From the FDA Drug Label
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.
The cause of hyperammonemia in a patient taking valproic acid (Valproate) may be due to several factors, including:
- Urea cycle disorders: Valproic acid is contraindicated in patients with known urea cycle disorders, as it can cause hyperammonemic encephalopathy, which can be fatal.
- Inborn errors of metabolism: Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy.
- Concomitant use of topiramate: Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. It is essential to investigate underlying urea cycle disorders and monitor plasma ammonia levels in patients who develop unexplained lethargy, vomiting, or changes in mental status while receiving valproate therapy 1, 1, 1.
From the Research
Valproic acid can cause hyperammonemia due to its interference with the urea cycle, and the proposed mechanism involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, which impairs ammonia elimination 2. The cause of hyperammonemia in a patient taking valproic acid is multifactorial, but it is primarily related to the drug's effect on the urea cycle. Valproic acid can interfere with the urea cycle, leading to an accumulation of ammonia in the blood. This can occur even in patients with normal liver function. The depletion of carnitine and the overproduction of 4-en-valproic acid are thought to contribute to this process.
Some key points to consider:
- Hyperammonemia can occur in patients taking valproic acid, even at therapeutic doses 3.
- Symptoms of hyperammonemia include confusion, lethargy, vomiting, and in severe cases, coma.
- L-carnitine supplementation may be beneficial in reducing ammonia levels in patients with valproic acid-induced hyperammonemia 4.
- In severe cases, temporary discontinuation of valproic acid and switching to an alternative antiepileptic medication may be necessary.
- Maintaining good hydration and avoiding high-protein diets may also help manage ammonia levels while on this medication.
It is essential to note that the most recent and highest quality study on this topic is from 2021, which recommends levocarnitine therapy for at least 72 hours, followed by an additional 24 hours of monitoring for symptom relapse and hyperammonaemia after levocarnitine discontinuation 5. Additionally, carglumic acid may be an effective treatment option for patients with recurrent valproic acid-induced hyperammonemia, particularly those with an underlying N-acetyl glutamate synthase (NAGS) deficiency 6.
The treatment of valproic acid-induced hyperammonemia should be individualized, and patients should be closely monitored for symptoms and ammonia levels, with consideration of L-carnitine supplementation, levocarnitine therapy, or alternative antiepileptic medications as needed 2, 5.