What are the common and serious side effects of levetiracetam (Keppra) and how should they be managed, including dose adjustments for impaired renal function?

Keppra (Levetiracetam) Side Effects

Levetiracetam is generally well-tolerated with the most common side effects being somnolence, asthenia, dizziness, and behavioral changes (particularly irritability and aggression), while serious adverse effects including acute kidney injury and psychiatric disturbances require vigilant monitoring. 1, 2

Common Side Effects

The most frequently reported adverse effects in clinical trials include:

• Somnolence occurs commonly and was one of the most prominent adverse effects in controlled trials 3, 1, 2
• Asthenia (fatigue/weakness) represents another major tolerability concern reported in 3-4% of patients 3, 1, 2
• Dizziness affects approximately 2-3% of patients and may limit dose escalation 3, 1, 2
• Headache occurs in roughly 2% of treated patients 3, 2
• Gastrointestinal symptoms including nausea (3%), diarrhea (4%), and vomiting are reported 3, 1
• Infection risk increases slightly, with nasopharyngitis and influenza being more common than placebo 3, 2

In clinical trials, discontinuation rates due to adverse events ranged from 6.9-10.9% for levetiracetam compared to 5.3-8.6% for placebo, indicating relatively good overall tolerability 1.

Serious Behavioral and Psychiatric Effects

Behavioral adverse effects have emerged as the most common reason for drug discontinuation in clinical practice, despite being less prominent in initial clinical trials. 1

• Irritability, agitation, anger, and aggressive behavior occur in approximately 12-15% of patients, representing a significant clinical concern 1, 2
• High-risk populations include learning disabled individuals, those with prior psychiatric history, and patients with symptomatic generalized epilepsy 1
• Psychiatric disturbances may manifest as mood changes, depression, or psychosis requiring immediate evaluation 1

These behavioral effects warrant careful patient counseling before initiating therapy and close monitoring during treatment, particularly in vulnerable populations 1.

Renal Toxicity

Acute kidney injury represents a rare but serious adverse effect that requires monitoring, particularly with high-dose therapy. 4, 5

• Acute kidney injury (AKI) has been reported in case reports, with creatinine elevation occurring as early as 1-2 days after initiation 4, 5
• High-dose administration (such as loading doses of 4g IV) appears to increase AKI risk, with one case report documenting creatinine rising to 12.2 mg/dL 5
• Renal function monitoring should occur during treatment, especially when using loading doses or in patients with pre-existing renal compromise 4, 5
• Recovery is typically complete within 30 days after discontinuation, though aggressive IV hydration may be necessary if rhabdomyolysis is present 5

Hematologic Effects

• Slight trends toward lower white and red blood cell counts have been detected in clinical studies, though clinically significant myelosuppression is rare 3, 1
• Weekly complete blood counts are recommended for the first 2 months when using related compounds like linezolid, though this is not standard practice for levetiracetam alone 3

Rare but Serious Adverse Effects

• Dermatologic reactions including urticaria, rash, and rarely Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported 3
• Neurologic complications such as peripheral neuropathy, seizures (paradoxically), and serotonin syndrome can occur 3
• Optic neuropathy risk increases with prolonged treatment duration 3
• Metabolic disturbances including lactic acidosis have been documented 3

Dose Adjustments for Renal Impairment

Levetiracetam requires mandatory dose reduction in renal dysfunction since it is predominantly eliminated unchanged in urine. 6, 1, 7

The recommended dosing adjustments based on creatinine clearance are:

• CrCl >80 mL/min (Normal): 500-1,500 mg every 12 hours 6
• CrCl 50-80 mL/min (Mild): 500-1,000 mg every 12 hours 6
• CrCl 30-50 mL/min (Moderate): 250-750 mg every 12 hours 6
• CrCl <30 mL/min (Severe): 250-500 mg every 12 hours 6
• ESRD on dialysis: 500-1,000 mg every 24 hours with supplemental dosing after dialysis 6

Special Consideration: Augmented Renal Clearance

Critically ill patients with augmented renal clearance (ARC) require significantly higher doses than standard recommendations to achieve therapeutic levels. 7

• ARC prevalence ranges from 30-90% in critically ill patients and dramatically increases levetiracetam clearance up to 6.5 L/h (versus 3.8 L/h in healthy individuals) 7
• Standard dosing is inadequate: The typical starting dose of 500 mg twice daily consistently produces subtherapeutic levels in ARC patients 7
• Recommended dosing for ARC: At least 1,500 mg twice daily is necessary to achieve exposures similar to non-ARC patients receiving 1,000 mg twice daily 7
• Monitoring strategy: Careful tracking of creatinine clearance and consideration of therapeutic drug monitoring is essential in critically ill patients 7

Monitoring Recommendations

• Renal function assessment should occur before initiation and periodically during treatment, particularly with high doses or in patients with baseline renal compromise 4, 5
• Behavioral monitoring through patient and family education about mood changes, irritability, and aggression is critical 1
• Seizure diaries help track treatment efficacy and identify breakthrough seizures 8
• Medical identification should be carried by patients indicating epilepsy diagnosis and antiepileptic medication use 8
• Liver function tests may be considered monthly in patients with pre-existing liver disease, though hepatotoxicity is not a primary concern with levetiracetam 8

Key Clinical Pitfalls

• Do not assume standard dosing is adequate in critically ill patients—ARC dramatically increases clearance and necessitates dose escalation to 1,500 mg twice daily or higher 7
• Do not overlook behavioral changes as minor side effects—these represent the leading cause of discontinuation in clinical practice and require proactive management 1
• Do not delay dose adjustment in renal impairment—levetiracetam's renal elimination pathway makes dose reduction mandatory to prevent accumulation 6, 7
• Do not dismiss acute rises in creatinine as unrelated—levetiracetam can cause AKI, particularly with loading doses, and requires prompt recognition 4, 5