What is the role of Levocarnitine and Valproate (Depakote) in managing hyperammonemia?

From the Guidelines

Levocarnitine is recommended as a treatment for hyperammonemia in patients taking Depakote (valproic acid), with a typical dose of 50-100 mg/kg/day divided into 2-3 doses, with a maximum of 3 grams daily, as it can help reduce ammonia levels by facilitating the transport of long-chain fatty acids into mitochondria for beta-oxidation 1.

Key Considerations

• Valproic acid can deplete carnitine stores and inhibit certain enzymes in the urea cycle, leading to hyperammonemia.
• Symptoms of hyperammonemia include lethargy, vomiting, mental status changes, and in severe cases, coma.
• Regular monitoring of ammonia levels is recommended for patients on Depakote, especially those with risk factors such as urea cycle disorders, malnutrition, or polypharmacy.
• Levocarnitine supplementation is generally well-tolerated, with mild gastrointestinal side effects being the most common adverse reactions.

Treatment Guidelines

• For adults, a typical dose is 50-100 mg/kg/day of levocarnitine divided into 2-3 doses, with a maximum of 3 grams daily.
• For children, 50-100 mg/kg/day divided into 2-3 doses is appropriate.
• Treatment should continue as long as the patient remains on Depakote therapy.

Additional Recommendations

• Stop protein intake and provide adequate calories (≥100 kcal/kg daily) as intravenous glucose and lipids 1.
• Use nitrogen-scavenging agents (such as sodium benzoate and sodium phenylacetate) and urea cycle intermediates (such as l-arginine and l-citrulline) at the recommended dosage 1.
• Consider dialysis in patients with severe encephalopathy and/or seizure, with consistent EEG findings, and ammonia levels > 300 μmol/l (513 μg/dl) 1.

From the FDA Drug Label

In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured Hyperammonemia should also be considered in patients who present with hypothermia If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered

Levocarnitine may be used to treat hyperammonemia.

• The use of levocarnitine and Depakote (valproate) for ammonia requires careful monitoring of ammonia levels.
• Depakote (valproate) can cause hyperammonemia, and levocarnitine may help alleviate this condition.
• However, the FDA label does not provide direct guidance on the use of levocarnitine and Depakote (valproate) together for ammonia. 2

From the Research

Treatment of Hyperammonemia with Levocarnitine and Depakote

• Levocarnitine has been shown to be effective in treating valproic acid-induced hyperammonemic encephalopathy (VHE) 3, 4, 5.
• The exact mechanism of VHE is unclear, but it is thought to relate to the accumulation of toxic valproic acid metabolites and elevated ammonia levels 3.
• Carnitine is an essential cofactor in the proper metabolism of valproic acid and ammonia elimination, and a lack of carnitine is thought to contribute to hyperammonemia 3.
• Levocarnitine, the active isomer of carnitine, has been used to treat VHE resulting from valproic acid overdose as well as usual dosages of valproic acid 3, 4.

Efficacy of Levocarnitine in Reducing Ammonia Levels

• Studies have shown that levocarnitine can reduce ammonia levels in patients with valproic acid-induced hyperammonemia 4, 5, 6.
• In one case series, levocarnitine supplementation reduced ammonia levels to normal in all cases, and no symptoms consistent with encephalopathy were reported 4.
• Another study found that levocarnitine therapy controlled ammonia levels and improved mental status in a patient with hyperammonemia of unknown etiology 6.

Comparison of Levocarnitine with Other Treatments

• A retrospective study compared the effect of levocarnitine, lactulose, and combination therapy for the treatment of valproic acid-induced hyperammonemia in critically ill patients 7.
• The study found no significant difference in the reduction in ammonia levels in the first 48 hours of treatment between levocarnitine, lactulose, and combination therapy 7.
• However, the study suggests that levocarnitine may be an effective treatment for certain cases of hyperammonia-induced encephalopathy with unknown etiology 6.