What are the long‑term adverse effects of levetiracetam?

Long-Term Adverse Effects of Levetiracetam

Levetiracetam demonstrates a favorable long-term safety profile compared to older antiepileptic drugs, with behavioral disturbances (irritability, aggression, mood changes) being the most clinically significant adverse effect, occurring in approximately 12–15% of patients, particularly in those with pre-existing psychiatric history, learning disabilities, or symptomatic generalized epilepsy. 1, 2

Comparative Safety Profile

Levetiracetam is significantly better tolerated than phenytoin and valproic acid, as demonstrated by lower incidence of adverse effects measured by Glasgow Outcome Scale-Extended and Disability Rating Scale in patients with aneurysmal subarachnoid hemorrhage. 3, 1 The American Heart Association specifically recommends levetiracetam over phenytoin due to phenytoin's association with poorer cognitive outcomes and excess morbidity. 3, 1

In brain tumor patients, levetiracetam shows superior tolerability compared to older antiepileptic drugs, with comparable efficacy for preventing early postoperative seizures within 7 days of surgery. 3

Neuropsychiatric Adverse Effects (Most Common Reason for Discontinuation)

Behavioral Disturbances

• Irritability, agitation, anger, and aggressive behavior occur in approximately 12–15% of patients on long-term therapy. 1, 2
• These behavioral effects are more likely in specific high-risk populations: patients with learning disabilities, prior psychiatric history, symptomatic generalized epilepsy, mental retardation, or pre-existing behavioral problems. 2, 4, 5
• Behavioral adverse events have become the most common reason for drug discontinuation in clinical practice, despite being less prominent than somnolence in initial clinical trials. 2

Psychiatric Complications

• Neuropsychiatric side effects occur in approximately 13.3% of adults, with only 0.7% presenting with severe symptoms such as depression, agitation, or hostility. 6
• Psychosis develops in approximately 1.4% of patients treated with levetiracetam. 6
• Psychiatric adverse effects including mood symptoms, suicidality, paranoia, and severe hostility have been reported, particularly in patients with pre-existing schizoaffective disorder or other psychiatric conditions. 6, 5
• These behavioral changes can emerge beyond the initial titration period, making ongoing surveillance necessary throughout treatment. 6

Common Dose-Related Adverse Effects

Central Nervous System Effects

• Somnolence, asthenia (fatigue/weakness), and dizziness were the most prominent adverse effects in clinical trials, though these are typically less problematic than behavioral effects in long-term practice. 2, 5
• Tiredness occurred in 32–43% of patients during the first 12 weeks, with no statistically significant difference between fast and slow titration schedules. 4
• Headaches and nausea are also commonly reported. 5

Discontinuation Rates

• In major double-blind, placebo-controlled trials, discontinuation rates due to adverse events were 6.9–10.9% for levetiracetam-treated patients (all doses) compared with 5.3–8.6% for placebo. 2
• In long-term follow-up studies, 17 out of 38 discontinuations (45%) were due to adverse effects, with the remainder due to lack of efficacy. 4

Hematologic Effects

• Slight trends toward lower white and red blood cell counts have been detected in clinical studies, though these changes are generally not clinically significant. 2
• Laboratory parameters overall are not significantly affected by levetiracetam. 2

Renal Considerations

• Levetiracetam is predominantly eliminated unchanged in the urine, necessitating dose adjustments in patients with renal dysfunction. 1, 2
• Rare cases of acute kidney injury have been reported following levetiracetam initiation, suggesting that renal function should be monitored during treatment, particularly in the early phases. 7

Hepatotoxicity and Drug Interactions

• No organ toxicity has been described with patient exposures exceeding 500,000, representing a significant safety advantage. 2
• Levetiracetam metabolism is independent of the cytochrome P450 enzyme system, and it does not induce cytochrome P450 enzymes, resulting in minimal drug-drug interactions. 2
• This contrasts sharply with valproic acid, which has been associated with hepatotoxicity and thrombocytopenia, particularly in brain tumor patients on chemotherapy. 3

Long-Term Efficacy and Tolerance

• Efficacy appears to be maintained in long-term studies with no evidence of tolerance, a critical advantage for chronic epilepsy management. 2
• In one-year follow-up studies, 14 patients became completely seizure-free and 57 were responders with >50% seizure reduction. 4

Critical Clinical Pitfalls to Avoid

• Do not dismiss new-onset behavioral changes as unrelated to levetiracetam, especially if they emerge weeks to months after stable dosing—these can occur beyond the initial titration period. 6
• Screen carefully for psychiatric history, learning disabilities, and prior behavioral problems before initiating levetiracetam, as these patients have substantially higher risk of behavioral adverse effects. 2, 4, 5
• Monitor renal function, particularly in elderly patients or those with baseline renal impairment, as dose adjustments are necessary and rare cases of acute kidney injury have been reported. 1, 7
• Maintain high index of suspicion for behavioral adverse effects in high-risk populations, including those with mental retardation, symptomatic generalized epilepsy, or concomitant psychiatric disorders. 6, 4

Special Populations

• In women of childbearing potential, levetiracetam is strongly preferred over valproic acid due to valproate's significantly increased risks of fetal malformations and neurodevelopmental delay. 3
• In brain tumor patients, levetiracetam demonstrates better tolerability than older antiepileptic drugs while maintaining comparable efficacy for seizure prevention. 3