DESCRIPTION
SUBSTANCE CLASS
Carboxylic Acid Derivative |
INTERVENTION CRITERIA
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 |
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 |
Medical assessment and observation is recommended for: - Any symptomatic chronic ingestion |
If the patient does not require medical observation they can be monitored 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 |
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. |
Valproic acid serum concentrations should be measured following ingestion of immediate- and sustained release-preparations when the suspected dose is > 200 mg/kg. 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. |
Monitor: Level of consciousness Respiratory rate Oxygen saturations Heart rate Blood pressure ECG Seizure activity Blood gas analysis Blood glucose Urea and electrolytes |
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.  M ultiple dose activated charcoal and hemodialysis may be useful in severe toxicity. 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 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. |
Seizures are uncommon with valproate overdose. |
Administer a benzodiazepine as first-line treatment to patients with seizure activity. Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, supplemental dextrose should be administered IV. |
Follow standard protocols for the management of metabolic acidosis.
|
Level of consciousness Respiratory rate Heart rate ECG Blood pressure Seizure activity Acid-base balance |
DECONTAMINATION
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 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. |
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. 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 |
Evidence supporting clinical efficacy and safety of L-carnitine in acute valproic acid poisoning is limited. The primary route of metabolism of valproic acid by beta-oxidation is inhibited by hypocarnitemia, a state which is commonly observed in chronic, supratherapeutic valproic acid poisoning. Administration of L-carnitine is thought to normalize metabolism 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. 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. |
L-carnitine administration is indicated in patients with: Decreased level of consciousness Some authors also recommend considering L-carnitine administration if severe toxicity is present or likely: Ingestions > 100 mg/kg valproic acid Hepatotoxicity |
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) 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 either as bolus over 2 to 3 minutes or infusion over 15 to 30 minutes End Point: Ammonia levels decreasing, patient demonstrates clinical improvement, or significant adverse effects occur. |
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. |
L-carnitine does not have any contraindications. |
Seizures are reported, both in patients with or without a prior history of convulsive disorder. Tachydysrhythmias, hypertension, and hypotension are also noted. Gastrointestinal upset and an unpleasant, fishy body odor may occur. No allergic reactions or adverse effects were observed when L-carnitine was administered in 215 acute valproic acid poisoning cases. |
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. 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. Charcoal should not be administered to a patient with ileus. |
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. Hemodialysis has resulted in clinical improvement and/or enhanced elimination in the treatment of valproate overdose. Hemodialysis is recommended in any of the following situations: 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: 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. Hemodialysis should continue until sustained clinical improvement is observed or the serum valproic acid concentration is below 100 mg/L (700 umol/L). |
Other Forms of Enhanced Elimination |
SUPPORTIVE CARE
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). Initial serum concentrations may be misleading, especially with the ingestion of enteric-coated formulations. Valproic acid concentrations should be repeated every three to four hours and closely monitored. Declining concentrations should be documented before discharge is considered. |
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. |
Closely monitor level of consciousness. |
Manage depressed level of consciousness following standard treatment protocols. |
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. |
Observe the patient closely for onset of seizure activity. |
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 is uncommon following valproate intoxication. Onset is usually delayed. It may develop two to three days into the course of severe valproate poisoning. |
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. |
Monitor: Respiratory rate Pulse oximetry Blood gas analysis |
Manage respiratory depression following standard treatment protocols. |
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. |
Monitor: Heart rate/rhythm Blood pressure ECG |
Manage hypotension following standard treatment protocols. |
Hypoglycemia is uncommon following valproate overdose, but may be prolonged and severe. |
Manage hypoglycemia following standard treatment protocols. |
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). |
Monitor: Blood gas analysis Plasma lactate Base deficit |
Manage metabolic acidosis following standard treatment protocols. |
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. |
Monitor serum electrolytes. |
Manage serum electrolyte abnormalities following standard treatment protocols. |
Clinically significant thrombocytopenia may occur following overdoses of large amounts of valproate. Transfusions have been required. |
Monitor: White blood cell count Platelet count |
Manage thrombocytopenia following standard treatment protocols. |
Bone marrow suppression may present three to five days after a massive overdose, and usually resolves spontaneously a few days later.However, severe bone marrow depression requiring transfusion has occurred with overdose and fatal bone marrow failure with therapeutic doses. |
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 monitoring should include: Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) International normalized ratio (INR) Serum bilirubin Plasma glucose |
Manage acute hepatotoxicity following standard treatment protocols. |
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. 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. |
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. 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. |
| Mild Valproate Toxicity | Moderate Valproate Toxicity | Severe 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)
Drowsiness Lethargy Dizziness Confusion Withdrawal Stupor Hyporeflexia Hypotonia Cerebral edema (may be delayed) Asterixis Hyperammonemic encephalopathy Myoclonic movements (rare) Seizures (rare) |
Nausea Vomiting Pancreatitis (rare) |
Tachycardia Bradycardia Hypotension Atrial fibrillation QT prolongation Cardiac arrest |
Respiratory depression Respiratory acidosis Aspiration pneumonitis Respiratory arrest |
Fever Hypoglycemia Hyperammonemia Hyperlactacidemia Metabolic acidosis |
Hypocalcemia Hypernatremia Hypophosphatemia |
Elevation of serum ammonia and hepatic enzymes Hepatotoxicity (rare) |
Thrombocytopenia Bone marrow suppression Leukopenia Anemia Decreased ESR Decreased fibrinogen Abnormal bleeding, partial thromboplastin, and prothrombin times Methemoglobinemia |
Renal failure (rare)
|
Miosis Pupils sluggishly reactive to light Nystagmus Optic nerve atrophy
|
Macular pruritic rash Bullous lesions Alopecia
|
Elevated creatine kinase Rhabdomyolysis Stevens-Johnson syndrome Toxic epidermal necrolysis |
ACUTE EFFECTS (ROUTE OF EXPOSURE)
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 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,pancreatitis,and severe hyperammonemic encephalopathy. 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. Individuals with underlying genetic urea cycle disorders, such as ornithine transcarbamylase deficiency, may develop hyperammonemic encephalopathy following initiation of valproate therapy at normal doses. |
TOXICITY
HUMAN
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. |
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 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 ~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 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 Valproate semisodium Unknown amount of Valproate semisodium 3 year old child: methemoglobinemia, metabolic acidosis, hypoxia Recovered after treatment with methylene blue Unknown (large amount ingested) 4 year old child: bullous lesions, hypotension, rhabdomyolysis, bone marrow suppression, prolonged coma Outcome not stated |
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. > 200 mg/kg Mild to moderate toxicity > 400 mg/kg Severe toxicity, including coma > 1,000 mg/kg Expected to be lethal without treatment |
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 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 50 g Valproic acid extended release (714 mg/kg) 41 year old male: lethargy Recovered after gastric lavage, activated charcoal and hemodialysis 56.4 g Valproic acid Clinical details not available Fatal 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 19 g Sodium valproate slow release 43 year old female: coma, metabolic acidosis, hypotension, thrombocytopenia Recovered with hemodialysis 20 g Sodium valproate (330 mg/kg) 15 year old female: coma, metabolic acidosis, cerebral edema, hyperammonemia, hyperlactacidemia Fatal 4 days after ingestion 25 g Sodium valproate, 30 mg Diazepam 18 year old female: unconsciousness, hypotonia, respiratory arrest Recovered after three days of artificial respiration 45 g Sodium valproate 18 year old male: unconsciousness, metabolic acidosis, hyperammonemia, increased serum transaminases, hypernatremia, hypocalcemia Recovered with supportive treatment 75 g Sodium valproate 20 year old female: coma Recovered with supportive treatment, hemoperfusion and hemodialysis Unknown amount Sodium valproate 40 year old female: coma, hypotension, respiratory depression, acute renal failure, hypothermia Fatal 72 hours after admission despite supportive treatment Valproate Semisodium 28.75 g Valproate semisodium 15 year old male: vomiting, delirium, miosis, transient nephropathy Recovered after multiple dose activated charcoal 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 350 g Valproate semisodium 24 year old female: coma, metabolic acidosis, renal insufficiency, hypotension Fatal, 48 hours post-ingestion despite aggressive treatment 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 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 |
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. 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. |
ANIMAL
Sodium valproate, valproate pivoxil, valproate semisodium and valpromide are rapidly metabolized to valproic acid in vivo. |
LD50 Oral, Rat | 670 mg/kg (Valproic acid) | LD50 Oral, Mouse | 1,700 mg/kg (Sodium valproate) |
|
BIOLOGICAL LEVELS - TOXIC
Usual Therapeutic Concentration 50 to 100 mg/L (350 to 690 umol/L) valproic acid Note: Higher concentrations are used by some clinicians |
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. |
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. 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. Similar results were found in other studies. |
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. Valproic acid and its salts are human teratogens. Anomalies observed can affect the neural tube, genitourinary system, heart, limbs, skin, and face. Furthermore developmental delays are also common. Reports estimate that between 6.7% to 12.4% of children exposed to valproate develop congenital malformations. The most serious abnormalities observed are defects in neural tube closure. A characteristic pattern of minor facial defects is also associated with valproic acid. Other predominant effects involve the heart and limbs. 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: |
FDA Classification (before July 2015): |
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. 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. The American Academy of Pediatrics considers valproic acid to be compatible with breast feeding. |
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. 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. 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. 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. |
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: Epilepsy Mania Generally, indicated for the prophylaxis of: Migraine |
THERAPEUTIC DOSE RANGE
This is intended as a guide only. For a more comprehensive list, refer to manufacturer's information. |
Epilepsy 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 |
Epilepsy 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 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. 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. |
BIOLOGICAL LEVELS - THERAPEUTIC
Usual Therapeutic Concentration 50 to 100 mg/L (350 to 690 umol/L) valproic acid 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 Effect of Food Absorption is delayed but not decreased Milk products do not affect the rate or degree of absorption Other Factors Affecting Absorption Significant delays in overdose Bioavailability Close to 100% Onset of Action Onset of therapeutic action is several days to more than one week |
DISTRIBUTION
Distribution - Rapid
- Probably restricted to the circulation and rapidly exchangeable extracellular water
Volume of Distribution - 0.1 to 0.4 L/kg
Plasma Protein Binding - 80 to 95%
- Decreases with:
- - Increasing drug concentration
- - In geriatric patients
- - In those with renal or hepatic impairment
- - In presence of other protein-bound drugs
- Saturation of binding sites may occur with lowered serum albumin concentrations, causing free drug concentrations to rise rapidly
Lipid Solubility Crosses the blood brain barrier - CSF concentrations 5 to 15 % of plasma concentrations
Crosses the placenta Is excreted in breast milk - Breast milk concentrations 1 to 10 % of plasma concentrations
|
METABOLISM
Metabolism - Extensive hepatic
Metabolites Active: - Glucuronide conjugate of parent drug (up to 59% of dose)
- 3-Ketovalproic acid (23%)
- 3-Hydroxyvalproic acid (3%)
- 4-Hydroxyvalproic acid (3%)
- 5-Hydroxyvalproic acid (3%)
- 2-Propylglutaric acid (5%)
- Conjugated forms of 2-en-valproic acid, 3-en-valproic acid, 4-en-valproic acid
Major Metabolic Pathways Parent: - Glucuronidation: 40 to 60%
- Beta-oxidation: 30 to 40%
- Omega-oxidation: up to 30%
|
ELIMINATION
Excretion Urine - Metabolites excreted in urine
- 1 to 3% excreted unchanged
Feces - Small amounts
Expired in air - Small amounts
Half-life Therapeutic - 10 to 20 hours (adults)
- 6 to 9 hours (children)
Overdose - Up to 30 hours
Clearance Rate - 4.8 to 8.3 mL/h/kg (following 500 to 1,500 mg/day)
Other Factors Affecting Elimination - Studies in rats suggest enterohepatic circulation 7%
|
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)
- Sodium valproate
- Valproate sodium
|
|
Sodium Valproate: 2-Propylpentanoic acid; sodium salt |
CODES
ATC CLASSIFICATION
Antiepileptics - Fatty Acid DerivativesAntiepileptics 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 |
pKa | 4.8 4.8% degrees C |
Solubility | Water: freely soluble Ethanol: freely soluble |
|
Do Not Archive. This document is current on day of issue,
NZ: 18.Jul.2019 |
