What is the relationship between Levetiracetam (Keppra) and liver disease?

From the Guidelines

Levetiracetam (Keppra) is a suitable option for patients with liver disease due to its minimal hepatic metabolism and primary elimination through the kidneys. When considering the management of seizures in patients with liver disease, it's crucial to prioritize medications that do not rely heavily on liver metabolism to avoid exacerbating liver dysfunction. According to the most recent guidelines, such as those outlined in the clinical policy approved by the ACEP board of directors in 2024 1, the focus is on effective seizure management to reduce morbidity and mortality.

Key Considerations for Levetiracetam Use in Liver Disease

• Levetiracetam is primarily eliminated unchanged through the kidneys, with about 66% of the dose excreted via this route, making it less dependent on liver function for its clearance.
• The medication's pharmacokinetic profile, including minimal protein binding (less than 10%), supports its use in patients with compromised liver function who may be on multiple medications, as it reduces the risk of significant drug interactions.
• Common side effects of levetiracetam, such as somnolence, dizziness, and behavioral changes, are not directly influenced by liver function, although monitoring for these effects is still necessary.
• For patients with both liver disease and kidney impairment, dose adjustments may be required based on creatinine clearance, given the drug's reliance on renal excretion.

Clinical Implications

The use of levetiracetam in the context of benzodiazepine-resistant status epilepticus, as discussed in the 2024 clinical policy 1, highlights its effectiveness in cessation of seizures in approximately half of all patients, without the outcome being influenced by the patient’s home medications or age. This supports the consideration of levetiracetam as a viable option for seizure management in patients with liver disease, given its favorable profile and the critical need to control seizures to reduce morbidity and mortality.

From the FDA Drug Label

In subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of levetiracetam were unchanged. In patients with severe hepatic impairment (Child-Pugh C), total body clearance was 50% that of normal subjects, but decreased renal clearance accounted for most of the decrease. No dose adjustment is needed for patients with hepatic impairment.

Keppra (Levetiracetam) and Liver Disease:

• The pharmacokinetics of levetiracetam are not significantly affected in patients with mild to moderate hepatic impairment.
• In patients with severe hepatic impairment, total body clearance is reduced by 50%, but this is primarily due to decreased renal clearance.
• No dose adjustment is necessary for patients with hepatic impairment, including those with liver disease 2.
• It is essential to note that levetiracetam is not extensively metabolized in the liver and its major metabolic pathway is not dependent on liver cytochrome P450 isoenzymes 2.

From the Research

Keppra (Levetiracetam) and Liver Disease

• Levetiracetam is an antiepileptic drug that can be used in patients with liver disease, but its pharmacokinetics may be affected in severe liver impairment 3.
• In patients with mild to moderate liver impairment, no dose adjustment of levetiracetam is necessary, but in patients with severe cirrhosis, the initial dose should be reduced to half of the commonly recommended dose 3.
• Levetiracetam has been shown to be well-tolerated in patients with epilepsy and chronic liver disease, with some patients experiencing a reduction in seizure frequency and improvement in liver function 4.
• In patients with acute liver dysfunction and renal failure, levetiracetam pharmacokinetics may be altered, and dose adjustments may be necessary 5.
• Levetiracetam is considered a safe option for patients with liver disease, as it has minimal hepatic metabolism and is not associated with significant hepatotoxicity 6.
• However, rare cases of severe drug-induced liver injury have been reported with levetiracetam, emphasizing the importance of monitoring serum transaminase values and discontinuing the drug if liver injury is suspected 7.

Pharmacokinetics and Dosing

• Levetiracetam clearance is dependent on renal and hepatic elimination pathways, and dose reductions may be necessary in patients with organ dysfunction 3, 5.
• In patients with severe liver impairment, the total clearance of levetiracetam is reduced, and the half-life is increased 3.
• A dose of 1000 mg twice daily may be considered as an empiric levetiracetam regimen in patients with acute liver dysfunction on continuous venovenous hemofiltration 5.

Safety and Efficacy

• Levetiracetam is generally well-tolerated in patients with liver disease, but rare cases of severe liver injury have been reported 4, 7.
• Levetiracetam has been shown to be effective in reducing seizure frequency in patients with epilepsy and chronic liver disease 4.
• The drug should be used with caution in patients with a history of liver disease, and serum transaminase values should be monitored regularly 6, 7.