From the Guidelines
Epidiolex (cannabidiol) can potentially cause hyperammonemia, especially in patients with underlying urea cycle disorders or when used with valproate, and management includes dose reduction or discontinuation of Epidiolex, temporary discontinuation of valproate if co-administered, and supportive care, as recommended by recent guidelines 1.
Key Considerations
- The interaction between Epidiolex and hyperammonemia appears to be dose-dependent and requires monitoring of ammonia levels, particularly during dose adjustments.
- Patients with risk factors such as underlying liver disease, urea cycle disorders, or concomitant valproate therapy should have baseline ammonia levels checked before starting Epidiolex and monitored periodically during treatment.
- Healthcare providers should educate patients and caregivers about potential symptoms of hyperammonemia, including lethargy, vomiting, or mental status changes, to ensure early recognition and intervention.
Management of Hyperammonemia
- Discontinue all oral feeds and provide adequate calories (≥100 kcal/kg daily) as intravenous glucose and lipids, as recommended by consensus guidelines 1.
- Use nitrogen-scavenging agents, such as sodium benzoate and sodium phenylacetate, at the recommended dosage, as outlined in Box 2 of the consensus guidelines 1.
- Consider continuous kidney replacement therapy (CKRT) or haemodialysis (HD) in patients with severe hyperammonemia or those who are refractory to medical management, as recommended by the consensus guidelines 1.
Monitoring and Education
- Monitor ammonia levels closely in patients on Epidiolex, particularly during dose adjustments, and educate patients and caregivers about the potential symptoms of hyperammonemia.
- Ensure that patients and caregivers are aware of the importance of prompt medical attention if symptoms of hyperammonemia occur.
From the Research
Epidiolex and Hyperammonemia
- There is no direct evidence in the provided studies that Epidiolex causes hyperammonemia 2, 3.
- The studies on Epidiolex focus on its efficacy and tolerability in patients with refractory epilepsy, and do not mention hyperammonemia as a side effect 2, 3.
- Hyperammonemia is mentioned in the context of valproic acid treatment, where L-carnitine supplementation has been shown to be effective in reversing hyperammonemia 4, 5, 6.
Hyperammonemia and L-Carnitine
- L-carnitine has been shown to have a protective effect against hyperammonemia in various studies 4, 5, 6.
- The mechanism of protection is thought to involve the facilitation of fatty acid entry into mitochondria, possibly increasing ATP or reducing equivalents 5.
- L-carnitine has been used to treat valproate-induced hyperammonemia, and has been shown to be effective in reducing ammonia levels and improving symptoms 4, 6.
Valproate-Induced Hyperammonemia
- Valproic acid can induce hyperammonemia, which can cause a range of symptoms from irritability to coma 4.
- The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, which impairs the urea cycle and ammonia elimination 4.
- Sodium benzoate and phenylacetate have also been studied as potential treatments for valproate-induced hyperammonemia, with phenylacetate showing promise in reducing ammonia levels 6.