Is Levipil (levetiracetam) hepatotoxic?

Levetiracetam (Levipil) and Hepatotoxicity

Levetiracetam (Levipil) has a low risk of hepatotoxicity due to its minimal hepatic metabolism and is considered a safe option for patients with liver disease. 1

Pharmacokinetic Profile and Hepatic Safety

Levetiracetam has a favorable hepatic safety profile for several reasons:

• Minimal hepatic metabolism: Only about 24% of levetiracetam undergoes hepatic metabolism, with the majority (66%) being excreted unchanged in urine
• No cytochrome P450 involvement: Unlike many other antiepileptic drugs, levetiracetam does not rely on the cytochrome P450 system for metabolism
• Low protein binding: Levetiracetam has minimal protein binding (<10%), reducing the risk of drug interactions

This pharmacokinetic profile makes levetiracetam one of the preferred antiepileptic drugs for patients with liver disease. It is recommended as a first-line therapy for seizure management in patients with hepatic impairment 1.

Evidence on Hepatotoxicity Risk

While levetiracetam is generally considered hepatically safe, there are some important considerations:

• Rare cases of hepatotoxicity: A 2022 study analyzing levetiracetam-induced liver injury found that it is a rare adverse reaction, ranging from asymptomatic elevated transaminases to fulminant liver failure 2
• Time to onset: When liver injury does occur, the median time for development is approximately 19 days (range 3-120 days) after starting treatment 2
• Clinical manifestations: Most patients (76.2%) with levetiracetam-induced liver injury present with fever, digestive symptoms, or skin rash, while 23.8% have asymptomatic elevated liver enzymes 2
• Recovery: Liver function typically returns to normal at a median time of 9 days (range 2-270 days) after discontinuation of levetiracetam 2

Use in Patients with Existing Liver Disease

Levetiracetam appears to be well-tolerated in patients with pre-existing liver disease:

• A study of patients with epilepsy and chronic liver disease found that most patients (10 out of 14) tolerated levetiracetam well during long-term follow-up (12-38 months) 3
• No worsening of liver function was observed based on blood chemistry in these patients
• Some patients (4 out of 10) even showed complete normalization or improvement in transaminase and/or gamma-glutamyltransferase levels 3

Dosing Considerations in Liver Disease

Pharmacokinetic studies provide guidance on dosing in hepatic impairment:

• Mild to moderate liver impairment: No dose adjustment is necessary for patients with Child-Pugh class A or B cirrhosis 4
• Severe liver impairment: Patients with Child-Pugh class C cirrhosis should initially receive only half of the commonly recommended dose due to reduced total clearance (57% reduction) 4
• The reduced clearance in severe liver disease is primarily related to deterioration of renal function rather than impaired hepatic metabolism 4

Monitoring Recommendations

For patients on levetiracetam therapy:

• Baseline liver function tests should be obtained before initiating therapy
• Periodic monitoring of liver function is advisable, especially during the first few months of treatment
• Increased vigilance is warranted in patients with pre-existing liver disease or those taking other potentially hepatotoxic medications
• Immediate evaluation is necessary if symptoms suggestive of liver injury develop (jaundice, right upper quadrant pain, fatigue, nausea, vomiting)

Conclusion

While rare cases of levetiracetam-induced liver injury have been reported, the overall hepatotoxicity risk is low compared to many other antiepileptic drugs. Its minimal hepatic metabolism makes it a preferred choice for patients with liver disease or at risk for drug-induced liver injury.