What are the effects of accidental double dosing of divalproex (valproate) at 1500mg daily for three days on its metabolism in a patient?

From the Guidelines

The patient should be immediately monitored for signs of divalproex toxicity and a serum valproic acid level should be obtained to guide further management. The patient has been taking 1500 mg daily for three days, which is double their prescribed dose and may lead to toxic levels, as valproate can be given with fewer adverse effects compared to other antiepileptic drugs, but still carries risks of toxicity 1. Symptoms of toxicity include drowsiness, confusion, tremor, nausea, vomiting, and in severe cases, coma or hepatic failure. Once the level is obtained, the medication should be temporarily held if levels are elevated. Resumption of divalproex should occur at the correct prescribed dose only after discussion with the prescribing physician.

Key Considerations

• Divalproex is primarily metabolized by the liver, and excessive doses can saturate metabolic pathways, leading to nonlinear increases in serum levels 1.
• The drug has a half-life of approximately 9-16 hours, so it may take several days for levels to normalize after the excessive dosing.
• During this time, supportive care and symptom management are essential, and the patient should be educated about proper medication administration and the importance of adhering to prescribed dosages to prevent future medication errors.

Management

• Monitoring for signs of toxicity, such as dizziness, thrombocytopenia, liver toxicity, and hyperammonemia, is crucial, as valproate has been shown to be effective in treating status epilepticus with potentially fewer adverse effects compared to phenytoin 1.
• The patient's liver function and complete blood count should be closely monitored, as valproate can cause liver toxicity and thrombocytopenia.
• In cases of severe toxicity, more intensive interventions, such as hemodialysis or liver transplantation, may be necessary, although the current evidence does not suggest a high risk of such severe outcomes with valproate compared to other antiepileptic drugs 1.

From the Research

Divalproex Metabolism and Double Dosing

• The patient has been taking 1500mg of divalproex per day for three days, which is a double dose of the typical daily dose.
• According to the study 2, missing one or two doses of divalproex for up to 24 hours can lead to a decrease in plasma valproic acid (VPA) concentrations, which can increase the risk of breakthrough seizures.
• Replacing a missed dose of divalproex can increase the risk of high VPA concentrations, which may lead to clinical toxicity, especially in patients taking enzyme-inducing antiepileptic drugs 2.
• However, the study 2 also suggests that the risk of high VPA concentrations is low for patients not taking enzyme-inducing antiepileptic drugs, even when divalproex doses are replaced at 24 hours.

Valproic Acid Toxicity and Monitoring

• Valproic acid is associated with rare but serious adverse effects, such as liver failure, which can be fatal if not detected early 3.
• Clinical symptoms, such as impairment of the patient's well-being, are the most relevant indicators of impending complications, and laboratory findings can support the diagnosis 3.
• The study 4 found that patients taking valproic acid had lower plasma free carnitine levels, which can increase the risk of carnitine deficiency.
• The study 5 also found that patients taking valproic acid had lower plasma free carnitine levels and increased acylcarnitine levels, which can lead to clinical manifestations of carnitine deficiency.

Treatment and Monitoring Recommendations

• The study 2 recommends that patients who miss a dose of divalproex should replace the dose as soon as possible, but the optimal regimen for replacing a missed dose beyond 12 hours remains to be determined.
• The study 3 recommends that patients taking valproic acid should be monitored closely for clinical symptoms and laboratory findings, and that prophylactic blood screening cannot predict complications.
• The study 6 found that valproate is effective in preventing new episodes of bipolar disorder, but carries appreciable risks, and that long-term treatment with valproate requires careful monitoring and evaluation of the evidence regarding its effectiveness.