What are the adverse effects of levetiracetam (Keppra)?

Adverse Effects of Levetiracetam

Levetiracetam is generally well-tolerated with the most common adverse effects being somnolence, headache, and behavioral disturbances, though serious neuropsychiatric effects including aggression, psychosis, and delirium can occur, particularly in patients with prior psychiatric history. 1, 2

Most Common Adverse Effects

Neurological Effects

• Somnolence is the most frequently reported adverse effect, occurring in 15% of adult patients versus 8% on placebo 2
• Dizziness affects 9% of patients compared to 4% on placebo 2
• Asthenia (weakness/fatigue) occurs in approximately 15% of patients 2
• Headache is commonly reported but occurs at similar rates to placebo 3
• Ataxia affects 3% of patients versus 1% on placebo 2

Gastrointestinal Effects

• Anorexia occurs in 3% of patients versus 2% on placebo 2
• Nausea, vomiting, and diarrhea are reported but generally at low frequencies 2

Infectious Complications

• Pharyngitis affects 6% of patients versus 4% on placebo 2
• Rhinitis occurs in 4% versus 3% on placebo 2
• Combined infection-related adverse effects affect 19.7% on levetiracetam versus 15.1% on placebo, though this difference is not statistically significant 3

Serious Neuropsychiatric Adverse Effects

Behavioral Disturbances (High-Risk Profile)

• Behavioral adverse effects occur in 12-15% of patients overall and represent the most common reason for drug discontinuation in clinical practice 4
• Irritability, agitation, anger, and aggressive behavior are well-documented, with higher risk in specific populations 4, 5
• Risk factors for behavioral effects include:
  • Learning disabilities 4
  • Prior psychiatric history 4, 5
  • Symptomatic generalized epilepsy 4

Psychiatric Complications

• Depression occurs in 4% of adult patients versus 2% on placebo 2
• Psychosis develops in approximately 1.4% of patients 5
• Hostility and personality disorder affect 2% of pediatric patients versus 1% on placebo 2
• Psychiatric adverse effects occur in 13.3% of adults, with 0.7% presenting with severe symptoms 5

Delirium

• Delirium is an uncommon but documented adverse effect, characterized by fluctuating consciousness, disorientation, and inability to follow commands 6
• Symptoms typically resolve within 24 hours of drug discontinuation 6

Time Course and Discontinuation

Onset Pattern

• Asthenia, somnolence, and dizziness predominantly occur during the first 4 weeks of treatment 2
• Neuropsychiatric effects can emerge beyond the initial titration period 5

Discontinuation Rates

• 15.0% of patients discontinue or require dose reduction due to adverse events versus 11.6% on placebo 2
• In oral loading studies, 89% of patients reported no adverse effects, while 11% experienced transient irritability, imbalance, tiredness, or lightheadedness 1

Comparative Safety Profile

Advantages Over Older Antiepileptics

• Levetiracetam is generally better tolerated than phenytoin or valproic acid 1
• In aneurysmal subarachnoid hemorrhage, levetiracetam results in lower incidence of adverse effects compared to phenytoin as measured by Glasgow Outcome Scale-Extended and Disability Rating Scale 7
• Phenytoin causes poorer cognitive outcomes and excess morbidity, prompting use of alternative antiseizure medications like levetiracetam 7

Hematologic Safety

• In patients with brain tumors receiving chemotherapy, levetiracetam has lower risk of hematologic toxicities compared to valproic acid 8
• Slight trends toward lower white and red blood cell counts have been detected, though no significant laboratory parameter changes occur 4

Special Monitoring Considerations

Renal Function

• Dose adjustments are necessary in patients with renal dysfunction due to predominant renal elimination 1, 4

Status Epilepticus Use

• In status epilepticus studies using doses up to 2,500 mg IV, only isolated cases of nausea and transient transaminitis were noted 7
• No serious adverse effects were attributable to rapid infusion at 5 mg/kg per minute 7

Critical Clinical Pitfalls

• Do not overlook behavioral changes in patients with psychiatric history - maintain high index of suspicion for levetiracetam-induced behavioral disturbances 5
• Behavioral symptoms can be severe enough to require restraints and typically reverse with drug cessation 6
• No organ toxicity has been described with patient exposures exceeding 500,000 4