
Cerebral edema
Hypotension
Respiratory depression
Respiratory or metabolic acidosis
Seizures
Cardiac or respiratory arrest
 

ACUTE EFFECTS (ORGAN SYSTEM)

Neurologic

Drowsiness[50]
Lethargy[67]
Dizziness[77]
Confusion[50]
Withdrawal
Stupor[78]
Hyporeflexia[55]
Hypotonia[53]
Cerebral edema (may be delayed)[63][64]
Asterixis[80]
Hyperammonemic encephalopathy[55]
Myoclonic movements[81] (rare)
Seizures (rare)[52]
 

Gastrointestinal

Nausea
Vomiting[77]
Pancreatitis (rare)[51][18]
 

Cardiovascular

Tachycardia[67]
Bradycardia[79]
Hypotension[51][79]
Atrial fibrillation[79]
QT prolongation[82]
Cardiac arrest[83]
 

Respiratory

Respiratory depression[65]
Respiratory acidosis[79]
Aspiration pneumonitis[67]
Respiratory arrest[51]
 

Metabolic

Fever[84]
Hypothermia[18][85][79]
Hypoglycemia[67][79]
Hyperammonemia
Hyperlactacidemia
Metabolic acidosis[51]
 

Fluid and Electrolytes

Hypocalcemia[67]
Hypernatremia[79][67]
Hypophosphatemia[67]
 

Hepatic

Elevation of serum ammonia and hepatic enzymes[86]
Hepatotoxicity (rare)[67]
 

Hematologic

Thrombocytopenia[51]
Bone marrow suppression[51]
Leukopenia[67]
Anemia
Decreased ESR
Decreased fibrinogen
Abnormal bleeding, partial thromboplastin, and prothrombin times
Methemoglobinemia[87]
 

Renal

Renal failure (rare)[66][38]

Ocular

Miosis[11]
Pupils sluggishly reactive to light
Nystagmus[77]
Optic nerve atrophy[84]

Dermatologic

Macular pruritic rash
Bullous lesions[68]
Alopecia[20]

Other

Elevated creatine kinase[67]
Rhabdomyolysis[68]
Stevens-Johnson syndrome[74]
Toxic epidermal necrolysis[74]
 

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.
 

CHRONIC EFFECTS

Adverse Effects

Adverse effects in patients taking valproate drugs therapeutically are not uncommon, and may also occur in overdose. Some effects such as increases in hepatic enzymes, bone marrow suppression, sedation or ataxia may be misleading, suggesting a higher degree of toxicity following overdose than is present.
 
There are also some serious adverse effects that occur at therapeutic doses which may occur in overdose. These include fatal hepatotoxicity such as toxic cholestatic hepatitis and hepatocellular necrosis,[24][69]pancreatitis,[88]and severe hyperammonemic encephalopathy.[56][58]
 
Hepatotoxicity, and rarely hepatic failure, occur most commonly in the first few months of treatment. Young children with multiple medical problems, on multiple antiepileptic agents are at highest risk of fatal hepatotoxicity. Fatalities due to pancreatitis have also occurred.[69][70][71][72]
 
Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, may develop hyperammonemic encephalopathy following initiation of valproate therapy at normal doses.[49]
 

TOXICITY

HUMAN

Acute

Minor toxicity (e.g. drowsiness) may occur at therapeutic doses (20 mg/kg valproate). The lowest dose to have caused seizures is 100 mg/kg. Loss of consciousness generally does not occur at doses less than 200 mg/kg,[89] but has occurred at 38 mg/kg in a 3 year old child,[12] and approximately 20 mg/kg in an adult.[63]
 
The lowest fatal dose is 330 mg/kg,[90] and doses greater than 400 mg/kg are considered potentially life-threatening.[86] However, fatalities are relatively uncommon, and doses of between 20 to 160 g (~300 to 2,300 mg/kg) have been survived with supportive care.[91]
 
Medical observation is recommended for ingestions greater than 50 mg/kg, and decontamination with activated charcoal is recommended for ingestions greater than 400 mg/kg.[91]
 

Child

There are limited reports in the literature of valproate overdose in children. Serious toxicity has been described; as has a fatality following ingestion of 750 mg/kg. However in most cases the dose ingested is unknown or is massive, making estimation of a toxic or fatal dose difficult. Because of these limitations the intervention levels for children have been based on adult toxicity.
 
Case Studies
Sodium valproate, valproate pivoxil, valproate semisodium and valpromide are rapidly metabolized to valproic acid in vivo.
 
Valproic acid
~7.5 g Valproic acid (625 mg/kg)
26 month old female: cerebral edema, also serious metabolic, hematological and respiratory symptoms
Recovered after ventriculostomy and supportive treatment[64]
 
Sodium valproate
4.5 g Sodium valproate (~375 mg/kg)
26 month old child: apneic episodes
Recovered after naloxone and continuous nasogastric infusion of activated charcoal[35]
~15 g Sodium valproate (~750 mg/kg absorbed)
20 month old male: coma, metabolic acidosis, electrolyte abnormalities, cerebral edema, severe bronchial pneumonia, cardiorespiratory failure
Fatal, 47 hours post-ingestion[83]
Unknown amount of Sodium valproate
2 month old female: generalized seizures, progressive coma, anuria, electrolyte disturbances, anemia, coagulopathy
Recovered after treatment with hemoperfusion, hemodialysis, peritoneal dialysis[53]
 
Valproate semisodium
Unknown amount of Valproate semisodium
3 year old child: methemoglobinemia, metabolic acidosis, hypoxia
Recovered after treatment with methylene blue[87]
Unknown (large amount ingested)
4 year old child: bullous lesions, hypotension, rhabdomyolysis, bone marrow suppression, prolonged coma
Outcome not stated[68]
 

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 extremely unlikely at doses less than 200 mg/kg.[86][52][67]
 
> 200 mg/kg
Mild to moderate toxicity
> 400 mg/kg
Severe toxicity, including coma
> 1,000 mg/kg
Expected to be lethal without treatment[52][86]
 
Case Studies
Sodium valproate, valproate pivoxil, valproate semisodium and valpromide are rapidly metabolized to valproic acid in vivo.
 
Valproic acid
30 g Valproic acid
16 year old female: drowsiness, thrombocytopenia
Recovered[78]
30 g Valproic acid (435 mg/kg)
24 year old male: severe coma, hypotension, thrombocytopenia, hyperammonemia, acute-on-chronic renal failure
Recovered after gastric lavage, activated charcoal, hemodialysis[38]
50 g Valproic acid extended release (714 mg/kg)
41 year old male: lethargy
Recovered after gastric lavage, activated charcoal and hemodialysis[92]
56.4 g Valproic acid
Clinical details not available
Fatal[93]
 
Sodium valproate
8 g Sodium valproate
22 year old male: coma, apnea, respiratory acidosis, bradycardia, hypotension, atrial fibrillation, severe hypothermia, hypernatremia, hypoglycemia, elevated creatine kinase
Recovered fully after supportive care in ICU including intubation, ventilation, glucose and rewarming[79]
19 g Sodium valproate slow release
43 year old female: coma, metabolic acidosis, hypotension, thrombocytopenia
Recovered with hemodialysis[42]
20 g Sodium valproate (330 mg/kg)
15 year old female: coma, metabolic acidosis, cerebral edema, hyperammonemia, hyperlactacidemia
Fatal 4 days after ingestion[90]
25 g Sodium valproate, 30 mg Diazepam
18 year old female: unconsciousness, hypotonia, respiratory arrest
Recovered after three days of artificial respiration[94]
45 g Sodium valproate
18 year old male: unconsciousness, metabolic acidosis, hyperammonemia, increased serum transaminases, hypernatremia, hypocalcemia
Recovered with supportive treatment[95]
75 g Sodium valproate
20 year old female: coma
Recovered with supportive treatment, hemoperfusion and hemodialysis[19]
Unknown amount Sodium valproate
40 year old female: coma, hypotension, respiratory depression, acute renal failure, hypothermia
Fatal 72 hours after admission despite supportive treatment[18] 
 
Valproate Semisodium
28.75 g Valproate semisodium
15 year old male: vomiting, delirium, miosis, transient nephropathy
Recovered after multiple dose activated charcoal[96]
207.5 g Valproate semisodium
45 year old male: coma, respiratory arrest, metabolic acidosis, renal failure, multi-organ failure
Fatal, 79 hours post-ingestion despite aggressive treatment[66]
350 g Valproate semisodium
24 year old female: coma, metabolic acidosis, renal insufficiency, hypotension
Fatal, 48 hours post-ingestion despite aggressive treatment[66]
 
Valpromide
18 g Valpromide, unknown amount of Olanzepine
29 year old male: initially drowsiness; coma developed 20 h post-ingestion
Recovered after activated charcoal, ICU care and mechanical ventilation for two days[1]
36 g Valpromide
29 year old male: initially asymptomatic; coma, hyperammonemia, hyperlactacidemia developing 44 h post-ingestion
Recovered after activated charcoal, ICU care and mechanical ventilation for three days[1]
 

Chronic

Toxic effects are frequently associated with daily doses over 1,800 mg valproic acid and blood concentrations over 100 mg/L.
 
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.[97]
 
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.[98]
 

ANIMAL

Acute

Sodium valproate, valproate pivoxil, valproate semisodium and valpromide are rapidly metabolized to valproic acid in vivo.
 
LD50 Oral, Rat
670 mg/kg (Valproic acid)[99]
LD50 Oral, Mouse
1,700 mg/kg (Sodium valproate)[99]

BIOLOGICAL LEVELS - TOXIC

Normal Plasma Level

Usual Therapeutic Concentration
50 to 100 mg/L (350 to 690 umol/L) valproic acid[100]
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.
 
Greater than 3,128 umol/L (450 mg/L) valproic acid may result in moderate or major toxic effects.
 
Greater than 5,908 umol/L (850 mg/L) valproic acid may result in major toxic effects, including, coma, respiratory depression, or metabolic acidosis.
 
Greater than 13,900 umol/L (2,000 mg/L) valproic acid may result in death.[67]
 

REPRODUCTION

Sodium valproate is rapidly metabolized to valproic acid in vivo.
 

FERTILITY

Animal studies have shown that valproic acid does affect fertility at very high doses.
 
Male
 
Increased serum androgen concentrations, without increased circulating LH or insulin concentrations, were found in 57% of 21 men taking valproic acid. Mean serum concentrations of androstenedione were high in these patients.[101]
 
No effect on fertility in male rats was observed with doses up to 500 mg/kg valproic acid over a 10 week period. Doses of 500 mg/kg decreased the weight of several male sexual organs, and decreased the number of normal motile sperm present. Doses of 1,000 mg/kg were fatal.[102] Similar results were found in other studies.[103][104]
 

PREGNANCY

Valproic acid crosses the placenta and is likely to affect the fetus. Taking valproic acid is not considered safe during pregnancy and should not be used in female children, in female adolescents, or in women of child-bearing age, unless alternative treatments are not tolerated or ineffective.[49]
 
Valproic acid and its salts are human teratogens. Anomalies observed can affect the neural tube, genitourinary system, heart, limbs, skin, and face.[105] Furthermore developmental delays are also common.[105] Reports estimate that between 6.7% to 12.4% of children exposed to valproate develop congenital malformations.[106][105]
 
The most serious abnormalities observed are defects in neural tube closure.[107][108] A characteristic pattern of minor facial defects is also associated with valproic acid.[109][108] Other predominant effects involve the heart and limbs.[109] However, as epileptic women have a two to three times greater risk of delivering a child with congenital defects over the general population, it is difficult to establish if these defects are related to valproic acid therapy.
 
Australian Classification:
D
 
FDA Classification (before July 2015):
D
 
For full details of the Australian ADC pregnancy classification, as well as the FDA classification (used prior to July 2015), Click here.
 

LACTATION

Valproic acid is excreted into human breast milk in low concentrations. and is unlikely to affect the nursing infant. 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.[110] 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.[111]
 
The American Academy of Pediatrics considers valproic acid to be compatible with breast feeding.[112]
 

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 also occurs at therapeutic doses, may be expected to arise as an extension of the normal pharmacological action of valproate. This is thought to be related to increasing brain GABA concentrations. Unfortunately, the mechanism is not clear. 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.[30]
 
Carnitine deficiency is common in those taking valproate therapeutically and is also found in overdose. 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.[30]
 
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.[113]
 
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. Patients with carnitine deficiency also appear to be at increased risk of this condition.[54]
 

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:[49]
Epilepsy
Mania
 
Generally, indicated for the prophylaxis of:[114]
Migraine
 

THERAPEUTIC DOSE RANGE

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

Child

Epilepsy[49]
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
 

Adult

Epilepsy[49]
Oral
Initially 600 mg daily in two divided doses, increasing by 200 mg at three day intervals until control is achieved
Usual dose range is 1,000 to 2,000 mg daily (20 to 30 mg/kg)
Maximum 2,500 mg daily
 
Mania[49]
Oral
Initially 600 mg daily in two divided doses, increasing by 200 mg at three day intervals until control is achieved
Usual dose range is 1,000 to 2,000 mg daily (20 to 30 mg/kg)
Maximum 2,500 mg daily
 
Elderly
Dose must be titrated against response
Renal/Hepatic Impairment
May be necessary to decrease dose. Dose should be adjusted according to clinical monitoring
 
IV
If already satisfactorily treated with sodium valproate
Continue at current oral dosage using continuous or repeated infusion
If not currently treated with sodium valproate
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
 

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.[115]
 
Normally, in the GABA shunt alpha-ketoglutarate is converted to glutamate rather than continuing through 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 contributes to increased GABA levels. Activation of glutamic acid decarboxylase (GAD), the enzyme catalysing the synthesis of GABA from glutamate, may also be involved.[116][117][118][119]
 
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.[119][116]
 

BIOLOGICAL LEVELS - THERAPEUTIC

Normal Plasma Level

Usual Therapeutic Concentration
50 to 100 mg/L (350 to 690 umol/L) valproic acid[100]
Note: Higher concentrations are used by some clinicians
 

KINETICS

Sodium valproate is rapidly metabolized to valproic acid in vivo.
 

ABSORPTION

Oral Absorption
Rapid and almost complete absorption[49]
Effect of Food
Absorption is delayed but not decreased[49]
Milk products do not affect the rate or degree of absorption[49]
Other Factors Affecting Absorption
Significant delays in overdose[120]
Bioavailability
Close to 100%[121]
Onset of Action
Onset of therapeutic action is several days to more than one week[114]
Time to Peak Plasma Levels
15 minutes to 2 hours (syrup)[115]
1 to 4 hours (capsules)[114]
3 to 7 hours (enteric coated tablets)[49]
7 to 14 hours (slow release formulation)[122]
 

DISTRIBUTION

Distribution
  1. Rapid
  2. Probably restricted to the circulation and rapidly exchangeable extracellular water[49]
Volume of Distribution
  1. 0.1 to 0.4 L/kg[123]
Plasma Protein Binding
  1. 80 to 95%[114]
  2. Decreases with:
  3. - Increasing drug concentration
  4. - In geriatric patients
  5. - In those with renal or hepatic impairment
  6. - In presence of other protein-bound drugs
  7. Saturation of binding sites may occur with lowered serum albumin concentrations, causing free drug concentrations to rise rapidly[49]
Lipid Solubility
Crosses the blood brain barrier
  1. CSF concentrations 5 to 15 % of plasma concentrations[49]
Crosses the placenta[49]
Is excreted in breast milk
  1. Breast milk concentrations 1 to 10 % of plasma concentrations[49]
 

METABOLISM

Metabolism
  1. Extensive hepatic[114]
Metabolites
Active:
  1. Glucuronide conjugate of parent drug (up to 59% of dose)
  2. 3-Ketovalproic acid (23%)
  3. 3-Hydroxyvalproic acid (3%)
  4. 4-Hydroxyvalproic acid (3%)
  5. 5-Hydroxyvalproic acid (3%)
  6. 2-Propylglutaric acid (5%)
  7. Conjugated forms of 2-en-valproic acid, 3-en-valproic acid, 4-en-valproic acid[123]
Major Metabolic Pathways
Parent:
  1. Glucuronidation: 40 to 60%
  2. Beta-oxidation: 30 to 40%
  3. Omega-oxidation: up to 30%[124]
 

ELIMINATION

Excretion
Urine
  1. Metabolites excreted in urine[49]
  2. 1 to 3% excreted unchanged[49]
Feces
  1. Small amounts[114]
Expired in air
  1. Small amounts[114]
Half-life
Therapeutic
  1. 10 to 20 hours (adults)[121]
  2. 6 to 9 hours (children)[121]
Overdose
  1. Up to 30 hours[121]
Clearance Rate
  1. 4.8 to 8.3 mL/h/kg (following 500 to 1,500 mg/day)[125][126]
Other Factors Affecting Elimination
  1. Studies in rats suggest enterohepatic circulation 7%[127]
 

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[99]
pKa
4.8 4.8% degrees C[99]
Solubility
Water: freely soluble[99]
Ethanol: freely soluble[99]
 

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