Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) 2-Propylpentanoic acid
2) 2-Propylvaleric acid
3) Abbott 44089
4) Acetic acid, dipropyl-
5) Acido valproico (Spanish)
6) Depakene(R) (Abbott)
7) Depakine
8) Dipropylacetic acid
9) Di-n-propylacetic acid
10) n-Dipropylacetic acid
11) Di-n-propylessigsaure (German)
12) n-DPA
13) Epilim
14) Kyselina 2-propylpentanoic acid
15) 2-Propylpentanioc acid
16) 2-Propylvaleric acid
17) Valproate
18) Valpromide
19) Valproato (Spanish)

1) Abbott 44090
2) Depakene
3) Depakine
4) Depakane
5) Depakote(R) (Abbott)
6) Dipropylacetate sodium
7) Divalproex sodium (Depakote(R))
8) DPA sodium
9) Epilim
10) Ergenyl
11) Eurekene
12) KW-066
13) Labazene
14) Pentanoic acid, 2-propyl-, sodium salt
15) 2-propylpentanoic acid sodium salt
16) 2-Propylvaleric acid sodium salt
17) Sodium bispropylacetate
18) Sodium Dipropylacetate
19) Sodium alpha, alpha-dipropylacetate
20) Sodium n-dipropylacetate
21) Sodium 2-propylpentanoate
22) Sodium 2-propylvalerate
23) Sodium valproate
24) Valproic acid, sodium salt

Available Forms Sources

A)

1) Valproic acid is available in the following formulations:

a) Liquid filled soft gelatin 250 mg capsules (orange-colored) in bottles of 100 capsules; oral syrup, 250 mg/5 mL (Prod Info DEPAKENE(R) oral capsules, oral solution, 2007)
b) Oral capsule, delayed release: 125, 250, 500 mg (Prod Info STAVZOR(R) delayed release oral capsules, 2008)

B)

1) Valproic acid is approved as monotherapy or adjunctive therapy for the prophylactic treatment of complex partial seizures occurring alone or in association with other seizure types (Prod Info DEPAKENE(R) oral capsules, oral solution, 2007). It is also used for treatment of mania associated with bipolar affective disorder, and for prophylaxis of migraine headaches. An unapproved use of valproic acid includes treatment of neuropathic pain (Chappell et al, 1999).
2) Recent studies have shown that valproic acid may be associated with anti-cancer activity, suppressing not only tumor growth and metastasis, but also inducing tumor differentiation in vitro and in vivo. These findings open novel aspects for the treatment of tumor patients (Blaheta & Cinatl, 2002; Blaheta & Cinatl, 2002).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Anticonvulsant for a broad spectrum of seizure disorders. Also used as a mood stabilizer in the treatment of bipolar affective disorder, used to treat chronic pain and as prophylaxis for migraine headaches.
B) PHARMACOLOGY: Inhibits voltage-gated sodium channels (membrane stabilizing effects). Inhibits T-type calcium channels (excessive conductance causes seizures). Competitive antagonist of N-methyl-D-aspartic acid (NMDA) {excitatory} neuroreceptor. Inhibits GABA transaminase, increasing GABA (inhibitory neurotransmitter) concentrations in the brain.
C) TOXICOLOGY: Causes CNS depression in overdose by extension of the pharmacologic mechanisms. Valproic acid depletes hepatic carnitine stores by forming valproylcarnitine, which inhibits the carnitine transported on the plasma membrane. Fatty acids cannot be metabolized due to lack of carnitine, resulting in chronic fatty liver. Valproic acid also depletes coenzyme A (CoA) stores in the liver by trapping CoA in the mitochondria by the valproic acid beta-oxidation metabolites. Depletion of CoA affects the activation of the carbamyl phosphate synthetase I (CPS I), which is needed for incorporating ammonia into the urea cycle, leading to hyperammonemia.
D) EPIDEMIOLOGY: Poisoning is common with moderate severity.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: COMMON: Anorexia, nausea, alopecia, peripheral edema, rash, sedation, weight gain, and teratogenicity. IDIOSYNCRATIC: Pancreatitis, hepatotoxicity, thrombocytopenia, hyperammonemia, and encephalopathy.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Primary effect is CNS depression, generally lethargy and sedation, vomiting and tachycardia.
2) SEVERE TOXICITY: Patients typically develop more severe CNS depression, coma, miotic pupils, tachycardia, hypotension, QTc prolongation, and respiratory depression following severe poisoning. Seizures and cerebral edema are less common. Laboratory abnormalities may include hypernatremia, hypocalcemia and hyperammonemia. Bone marrow suppression may develop 3 to 5 days after massive overdose, and usually resolves spontaneously. Pancreatitis, acute hepatotoxicity, renal insufficiency, and acute lung injury are uncommon, but have been reported. Valproate-induced hyperammonemic encephalopathy can develop after overdose or therapeutic use. It is characterized by deterioration of mental status (i.e., lethargy, confusion, coma) AND an elevated ammonia concentration; it may also be associated with hepatotoxicity.

0.2.3)

A) WITH THERAPEUTIC USE

1) Hypothermia has been reported with therapeutic valproic acid use.

B) WITH POISONING/EXPOSURE

1) Both fever and hypothermia have been reported following valproic acid overdose. Hypotension may occur following severe overdose.

0.2.20)

A) Valproic acid is a known teratogen to humans. Maternal use of valproic acid alone or in combination with other antiepileptic drugs has been found to cause valproic acid syndrome in infants. Facial dysmorphology, congenital heart defects, spina bifida, cleft lip and palate, and developmental delays are some of the teratogenic effects seen.
B) In 2009, the FDA notified healthcare professionals and patients about an increased risk of congenital malformations (ie, neural tube defects, craniofacial defects, cardiovascular malformations, and other body system malformations) in infants born of women exposed to valproate sodium and related products during pregnancy.
C) The FDA has classified valproic acid as pregnancy category X and its use in pregnant women is contraindicated for the prevention of migraine headaches. However, valproate products continue to have a pregnancy category of D for treatment of epilepsy and manic episodes associated with bipolar disorder. Valproate products should only be used in pregnant women with epilepsy or bipolar disorder if other medications are not effective or are otherwise unacceptable in treating the condition.
D) Valproic acid is excreted in breast milk with low concentrations and is not contraindicated during breastfeeding.

0.2.21)

A) At the time of this review, no data were found as to the carcinogenic effects of valproic acid in humans.

Laboratory Monitoring

A)

B)

C)

D)

Treatment Overview

0.4.2)

A) DECONTAMINATION

1) PREHOSPITAL: Ipecac-induced emesis is not recommended in the prehospital setting because of the potential for aspiration. Activated charcoal may be considered in the prehospital setting by a healthcare professional only, if the patient is asymptomatic, a recent ingestion, and there are no contraindications. However, transportation to an emergency center should NOT be delayed to administer activated charcoal.
2) HOSPITAL: Administer activated charcoal if the patient presents early after a significant ingestion if the patient is awake and can protect their airway, or the airway is protected. Administer a second dose of charcoal in patients who have ingested a sustained release formulation, or in patients with rising serum concentrations despite therapy. MULTIDOSE ACTIVATED CHARCOAL: Consider if valproic acid level is continuously rising and gastrointestinal function is intact (Note: patients with severe toxicity often have depressed gastrointestinal motility and may not tolerate multiple dose charcoal).

B) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Symptomatic and supportive care in all patients. Monitor for progression of sedation. Repeat valproic acid levels every 4 to 6 hours and consider multidose activated charcoal if the level is continuously rising.

C) MANAGEMENT OF SEVERE TOXICITY

1) Resuscitation, symptomatic and supportive care in all patients. Early intubation in patient with declining level of consciousness. Hypotension: Treat with IV fluids, if no response start vasopressors. Consider hemodialysis in patients with severe toxicity who are not responding to supportive care. Consider carnitine in patients with coma, hepatotoxicity, elevated ammonia concentration, or a valproate concentration above 450 mcg/mL.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation should be considered early if the patient presents with altered level of consciousness, hemodynamic instability, or multiorgan toxicity.

E) ANTIDOTE

1) NALOXONE has been used to reverse valproic acid induced CNS depression and coma, with variable success. GENERAL: Risk of naloxone administration is low; it is reasonable to administer in patients with significant CNS depression.
2) L-CARNITINE: Orphan drug approved by FDA for the treatment of L-carnitine deficiency secondary to valproic acid toxicity. Appears effective in increasing survival in patients with valproate-induced hepatotoxicity and encephalopathy after therapeutic administration. INDICATION: Patients with coma, hepatotoxicity, hyperammonemia, or serum valproate concentration greater than 450 mcg/mL. While there are no controlled studies to support its use after acute overdose, there are several reports suggesting it lowers serum ammonia concentrations, and it is associated with few adverse effects. DOSE: IV 100 mg/kg over 30 minutes (maximum: 6 g) followed by 15 mg/kg IV every 4 hours until clinical improvement.

F) ENHANCED ELIMINATION PROCEDURE

1) Hemodialysis and hemoperfusion are reserved for severe toxicity with failure of improvement or deterioration despite supportive management, especially with concomitant severe metabolic disturbance, and/or serum valproic acid concentration of greater than 1000 mg/L. Because protein binding is saturated at a high serum concentration (resulting in higher free valproate concentrations), hemodialysis appears to be useful with severe overdose.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic patients with unintentional ingestion of less than 50 mg/kg can be observed at home.
2) OBSERVATION CRITERIA: Symptomatic patients, those with deliberate ingestions, and those with unintentional ingestions of 50 mg/kg or more should be referred to a medical facility for evaluation and treatment. Obtain serial valproate concentrations every 2 to 3 hours. Patients should be observed until valproate concentrations are clearly declining on at least two sequential measurements, and symptoms have resolved. IMMEDIATE RELEASE: Patients should be observed for a minimum of 6 hours after immediate release valproate ingestions. EXTENDED RELEASE: Monitor patients for a minimum of 12 hours following extended release preparations and should be admitted if symptoms develop.
3) ADMISSION CRITERIA: Patients with rising valproate concentrations and those developing CNS depression or other clinical or laboratory evidence of toxicity should be admitted. Patients with persistent altered mental status, abnormal vital signs, acidosis, renal or hepatic involvement should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity, or in whom the diagnosis is not clear.

H) PITFALLS

1) Inadequate observation for respiratory depression.
2) Insufficient duration of monitoring, particularly after ingestion of an extended release formulation. After a large ingestion, absorption can be slow and erratic. Coma may be delayed for up to 12 hours.
3) Failure to repeat serial valproic acid concentrations until it is declining. Initial valproic acid concentration can be within therapeutic range even after a large ingestion.

I) PHARMACOKINETICS

1) Valproic acid is well absorbed (almost 100%). IMMEDIATE RELEASE: Peak serum concentration occurs 6 hours after immediate release. The Tmax for valproate is 4 hours following oral dosing. Highly protein bound (90%); volume of distribution is 0.1 to 0.2 L/kg; hepatic metabolism; and elimination half-life is 6 to 18 hours. EXTENDED RELEASE: The median time to maximum plasma valproate concentration (Cmax) after an extended release product can range from 4 to 17 hours. Peak serum concentration can be up to 24 hours after an extended-release product. The mean terminal half-life ranges from 9 to 16 hours following an oral dose regimen of 250 to 1000 mg. Hepatic metabolism. INTRAVENOUS: The Tmax for IV valproate sodium (sodium salt of valproic acid) is reached at the end of a 1 hour infusion.
2) Therapeutic serum concentration: between 50 and 100 mg/L (350 to 700 micromol/L).

J) TOXICOKINETICS

1) Absorption may be slow and erratic after overdose, particularly for an extended release formulation. Protein binding is saturated in overdose (higher proportion of unbound valproate); protein binding can decrease as lows as 15% as serum concentrations rise to greater than 1000 mg/L (likely leading to greater clinical toxicity). Active metabolites contribute to toxicity. Prolonged elimination half-life in overdose (30 hours). Peak plasma concentration was delayed for 17 hours after ingestion of divalproex sodium and chlorpheniramine in overdose.
2) Serum concentrations of greater than 450 mg/L (3125 micromol/L) are likely to result in moderate or major adverse clinical effects; concentrations of greater than 850 mg/L (5900 micromol/L) are likely to result in coma and metabolic acidosis.

K) DIFFERENTIAL DIAGNOSIS

1) The following should be considered: other anticonvulsants, opioid overdose, sedative hypnotics, alcohol ingestion, other drug-induced hepatitis, or herbal hepatitis.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) ADVERSE EFFECTS: COMMON: Anorexia, nausea, alopecia, peripheral edema, rash, sedation, weight gain, and teratogenicity. IDIOSYNCRATIC: Pancreatitis, hepatotoxicity, thrombocytopenia, hyperammonemia, and encephalopathy.

F)

1) MILD TO MODERATE TOXICITY: Primary effect is CNS depression, generally lethargy and sedation, vomiting and tachycardia.
2) SEVERE TOXICITY: Patients typically develop more severe CNS depression, coma, miotic pupils, tachycardia, hypotension, QTc prolongation, and respiratory depression following severe poisoning. Seizures and cerebral edema are less common. Laboratory abnormalities may include hypernatremia, hypocalcemia and hyperammonemia. Bone marrow suppression may develop 3 to 5 days after massive overdose, and usually resolves spontaneously. Pancreatitis, acute hepatotoxicity, renal insufficiency, and acute lung injury are uncommon, but have been reported. Valproate-induced hyperammonemic encephalopathy can develop after overdose or therapeutic use. It is characterized by deterioration of mental status (i.e., lethargy, confusion, coma) AND an elevated ammonia concentration; it may also be associated with hepatotoxicity.

Vital Signs

3.3.1)

A) WITH THERAPEUTIC USE

1) Hypothermia has been reported with therapeutic valproic acid use.

B) WITH POISONING/EXPOSURE

1) Both fever and hypothermia have been reported following valproic acid overdose. Hypotension may occur following severe overdose.

3.3.3)

A) HYPOTHERMIA

1) WITH POISONING/EXPOSURE

a) Hypothermia has been reported in epileptic adult patients following acute overdoses of sodium valproate (Connacher et al, 1987; Hintze et al, 1987).
b) CASE REPORT: A 22-year-old man developed a core rectal temperature of 27 degrees Celsius following an overdose of sodium valproate. The patient required aggressive rewarming including external rewarming therapy and invasive rewarming with warmed bladder lavage. The patient fully recovered with no neurologic deficit by day 2. Although the authors concluded that the etiology of hypothermia was likely multifactorial, sodium valproate was thought to significantly contributed to the development of severe hypothermia in this case (Robinson & Abbott, 2005).

2) WITH THERAPEUTIC USE

a) Hypothermia has been reported in children following short-term therapeutic dosing (Nagarajan et al, 2001).

B) WITH POISONING/EXPOSURE

1) FEVER

a) Fever has been reported following valproic acid overdose (Bigler, 1985; Hintze et al, 1987).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION

a) Hypotension has been reported with severe overdoses (Tank & Palmer, 1993; Farrar et al, 1993) Anderson & Ritland, 1995; (Williams & Clark, 1995; Kuperschmidt et al, 1998).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MIOSIS

a) Miosis has been reported following acute overdose (Steiman et al, 1979; Alberto et al, 1989; Hicks & McFarlane, 2001).

2) OPTIC NERVE ATROPHY

a) Optic nerve atrophy has been reported following an acute overdose (Bigler, 1985).
b) CASE REPORT: Neurologic sequelae were reported in a 24-year-old man following an ingestion of more than 100 grams of sodium valproate who presented late to the emergency department (18 hours postingestion).

1) The patient was comatose and febrile for 10 days despite antibiotic therapy. After 2 months there was severe reduction of vision due to optic nerve atrophy (Bigler, 1985).

3) NYSTAGMUS

a) A 16-year-old boy was reported to have reactive pupils of 4 mm and horizontal nystagmus following an overdose of 38 delayed-release tablets of 250 mg each (Wasserman et al, 2001).

4) SALIVARY GLANDS

a) THERAPEUTIC USE: A 26-year-old woman developed bilateral sialadenosis (benign, noninflammatory enlargement) of the parotid glands following 4 years of valproic acid therapy for seizures. Enlargement persisted despite discontinuation of valproic acid, eventually requiring surgical excision (Mauz et al, 2005).

Cardiovascular

3.5.2)

A) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) Cardiorespiratory arrest has been reported following the ingestion of an unknown amount of sodium valproate (plasma valproate concentration 13,672 mcmol/L) (Gourru, 1981).
b) CASE REPORT: Cardiorespiratory arrest was reported in a 20-month-old boy who unintentionally ingested 15 g of sodium valproate. Peak serum concentration was reported to be 1061 micrograms/milliliter within three hours of the time of ingestion (Janssen et al, 1985). Death was thought to be caused by severe bronchial pneumonia.

B) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension, often refractory to fluid resuscitation and vasopressor therapy, has been reported with severe overdoses (Singh et al, 2004; Tank & Palmer, 1993; Farrar et al, 1993; Andersen & Ritland, 1995; Williams & Clark, 1995; Kuperschmidt et al, 1998; Johnson et al, 1999; Christianson et al, 2001).
b) INCIDENCE: In a series of 133 patients with valproate only overdose reported to a group of poison centers, 4 (3%) developed hypotension (Spiller et al, 2000).
c) CASE REPORT: A 40-year-old epileptic woman became hypotensive (BP 60/40 mmHg) following an overdose of sodium valproate. The hypotension was difficult to correct despite infusion of intravenous fluids, careful central venous pressure monitoring, and administration of dopamine and dobutamine. Valproate concentration shortly after onset of hypotension was 17,200 micromoles/liter (Connacher et al, 1987).

C) PROLONGED QT INTERVAL

1) WITH POISONING/EXPOSURE

a) Significant QT interval prolongation appears to be a common effect of acute valproic acid (VPA) poisoning. Kupferschmidt et al (1999) retrospectively examined 16 cases of acute valproic acid poisonings, with no other coingestants. Twelve of the 16 patients were reported to have significantly longer QTc during the acute stage than at baseline. Nine of the 16 had acute QT values greater than 450 msec (6 cases greater than 500 msec). The authors suggested that VPA-related QT prolongation may be due to diminished potassium currents in cardiomyocytes.
b) CASE REPORT: Following ingestion of an unknown amount of valproic acid (VPA), a 29-year-old woman was admitted 30 hours later to the ED. She was unresponsive, hypotensive (systolic BP 70 mmHg), and an ECG revealed peaked T-waves with a prolonged QTc interval of 593 msec. The plasma VPA concentration at 36 hours postingestion was 660 mg/L and the patient also had hypocalcemia, hyperkalemia and acute renal insufficiency. QTc normalized within 56 hours. The patient was discharged on day 18 with only mild neurological deficits (Kuperschmidt et al, 1998).

D) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia has been reported following an overdose (Meyer et al, 2005; Camilleri et al, 2005; Ibister et al, 2003; Spiller et al, 2000).

1) INCIDENCE: In a series of 133 patients with valproate only overdose reported to a group of poison centers, 24 (17%) developed tachycardia (Spiller et al, 2000).
2) In a small case series of 15 patients with valproate only overdose, 5 patients developed tachycardia. There were no reports of dysrhythmias or hypotension (Ibister et al, 2003).

Respiratory

3.6.2)

A) RESPIRATORY FAILURE

1) WITH POISONING/EXPOSURE

a) Respiratory arrest requiring artificial ventilation is common in patients with severe overdose (Eyer et al, 2005; Minari et al, 2002; Christianson et al, 2001; Williams & Clark, 1995; Graudins & Aaron, 1996; Andersen & Ritland, 1995; Gourru, 1981; Fuller et al, 1981; p 87) .
b) CASE REPORT: Apneic episodes developed in a 26 month old after ingesting 4.5 grams. Naloxone appeared to reverse the apnea (Farrar et al, 1993).

B) PULMONARY ASPIRATION

1) WITH POISONING/EXPOSURE

a) INCIDENCE: In a series of 133 patients with valproate only overdose reported to a group of poison centers, 8 (6%) developed aspiration pneumonitis (Spiller et al, 2000).

C) PNEUMONIA

1) WITH THERAPEUTIC USE

a) Apnea, pulmonary hemorrhage, and bronchopneumonia have been associated with chronic valproate administration (Gerber et al, 1979). A case of thrombocytopenia-induced fatal pulmonary hemorrhage was reported in a 30-year-old woman on chronic valproate monotherapy, with a history of a viral illness 3 weeks earlier (Sleiman et al, 2000). Initial serum valproate concentration was 124 micrograms/mL (normal 50 to 100 micrograms/mL). The authors suggested that viral infections may be associated with thrombocytopenia in patients on valproate therapy.

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Confusion, somnolence, acute toxic encephalopathy with behavior disturbances, worsened seizure control, and coma have been associated with ingestions of overdose amounts of sodium valproate. When ingestions of sustained-release or enteric-coated divalproex sodium are taken, delayed toxicity may occur, with CNS depression occurring as long as 8 to 13 hours postingestion (Weiner et al, 2013; Steiman et al, 1979; Simon & Penry, 1975; Eeg-Olofsson & Linkskog, 1982; Fuller et al, 1981; Gourru, 1981; Garnier & Fournier, 1982; p 87; Chadwick et al, 1979; Andersen & Ritland, 1995; Graudins & Aaron, 1996; Lee et al, 1998; Johnson et al, 1999; Montero, 1999; Brubacher et al, 1999; Hicks & McFarlane, 2001; Thole et al, 2001; Kroll & Nand, 2002; Minari et al, 2002).
b) One reference states coma occurs at doses of about 20 mg/kg or more (Garnier & Fournier, 1982).
c) CASE REPORT: A 41-year-old epileptic man was admitted comatose with an initial valproic plasma concentration of 1308 mg/L (therapeutic range: 50-150 mg/L) (estimated ingestion was more than 100 tablets of 1 g of valproic acid). Laboratory studies included hyperammonemia, elevated liver enzymes, and an elevated creatinine kinase (10,000 U/L). The patient was treated with activated charcoal and L-carnitine and the patient awoke 36 hours after admission. The patient fully recovered and was discharged to home on hospital day 17 (Sikma et al, 2008).
d) INCIDENCE: In a series of 133 patients with valproate only overdose reported to a group of poison centers, 94 (71%) developed lethargy and 19 (15%) developed coma (Spiller et al, 2000). Coma was more common in patients with peak valproate levels of more than 850 mcg/ml.
e) ELECTROENCEPHALOGRAM/CASE REPORT: A 20-year-old woman ingested approximately 75 grams of sodium valproate and had a serum concentration of 1500 mcg/mL 3 hours postingestion. The EEG revealed decreased dominant frequency and some theta and delta activity.

1) At 8 hours the level was 1800 mcg/mL and the EEG was dominated by delta activity of low amplitude. Following hemodialysis and hemoperfusion, levels decreased to 100 mcg/mL (36 hours postingestion) and the EEG had slight activity with low voltage. Four days after the overdose the valproate level was in the normal range (40 to 100 mcg/mL) and the EEG was dominated by delta activity of high amplitude, especially in the frontal lobe. At 6 days the EEG was normal (Pedersen & Juul-Jensen, 1984).

f) CHRONIC EXPOSURE: A 7-year-old girl, with severe cerebral palsy and severe developmental delay and chronic epilepsy that was treated with valproic acid, developed further development deterioration (ie, more sleepy, poor feeding and decreased responsiveness) over a period of a few weeks. Upon admission, an arterial blood gas showed compensated respiratory acidosis. Thrombocytopenia was also present. Her valproic acid concentration was 700 mcg/mL (therapeutic range, 50 to 100 mcg/mL). Two months prior to admission the patient's valproic acid had been changed from 250 mg/5 mL to a concentration of 200 mg/mL. The patient continued to receive the same volume resulting in a dosage that was approximately 4 times her usual dose. Valproic acid was stopped and the patient gradually became more alert; valproic acid and laboratory concentrations also normalized (Weiner et al, 2013).
g) VALPROMIDE: Delayed CNS depression and coma have been reported after overdose of valpromide in several patients. Three patients who presented after deliberate overdose were initially asymptomatic with therapeutic concentrations. Two were transferred to a psychiatric facility and developed mental status depression progressing to coma 20 and 44 hours after ingestion associated with valproic acid concentrations of 295 and 256 mg/L (peak serum levels not determined). A third patient developed dyspnea after 10 hours of observation, and progressed to metabolic acidosis, respiratory failure and encephalopathy with a serum valproate concentration of 200 mg/L. All patients recovered (Payen et al, 2004).

B) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) Severe encephalopathy associated with hyperammonemia has been reported following chronic therapy, and as a synergistic effect of other anticonvulsants (phenobarbital, phenytoin, and topiramate) administered with valproic acid (Lheureux et al, 2005; Borbath et al, 2000; Hamer et al, 2000).
b) CASE REPORTS

1) PEDIATRIC: A 9-year-old boy diagnosed with intermittent explosive disorder was admitted to the hospital for aggressive behavior after being treated fro 7 months with valproate (100 mg daily) and quetiapine. He had a therapeutic valproate serum concentration (113 mcg/mL) and normal liver enzymes, but an elevated serum ammonia concentration (127 mcg/dL) with EEG patterns consistent with diffuse encephalopathy. Symptoms were controlled with chlorpromazine, diazepam, lithium carbonate, and discontinuation of valproate (Yehya et al, 2004).
2) ADULT: A 50-year-old woman taking carbamazepine 1200 mg daily for partial epilepsy developed acute confusion after valproate was added, initially in a 1000 mg per day dose, which was increased to 1500 mg after three days. A mildly elevated serum ammonia concentration (81 microg/dL) was noted. Her electroencephalogram indicated encephalopathy with diffuse background slowing mixed with high-amplitude slow waves. Serum concentrations of valproic acid and carbamazepine were 49.1 mg/L and 8.6 mg/L, respectively. Both concentrations were nontoxic. The patient improved rapidly after the valproate was discontinued (Chen et al, 2001). Although a safe previous administration of valproic acid did not preclude the occurrence of encephalopathy in this patient. Its suggested that a relatively large initial valproic acid dose could possibly have caused the symptoms observed in this patient.

2) WITH POISONING/EXPOSURE

a) Severe encephalopathy associated with hyperammonemia has been reported following acute overdoses (Unal et al, 2007; Borbath et al, 2000; Hamer et al, 2000).
b) CASE REPORT: A 9-year-old, 50 kg, girl intentionally ingested 196 mg/kg of valproic acid and upon admission 4 hours after ingestion she was stuporous and required immediate intubation and ventilation. Serum valproic acid level was 599.2 mcg/mL (reference range: 50 to 100 mcg/mL). Hyperammonemia (serum ammonia: 111 mcg/dL) was observed and treated with L-carnitine. Hemoperfusion was started within 8 hours of exposure that was repeated on day 2 for 3 hours; serum valproic level rapidly improved with therapy. The patient was also treated with fresh frozen plasma for an increased prothrombin and activated partial thromboplastin time. The child gradually improved and was extubated on day 4. She was discharged to home on day 9 with no permanent sequelae (Colak et al, 2011).
c) CASE REPORT/INFANT: A 26-day-old full term infant (4500 g) was unintentionally given 300 mg valproate (intended dose 30 mg/kg twice daily); symptoms began within 12 hours. Within 36 hours, the pupils were fixed and dilated. A CT scan of the head showed cerebral edema, and a serum ammonia of 279 mcg/dL (normal 15 to 56 mcg/dL) was also present. Despite aggressive care, the patient died of a cardiorespiratory arrest secondary to severe brain edema 42 hours after exposure (Unal et al, 2007).

C) CEREBRAL EDEMA

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Cerebral edema and coma have been reported in fatal cases; the etiology is unclear (Unal et al, 2007; Camilleri et al, 2005; Eyer et al, 2005; Poklis et al, 1998), but may be due to a direct toxic effect of VPA or its metabolites and hyperammonemia, increasing intracellular osmolarity, promoting an influx of water, cerebral edema, and increased intracranial pressure (Camilleri et al, 2005; Thabet et al, 2000; Eyer et al, 2005).

b) CASE REPORTS

1) PEDIATRIC

a) INFANT: A 26-day-old full term infant (4500 g) was unintentionally given 300 mg valproate (intended dose 30 mg/kg twice daily); symptoms began within 12 hours. Within 36 hours, the pupils were fixed and dilated. A CT scan of the head showed cerebral edema, and serum ammonia of 279 mcg/dL (normal 15 to 56 mcg/dL) was also present. Despite aggressive care, the patient died of cardiorespiratory arrest secondary to severe brain edema 42 hours after exposure (Unal et al, 2007).
b) TODDLER: Cerebral edema occurred in a previously healthy 26-month-old girl who ingested 625 mg/kg of valproic acid. Evidence of elevated pressure was observed 48 hours after ingestion. Resolution occurred by day 5 following placement of ventriculostomy, hyperventilation to maintain cerebral perfusion pressure at 60 to 70 mmHg, and administration of mannitol 25 g (one dose) and dopamine 1 to 8 mcg/kg/minute (Dupuis et al, 1990).
c) TEENAGER: Following an intentional overdose of 20 grams VPA (330 mg/kg), a 15-year-old girl was admitted with coma, metabolic acidosis, hyperammonemia, and hyperlactacidemia. Valproate serum concentration was reported to be 1550 mg/L at hour 10. The patient died 4 days after ingestion due to cerebral edema with irreversible coma (Thabet et al, 2000).

2) ADULT

a) CASE REPORT: A 29-year-old man with bipolar affective disorder sustained permanent injury when he developed cerebral edema, herniation, and infarct after intentionally ingesting 4 g of valproic acid (VPA) and 75 mg of diazepam (10 hours prior to ingesting VPA). He presented to the emergency department 5 hours after ingestion of VPA with agitation, an unsteady gait, and vomiting. At that time, his vital signs and neurologic examination were normal. Initial lab analyses showed a VPA level of 5469 micromol/L (therapeutic: 350 to 700 micromol/L), serum ammonia of 348 micromol/L (normal: 0 to 50 micromol/L), and a pH of 7.34. CT scan confirmed diffuse cerebral edema with early herniation. Nine hours after ingestion, his Glasgow coma scale score deteriorated to 8/15. He was intubated, gastric contents were aspirated, and he was treated with a single 50 g dose of activated charcoal followed by 4 doses of L-carnitine (900 mg each, 1 hour apart), and mannitol. Thirty-eight hours after ingestion, VPA levels were therapeutic. A dilated right pupil, absent right papillary reflex, reduced visual acuity with skew deviation of the right eye, and right-sided weakness were observed on day 5. At that point, MRI findings confirmed cerebral infarct and ECG findings were consistent with encephalopathy. Ammonia levels normalized on day 6 and on day 8 he was extubated. After 150 days of hospitalization including extensive rehabilitation he was discharged to an assisted living facility with residual right-sided weakness and a modified Rankin scale score of 3 (moderate disability; requiring some help, but able to walk without assistance) (Rupasinghe & Jasinarachchi, 2011; van Swieten et al, 1988).
b) CASE REPORT: After ingesting 20 g (333 mg/kg) of valproic acid extended release, 60 mg of risperidone, and 3 g of venlafaxine extended release, a 19-year-old man developed hyperammonemia (peak ammonia concentration 1,191 mcg/dL at 65 hours postingestion). The valproic acid concentration peaked at 305.4 mcg/dL. Despite decontamination with activated charcoal with sorbitol and lactulose, the patient's condition deteriorated. The brain CT scan revealed cerebral edema and possible tentorial herniation. At approximately 120 hours after ingestion, cerebral blood flow studies showed an absence of cerebral perfusion, and the patient was pronounced brain dead (Camilleri et al, 2005).
c) CASE REPORT: An adult presented with drowsiness 6 hours after ingesting 60 g of sodium valproate. By 9 hours postingestion, the patient became apneic and comatose. Peak serum valproate concentration was 1361 mcg/mL and peak ammonia concentration was 541 mcg/dL 10 hours postingestion. Cerebral edema was evident on CT scan by day 2. Multiorgan failure developed and the patient died 8 days after exposure (Eyer et al, 2005).
d) CASE REPORT: A 29-year-old epileptic man developed massive cerebral edema following an acute overdose of sodium valproate. The diagnosis of cerebral edema was supported by computerized tomography (CT) and electroencephalography (EEG). A normal CT was reported 9 days later after successful treatment of cerebral edema with sodium thiopental, glycerol, and glucocorticoids (Hintze et al, 1987). It is uncertain whether the cerebral edema was the result of hypoxia or valproate intoxication.

D) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 26-year-old man, with a history of bipolar disease, intentionally ingested an unknown amount of valproic acid and was admitted a few hours later with sopor without focal neurologic deficits. There were no signs of trauma and a CT of the brain was negative. Laboratory studies were normal. A valproic acid serum level was 2896 micromol/L (therapeutic range: 350 to 690 micromol/L). His cognitive function gradually improved over several days. The patient reported weakness in his right arm on day 3 and he had evidence of weakness of flexion and abduction of the right arm and loss of sensation in the skin over the lateral upper right arm. Radiographic and MR studies showed no evidence of fracture or neurologic dysfunction of the shoulder or cord or nerve root of the spine. Paresis of the right axillary nerve was detected on physical exam and electrodiagnostic studies. A physical therapy program resulted in gradual improvement (Marusic et al, 2014).

E) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A report of paradoxical increasing electrical seizures in a 25-year-old with a hypothalamic hamartoma is reported shortly after initiation with valproic acid therapy. A positive correlation was shown between the prevalence of spike and wave activity and serum valproate concentrations (Stecker & Kita, 1998).

2) WITH POISONING/EXPOSURE

a) Seizures may occur after intoxication (Chadwick et al, 1979).
b) CASE REPORT: Seizures and myoclonic jerking developed in a 44-year-old woman after overdose with valproic acid and trazodone (Williams & Clark, 1995).
c) CASE REPORT: Generalized seizures, progressive coma, and anuria in a 2-month-old girl were associated with serum sodium valproate concentration of 1299 mcg/mL (Roodhooft et al, 1990).

F) DROWSY

1) WITH POISONING/EXPOSURE

a) In a series of 15 patients with valproate only overdose, 2 patients experienced drowsiness after ingesting 300 to 400 mg/kg. No other neurological deficits were reported (Ibister et al, 2003).

G) NEUROLOGICAL FINDING

1) WITH THERAPEUTIC USE

a) Increased serum drug concentrations may cause unusual neurological effects. The following may be due to increased blood ammonia concentration.

1) Chronic high doses of valproic acid (2.2 to 2.5 gm/daily) in two adults produced drowsiness, confusion, irritability, apathy, withdrawn behavior, and visual hallucinations (Chadwick et al, 1979).
2) Drowsiness, twitching of limbs, deep coma, sedation, emotional disturbances, weakness, lethargy, ataxia, mental stimulation, excitement, aggressiveness, hyperactivity, headache, and tremor have been reported following chronic valproate administration (Lewis, 1978; Gerber et al, 1979) .

H) ABNORMAL BEHAVIOR

1) WITH THERAPEUTIC USE

a) NORMAL BLOOD CONCENTRATIONS: Behavioral changes were seen in 56/88 pediatric patients receiving sodium valproate monotherapy.

1) These included irritability, longer and deeper sleep, superficial sleep, hyperactivity, increased alertness, lassitude, drowsiness, increased sociability, calmness, increased sadness, happiness, and aggression.
2) It was emphasized that stimulant-like reactions were as frequent as depressive effects (Herranz, 1982).

I) MULTIPLE SYSTEM ATROPHY

1) WITH THERAPEUTIC USE

a) CASE REPORT: Valproic acid toxicity, mimicking multiple system atrophy, was reported in a 67-year-old woman taking the drug for a total of 8 years. Over the last 5 years she developed dysarthria, progressive action tremor, worsened bradykinesia, and ataxia. The patient was diagnosed with multiple system atrophy and finally was wheelchair bound, ataxic and incontinent. Three months after stopping valproic acid, symptoms began to improve. At three year follow-up, her neurologic examination was normal (Shill & Fife, 2000).

J) EXTRAPYRAMIDAL DISEASE

1) WITH THERAPEUTIC USE

a) Parkinson's syndrome has been associated with chronic valproate therapy. In a series of 36 patients treated with valproate, 27 (75%) had clinical evidence of Parkinsonism (Armon et al, 1996). Of these patients 19 (53%) complained of instability, 16 (44%) reported tremor, 30 (80%) demonstrated cognitive impairment, 22 (62%) had bradykinesia, 20 (55%) had abulia and 16 (44%) had upper motor neuron signs (Armon et al, 1996). Most patients improved after valproate was discontinued.
b) An extrapyramidal syndrome, unresponsive to antiparkinson medication (benztropine), developed in a 52-year-old man with schizophrenia who was given sodium valproate 1 to 2 g/d (Lautin, 1979).

K) CEREBELLAR DISORDER

1) WITH THERAPEUTIC USE

a) CASE SERIES: In a series of 16 patients treated with valproate in whom cranial CTs were performed, 11 (69%) demonstrated new or progressive cerebral atrophy (Armon et al, 1996). The atrophy improved in the two patients in whom cranial CTs were repeated after valproate was discontinued.

Gastrointestinal

3.8.2)

A) PANCREATITIS

1) WITH THERAPEUTIC USE

a) Some cases of hemorrhagic pancreatitis with rapid progression from initial symptoms to death have been described. Onset of pancreatitis may be shortly after initiation of valproic acid therapy or following several years of use (Chapman et al, 2001; (Anon, 2000)). Patients on valproate polytherapy may be at a higher risk of developing pancreatitis (Yazdani et al, 2002).
b) CASE SERIES: Fourteen cases of valproate-associated pancreatitis are reviewed. None of the cases experienced other valproate toxic effects and pancreatitis was not dose-related. It developed as early as one week and as late as 4.5 years after starting treatment. Two of 14 patients died. Of 7 rechallenged with VPA, 6 had recurrence of pancreatitis (Wyllie et al, 1984).
c) Development of VPA-associated pancreatitis is a relative contraindication to further treatment. However, routine monitoring of serum amylase is not necessary in asymptomatic patients.
d) Other cases of fatal and nonfatal valproate induced pancreatitis have been described (Evans et al, 1995; Pinkston & Walker, 1997).
e) CASE REPORT: A 23-year-old man, on hemodialysis for endstage renal disease secondary to hemolytic uremic syndrome, developed pancreatitis following a 3 month course of valproic acid (2500 mg/day) and phenobarbital (200 mg/day). After stopping valproic acid and administering symptomatic therapy, the pancreatitis resolved. Phenobarbital was continued, with no further pancreatic symptoms (Plaza et al, 1999).
f) CASE REPORT/SUDDEN DEATH: A 4.5 year old girl, with a history of epilepsy and receiving valproic acid (375 mg three times daily) and topiramate (25 mg twice daily) therapy for approximately four months, developed acute abdominal pain with uncontrollable vomiting and then sudden death (Mileusnic et al, 2002). Postmortem findings were consistent with hemorrhagic pancreatitis due to valproic acid therapy.

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Hemorrhagic pancreatitis was found on postmortem examination of a 40-year-old epileptic woman following an overdose of sodium valproate (Connacher et al, 1987).
b) CASE REPORT - Elevated amylase and lipase concentrations developed in a 27-year-old woman after severe valproate overdose (Andersen & Ritland, 1995).
c) CASE REPORT: An adult developed pancreatitis and cerebral edema and eventually died after a large valproate overdose of unknown size. Autopsy revealed hemorrhagic necrotic pancreatitis (Eyer et al, 2005).

B) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Vomiting as well as nausea, and abdominal pain have been reported (Egger & Brett, 1981; Lewis, 1978; Herranz, 1982).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting may occur and may be prolonged following ingestions of sustained-release products (Wasserman et al, 2001).
b) In a series of 15 patients with valproate only overdose, 4 developed vomiting (Ibister et al, 2003).

C) BEZOAR

1) WITH POISONING/EXPOSURE

a) Due to the enteric-coated formulation of valproic acid, large overdoses may potentially result in tablet bezoars (Graudins & Aaron, 1996).

D) INCREASED APPETITE

1) WITH THERAPEUTIC USE

a) Anorexia and increased appetite as well as weight gain have been reported (Bruni & Wilder, 1979).

E) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea has been reported, as has transient enuresis (Gerber et al, 1979; Suchy et al, 1979).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) Garnier reported 516 acute valproate overdoses, in which liver function was normal (Garnier et al, 1982). Risk factors for developing hepatotoxicity during therapeutic use include age under 2 years, previous liver disease, developmental delay, coincident metabolic disorders and severe seizures requiring multiple drugs or ketogenic diets for control (Lheureux et al, 2005). Valproic acid-induced hepatotoxicity is thought to be due to carnitine depletion, based on limited clinical evidence (Lheureux & Hantson, 2009).
b) CASE REPORT: A 33-year-old man on combined valproic acid and phenytoin therapy for seizures developed severe AST elevations (over 100 times normal upper limit) (McLaughlin et al, 2000).
c) CASE REPORT: Elevated aminotransferase concentrations developed in 2 women after valproate overdose (Andersen & Ritland, 1995).

B) HYPERAMMONEMIA

1) WITH THERAPEUTIC USE

a) SUMMARY: Valproic acid-induced hyperammonemia may develop after an acute overdose or following chronic therapy (Lheureux & Hantson, 2009; Halaby et al, 2013).
b) Severe encephalopathy associated with hyperammonemia has been reported following early therapeutic dosing and as a synergistic effect of other anticonvulsants (phenobarbital, phenytoin, and topiramate) with valproic acid (Lheureux et al, 2005; Raskind & El-Chaar, 2000; Borbath et al, 2000; Hamer et al, 2000; Ellaway et al, 1999). Hyperammonemia (plasma ammonia >80 mcg/dL) has also been reported in the psychiatric setting following initiation of valproic acid therapy (Eubanks et al, 2008; Panikkar & Gilman, 1999).
c) CLINICAL SYNDROMES: Hyperammonemia in the setting of valproate use or overdose can be associated with any of the following clinical syndromes:(Halaby et al, 2013; Chan et al, 2007):

1) hyperammonemia without significant CNS or liver toxicity;
2) valproic acid-induced hyperammonemic encephalopathy (VHE);
3) valproic acid-induced hepatotoxicity

d) PREVALENCE: In prospective studies of valproate overdose, the prevalence of hyperammonemia ranges from 70% to 100%, although 50% of patients will not have associated CNS or hepatic toxicity (Lheureux & Hantson, 2009).
e) CASE REPORTS: A 31-year-old man with a new onset of agitation and aggressive behavior was newly diagnosed with bipolar type I disorder and started on lithium, valproic acid and quetiapine. No improvement was noted after 3 weeks of treatment. Despite a normal valproic acid level, his ammonia plasma level was elevated (1.37 mg/L, reference range 0.1 and 05. mg). Hepatic function was normal. Valproic acid was stopped and confusion cleared within 24 hours along with a gradual decrease in his ammonia level over 48 hours (Halaby et al, 2013).

1) In the second case, a 21-year-old man, with a history of bipolar disorder type II for 2 years, was admitted for medical detoxification secondary to opioid and cannabis abuse. He remained on valproic acid (500 mg twice daily) and was started on analgesics, tranquilizers and sedatives (ie, diazepam and quetiapine) for potential withdrawal symptoms. About 4 days after the start of therapy, he became confused and disoriented. His valproic acid level was only slightly elevated (55 mcg/mL (reference range, 50 to 100 mcg/mL). Other laboratory studies included normal hepatic function, a negative toxicology screen for illicit drugs, and an ammonia level of 4.8 mg/L (4 times the upper limit of normal). Two days after stopping valproic acid his mentation was normal and his ammonia level was within normal limits (Halaby et al, 2013). The possible increased risk of hyperammonemia due to the coadministration of valproic acid and quetiapine remains unclear.

f) CASE REPORT: Ten days following initiation of valproic acid (10 mg/kg/day), a 51-year-old woman presented with a rapidly declining level of consciousness (Glasgow coma score 5/15). EEG showed triphasic waves consistent with hepatic encephalopathy. Serum valproic acid and liver enzyme concentrations were normal; blood arterial ammonia concentration was significantly increased (234 micromole/L) 10 hours after presentation. Following discontinuation of valproic acid and administration of levocarnitine, her neurological condition improved within 18 hours (Borbath et al, 2000).
g) CASE REPORT: A 33-year-old woman with bipolar disorder was started on daily divalproex sodium 1500 mg daily for 2 days and was noted to be lethargic by her caregivers. Her initial ammonia concentration was 283 mcmol/L (reference range: 2-30), along with a valproate serum concentration of 120 mg/L (reference range: 50-100). The patient received an initial 3 g IV of carnitine followed by carnitine 990 mg three times daily and lactulose 30 cc every 6 hours. Mental status improved within several hours of therapy. The concentration dropped to 25 on hospital day 4, the patient was discharged with a valproate concentration of less than 10 (Eubanks et al, 2008).
h) CASE REPORT: In another study, a 32-year-old man on daily valproate therapy alone developed hyperammonic encephalopathy (Ziyeh et al, 2002). Valproic acid serum concentrations were within normal limits (68 mg/L) on admission, and laboratory and sonographic studies were negative for hepatic disease. However, evaluation with MRI indicated a pattern that was compatible with a toxic-metabolic encephalopathy. In addition, MR spectroscopic findings were also consistent with hepatic encephalopathy based on severe depletion of myoinositol and choline along with glutamate excess. The exact mechanism for choline depletion has yet to be determined, but may be based on a disturbance of osmotic homeostasis at the cellular level.
i) PEDIATRIC: A 9-year-old boy was treated over 7 months with valproate for intermittent explosive disorder. During hospital admission for aggressive behavior he had a serum concentration of 99 mcg/mL on a dose of 100 mg valproate daily. The patient was also treated with quetiapine. Over one week, the patient developed worsening irritability and aggression, despite addition of lithium carbonate. Valproate serum concentration was 113 mcg/mL with an elevated serum ammonia concentration of 127 mcg/dL. Liver enzymes were normal. An EEG showed a pattern consistent with diffuse encephalopathy. Serum valproate concentration dropped to 55 mcg/mL 4 days after cessation of medication. It is unclear if the withdrawal of valproate was effective, because the patient's behavioral problems required chlorpromazine and diazepam for symptom control (Yehya et al, 2004).

2) WITH POISONING/EXPOSURE

a) Severe encephalopathy associated with hyperammonemia has been reported following acute overdoses (Unal et al, 2007; Raskind & El-Chaar, 2000; Borbath et al, 2000; Hamer et al, 2000; Ellaway et al, 1999). Hyperammonemia has been reported even in the absence of hepatic failure following acute overdose (Rupasinghe & Jasinarachchi, 2011; Thabet et al, 2000).
b) CASE REPORT: Hyperammonemia developed after acute overdose in a 20-year-old man with a partial deficiency of the enzyme carbamyl phosphate synthetase I. It was postulated that valproate induced further inhibition of the enzyme, preventing conversion of ammonia to urea (Felgenhauer et al, 1993).
c) CASE REPORT: Severe hyperammonemia (623 mcg/dL) and increased serum aminotransferase concentrations were reported in an 18-year-old man following an overdose of 45 grams of sodium valproate. The patient recovered following supportive care (Lee et al, 1998).
d) CASE REPORT: After ingesting 20 g (333 mg/kg) of valproic acid extended release, 60 mg of risperidone, and 3 g of venlafaxine extended release, a 19-year-old man developed hyperammonemia (peak ammonia concentration 1,191 mcg/dL at 65 hours postingestion). The valproic acid concentration peaked at 305.4 mcg/dL. Despite treatment with activated charcoal with sorbitol, and lactulose, the patient's condition deteriorated. The brain CT scan revealed cerebral edema and possible tentorial herniation. At approximately 120 hours after ingestion, cerebral blood flow studies showed an absence of cerebral perfusion, and the patient was pronounced brain dead (Camilleri et al, 2005).
e) The exact mechanism of valproic acid induced hyperammonemia is unclear. Metabolites of valproic acid may inhibit CPS I, the first enzyme needed for ammonia elimination via the urea cycle. Production of these metabolites may be increased due to valproic acid induced deficiency of carnitine. Other studies have implicated increased renal production of ammonia in patients treated with valproic acid (Lheureux et al, 2005; Sztajnkrycer, 2002).

C) INJURY OF LIVER

1) WITH THERAPEUTIC USE

a) Jaundice, drug-induced hepatitis, hepatocellular necrosis, transient elevated liver enzymes (SGPT/ALT, SGOT/AST), and fatal cholestatic hepatitis have been associated with chronic valproate administration (Lewis, 1978; Bruni & Wilder, 1979; Gerber et al, 1979; Addison & Gordon, 1980; Thruston et al, 1981; Suchy et al, 1979; Pinkston & Walker, 1997). Microvesicular steatosis is a characteristic lesion of VPA-induced hepatotoxicity (Thabet et al, 2000).
b) CASE SERIES: Dreifuss et al (1987) reviewed all US cases of fatal hepatotoxicity coincident with valproate anticonvulsant therapy reported between 1978-1984 (Dreifuss et al, 1987). Thirty-seven fatalities were reported.

1) All but one patient had other medical problems (mental retardation, developmental delay, congenital abnormalities, and other neurological diseases).
2) The primary risk of fatal hepatic dysfunction (1/500) was found to be in children 0 to 2 years old receiving valproate as polytherapy. The risk declined with age and was low in patients receiving valproate as monotherapy (1/37,000).
3) No hepatic fatalities occurred in patients above the age of 10 years receiving valproate as monotherapy.

c) INCIDENCE/PEDIATRICS: Fatal hepatotoxicity is reported in 1/800 children under the age of 2 years following antiepileptic therapy with valproic acid (Raskind & El-Chaar, 2000). It is suggested that valproic acid may induce a carnitine deficiency in young children and result in nonspecific symptoms of deficiency, hepatotoxicity, and hyperammonemia. Carnitine supplementation may help prevent the onset of hepatotoxicity.

D) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Elevated liver enzymes, and hyperammonemia have been reported following chronic administration of valproate (Lewis, 1978; Bruni & Wilder, 1979; Gerber et al, 1979; Addison & Gordon, 1980; Coulter & Allen, 1981; Rawat et al, 1981).

1) NOTE: Increased blood ammonia concentrations have been seen with doses of 52 to 60 mg/kg/day and 500 mg twice daily chronically.

b) CASE REPORT: A 33-year-old man on a combination of valproic acid and phenytoin therapy for seizures developed severe AST elevations (over 100 times normal upper limit) (McLaughlin et al, 2000).

Genitourinary

3.10.2)

A) RENAL FAILURE SYNDROME

1) WITH THERAPEUTIC USE

a) CASE REPORT: Idiosyncratic acute renal failure, with acute tubular necrosis, and rhabdomyolysis were reported in conjunction with multiorgan system failure in a 52-year-old man diagnosed with valproic acid toxicity. Renal function returned to normal after hydration therapy and stopping valproic acid therapy (Pinkston & Walker, 1997).
b) CASE REPORT: A 14-year-old handicapped girl with epilepsy was found to have a fever and hypokalemia after treatment with valproic acid for 7 years. Lab results revealed Fanconi syndrome. A renal biopsy showed interstitial nephritis. An alternative seizure drug was substituted and clinical symptoms improved (Yoshikawa et al, 2002).

2) WITH POISONING/EXPOSURE

a) Following a massive overdose, persistent metabolic acidosis and renal failure, without evidence of hepatic injury, have been reported (Christianson et al, 2001).
b) CASE REPORT: A 2-month-old girl presented with generalized seizures, progressive coma, and anuria associated with a serum sodium valproate concentration of 1299 mcg/mL (Roodhooft et al, 1990).

B) FANCONI SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A transient nephropathy syndrome similar to Fanconi syndrome (i.e., phosphaturia, kaliuria, proteinuria) was reported in a 15-year-old boy 2 days following the ingestion of 115 250-mg tablets. It resolved by the third day and the patient made a complete recovery (Su et al, 2002).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH THERAPEUTIC USE

a) Acidosis has also been reported following therapeutic use of valproic acid.

2) WITH POISONING/EXPOSURE

a) Metabolic acidosis and elevated lactate concentrations, which may be persistent, have been reported in patients with severe overdose and hypotension (Farrar et al, 1993; Tank & Palmer, 1993; Lee et al, 1998; Johnson et al, 1999; Christianson et al, 2001; Kroll & Nand, 2002). Kupferschmidt et al (1998) reported an adult with hypotension and metabolic acidosis (pH 7.20) with an elevated anion gap (34 mmol/L) after ingestion of an unknown quantity of valproic acid (Kuperschmidt et al, 1998).
b) INCIDENCE: In a series of 133 patients with valproate only overdose reported to a group of poison centers, 8 (6%) developed acidosis (Spiller et al, 2000). Acidosis was more common in patients with peak valproate concentrations of greater than 850 mcg/mL.
c) CASE REPORT: Metabolic acidosis was reported in a 20-month-old who unintentionally ingested 1.5 grams of sodium valproate (Janssen et al, 1985).

Hematologic

3.13.2)

A) MYELOSUPPRESSION

1) WITH POISONING/EXPOSURE

a) Severe bone marrow depression, requiring transfusions, has been reported following severe acute valproic acid ingestions (Koelliker et al, 1999).
b) CASE REPORT: Two women developed severe thrombocytopenia (platelets less than 20,000/mm3) and anemia after severe valproate overdose (Andersen & Ritland, 1995). One of them also developed leukopenia (WBC 1,200/mm3). Bone marrow suppression was most severe 4 to 5 days postingestion.
c) CASE REPORT: A 43-year-old woman developed thrombocytopenia (platelet count 87,000/mm(3)) following an ingestion of approximately 19 grams of a slow-release form of valproate (Johnson et al, 1999).

B) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) Symptomatic methemoglobinemia has been described after acute valproate ingestion in a 3-year-old child. The child was admitted to the ED approximately 6 hours postingestion with initial oxygen saturation by pulse oximetry of 75% on an FiO2 of 1.00. Arterial blood was dark brown in color. Significant metabolic acidosis (pH 7.23) was noted. Initial methemoglobin concentration was 38.8%. Complete resolution of methemoglobinemia occurred after administration of a total of 4 mg/kg of methylene blue over 90 minutes (Lynch & Tobias, 1998).

C) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) Inhibition of secondary platelet aggregation, prolonged bleeding times, and thrombocytopenia have been reported following therapeutic use (Lewis, 1978; Bruni & Wilder, 1979; Gerber et al, 1979; Addison & Gordon, 1980; Hintze et al, 1987; Gidal et al, 1994). In most cases, abnormalities resolve with dose reduction alone; discontinuation of drug use is usually not necessary (Acharya & Bussel, 2000).
b) Significant risk factors for developing thrombocytopenia or a clinically significant drop in platelets are dosage greater than 1000 mg/day and age older than 65 years (Conley et al, 2001).
c) A case of thrombocytopenia-induced fatal pulmonary hemorrhage was reported in a 30-year-old woman receiving valproate monotherapy (Sleiman et al, 2000). It has been suggested that viral infections may be associated with thrombocytopenia in individuals receiving valproate therapy.
d) A 67-year-old woman, with Lennox-Gasteau syndrome, developed severe, isolated thrombocytopenia after being placed on a combination of carbamazepine and valproate for the treatment of generalized tonic-clonic seizures. The patient received carbamazepine 150 mg/day for 7 days, 600 mg/day on day 8, and received 1200 mg/day by day 9. On day 10, valproate 300 mg/day was added because of nonconvulsive status epilepticus. The valproate was discontinued 5 days later because the patient developed urticaria and a maculopapulous exanthema. The thrombocyte count was 262 GIGA/L (normal: 150-360 GIGA/L) on day 5 and had dropped to 5 GIGA/L by day 15, at which time carbamazepine was also discontinued. The patient received two thrombocyte transfusions and her thrombocyte count was within normal limits 3 days after the carbamazepine was discontinued. It could not be determined whether it was carbamazepine alone or the combination of carbamazepine and valproate that was responsible for the severe thrombocytopenia (Finsterer et al, 2001).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 39-year-old woman with epilepsy ingested approximately 50,000 mg of valproic acid (VPA) with an initial serum concentration above 110 mcg/mL (above the level detectable by the laboratory) and a platelet count of 261 k/cumm. She was decontaminated and admitted to ICU for persistent drowsiness. On day 4, the patient developed a sudden drop in her platelet count to 46 k/cumm, with a VPA level of 12 mcg/mL. By the eighth day, her serum VPA level was 22.7 mcg/mL with a platelet count of 55 k/cumm. By day 11, her platelet count had normalized and she was discharged to home (Lin et al, 2008). The authors suggest that inadvertent or intentional exposures can result in delayed thrombocytopenia and monitoring may be required for approximately a week after exposure.
b) INCIDENCE: In a series of 133 patients with valproate only overdose reported to a group of poison centers, 11(8%) developed thrombocytopenia (less than 150,000/mm3) (Spiller et al, 2000).

D) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) CASE SERIES: In a on year prospective study involving 45 patients receiving valproic acid, neutropenia developed in 12 and thrombocytopenia in 15, but both disorders were transient and self-limiting despite continued treatment (Barr et al, 1982).
b) CASE REPORT: A later case report described severe neutropenia in a child which necessitated withdrawal of the drug (Symon & Russell, 1983).
c) CASE SERIES: In a study of 1,251 hospitalized patients receiving valproate therapy, 6 developed moderate to severe leukopenia (WBC less than 4,000/mm3); 2 of these patients were also taking carbamazepine (Tohen et al, 1995).

2) WITH POISONING/EXPOSURE

a) INCIDENCE: In a series of 133 patients with valproate only overdose reported to a group of poison centers, 4 (3%) developed leukopenia (Spiller et al, 2000).

E) PANCYTOPENIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Fatal pancytopenia developed in a 3-year-old child administered high-dose valproate therapy (Rajantie et al, 1992).

F) APLASTIC ANEMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Red cell aplasia in one child, on 2 occasions appeared to be associated with sodium valproate administration. The aplasia promptly resolved after drug withdrawal (MacDougall, 1982).

G) HEMATOLOGY FINDING

1) WITH THERAPEUTIC USE

a) In a cohort study, involving 29,357 recipients of anticonvulsive therapy receiving 684,706 prescriptions of 4 different drugs, one being valproate, serious blood dyscrasias were rarely found in these patients. Among the 4 drugs, rates did not appear different. An overall rate of blood dyscrasias was reported to be 3 to 4 per 100,000 prescriptions for all 4 drugs (Blackburn et al, 1998).

H) BLOOD COAGULATION DISORDER

1) WITH THERAPEUTIC USE

a) Below-normal concentrations of von Willebrand Factor activity was observed in 6 of 29 (21%) children who had been taking valproic acid for at least 6 months for the treatment of epilepsy. The 6 children were regarded as having "acquired von Willebrand's Disease." No correlation was found between von Willebrand factor activity and dose or blood concentration of valproic acid or duration of therapy. The authors cautioned that when surgery is necessary, factor VIII von Willebrand factor concentrations should be supplemented (Serdaroglu et al, 2002).

Dermatologic

3.14.2)

A) ALOPECIA

1) WITH THERAPEUTIC USE

a) Skin rashes and hair loss may occur (Lewis, 1978; Bruni & Wilder, 1979; Gerber et al, 1979). Five of 250 patients developed curly hair at dosage of 1 g/day. In 3/5 patients, this effect followed temporary alopecia (Jearons, 1977).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Alopecia developed in a 37-year-old woman after massive acute ingestion of valproic acid. Initial serum valproate concentration was 1579 mcg/mL (Palatnick et al, 1989).

B) BULLOUS ERUPTION

1) WITH POISONING/EXPOSURE

a) Superficial bullous lesions associated with a severe valproic acid ingestion in a 4-year-old child was reported. A serum valproic acid concentration of 804 mcg/mL was noted approximately 22 hours after ingestion. During the 4 days following ingestion, progression of the bullous skin lesions occurred and new regions of fluid-filled bullae developed (Koelliker et al, 1999).

C) DERMATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Pellagra-like syndrome developed in a young boy caused by valproate-induced niacin deficiency (Gillman & Sandyk, 1984).

D) STEVENS-JOHNSON SYNDROME

1) WITH THERAPEUTIC USE

a) Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been described occasionally during the early stages of valproic acid therapy. In a case-control study of patients taking various antiepileptic agents, 73 cases of SJS or TEN were identified; of these, 13 were due to valproic acid ingestion. SJS/TEN generally occurred during the first 8 weeks of therapy (Rzany et al, 1999).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis may occur following a massive acute overdose. Rhabdomyolysis, with a serum CPK greater than 32,000 U/L, was reported in a 4-year-old child following a severe valproic acid overdose with prolonged coma (Koelliker et al, 1999).

B) MUSCULOSKELETAL FINDING

1) WITH THERAPEUTIC USE

a) CASE REPORT: Valproate-induced systemic lupus erythematosus (SLE) was reported in a 30-year-old woman with partial trisomy of chromosome 9 treated for one year with valproate and ethosuximide polytherapy. She developed arthralgias, muscle weakness, fatigue and fever. Lab results showed increased sedimentation rate, hypergammaglobulinemia and high antinuclear antibodies titers. Antihistone antibodies and HLA-DR4 antigen were detected. All symptoms of SLE were resolved after the valproate was discontinued (Gigli et al, 1996).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH THERAPEUTIC USE

a) Hyperglycemia has been reported following chronic administration of valproate.

B) HYPOGLYCEMIA

1) WITH THERAPEUTIC USE

a) IN UTERO EXPOSURE

1) CASE REPORT: An infant born at 35 weeks gestation secondary to placenta previa was exposed in utero (mother with a history of complex partial epilepsy) to valproic acid (600 mg/day) and phenytoin (200 mg/day) developed jitteriness and hypoglycemia (32 mg/dL) on the second day of life. A glucose infusion was started and the jitteriness resolved. Due to suspected withdrawal, serum valproic acid (37.8 mcg/mL {normal: 50 to 100 mcg/mL} and phenytoin (6.37 mcg/dL {normal: 10 to 20 mcg/mL} levels were measured. A second episode of hypoglycemia (38 mg/dL) occurred on day 6, and IV glucose was continued until day 10 when the infant was fully tolerating oral feedings. No further episodes of hypoglycemia were reported and the infant was discharged to home (Coban et al, 2010).
2) CASE SERIES: Thirteen of 22 infants exposed in utero (throughout pregnancy) to valproic acid became hypoglycemic (lowest blood glucose concentration reported was 1.0 mmol/L). No episode was reported as symptomatic. No evidence for hyperinsulinemia as a cause for hypoglycemia existed. All infants were treated with glucose infusions. Withdrawal syndrome (irritability, jitteriness, hypertonia, seizures, vomiting) was reported in 10 of the infants, beginning 12 to 24 hours after birth and lasting 2 to 7 days (Ebbesen et al, 2000a).

2) WITH POISONING/EXPOSURE

a) In a series of 133 patients with valproate only overdose reported to a group of poison centers, one patient developed hypoglycemia (Spiller et al, 2000).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: After 5 weeks of treatment with sodium valproate, a 28-year-old woman suddenly developed a generalized maculo-papulous eruption with fever, lymph node enlargement, hypereosinophilia and altered liver function. Drug-induced hypersensitivity to valproic acid is reported as rare (Picart et al, 2000).

B) AIDS

1) WITH THERAPEUTIC USE

a) Valproate therapy may reduce intracellular concentrations of glutathione and inhibit activity of glutathione reductase in human red blood cells. There may be a link between intracellular concentrations of glutathione and the progression of HIV disease. Decreased glutathione concentrations may activate the replication of HIV. In vitro studies with cell lines infected with HIV showed the addition of valproate increased viral expression and replication at therapeutic drug concentrations (Hardy & Nardacci, 1999).

Reproductive

3.20.1)

A) Valproic acid is a known teratogen to humans. Maternal use of valproic acid alone or in combination with other antiepileptic drugs has been found to cause valproic acid syndrome in infants. Facial dysmorphology, congenital heart defects, spina bifida, cleft lip and palate, and developmental delays are some of the teratogenic effects seen.
B) In 2009, the FDA notified healthcare professionals and patients about an increased risk of congenital malformations (ie, neural tube defects, craniofacial defects, cardiovascular malformations, and other body system malformations) in infants born of women exposed to valproate sodium and related products during pregnancy.
C) The FDA has classified valproic acid as pregnancy category X and its use in pregnant women is contraindicated for the prevention of migraine headaches. However, valproate products continue to have a pregnancy category of D for treatment of epilepsy and manic episodes associated with bipolar disorder. Valproate products should only be used in pregnant women with epilepsy or bipolar disorder if other medications are not effective or are otherwise unacceptable in treating the condition.
D) Valproic acid is excreted in breast milk with low concentrations and is not contraindicated during breastfeeding.

3.20.2)

A) CONGENITAL MALFORMATIONS

1) In a retrospective review, valproic acid monotherapy during the first trimester resulted in a significantly increased risk of 14 major fetal congenital malformations. Overall, there were 118 infants with malformations out of all exposed pregnancies (n=1565), resulting in a malformation rate of 7.5% (95% confidence interval (CI), 6.3% to 9%). In an adjusted case-control subgroup analysis of infants with malformations, women who received valproic acid during the first trimester (n=122) had a significantly increased risk of delivering an infant with spina bifida (odds ratio (OR), 12.7; 95% CI, 7.7 to 20.7), atrial septal defect (OR, 2.5; 95% CI, 1.4 to 4.4), cleft palate (OR, 5.2; 95% CI, 2.8 to 9.9), hypospadias (OR, 4.8; 95% CI, 2.9 to 8.1), polydactyly (OR, 2.2; 95% CI, 1 to 4.5), or craniosynostosis (OR, 6.8; 95% CI, 1.8 to 18.8) compared with controls with no valproic acid exposure (n=45). Compared with other antiepileptic monotherapies, valproic acid monotherapy resulted in a significantly increased risk of ventricular septal defect, but not craniosynostosis. There was also a significantly increased risk of limb reduction (crude OR, 3.4; 95% CI, 1.6 to 7.2) in infants exposed to valproic acid compared with no exposure (Jentink et al, 2010).
2) According to data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry, infants born to women with epilepsy treated with valproate monotherapy had an almost 5-fold increased risk of major malformations (ie, neural tube defects, craniofacial defects, cardiovascular malformations, and other body system malformations) compared with those who received a different antiepileptic drug. The major malformation rate was 10.7% (95% CI, 6.3% to 16.9%) among infants born to women who received valproic acid 500 mg to 2000 mg/day during pregnancy (n=149) compared with 2.9% (95% CI, 2% to 4.1%) among infants of women who received any other antiepileptic drug monotherapy (n=1048) (Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015; Prod Info Stavzor(R) oral delayed release capsules, 2013; US Food and Drug Administration, 2009).
3) Congenital malformations in a study of 715 cases included neural tube defects in 7 (1%), facial cleft in 11 (1.5%), cardiac anomalies in 5 (0.7%), hypospadias and genitourinary defects in 9 (1.3%), gastrointestinal tract defects in 2 (0.3%), and skeletal malformations in 8 (1.1%) (Morrow et al, 2006).
4) CASE REPORT: An infant exposed in utero to valproic acid 250 mg/day was born at 38-weeks gestation with characteristics of fetal valproate syndrome (including neural tube defects) to a 21-year-old woman with a history of seizures and incomplete prenatal care. Her routine dose was 500 mg/day, but was decreased to 250 mg/day when the pregnancy was diagnosed during the first month. At 36-weeks gestation, an ultrasound (US) revealed craniosynostosis, extremity flexion abnormalities, cardiomegaly, bilateral renal hypoplasia, and hydrocephaly. A fetal echocardiography revealed Ebstein anomaly, secundum atrial septal defect, right ventricle hypertrophy, and pulmonary stenosis. Multiple facial, limb, and abdominal wall defects (ie, frontal bossing, micrognathia, arachnodactyly, and pectus excavatum) were observed upon examination at birth. Abdominal US of the infant at birth showed a right multicystic dysplastic kidney and ophthalmologic examination revealed bilateral optic nerve hypoplasia. A head CT confirmed trigonocephaly, hydrocephaly, and craniosynostosis. The infant was intubated and received supportive care, but died 15 days after birth as a result of respiratory failure (Ozkan et al, 2011).

B) SPINA BIFIDA

1) Exposure to valproic acid during pregnancy has been associated with fetal effects, primarily neural tube effects. There are several studies which support the association of neural tube defects (spina bifida) with valproic acid exposure during the first trimester (Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Depakote oral tablets, 2015; Robert et al, 1983; Robert, 1988; Jeavons, 1982; Verloes et al, 1990; Ardinger et al, 1988).

C) SKELETAL MALFORMATION

1) Valproic acid may also be associated with a specific syndrome of facial anomalies. One study evaluated 7 children who had been exposed to valproic acid in utero. A consistent facial phenotype was observed in all 7. The facial changes consisted of epicanthal folds which continued to form a crease or groove just under the eye socket, a flat nasal bridge, small upturned folds, long upper lip and down turned angles of the mouth. Major anomalies also consist of congenital heart defects and developmental delay in more than two-thirds of cases (DiLiberti et al, 1984). This valproic acid syndrome has also been noted by other authors (Verloes et al, 1990; Ardinger et al, 1988; Lewis et al, 1998). Another study reported an infant with facial dysmorphology (Dalens et al, 1980).
2) Two studies of anomalous right pulmonary artery origin confirmed by cardiac catheterization were reported in infants diagnosed with valproate syndrome (Mo & Ladusans, 1999).
3) The risk of congenital anomalies is greater in infants whose mothers were treated with multiple antiepileptic drugs at the same time. Valproic acid in combination with other primary antiepileptic drugs may be more teratogenic than other combinations of antiepileptic drugs.

a) Women who took only 1 antiepileptic during pregnancy had a 3% risk factor for giving birth to an infant with congenital anomalies. This compares with a 2% risk in the untreated epileptic mother. This risk increased to 5% in women who took 2 antiepileptics during pregnancy, 10% with 3 antiepileptics taken, and 20% in women who took 4 antiepileptics during pregnancy (Polifka & Friedman, 2002).

D) EYE ABNORMALITY

1) Septo-optical dysplasia and hypoplasia of the optic chiasm on MRI have been reported from maternal exposure to valproic acid (McMahon & Braddock, 2001).
2) CASE STUDY: A group of 46 children, ages 8 months to 16 years 5 months, diagnosed with fetal anticonvulsant syndrome were exposed in utero to valproic acid (29 as monotherapy). The remainder were exposed to other anticonvulsants. Thirty-one of 46 children (67%) had ocular abnormalities. Myopia was the most common (14 of 28 or 50%) in those exposed to valproic monotherapy. Strabismus, astigmatism, and anisometropia were also common (Glover et al, 2002).

E) CLEFT PALATE

1) Other fetal abnormalities have included cleft lip and palate with low birth weight, birth marks, abnormally long thin fingers, laryngeal hypoplasia, hydranencephaly, and severe problems in the respiratory system (Pinder et al, 1977; Huot et al, 1987) (Barrera et al, 1994).

F) FIBRINOGEN PLASMA DECREASED

1) Cases of neonatal fibrinogen depletion associated with sodium valproate ingestion in epileptic mothers have been reported. In 2 cases, no other medications were taken by the mothers and the pregnancies were described as uneventful. In 1 case, the newborn died within a few hours of afibrinogenemia (Bavoux et al, 1994).

G) LEARNING DISABILITIES

1) A case series of 39 children exposed to valproic acid in utero noted a trend towards lower IQ compared with controls, though this trend was not statistically significant. However, the mothers of these children had a statistically significant lower average IQ compared with controls, further confounding the study results (Eriksson et al, 2005).
2) Children who were exposed to valproate prenatally (n=62) had lower IQ scores at age 6 (IQ, 97; 95% CI, 94 to 101) compared with children who had prenatal exposure to other antiepileptic drugs, including lamotrigine (IQ, 108; 95% CI, 105 to 110), carbamazepine (IQ, 105; 95% CI, 102 to 108), and phenytoin (IQ 108; 95% CI, 104 to 112) (Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015).

H) BALLER-GEROLD SYNDROME

1) CASE REPORTS: Three infants with a history of maternal sodium valproate use (1500 to 2000 mg/day) presented with a combination of metopic suture synostosis and preaxial upper limb malformations (absence or hypoplasia of the radius and/or thumb), which could be diagnosed as Baller-Gerold syndrome. All 3 patients underwent surgery for the craniofacial deformities; standard frontocranial reconstruction was performed. Some degree of mental retardation was documented in 2 of the patients (SantosdeOliveira et al, 2006).

I) ANIMAL STUDIES

1) RAT, MOUSE, RABBIT, HAMSTER, MONKEY: There is a large volume of data in many animal species. There are several studies which report post-implantation mortality in the rat, mouse, and rabbit. Valproic acid is a teratogen in the rat, mouse, rabbit, hamster, and monkey (RTECS , 1996). Exposure of pregnant mice or rats to valproic doses several times greater than those used in human, but which produce serum valproic acid levels within the human therapeutic range, produces embryonic death and malformations in offspring (Nau & Loscher, 1986; Nau & Scott, 1986; Vorhees, 1987; Ritter et al, 1987; Binkerd et al, 1988; Finnell et al, 1988).
2) MICE, RATS, HAMSTERS: Exencephaly and skeletal anomalies are among the most common malformations observed in mice. Cardiac, skeletal, and urinary tract anomalies are seen most often in rats. In both species there is a dose-response relationship in the teratogenic effect. Hamsters treated with 5 times the human dose of valproic acid during pregnancy produce offspring with an increased frequency of neural tube defects (Moffa et al, 1984). Spina bifida occulta, exencephaly, and exophthalmia were reported in mice (Emmanouil-Nikoloussi et al, 2004). Conn et al (1982) reported a study on the effects of valproic acid on the fertility of male rats. There was a decrease in the prostate and epididymal weights. The rats also exhibited diminished sperm content and motility and their fertility was decreased. Valproic acid decreased cartilage formation within the growth plate of cultured rat metatarsal bones, leading to shorter overall length (Wu et al, 2004).
3) MICE: Valproic acid-induced neural tube defects were diminished in mice by coadministration of pantothenic acid; however, the latter did not affect incidence of other external or skeletal malformations (Sato et al, 1995).
4) RATS, MICE: Rats were less sensitive than mice for induction of structural defects: a dose of 150 mg/kg produced approximately 8.5% malformations in rats and 32% in mice. The most common defect in mice was encephalopathies, while rats were most susceptible to axial skeletal defects (Menegola et al, 1996).

3.20.3)

A) PREGNANCY CATEGORY

1) Valproate products are classified as FDA pregnancy category X in women treated for migraine prophylaxis and pregnancy category of D in women treated for epilepsy or manic episodes associated with bipolar disorder. Valproate products should only be used in pregnant women with epilepsy or bipolar disorder if other medications are not effective or are otherwise unacceptable in treating the condition (Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015; US Food and Drug FDA Drug Safety Valproate).
2) Valproate should not be administered to women of childbearing age unless absolutely necessary for the treatment of a medical condition. The risks and benefits of this drug should be weighed in women who are pregnant or of childbearing age (Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015).
3) Women treated with valproate for epilepsy should not abruptly discontinue this drug as it may precipitate seizures that endanger the mother and fetus (Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015).
4) For women using valproate during pregnancy, dietary folic acid supplementation should be recommended both prior to conception and during pregnancy to reduce the risk of neural tube defects, prenatal diagnostic testing should be offered, and clotting parameters should be carefully monitored in the mother and, if necessary, the fetus (Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015).
5) Infants born to mothers treated with valproate during pregnancy should have blood glucose levels monitored during the first several hours of life (Ebbesen et al, 2000).
6) The North American Antiepileptic Drug (NAAED) Pregnancy Registry has been established, and prescribers can register patients by calling 1-888-233-2334 (Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015; Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Stavzor(R) oral delayed release capsules, 2013; US Food and Drug Administration, 2009).

B) AUTISM SPECTRUM DISORDERS

1) In a large cohort study, an increased risk of autism spectrum disorders and childhood autism was seen among children with prenatal exposure to valproate (n=508) compared with children with no prenatal valproate exposure (n=655,107). Analyses of population records over a 10-year period identified children of mothers who filled prescriptions of valproate within a range of 30 days before estimated conception to birth. After 14 years of followup, prenatal valproate exposure was associated with adjusted hazard ratios for autism spectrum disorder of 2.9 (95% CI, 1.7 to 4.9) (n=14) and 5.2 (95% CI, 2.7 to 10) for childhood autism (n=9). The adjusted hazard ratios for autism spectrum disorder (1.7 [95% CI, 0.9 to 3.2]; n=11) and childhood autism (2.9 [95% CI, 1.4 to 6]; n=8) in 432 valproate exposed offspring of mothers with epilepsy were lower when compared to the risk of autism spectrum disorder (4.4 [95% CI, 1.4 to 13.6]; n=3) and childhood autism (3.9 [95% CI, 0.5 to 28.9]; n=1) among 76 valproate exposed children of mothers without epilepsy (Christensen et al, 2013).

C) COGNITIVE IMPAIRMENT

1) Adjusted analyses of the prospective, observational Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study found that mean IQ at ages 2, 3, 4.5, and 6 years (n=311) following prenatal exposure to antiepileptic drugs (AEDs) valproate, carbamazepine, lamotrigine, or phenytoin correlated with maternal IQ for all AEDs but valproate and remained consistent over time. Dose-dependent effects were observed for valproate but not for each of the other AEDs. At age 6 years, children with prenatal valproate exposure exhibited IQ reductions of 7 to 10 points compared with children treated with the other AEDs. Using the Bayley Scale of Infant Development (BSID) at age 2 and the Differential Ability Scale (DAS) at ages 3, 4.5, and 6 to assess cognitive development, adjusted mean IQ at age 6 in the carbamazepine group was 106 (n=61; range, 103 to 109); 108 in the lamotrigine group (n=74; range, 105 to 111); 109 in the phenytoin group (n=40; range, 105 to 113), and 98 in the valproate group (n=49; range, 95 to 102). IQ improved as children aged and percentages of cognitively impaired children decreased across all groups. However, children in the valproate group showed significantly lower adjusted mean verbal index scores (97; range, 94 to 100; p value not applicable) compared with children in the carbamazepine (104; range, 102 to 107; p vs valproate 0.0005), lamotrigine (105; range, 102 to 107; p vs valproate 0.0003), and phenytoin (106; range, 102 to 109; p vs valproate 0.0005) groups at age 6. In addition, adjusted mean non-verbal index scores were significantly lower in the valproate group (101; range, 98 to 104; p value not applicable) compared with the lamotrigine group (108; range, 105 to 110; p vs valproate 0.0015) (Meador et al, 2013).
2) Children who were exposed to valproate medications during pregnancy had statistically significant lower IQ scores at age 6 compared with children who had prenatal exposure to other antiepileptic drugs. The mean IQ score for children exposed to valproate products (n=62) in utero was 97 (95% CI, 94 to 101) as compared with 105 (95% CI, 102 to 108) for carbamazepine (n=94), 108 (95% CI, 105 to 110) for lamotrigine (n=100), and 108 (95% CI, 104 to 112) for phenytoin (n=55). However, these findings should be interpreted with caution, as the effect of periconceptional folate use, which is associated with higher mean IQs in children, was not a primary outcome of the study and information about its use were collected retrospectively (Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015; Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; US Food and Drug FDA Drug Safety Valproate).
3) In epidemiologic studies, children (ages 3 to 16) born to women who took valproate sodium or related antiseizure drugs (valproic acid and divalproex sodium) throughout pregnancy had lower cognitive test scores compared with children that were exposed in utero to other antiseizure medicines and those with no antiepileptic drug exposure. In the largest of the studies, a prospective cohort trial conducted in the United States and United Kingdom, children with prenatal exposure to valproate tested lower on the Differential Ability Scale (92; 95% confidence interval (CI), 88 to 97) compared with those exposed to lamotrigine (101; 95% CI, 98 to 104), carbamazepine (98; 95% CI, 95 to 102), or phenytoin (99; 95% CI, 94 to 104). Risk associated with less than full-term fetal exposure to valproate sodium has not been determined (U.S. Food and Drug Administration (FDA), 2011).
4) In children born to mothers who were taking valproic acid monotherapy during pregnancy, 4 of 21 (19%) had a score less than 80 on the full scale intelligence quotient (FIQ) and 2 of 21 (10%) had a score less than 70. The mothers taking valproic acid during pregnancy scored significantly lower in FIQ, verbal IQ, and performance IQ tests although most results fell within the normal range. In this study, mothers taking valproic acid also had significantly fewer years of education compared with mothers taking carbamazepine monotherapy and those without antiepileptic drug treatment (Eriksson et al, 2005).

D) HYPOGLYCEMIA

1) CASE REPORT: An infant born at 35 weeks gestation secondary to placenta previa was exposed in utero (mother with a history of complex partial epilepsy) to valproic acid (600 mg/day) and phenytoin (200 mg/day) developed jitteriness and hypoglycemia (32 mg/dL) on the second day of life. A glucose infusion was started and the jitteriness resolved. Due to suspected withdrawal, serum valproic acid (37.8 mcg/mL {normal: 50 to 100 mcg/mL} and phenytoin (6.37 mcg/dL {normal: 10 to 20 mcg/mL} levels were measured. A second episode of hypoglycemia (38 mg/dL) occurred on day 6, and IV glucose was continued until day 10 when the infant was fully tolerating oral feedings. No further episodes of hypoglycemia were reported and the infant was discharged to home (Coban et al, 2010).
2) CASE SERIES: Thirteen of 22 infants exposed in utero (throughout pregnancy) to valproic acid became hypoglycemic (lowest blood glucose concentration reported was 1 mmol/L). No episode was reported as symptomatic. No evidence for hyperinsulinemia as a cause for hypoglycemia existed. All infants were treated with glucose infusions. Withdrawal syndrome (irritability, jitteriness, hypertonia, seizures, vomiting) was reported in 10 of the infants, beginning 12 to 24 hours after birth and lasting 2 to 7 days (Ebbesen et al, 2000a).

E) RESPIRATORY DISTRESS

1) CASE REPORT: An infant exposed in utero to valproic acid 250 mg/day was born at 38-weeks gestation with respiratory distress and characteristics of fetal valproate syndrome (including neural tube defects) to a 21-year old woman with a history of seizures who received incomplete prenatal care. Her routine dose was 500 mg/day, but was decreased to 250 mg/day when the pregnancy was diagnosed during the first month. The infant was intubated and treated with supportive care, but died 15 days after birth as a result of respiratory failure (Ozkan et al, 2011).

3.20.4)

A) BREAST MILK

1) Valproic acid is excreted into breast milk (Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015; Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Stavzor(R) oral delayed release capsules, 2013), with concentrations of about 1% to 15% of maternal serum concentrations; therefore, the drug is NOT contraindicated during breastfeeding (Dickinson et al, 1979; Von Uhruh et al, 1984; Rimmer & Richens, 1985; Briggs et al, 1998; Iqbal et al, 2001). The American Academy of Pediatrics has concluded that use of valproic acid is compatible with breastfeeding (AAP, 1994).
2) In 2 mother-infant pairs, serum valproate concentrations were 1.5% and 6%, respectively, of the maternal values (Wisner & Perel, 1998).
3) In a series of 6 breastfeeding mother-infant pairs, one study reported serum valproate concentrations in nursing mothers to be near or within the therapeutic range while serum concentrations in the infants were low, ranging from 0.7 to 1.5 mcg/mL (0.9% to 2.3% of maternal serum concentrations) (Piontek et al, 2000).
4) CASE REPORT: A 3-month-old breastfed infant, whose mother was treated with sodium valproate (1200 mg/day), presented to the hospital with thrombocytopenic purpura and anemia. Following discontinuation of breastfeeding, the infant recovered (Stahl et al, 1997).
5) Exercise caution when administering a valproate product to a nursing woman (Prod Info Depacon intravenous injection, 2015; Prod Info DEPAKENE oral capsules, oral solution, 2015; Prod Info Depakote oral tablets, 2015a; Prod Info Depakote ER oral extended-release tablets, 2015; Prod Info DEPAKOTE(R) Sprinkle Capsules oral delayed release capsules, 2015).

3.20.5)

A) ENDOCRINE DISORDER

1) In a study of men (n=21) taking valproic acid for epileptic control, 12 men (57%) developed increased serum androgen concentrations, but this was not associated with elevations in circulating LH or insulin concentrations. Mean serum concentration of androstenedione was high (3.7 mcg/L) in these patients (Rattya et al, 2001).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS99-66-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) At the time of this review, no data were found as to the carcinogenic effects of valproic acid in humans.

3.21.4)

A) CARCINOMA

1) A study of Wistar rats and B6C3F1 mice showed adenocarcinomas of the uterus and cervix when exposed to calcium valproate. The statistically significant (P<0.01) increase in uterine adenocarcinomas found in females contrasts the absence of this tumor type in a previous rat bioassay study with valproic acid Subcutaneous fibrosarcomas were significantly increased in valproic acid treated males, but no uterine tumors were reported in females. Researchers are unsure why carcinogenic potential in the calcium salt of valproic acid would be expressed in markedly different target organs (Watkins et al, 1992).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Valproate concentration should be measured (therapeutic level 50 to 100 mcg/mL) and repeated every 4 to 6 hours until downward trend is established.
B) Serum concentrations greater than 450 mcg/mL is associated with drowsiness/obtundation; greater than 850 mcg/mL is associated with coma.
C) Monitor blood gases, liver enzymes, ammonia concentration, lactic acid, electrolytes, blood sugar, renal function and ECG in patients with significant toxicity.
D) Valproate causes false elevation of urine ketones.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Peak concentrations may be delayed 6 to 8 hours or longer after overdose, particularly with enteric coated formulations (Meyer et al, 2005; Kay et al, 2003; Tank & Palmer, 1993). Therapeutic concentrations are considered to be between 50 and 100 mcg/mL. Serum concentrations are not reliable for predicting severity of CNS depression in valproic acid poisoning cases; however, more serious effects (e.g., coma, acidosis, aspiration, respiratory depression) are generally seen at concentrations >850 mcg/mL (Spiller et al, 2000).
2) Follow serum electrolytes, hepatic enzymes and serum ammonia concentrations in patients with significant symptoms. Hyperammonemia and hyperlactacidemia may be significant following severe overdose.

B) HEMATOLOGY

1) Monitor platelet count in symptomatic patients; thrombocytopenia has been reported (Lin et al, 2008).

C) ACID/BASE

1) Follow arterial blood gases or pulse oximetry in patients with significant CNS depression.

4.1.3)

A) URINALYSIS

1) False urinary tests for ketones and glucose have been noted following daily therapeutic doses.

Methods

A)

1) Serum valproic acid concentrations should be available from all laboratories doing anticonvulsant screens. An anticonvulsant screen should be obtained on all patients due to the common availability of other anticonvulsant agents to the epileptic patient.

a) Inter- and intra-assay measurement differences may become clinically significant at very elevated valproic acid concentrations after overdose. Benton et al (2001) reported the CEDIA immunoassay produced consistently higher readings for valproic acid than three other assays it was compared with.

2) An EMIT(R) homogeneous enzyme immunoassay is available for quantitation of valproic acid in serum or plasma. The assay's range of quantitation is 10 to 150 mcg/mL valproic acid. Clinical studies show excellent correlation between this method and GLC.

a) In a single patient, on the average, the Emit assay overestimated the true valproic acid concentration by 50%. The overestimate by EMIT reduced to 16% when concentrations of measured metabolites were added to that of valproic acid as determined by GLC (Dupuis et al, 1990).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with rising valproate concentrations and those developing CNS depression or other clinical or laboratory evidence of toxicity should be admitted. Patients with persistent altered mental status, abnormal vital signs, acidosis, renal or hepatic involvement should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic patients with unintentional ingestion of less than 50 mg/kg can be observed at home (Manoguerra et al, 2008).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity, or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Symptomatic patients, those with deliberate ingestions, and those with unintentional ingestions of 50 mg/kg or more should be referred to a medical facility for evaluation and treatment (Manoguerra et al, 2008). Monitor serial valproate concentrations every 2 to 3 hours. Patients should be observed until serial valproate concentrations are clearly declining on at least two sequential measurements, and symptoms have resolved. Patients should be observed for a minimum of 6 hours after immediate release valproate ingestions, and for a minimum of 12 hours following delayed release preparations (time to maximum concentration after therapeutic dose of extended release formulation is 4 to 17 hours) (Prod Info Depakote ER oral extended release tablets, 2013).

Monitoring

A)

B)

C)

D)

Oral Exposure

6.5.1)

A) PREHOSPITAL

1) Ipecac-induced emesis is not recommended in the prehospital setting because of the potential for aspiration.

B) NALOXONE

1) In patients with valproic-induced coma and/or significant respiratory depression, naloxone may be considered in the prehospital setting (Manoguerra et al, 2008).

C) ACTIVATED CHARCOAL

1) Activated charcoal may be considered in the prehospital setting by a healthcare professional only, if the patient is asymptomatic, the ingestion is recent, and there are no contraindications. However, transportation to an emergency center should NOT be delayed to administer activated charcoal (Manoguerra et al, 2008).
2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) SUMMARY

1) GASTROINTESTINAL DECONTAMINATION RECOMMENDATIONS: In a systematic review of the literature, the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup (includes international experts from the US, Canada, Europe, Australia, Brazil and China) concluded that patients may benefit from a single dose of activated charcoal following a recent ingestion. Currently, the use of multiple dose activated charcoal is not recommended (Ghannoum et al, 2015).

B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

3) The absorption of valproate 300 mg was reduced by 65% by the administration of 50 g of activated charcoal 5 minutes postingestion (Neuvonen et al, 1983).
4) Consider a second dose of activated charcoal in a patient with rising concentrations after initial decontamination or following a large overdose of an enteric-coated or sustained-release valproate formulation.

C) MULTIPLE DOSE ACTIVATED CHARCOAL

1) Two case reports suggest that multiple dose activated charcoal may enhance valproate elimination in patients with large overdoses. There are no studies to determine if MDAC improves outcome or shortens the duration of toxicity after valproate overdose. MDAC has also been associated with adverse events including aspiration and bowel obstruction (Sztajnkrycer, 2002). Routine use is NOT recommended.
2) CASE REPORT: A 15-year-old boy ingested approximately 115 250-mg valproate tablets, and was successfully treated with multiple dose activated charcoal (MDAC) (Su et al, 2002). Activated charcoal 60 g via a nasogastric tube was administered after the patient's neurological status deteriorated (i.e., delirium and pinpoint pupils). Initial serum VPA was 915 mcg/mL, and peaked two hours later at 1183 mcg/mL. The patient was given three additional doses of AC (30 g) every 6 hours. A calculated serum half-life of 6.45 hours was reported while receiving MDAC, as compared to 24.75 hours after MDAC was discontinued.
3) CASE REPORT: A 26-month-old who ingested at least 4.5 grams (375 milligrams/kilogram) of valproate was treated with continuous nasogastric infusion of activated charcoal 3 grams/hour. Calculated elimination half life was 4.8 hours compared with and expected elimination half life of 10 to 16 hours in children taking therapeutic doses and 21 to 23 hours after overdose (Farrar et al, 1993).

D) GASTRIC LAVAGE

1) Gastric lavage should be reserved for patients with very large ingestions, generally 400 milligrams/kilogram or more.
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

4) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

E) WHOLE BOWEL IRRIGATION (WBI)

1) Whole bowel irrigation was used in the case of a massive overdose of divalproex with prolonged absorption and a delayed peak serum concentration (1380 micrograms/milliliter 17 hours after ingestion) (Graudins & Aaron, 1996). Whole bowel irrigation may be a useful adjunct in the treatment of overdoses of enteric coated valproate formulations or patients with rising concentrations despite activated charcoal therapy.

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

6.5.3)

A) SUPPORT

1) General and supportive care is indicated for the patient (Morrow & Routledge, 1989). Most patients with mild/moderate CNS depression may be safely managed with conservative, supportive respiratory and cardiovascular care. Respiratory arrest requiring artificial ventilation has been reported following severe overdose.
2) Patients ingesting less than 400 milligrams/kilogram are not likely to develop severe toxicity (Ibister et al, 2003). Patients with large ingestions may require resuscitation and intensive supportive care

B) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

C) NALOXONE

1) POSITIVE EFFECT: Intravenous administration of NALOXONE (0.01 milligram/kilogram and 2 milligrams, respectively in 2 cases) has reversed coma thought to be secondary to valproate ingestion in a limited number of case reports (Steiman et al, 1979; Alberto et al, 1989; Montero, 1999). It was suggested that naloxone can act by displacing GABA from its receptors and block or inhibit the effect of GABA, which was augmented by valproate (Thanacoody, 2007; Montero, 1999).

a) ACUTE TOXICITY

1) In addition, naloxone 2 mg was successfully used to reverse a depressed level of consciousness in a 22-year-old male whose admission valproate concentration was 180.4 micrograms/milliliter; other toxicological studies were negative (Popiel et al, 1989). Two mg naloxone was administered intravenously to a 44-year-old woman who ingested a "handful" of her valproic acid and gabapentin tablets as well as 4 mexilitine tablets and ethanol (Roberge & Francis, 2002). Within one minute the patient awoke and became conversant. A second dose was repeated in one hour due to increasing somnolence with a quick reversal of symptoms. Further support for the efficacy of naloxone in these patients has not yet appeared in the literature.

b) CHRONIC TOXICITY

1) A 76-year-old woman with bipolar depression, treated chronically with sodium valproate was admitted with acute confusion and tremulousness. Glasgow Coma Score decreased to 10/15 after admission. Serum valproate concentration was 848 micromol/L (normal 300 to 600 micromol/L). An intravenous bolus of 0.8 mg naloxone resulted in rapid improvement of mental status and blood pressure, and resolution of apneic episodes. A naloxone infusion was continued and symptoms resolved over 24 hours with no sequelae (Thanacoody, 2007) .

c) NO EFFECT

1) Naloxone 0.8 milligram intravenously was ineffective in a 40-year-old epileptic woman following a sodium valproate overdose.

a) The reported peak valproate concentration was 18,900 micromoles/liter 6 hours after admission (Connacher et al, 1987).
b) A 37-year-old woman ingested a massive amount of valproic acid resulting in a serum concentration of 1579 mcg/mL and profound coma. Aggressive naloxone therapy (total dose = 30 milligrams) was ineffective (Palatnick et al, 1989).

D) LEVOCARNITINE

1) Carnitine administration has been shown to lower serum ammonia concentrations and improve outcome in patients with valproate-induced hepatotoxicity and encephalopathy after chronic use (Ohtani et al, 1982).
2) Carnitine supplementation should be considered in patients with elevated valproic acid concentrations and hyperammonemic encephalopathy.
3) DOSE

a) The Pediatric Neurology Advisory Committee recommends carnitine replacement for valproate-induced hepatotoxicity and overdose. For carnitine replacement, oral doses of 100 mg/kg/day or 2 grams/day (divided into 3 or 4 doses) should be given. In cases of overdose or valproate-induced hepatotoxicity, rescue therapy with intravenous carnitine 150 to 500 mg/kg/day (up to maximum of 3 grams/day) should be administered (Lheureux & Hantson, 2009; Raskind & El-Chaar, 2000).
b) Based on a review of the literature, optimal dosing of L-carnitine for acute toxicity has not been established. Suggested guidelines for the use of L-carnitine following acute valproate toxicity are as follows (Russell, 2007):

1) Acute overdose with NO evidence of hepatotoxicity: Prophylactic dose of 100 mg/kg/day IV in divided doses every 6 hours (maximum 3 g)
2) Acute overdose and symptomatic hepatotoxicity or hyperammonemia:

a) Loading dose: 100 mg/kg IV over 30 minutes (maximum of 6 g)
b) Maintenance dose: 15 mg/kg every 4 hours administered over 10 to 30 minutes

4) EFFICACY

a) SUMMARY: Hyperammonemia may develop after acute overdose, or acute-on-therapeutic overdose, or following chronic valproic acid therapy (Lheureux & Hantson, 2009).
b) CHRONIC: In a series of 92 patients with severe valproate induced hepatotoxicity from chronic therapy, 48% of the 42 patients treated with L-carnitine survived, compared with only 10% of those treated with aggressive supportive care (Bohan et al, 2001). Patients treated with intravenous L-carnitine and those treated early in the course of illness appeared to do best. Most of these patients appeared to be malnourished. In a review, it was noted that levocarnitine supplementation improved hyperammonemia associated with chronic valproic acid therapy; however, ammonia concentrations did not necessarily correlate with clinical symptoms (Lheureux et al, 2005).
c) ACUTE: Carnitine has also been used in cases of valproic acid overdose (Papaseit et al, 2012; Sztajnkrycer et al, 2001; Thole et al, 2001). There are no studies demonstrating improved outcome in patients treated with L-carnitine after valproic acid overdose (Sztajnkrycer, 2002).

1) INDICATIONS: Despite a lack of controlled studies or limited evidence supporting the use of L-carnitine (Ghannoum et al, 2015), it is suggested that L-carnitine be used to treat acute valproic acid-induced toxicity under the following circumstances (Papaseit et al, 2012; Jung et al, 2008; Lheureux & Hantson, 2009; Russell, 2007):

1) Hepatotoxicity
2) Hyperammonemia
3) High risk patients; especially children or those who ingested a large amount of valproic acid
4) Valproic acid concentration greater than or equal to 450 mg/L

2) VALPROATE-INDUCED HYPERAMMONEMIC ENCEPHALOPATHY OCCURRING AT THERAPEUTIC LEVELS: In a small number of cases, valproate-induced hyperammonemic encephalopathy has been reported at therapeutic valproate dosages and has been successfully treated with levocarnitine. In one case, a 31-year-old man was started on valproate after developing a generalized tonic-clonic seizure and was later diagnosed with a glioma. Six days after surgery he became lethargic and his ammonia level was 204 micromol/L (normal, less than 32); valproate level was 95 ng/mL (normal, 50 to 100). He received levocarnitine at 100 mg/kg over 20 minutes, followed by 50 mg/kg every 8 hours for 24 hours. Within 24 hours, his neurologic status had improved along with a decrease in his ammonia levels (Rigamonti et al, 2014).
3) PEDIATRIC

a) CASE REPORT: L-carnitine was administered to a 16-month-old child who ingested approximately 4000 mg of valproate (Ishidura et al, 1996). L-carnitine administration was associated with increased urinary elimination of beta oxidation metabolites of valproate and decreased urinary elimination of omega and omega-1-oxidation metabolites and 4-en-valproate, a potential hepatotoxin. The child recovered without sequelae.

4) ADULT

a) CASE REPORT: L-carnitine (1 g 3 times per day) IV was administered for 24 hours in a 30-year-old man who intentionally ingested an estimated 35 g of extended-release valproate (VPA) 15 hours prior to admission. An initial VPA plasma concentration was 391 mcg/mL with clinical evidence of hyperammonemic encephalopathy (ie, lethargy, ammonia concentration: 256 micromoles/L) and no signs of liver failure. His level of consciousness improved with decreasing concentrations of both VPA (to therapeutic range) and ammonia concentrations (124 to 128 micromoles/L; normal range: 10 to 47) approximately 13 hours later (28 hours postingestion) (Papaseit et al, 2012).
b) CASE REPORT: Levocarnitine (100 mg/kg) was given IV to a 51-year-old woman who presented 10 days after initiation of valproate (10 mg/kg/day) therapy with severe hyperammonemic encephalopathy. Blood arterial ammonia concentration on presentation was 234 s/L, which decreased over a 10 hour period following intravenous L-carnitine to 35 mmol/L. Her neurologic condition improved within 18 hours (Borbath et al, 2000).
c) CASE REPORT: Following the ingestion of an unknown quantity of valproic acid, a 24-year-old man was treated for an elevated serum ammonia concentration (176 mEq/dL) with L-carnitine 25 mg/kg IV every 6 hours for about 30 hours, when his ammonia concentration dropped to 44 mEq/dL. At 46 hours postingestion the patient was asymptomatic with normal vital signs (Thole et al, 2001).
d) CASE REPORT: A single bolus dose of L-carnitine (20 mg/kg IV) was given postdialysis to a 41-year-old man, after reportedly ingesting 50,000 mg of valproic acid, for prophylaxis against hepatotoxicity and hyperammonemia (Guillaume et al, 2004).

5) SAFETY

a) A retrospective review of patients treated with L-carnitine after acute valproic acid (VPA) overdose and elevated ammonia concentrations was conducted. Fifty-five doses of L-carnitine were administered to 19 patients who had isolated VPA ingestions, and 196 doses of L-carnitine were administered to patients with mixed overdoses that included VPA. Of the 251 doses administered, there were no adverse events (defined as an allergic reaction or hypotension) reported (LoVecchio et al, 2005).

Enhanced Elimination

A)

1) Hemodialysis, hemoperfusion and hemofiltration enhance the clearance of valproic acid after severe overdose, because protein binding of the drug is saturated; however, it is not clear if these modalities affect outcome after overdose. They should be considered for patients with severe intoxication and rising concentrations despite supportive care. Because hemodialysis is most readily available in most practice settings, it is the method used most often for sever valproate poisoning.
2) In addition, clinical improvement has been noted to occur faster in patients that receive extracorporeal treatment within the first 24 hours of admission (Ghannoum et al, 2015).

B)

1) SUMMARY

a) THERAPEUTIC CONCENTRATIONS: Hemodialysis is NOT very effective for removal of therapeutic concentrations of valproic acid (VPA) since VPA is highly protein bound, but it is effective for VPA removal following overdose because the fraction of drug not bound to protein is high in this setting and hemodialysis (or tandem hemodialysis and hemoperfusion) may result in significant drug removal (Prod Info DEPAKENE(R) oral capsules, oral solution, 2007; Meek et al, 2004; Kay et al, 2003; Kroll & Nand, 2002; Hicks & McFarlane, 2001). Hemodialysis has been reported as effective in removing valproic acid (VPA) from uremic patients (Marbury et al, 1980).
b) OVERDOSE: In overdose, saturated protein binding results in an increased fraction of unbound valproic acid, resulting in more effective removal by hemodialysis (Ghannoum et al, 2015; Al Aly et al, 2005; Guillaume et al, 2004).
c) Most patients can be managed with supportive care alone. Hemodialysis should be considered in patients with hemodynamic instability. Some authors suggest that markedly elevated valproate (greater than 950 mcg/mL) may be an indication for hemodialysis or charcoal hemoperfusion. However, in a retrospective review of 50 cases of overdose, there were 4 patients who had documented peak valproate concentrations greater than 950 mcg/mL and did not have persistent hemodynamic instability or metabolic acidosis (Graeme et al, 1999). None received hemodialysis or hemoperfusion, and all recovered without sequelae.
d) The percent of total serum valproate that is not protein bound increases substantially in severe overdose, from 11% free drug at a level of 79 mcg/mL to 71% free drug at a concentration of 451 mcg/mL in one case report (Farrar et al, 1993). This suggests that hemodialysis might clear a significant amount of drug in severe overdose. Calculated VPA half-life was reported to be 2.48 hours during hemodialysis and 16.64 hours after dialysis in a VPA overdose patient. In the same patient, serum VPA concentration dropped from 752.7 mcg/mL to 269 mcg/mL after 3.5 hours of hemodialysis (Ruskosky et al, 1999).
e) High efficiency hemodialysis, which can be performed at the bedside and requires lower blood flow rates, may be used for severe valproic acid intoxications when high-flux hemodialysis is not readily available (Sharma et al, 2001).

2) SYSTEMATIC REVIEW AND RECOMMENDATIONS

a) In a systematic review of the literature that included 79 articles, including 1 observational study, 1 uncontrolled cohort with aggregate results, 70 case reports or case series and 7 pharmacokinetic studies, the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup (included international experts from the US, Canada, Europe, Australia, Brazil and China) concluded that valproic acid is moderately dialyzable (moderate level of evidence (grade B)). Of note, most reported poisonings involved regular-release formulations of valproic acid. Patient history alone was considered an unreliable indicator by the workgroup to begin ECTR considering the potential risks of treatment. Close monitoring was indicated to assess the patient and to determine if ECTR was needed. Despite a low quality of evidence for all recommendations, extracorporeal treatment was recommended in the setting of severe valproic acid poisoning. Intermittent hemodialysis is the preferred method. If unavailable, intermittent hemoperfusion or continuous renal replacement therapy are appropriate alternatives (Ghannoum et al, 2015).
b) ECTR is recommended if ANY of the following are present (Ghannoum et al, 2015):

1) Valproic acid concentration of greater than 1300 mg/L (9000 micromol/L)
2) Valproic acid poisoning-associated cerebral edema or shock

c) ECTR is suggested if ANY of the following are present (Ghannoum et al, 2015):

1) Valproic acid concentration of greater than 900 mg/L (6250 micromol/L)
2) Coma or respiratory depression requiring mechanical ventilation
3) Acute hyperammonemia
4) pH less than or equal to 7.10

d) DISCONTINUATION OF THERAPY: Hemodialysis should be discontinued when the patient is clinically improving (ie correction of severe manifestations including coma, acidemia, respiratory depression and hemodynamic instability) or the serum valproic acid concentration is between 50 and 100 mg/L (therapeutic concentration). In the presence of a mixed ingestion that may not be removed by ECTR, further evaluation and assessment of the patient may be indicated (Ghannoum et al, 2015).
e) REBOUND: Valproic acid concentrations may rebound after a session of ECTR and it is likely due to a redistribution from deeper compartments in the plasma. Although this event has been reported, it did not produce significant changes (ie, clinical deterioration) in most patients. If necessary, a second session of ECTR may be indicated to correct the effects of rebound (Ghannoum et al, 2015).

3) CASE SERIES

a) CASE SERIES: In a series of 32 patients with valproic acid overdose and peak serum concentrations greater than 100 mcg/mL reported to a single poison center, 6 were treated with hemodialysis. Valproic acid elimination was increased about ten fold during hemodialysis. Half-life during hemodialysis averaged 1.9 hours in the three patients in whom there was sufficient data to calculate, compared with 29.6 hours after hemodialysis. In the one patient treated with combined hemodialysis and hemoperfusion half life during the procedure was 4.3 hours. Complications included a seizure in a patient with a seizure disorder, and thrombocytopenia in the patient treated with hemoperfusion (Singh et al, 2004).
b) CASE SERIES: In a series of 6 patients with valproic acid intoxication, the half-life of valproic acid during hemodialysis was 2.5 to 5.2 hours, compared with half lives of 10.2 to 60.4 hours prior to dialysis and 10.3 to 62.7 hours after dialysis (Eyer et al, 2005).

4) CASE REPORTS

a) CASE REPORT: A 48-year-old unconscious female with a peak serum valproate concentration of 1402 mg/L (dose ingested 48 g) was initially started on continuous veno-venous hemodiafiltration (CVVHDF) with a high-flux membrane for 8 hours with no change in neuro status, and minimal change in valproate clearance. Estimated elimination half-life during hemodialysis was 2.2 hours, compared to 16.1 hours during CVVHDR and 28.5 hours without treatment. Plasma clearance was 90 mL/min during the first hour of dialysis, and 56 mL/min during the fourth hour. She had a complete recovery (Kay et al, 2003).
b) CASE REPORT: Hemodialysis was used to treat a 44-year-old woman with severe valproic acid and trazodone overdose complicated by seizures, myoclonic jerking, coma and hypotension (Williams & Clark, 1995). Initial valproate concentration was 995 mcg/mL falling to 949 mcg/mL 3.5 hours later. Within 30 minutes of initiating hemodialysis she was able to follow commands and after 4 hours of hemodialysis valproic acid concentration was 113 mcg/mL. Dialysis clearance of valproic acid was not determined.
c) CASE REPORT: Hemodialysis was used successfully for treatment of valproic acid (VPA) overdose (approximately 19 grams) in a 43-year-old woman (Johnson et al, 1999a). Renal and hepatic functions were normal. Four hours after hospital presentation hemodialysis was begun. Serum VPA concentration decreased from 940 mcg/mL to 164 mcg/mL after 6 hours of hemodialysis. Prior to hemodialysis VPA half-life was 7.2 hr and after hemodialysis VPA half-life was 2.4 hr. Valproate clearance was 76 to 100 milliliters/minute during dialysis.
d) CASE REPORT: High-flux hemodialysis without charcoal hemoperfusion was successfully used in a case of valproic acid overdose in a 25-year-old female. The amount ingested was unknown, and resulted in coma, hypotension and lactic acidosis, with serum a concentration greater than 1200 mcg/mL. During 4-hour high-flux hemodialysis, valproic acid half-life was calculated as 2.7 hours, compared to 23.4 hours post dialysis (Kane et al, 2000).
e) CASE REPORT: High-flux hemodialysis was used in a patient with acute-on-chronic renal failure (previous history of nephrosclerosis, hypertension, SLE and thrombocytopenia) and severe valproic acid poisoning (coma, hypotension, valproic acid concentration 650 mcg/mL). Serum valproate and ammonia concentrations declined rapidly. Dialyzer clearance was 121 mL/min during the first dialysis and 56 mL/min during the second. His course was complicated by thrombocytopenia and aspiration pneumonia but he recovered (Kielstein et al, 2003).
f) CASE REPORT: A 41-year-old man was treated with hemodialysis after reportedly ingesting 50,000 mg of valproic acid (100 500-mg extended release tablets) and subsequently developing lethargy and tachycardia. His plasma valproic acid (VPA) concentration on admission was 789 mg/L (therapeutic range 50 to 100 mg/L). Two hours later, his plasma VPA concentration increased to 1150 mg/L. Approximately 6 hours post-admission, hemodialysis was initiated, with a mean blood flow rate of 200 mL/min and a dialysate flow rate of 500 mL/min. Postdialysis, the patient was given a single bolus dose of L-carnitine (20 mg/kg) intravenously for prophylaxis against hepatotoxicity and hyperammonemia. The patient completely recovered and was discharged 48 hours later (Guillaume et al, 2004).

1) The calculated plasma half-life of VPA was approximately 4 hours during hemodialysis and 15.8 hours postdialysis. Prior to hemodialysis, the concentration of unbound VPA increased from 400 mg/L to 781 mg/L, resulting in a protein binding of approximately 35% (normal is greater than 80%). Twenty-eight hours postdialysis, the protein binding normalized (Guillaume et al, 2004).

C)

1) CASE REPORT: A 39-year-old woman became rapidly comatose with metabolic acidosis and refractory hypotension after ingesting 100 (1.2 g/kg) enteric coated sodium valproate tablets. Approximately, 18 hours after ingestion a peak valproate concentration of 12,488 micromol/L was observed. The patient was treated with slow low-efficient daily diafiltration using a Fresenius 408S ArRT-Plus online hemodiafiltration system with a Fresenius AV600S standard hollow-fiber polysulfone membrane. The plasma valproate concentration fell rapidly over 16 hours of therapy, along with clinical and laboratory improvement. No rebound phenomenon occurred. The patient was discharged 3 days after dialysis with no permanent sequelae (Khan et al, 2008). The authors suggest that this form of hybrid dialysis provides the benefit of continuous renal replacement therapy and intermittent hemodialysis.

D)

1) SUMMARY: Intermittent hemoperfusion can be useful to enhance elimination after a severe valproate overdose, however it is often less available than hemodialysis in most healthcare settings and can produce more complications that can be life threatening. It can also produce hypocalcemia or thrombocytopenia (Ghannoum et al, 2015).
2) RECOMMENDATIONS: Intermittent hemoperfusion is recommended as an alternative therapy when intermittent hemodialysis is not available (Ghannoum et al, 2015).
3) MECHANISM: Hemoperfusion may be effective in removing valproic acid (VPA) following overdose. VPA has a relatively low volume of distribution and small molecular weight (144 daltons), and hemoperfusion with charcoal is effective in removing protein bound drugs circulation (Jung et al, 2008).
4) CASE REPORT: A 23-year-old woman intentionally ingested approximately 24 g of valproic acid (VPA) and was found stuporous. A serum VPA concentration of 1159.4 mcg/mL (range: 50-100 mcg/mL) was reported on admission. The patient underwent three courses of hemoperfusion with activated charcoal for 6 hours (serum concentration decreased to 628.9 mcg/mL after the first session of hemoperfusion) with a normal serum level by day 3 and improving neurologic function. The patient was also treated with L-carnitine for hyperammonemia and metabolic acidosis. No permanent sequelae was reported (Jung et al, 2008).
5) CASE REPORT: Activated charcoal hemoperfusion was used to remove sodium valproate from a 38-year-old man with a documented sodium valproate blood concentration of 1080 mcg/mL. Activated charcoal hemoperfusion was performed for 8 hours initially and again later for 5 hours at 150 to 200 mL/min (18 hours after admission). When the patient awoke, his hematologic, liver enzymes and kidney function tests were all within normal limits (Van der Merwe et al, 1985) .
6) CASE REPORT/MIXED INGESTION: A 16-year-old girl intentionally ingested an estimated 16.4 g of carbamazepine (CBZ) (extended release tablets) and 14.5 g of valproic acid (extended release tablets) approximately 3 hours prior to admission. She was found unconscious by her parents. Five hours after ingestion, her CBZ level was 43.1 mcg/mL and her valproic acid level was 111.5 mcg/mL (peak, 283 mcg/mL). Activated charcoal was given every 6 hours for the first 24 hours along with enteral polyethylene glycol (Macrogol) to accelerate bowel elimination. However, 15 hours after ingestion, no neurologic improvement was observed and she was started on continuous charcoal hemoperfusion for 4 hours with significant laboratory improvement in drug levels, but a decrease in her platelet count (167,000/mcL to 45,000/mcL) occurred. Continuous venovenous hemodiafiltration (CVVHDF) was then performed for 48 hours. At the end of the treatment period, CBZ level was 17.8 mcg/l and valproic acid was 119 mcg/L and both were continuing to decrease. Ninety hours after ingestion, the patient became more alert and was successfully extubated at 120 hours. She continued to do well with no neurologic deficits and was discharged to home on day 8 with ongoing mental health support (Moinho et al, 2014).
7) CASE REPORT: Hemoperfusion was used to treat a 32-year-old woman with severe valproic acid and chlorpheniramine overdose, complicated by obtundation and hepatic injury. Peak valproic acid level was 1,380 mcg/mL 17 hours post ingestion. The initial extraction ratio of the hemoperfusion cartridge was 0.54 with a plasma clearance of 55 mL/min. Half-life during 3 hours of hemoperfusion was 3 hours compared with 4.8 hours after hemoperfusion with multiple dose activated charcoal (Graudins & Aaron, 1996).
8) CASE REPORT: Serum valproate levels of 1066 mg/L (2.2 hours postingestion) and 1562 mg/L (5 hours postingestion) were reported following an overdose of 22.5 g in a 21-year-old woman. Following 2 hemoperfusion sessions, resulting valproic acid levels of 835 and 413 mg/L after 4 and 8 hours, respectively, were reported (von Bardeleben et al, 1998).
9) CASE REPORT: A 50-year-old woman had a valproic acid level of 491 mcg/mL 5 to 6 hours after an ingestion of an unknown quantity. Hemoperfusion was initiated at a flow rate of 400 mL/min (standard for hemodialysis) instead of a typical rate of 150 to 250 mL/min. Within 2 hours the patient suffered severe intravascular hemolysis and renal failure. The patient required a total of 23 days of dialysis before recovery of renal function (Rahman et al, 2006).

E)

1) CASE REPORT: Simultaneous "in series" hemoperfusion and hemodialysis were used in a case of acute valproate toxicity (peak level 1,262 mcg/mL) (Tank & Palmer, 1993). Plasma valproate clearance was 91 mL/minute 20 minutes into the procedure and fell to 34 mL/minute at 4 hours. Half-life during the procedure was 1.7 hours compared with a half life of 8 hours prior to the procedure.
2) CASE REPORT: A 20-year-old woman presented with coma and a peak serum valproate level of 2120 mcg/mL at 8.5 hours postingestion. Hemodialysis was started 10.5 hours postingestion on a CDAK 1.3 square meter artificial kidney (blood flow was 150 to 200 mL/min; dialysate flow was 600 mL). Dialysis continued for 8 hours followed by 4 hours of activated charcoal hemoperfusion. The patient woke up gradually over the next 3 days (Mortensen et al, 1983).
3) CASE REPORT: Serial hemodialysis and hemoperfusion was used in a 27-year-old man following a massive overdose (Franssen et al, 1999). Reported VPA clearances during the treatments were 80 mL/min (hemodialysis); 40 mL/min (hemoperfusion by charcoal); and 80 mL/min (hemoperfusion by resin only in first hour). Because saturated protein binding resulted in an increased fraction of unbound valproic acid, hemodialysis was more effective than hemoperfusion in this case.
4) CASE REPORT: An "in series" treatment of hemodialysis and hemoperfusion, followed by continuous venovenous hemodiafiltration (CVVHDF), were performed on a 35-year-old man who reportedly ingested 30 g (120 capsules) of valproic acid (VPA). His peak VPA level, at the initiation of hemodialysis and hemoperfusion, was 573 mcg/mL. During the "in series" treatment, the blood flow was maintained at 240 to 330 mL/min and the dialysate flow was maintained at 500 mL/min; whole blood valproate clearance ranged from 87 to 160 ml/min and plasma clearance ranged from 42 to 88 mL/min during treatment. At the end of the 4-hour treatment, the VPA level had decreased to 268 mcg/mL, but 3 hours after the hemodialysis and hemoperfusion treatment, the VPA level increased to 343 mcg/mL. Due to the post-dialytic rebound of his VPA level, CVVHDF was initiated. The dialysate flow rate was maintained at 1000 mL/hour and the filtration rate was 1000 mL/hour. At the end of the treatment, 18 hours later, the patient's VPA level was 118 mcg/mL (Al Aly et al, 2005).

F)

1) RECOMMENDATIONS: Intermittent continuous renal replacement therapy (CRRT) is recommended as an alternative therapy when intermittent hemodialysis is not available (Ghannoum et al, 2015). It was found to be inferior to the high-efficiency of intermittent dialysis; however, it may be considered when technical or logistic reasons do not allow for the use of hemodialysis. CRRT has lower clearance rates and clinical improvement has been shown to be slower compared to hemodialysis or hemoperfusion (Ghannoum et al, 2015).

G)

1) Several cases have been reported concerning the use of combinations of multiple-dose activated charcoal, forced diuresis and continuous arteriovenous hemofiltration (CAVH) following severe valproic acid intoxications. CAVH is recommended when imminent hemodynamic instability is present. It has been hypothesized that efficient clearance of valproic acid metabolites rather than direct clearance of the drug occurs (van Keulen et al, 2001).
2) Continuous arteriovenous hemofiltration (CAVH) was used to treat a comatose 15-year-old boy after an ingestion of 30 g of slow release valproic acid (VPA) (van Keulen et al, 2001). During CAVH, plasma VPA concentration decreased from 350 mg/L to 68 mg/L over 17 hours. VPA half-life during CAVH was calculated as 7.3 hours, which increased to >300 hours after CAVH. The authors concluded that CAVH was superior to endogenous clearance, but less effective than clearance via hemoperfusion, as reported in the literature.
3) Single, conventional hemodiafiltration (HDF) without hemoperfusion was successfully used to treat a severe acute valproic acid ingestion (160 grams). Following 3 hours of HDF, valproic serum levels decreased from 2493 to 821 mg/L, with a rebound of 16% after one hour. Valproic acid clearance before HDF was 6.2 mL/min, during HDF was 93 mL/min, and after HDF was 6.9 mL/min (Minari et al, 2002).
4) CASE REPORT/MIXED INGESTION: A 16-year-old girl intentionally ingested an estimated 16.4 g of carbamazepine (CBZ) (extended release tablets) and 14.5 g of valproic acid (extended release tablets) approximately 3 hours prior to admission. She was found unconscious by her parents. Five hours after ingestion, her CBZ level was 43.1 mcg/mL and her valproic acid level was 111.5 mcg/mL (peak, 283 mcg/mL). Activated charcoal was given every 6 hours for the first 24 hours along with enteral polyethylene glycol (Macrogol) to accelerate bowel elimination. However, 15 hours after ingestion, no neurologic improvement was observed and she was started on continuous charcoal hemoperfusion for 4 hours with significant laboratory improvement in drug levels, but a decrease in her platelet count (167,000/mcL to 45,000/mcL) occurred. Continuous venovenous hemodiafiltration (CVVHDF) was then performed for 48 hours. At the end of the treatment period, CBZ level was 17.8 mcg/l and valproic acid was 119 mcg/L and both were continuing to decrease. Ninety hours after ingestion, the patient became more alert and was successfully extubated at 120 hours. She continued to do well with no neurologic deficits and was discharged to home on day 8 with ongoing mental health support (Moinho et al, 2014).
5) LACK OF BENEFIT: A 20-year-old man with a past history of head injury, epilepsy, and depression became obtunded following the ingestion of 40 g of sodium valproate. Serum valproic acid (VPA) reached 1136 mg/L within 24 hours of exposure. Continuous veno-venous hemodialfiltration (CVVHDF) was started, and within 4 hours the VPA was less than 500 mg/L. However, the patient remained unconscious and a head CT revealed cerebral edema (CT obtained approximately 36 hours earlier had been normal) . Mental status slowly improved and by day 7 a repeat head CT showed a gradual reduction in cerebral edema. By day 17, the patient was transferred from ICU with no evidence of neurologic deficits. The authors concluded that cerebral edema was not directly related to serum VPA levels and in this setting CVVHDF did not provide any clinical benefit (Field & Daly, 2002).

H)

1) SUMMARY

a) GASTROINTESTINAL DECONTAMINATION RECOMMENDATIONS: In a systematic review of the literature that included 79 articles, including 1 observational study, 1 uncontrolled cohort with aggregate results, 70 case reports or case series and 7 pharmacokinetic studies, the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup (includes international experts from the US, Canada, Europe, Australia, Brazil and China) concluded that patients may benefit from a single dose of activated charcoal following a recent ingestion. Currently, the use of multiple dose activated charcoal is NOT recommended (Ghannoum et al, 2015).

2) CASE REPORTS

a) Two case reports suggest that multiple dose activated charcoal may enhance valproate elimination in patients with large overdoses. There are no studies to determine if MDAC improves outcome or shortens the duration of toxicity after valproate overdose. MDAC has also been associated with adverse events including aspiration and bowel obstruction (Sztajnkrycer, 2002). Routine use is not recommended.
b) CASE REPORT: A 15-year-old boy ingested approximately 115 250-mg valproate tablets, and was treated with multiple dose activated charcoal (MDAC) (Su et al, 2002). Activated charcoal 60 g via a nasogastric tube was administered after the patient's neurological status deteriorated (i.e., delirium and pinpoint pupils). Initial serum VPA was 915 mcg/mL, and peaked two hours later at 1183 mcg/mL. The patient was given three additional doses of AC (30 g) every 6 hours. A calculated serum half-life of 6.45 hours was reported while receiving MDAC, as compared to 24.75 hours after MDAC was discontinued.
c) CASE REPORT: A 26-month-old who ingested at least 4.5 g (375 mg/kg) of valproate was treated with continuous nasogastric infusion of activated charcoal 3 grams/hour. Calculated elimination half-life was 4.8 hours compared with and expected elimination half-life of 10 to 16 hours in children taking therapeutic doses and 21 to 23 hours after overdose (Farrar et al, 1993).

3) LACK OF EFFECT

a) In healthy volunteers, multiple dose activated charcoal had NO effect on the elimination rate after therapeutic doses of valproic acid (Al-Shareef et al, 1997).
b) ANIMAL DATA: In a porcine model, multiple dose activated charcoal did not increase the clearance of intravenously administered valproic acid (Chuyka et al, 1995).

Abstracts

Case Reports

A)

1) CEREBRAL INFARCT: A 29-year-old man with bipolar affective disorder sustained permanent injury when he developed cerebral edema, herniation, and infarct after intentionally ingesting 4 g of valproic acid (VPA) and 75 mg of diazepam (10 hours prior to ingesting VPA). He presented to the emergency department 5 hours after ingestion of VPA with agitation, an unsteady gait, and vomiting. At that time, his vital signs and neurologic examination were normal. Initial lab analyses showed a VPA level of 5469 micromol/L (therapeutic: 350 to 700 micromol/L), serum ammonia of 348 micromol/L (normal: 0 to 50 micromol/L), and a pH of 7.34. CT scan confirmed diffuse cerebral edema with early herniation. Nine hours after ingestion, his Glasgow coma scale score deteriorated to 8/15. He was intubated, gastric contents were aspirated with a tube, and he was treated with a single 50 g dose of activated charcoal followed by 4 doses of L-carnitine (900 mg each, 1 hour apart), and mannitol. Thirty-eight hours after ingestion, VPA levels were therapeutic. A dilated right pupil, absent right papillary reflex, reduced visual acuity with skew deviation of the right eye, and right-sided weakness were observed on day 5. At that point, MRI findings confirmed cerebral infarct and ECG findings were consistent with encephalopathy. Ammonia levels normalized on day 6 and on day 8 he was extubated. After 150 days of hospitalization including extensive rehabilitation he was discharged to an assisted living facility with residual right-sided weakness and a modified Rankin scale score of 3 (moderate disability; requiring some help, but able to walk without assistance) (Rupasinghe & Jasinarachchi, 2011; van Swieten et al, 1988).
2) A 22-year-old man presented somnolent with depressed motor and respiratory activity following an ingestion of an unknown substance. Gag reflex was absent, breath sounds were diminished, and pupils were pinpoint and nonreactive. An IV of normal saline was started and naloxone 2 mg was administered by IV push. Approximately 1 minute after naloxone, before administration of any other medication, the patient became alert, responsive, and talking. He admitted taking only valproic acid 250 mg, about 20 tablets six hours prior to presentation. His initial valproic acid concentration was 180.4 mcg/mL (Alberto et al, 1989).

B)

1) FATALITY: A 20-month-old boy died from valproic acid overdose. He ingested 15 grams (12 grams reportedly absorbed). The boy was comatose and developed bronchopneumonia with high fever; death occurred from cardiorespiratory failure 46 hours following ingestion. Peak valproic acid concentrations were 1061 mcg/mL 3 hours postingestion; 15 minutes prior to death, concentrations were 187 mcg/mL with a normal half-life (16 hours). The most prominent findings on autopsy were acute hypoxic damage of the myocardium, kidneys and vulnerable cerebral neurons, as well as substantial cerebral edema (Schnabel et al, 1984).
2) A 2-month-old girl with epilepsy presented with generalized seizures, progressive coma, and anuria associated with a serum sodium valproate concentration of 1299 mcg/mL. Both parents had epilepsy and apparently accidentally overdosed this child. Two days prior to admission the toddler had a serum sodium valproate concentration of 53 mcg/mL. She was treated with hemoperfusion, serially connected with hemodialysis during 3 hours. On hospital day 2, peritoneal dialysis was started for persistent anuria and electrolyte disturbances and was maintained for 5 days. On the 5th day of hospitalization, a urine sample was obtained and found to contain myoglobin. Phenobarbital was given as an antiepileptic drug, beginning the 5th day of hospitalization (Roodhooft et al, 1990).
3) Eeg-Olofsson & Lindskog (1982) reported a 5-year-old severely mentally retarded boy who received valproate monotherapy in a daily dose of 40 mg/kg for treatment of minor motor seizures. Normal plasma concentrations fluctuated around 350 mcmol/L (50 mcg/mL). Presentation on admission revealed a somnolent boy with generalized myoclonic seizures which were treated with clonazepam. Very high plasma concentrations of valproate were noted (8130 mcmol/L) (1172 mcg/mL) on day one. In addition, elevated concentrations of urine metabolites of valproate, high serum concentrations of sodium, acidosis, and hypocalcemia were noted. Within 24 hours, the patient gradually awoke and was in his usual state. By day three, valproate concentrations had dropped to 437 mcmol/L (63 mcg/mL).
4) TEENAGER: Only minor CNS toxicity developed following overdose of 30 grams valproic acid in a 16-year-old girl. The patient had been taking the drug for 1.5 years. Five hours after ingestion the patient was admitted stuporous; physical examination was otherwise normal. The patients was fully awake 12 hours after ingestion and remained in the hospital for 3 days without complications. Serum concentration was 4925 micromoles/L (710 mcg/mL) on admission (6 hours postingestion). Slight liver function abnormalities were reported, but were not considered clinically significant (Karlsen et al, 1983).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) COMPLEX PARTIAL SEIZURES

1) MONOTHERAPY: INITIAL DOSE: 10 to 15 mg/kg/day, increasing by 5 to 10 mg/kg/week until optimal clinical response or obtain serum concentrations to determine if therapeutic levels (therapeutic range, 50 to 100 mcg/mL) have been reached. MAX: 60 mg/kg; if dose exceeds 250 mg, give in divided doses (Prod Info DEPAKENE oral capsules, oral solution, 2014; Prod Info STAVZOR(R) oral delayed release capsules, 2014).
2) ADJUNCTIVE THERAPY: May be added to a patient's regimen starting at 10 to 15 mg/kg/day with the dosage increased by 5 to 10 mg/kg/week to achieve an optimal response. MAX: 60 mg/kg. If the total daily dose exceeds 250 mg, it should be given in divided doses (Prod Info DEPAKENE oral capsules, oral solution, 2014; Prod Info STAVZOR(R) oral delayed release capsules, 2014)

B) MANIA

1) 750 mg daily in divided doses; MAX: 60 mg/kg/day (Prod Info STAVZOR(R) oral delayed release capsules, 2014).

C) MIGRAINE

1) INITIAL DOSE: 250 mg twice daily; MAX: 1000 mg/day (Prod Info STAVZOR(R) oral delayed release capsules, 2014).

7.2.2)

A) INTRAVENOUS

1) STATUS EPILEPTICUS, REFRACTORY

a) LOADING DOSE: 20 to 30 mg/kg IV bolus over 5 to 10 minutes (Agarwal et al, 2007; Mehta et al, 2007; Misra et al, 2006; Yu et al, 2003); a second bolus of 10 mg/kg has been given 10 to 15 minutes after the first bolus in patients with continued seizure activity (Mehta et al, 2007; Uberall et al, 2000).
b) Rapid IV infusions of 2 to 6 mg/kg/min have been given safely in children (Morton et al, 2007; Yu et al, 2003; Ramsay et al, 2003; Venkataraman & Wheless, 1999).
c) MAINTENANCE INFUSION: Maintenance infusions of 1 to 6 mg/kg/hour have been used to sustain a seizure-free period (Mehta et al, 2007; Uberall et al, 2000) or for continued seizure control (Hovinga et al, 1999). Following continuous infusion, conversion to equivalent scheduled IV or oral maintenance doses can be initiated (Mehta et al, 2007; Hovinga et al, 1999).

2) EPILEPSY (IF UNABLE TO TAKE ORAL)

a) Initial, 10 to 15 mg/kg/day IV divided every 6 hours, increasing at 1-week intervals by 5 to 10 mg/kg/day until optimal control achieved. Maximum recommended dose is 60 mg/kg/day (Prod Info DEPACON(R) IV injection, 2006).

B) ORAL

1) COMPLEX PARTIAL SEIZURES

a) CHILDREN: 10 YEARS OF AGE AND OLDER

1) MONOTHERAPY: INITIAL DOSE: 10 to 15 mg/kg/day, increasing by 5 to 10 mg/kg/week until optimal clinical response or obtain serum concentrations to determine if therapeutic levels (therapeutic range, 50 to 100 mcg/mL) have been reached. MAX: 60 mg/kg; if dose exceeds 250 mg, give in divided doses (Prod Info DEPAKENE oral capsules, oral solution, 2014; Prod Info STAVZOR(R) oral delayed release capsules, 2014).
2) ADJUNCTIVE THERAPY: May be added to a patient's regimen starting at 10 to 15 mg/kg/day with the dosage increased by 5 to 10 mg/kg/week to achieve an optimal response. MAX: 60 mg/kg. If the total daily dose exceeds 250 mg, it should be given in divided doses (Prod Info DEPAKENE oral capsules, oral solution, 2014; Prod Info STAVZOR(R) oral delayed release capsules, 2014).

2) BIPOLAR DISORDER

a) 5 YEARS AND OLDER: INITIAL: 15 to 20 mg/kg/day (maximum 759 mg) orally in 2 to 3 divided doses, titrated to serum trough level of 50 to 125 mcg/mL based on clinical effect and tolerability (Azorin & Findling, 2007; DelBello et al, 2006; Pavuluri et al, 2005; Findling et al, 2005; Danielyan & Kowatch, 2005; Wagner et al, 2002).
b) In a randomized, placebo-controlled, double-blind, clinical trial (n=144), extended-release divalproex was not significantly better than placebo in improving Young Mania Rating Scale (YMRS) scores from baseline (Wagner et al, 2009).

3) MIGRAINE PROPHYLAXIS

a) 3 TO 17 YEARS OF AGE: 10 to 30 mg/kg/day orally in 2 divided doses (Bidabadi & Mashouf, 2010; Ashrafi et al, 2005). One clinical trial initiated dosing at 30 mg/kg/day and decreased the dose to 15 mg/kg/day after the first month of therapy (Bidabadi & Mashouf, 2010). Another clinical trial initiated dosing at 10 mg/kg/day and slowly increased up to 40 mg/kg/day based on tolerance and efficacy (Ashrafi et al, 2005). Maximum doses were not reported.

Minimum Lethal Exposure

A)

1) ADULT

a) A 23-year-old man died following initiation of valproic acid therapy at a dose of 750 mg by mouth three times a day. The maximum daily dose recommended by the manufacturer for this patient should have been 960 mg/day (15 mg/kg/day). He received 2250 mg/day for 5 days (11.25 g over 5 days) (Tift, 1980).
b) A 24-year-old woman died approximately 48 hours after ingesting 350 g of Depakote(R). Upon arrival to ED, 3 hours after ingestions, the patient received gastric lavage and activated charcoal and was drowsy for 6 hours. Eleven hours postingestion she became unresponsive, requiring mechanical ventilation and dopamine for hypotension. Despite aggressive care the patient died (Christianson et al, 2001).
c) MIXED INGESTION: After ingesting 20 g (333 mg/kg) of valproic acid extended release, 60 mg of risperidone, and 3 g of venlafaxine extended release, a 19-year-old man developed hyperammonemia (peak ammonia concentration 1,191 mcg/dL at 65 hours postingestion). The valproic acid concentration peaked at 305.4 mcg/dL. Despite treatment with activated charcoal with sorbitol, and lactulose, the patient's condition deteriorated. CT scan revealed cerebral edema and possible tentorial herniation. At approximately 120 hours after ingestion, cerebral blood flow studies showed an absence of cerebral perfusion, and the patient was pronounced brain dead (Camilleri et al, 2005).

2) INFANT

a) A 26-day-old full term infant (4500 g) was inadvertently given 300 mg valproate (intended dose 30 mg/kg twice daily); symptoms began within 12 hours. Within 36 hours, the pupils were fixed and dilated. A CT scan of the head showed cerebral edema, and a serum ammonia of 279 mcg/dL (normal 15 to 56 mcg/dL) was also present. Despite aggressive care, the patient died of cardiorespiratory arrest secondary to severe brain edema 42 hours after ingestion (Unal et al, 2007).
b) Death due to cardiorespiratory failure occurred in a 20-month-old boy following an ingestion of 15 g (750 mg/kg) (Janssen et al, 1985).

Maximum Tolerated Exposure

A)

1) CASE SERIES: Based on a small case series of 8 of 15 valproate only overdoses, greater than 200 mg/kg (greater than 14 g) was ingested with no severe toxicity reported (Ibister et al, 2003). Drowsiness was reported in 2 patients ingesting 20 g and 25 g, respectively. Based on these findings, the authors concluded that doses less than 400 mg/kg (valproate only) were unlikely to cause severe toxicity.

B)

1) ADULT

a) A 29-year-old man with bipolar affective disorder sustained permanent injury when he developed cerebral edema, herniation, and infarct after intentionally ingesting 4 g of valproic acid (VPA) and 75 mg of diazepam (10 hours prior to ingesting VPA). The resulting serum VPA level was 5469 micromol/L (therapeutic; 350 to 700 micromol/L). After 150 days of hospitalization including extensive rehabilitation he was discharged to an assisted living facility with residual right-sided weakness and a modified Rankin scale score of 3 (moderate disability; requiring some help, but able to walk without assistance) (Rupasinghe & Jasinarachchi, 2011; van Swieten et al, 1988).
b) CASE REPORT: A 26-year-old man, with a history of bipolar disease, intentionally ingested an unknown amount of valproic acid and was admitted a few hours later with sopor without focal neurologic deficits. There were no signs of trauma and a CT of the brain was negative. Laboratory studies were normal. A valproic acid serum level was 2896 micromol/L (therapeutic range: 350 to 690 micromol/L). His cognitive function gradually improved over several days. The patient reported weakness in his right arm on day 3 and he had evidence of weakness of flexion and abduction of the right arm and loss of sensation in the skin over the lateral upper right arm. Multiple diagnostic studies (ie, radiography, MR) were negative. Paresis of the right axillary nerve was detected on physical exam and electrodiagnostic studies. A physical therapy program resulted in gradual improvement (Marusic et al, 2014).
c) Garnier et al (1982) reported 516 cases of acute valproate overdoses in which patients were unconscious only following ingestions greater than 200 mg/kg, and only 5 had seizures following the ingestion of 100 to 700 mg/kg (Garnier et al, 1982).
d) Karlsen et al (1983) reported a case where 30 g of sodium valproate was ingested (resulting in a serum concentration of 4925 micromol/L (710 mcg/mL) in 6 hours) but only mild CNS depression occurred for 12 hours (Karlsen et al, 1983).
e) Lee et al (1998) reported a case of a 45 g ingestion in an 18-year-old man, which resulted in coma, seizures, hyperammonemia, metabolic acidosis, elevated hepatic enzyme concentrations, hypernatremia, and hypocalcemia, with a serum valproate concentration of 575 mcg/mL (Lee et al, 1998).
f) Following the ingestion of approximately 19 g, a 43-year-old woman developed coma, severe hypotension refractory to fluid replacement and vasopressor therapy, metabolic acidosis, and thrombocytopenia, with a serum valproate concentration of 1,380 mcg/mL (Johnson et al, 1999).
g) A 41-year-old man developed lethargy and tachycardia approximately 2 hours after reportedly ingesting 50 g of valproate extended release tablets. The patient recovered following hemodialysis (Guillaume et al, 2004).

2) PEDIATRIC

a) CASE REPORT: A 9-year-old, 50 kg, girl intentionally ingested 196 mg/kg of valproic acid and upon admission 4 hours after ingestion she was stuporous and required immediate intubation and ventilation. Serum valproic acid level was 599.2 mcg/mL (reference range: 50 to 100 mcg/mL). Hyperammonemia (serum ammonia: 111 mcg/dL) was observed and treated with L-carnitine. Hemoperfusion was started within 8 hours of exposure that was repeated on day 2 for 3 hours; serum valproic level rapidly improved with therapy. The patient was also treated with fresh frozen plasma for an increased prothrombin and activated partial thromboplastin time. The child gradually improved and was extubated on day 4. She was discharged to home on day 9 with no permanent sequelae (Colak et al, 2011).

3) CHRONIC

a) Elevated blood ammonia concentrations of 80 (1360 mcg/mL) and 158 (2212 mcg/mL) micromol/L have been reported following chronic administration of 52 and 60 mg/kg/day of valproic acid, respectively (Coulter & Allen, 1981; Rawat et al, 1981).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) The therapeutic serum concentration of valproic acid ranges from 40 to 100 mg/L (Frankfort et al, 2004; Guillaume et al, 2004).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ACUTE

a) Toxicity was associated with serum concentrations exceeding 100 mcg/mL (Turnbull et al, 1983). Delayed peak serum concentrations may occur after overdose due to a delay in the absorption of valproic acid (Spiller & Krenzelok, 2001).
b) ADVERSE EVENTS: In a retrospective study (n=108) comparing serum drug concentrations with the incidence of adverse outcomes, a peak drug concentration of greater than 450 mcg/mL was associated with the vast majority of adverse outcomes (Beauchamp & Olson, 1999).
c) CASE SERIES: In a case series (n=133), patients with peak valproic acid concentrations greater than 450 mcg/mL were more likely to have more significant clinical adverse effects and have longer hospital stays (Spiller et al, 2000). Patients with peak concentrations greater than 850 mcg/mL were more likely to develop coma, respiratory depression, aspiration or metabolic acidosis.
d) SUSTAINED RELEASE PRODUCT: Delayed toxicity has been reported following ingestion of enteric coated and sustained release divalproex sodium. In one adult case a peak valproic acid serum concentration of 7,450 micromol/L (1075 mg/L) was reported 14 hours after ingestion of an unknown quantity of enteric-coated divalproex sodium (Brubacher et al, 1999).
e) Markedly elevated valproate (greater than 950 mg/L) have been an indication for hemodialysis or charcoal hemoperfusion. However, in one retrospective series of 50 cases of overdose, 4 had documented peak valproate concentrations greater than 950 mg/L (Graeme et al, 1999). None of these had persistent hemodynamic instability or metabolic acidosis and none received hemodialysis or hemoperfusion. All recovered without sequelae.

2) CASE REPORTS

a) ADULT

1) SURVIVAL: A 29-year-old man with bipolar affective disorder intentionally ingested 4 g of valproic acid (VPA) and 75 mg of diazepam and sustained permanent injury after developing cerebral edema, herniation, and infarct. The resulting serum VPA level was 5469 micromol/L (therapeutic: 350 to 700 micromol/L) along with hyperammonemia (348 micromol/L (normal: 0 to 50 micromol/L)) (Rupasinghe & Jasinarachchi, 2011).
2) SURVIVAL: Peak serum valproate concentration of 1,380 mcg/mL was reported in a 43-year-old woman following an approximate 19 g ingestion (Johnson et al, 1999).
3) SURVIVAL: A peak serum concentration of 2120 mcg/mL was reported in a 20-year-old, 8.5 hours following a 75 g valproic acid ingestion (Mortensen et al, 1983).
4) FATALITY: After ingesting 20 g (333 mg/kg) of valproic acid extended release, 60 mg of risperidone, and 3 g of venlafaxine extended release, a 19-year-old man developed hyperammonemia (peak ammonia concentration 1,191 mcg/dL at 65 hours postingestion). The valproic acid concentration peaked at 305.4 mcg/dL. Despite treatment with activated charcoal with sorbitol, and lactulose, the patient's condition deteriorated. The brain CT scan revealed cerebral edema and possible tentorial herniation. At approximately 120 hours after ingestion, cerebral blood flow studies showed an absence of cerebral perfusion and the patient was pronounced brain dead (Camilleri et al, 2005).
5) FATALITY: Peak serum valproic acid concentration of 2204 mg/L, at 14 hours postingestion, was reported after an overdose of 350 g Depakote(R) in a 24-year-old woman. She died approximately 48 hours postingestion (Christianson et al, 2001).
6) FATALITY: The peak valproate concentration was 18,900 micromol/L (2725.7 mg/L) at 6 hours postadmission in a 40-year-old epileptic woman who ingested a fatal overdose of an unknown amount of sodium valproate (Connacher et al, 1987).
7) POSTMORTEM: Postmortem blood concentrations of VPA following a 56 g suicidal ingestion were 720 mg/L. The liver concentration was 800 mg/kg (Lokan & Dinan, 1988).
8) POSTMORTEM: A 23-year-old man died following initiation of valproic acid therapy. He received a total of 11.25 g over a 5 day period. Serum concentration reported on autopsy was 52 mcg/mL (therapeutic: 50 to 100 mcg/mL). Concentrations were probably higher at the time the valproic acid was discontinued prior to death (Tift, 1980).

b) INFANT

1) FATALITY: Peak serum valproate concentration of 268.6 mcg/mL, approximately 12 hours after ingestion, was observed in a 26-day-old infant after being given 300 mg of valproate. By 36 hours, the serum concentration was 60.7 mcg/mL, but severe cerebral edema was present and the infant died 42 hours after exposure (Unal et al, 2007).
2) FATALITY: A peak serum concentration of 1061 mcg/mL was reported within 3 hours of a 15 g ingestion in a 20-month-old boy (Janssen et al, 1985).

c) PEDIATRIC

1) SURVIVAL: A serum concentration of 185 mcg/mL has been associated with coma in a child (Steiman et al, 1979). Serum concentrations of 113 mcg/mL and 120 mcg/mL were associated with mild CNS depression in two adults.

Workplace Standards

A)

1) Not Listed

B)

1) Not Listed

C)

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D)

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 470 mg/kg ((RTECS, 2002))

B) LD50- (ORAL)MOUSE:

1) 1098 mg/kg ((RTECS, 2002))

C) LD50- (SUBCUTANEOUS)MOUSE:

1) 860 mg/kg ((RTECS, 2002))

D) LD50- (ORAL)RAT:

1) 670 mg/kg ((RTECS, 2002))

Pharmacology Toxicology

Pharmacologic Mechanism

A)

1) The mechanism of action is currently unknown, however, it is postulated to interact with the brain gamma-aminobutyric acid (GABA), possibly increasing brain concentrations of this transmitter (Beckner, 1979).

a) Valproic acid may also inhibit the reuptake of GABA into the glia and nerve endings. It has been shown to be effective in grand mal, petit mal, absence seizures, myoclonic seizures and temporal lobe seizures.
b) Valproic acid may be effective in seizures resistant to other anticonvulsants.

Toxicologic Mechanism

A)

B)

C)

D)

E)

Physicochemical

Physical Characteristics

A)

Molecular Weight

A)

B)

Animal Toxicology

References

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VALPROIC ACID

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography