What are the dosing recommendations, side effects, and precautions for Keppra (levetiracetam) in adults and children, including adjustments for renal impairment?

Keppra (Levetiracetam): Dosing, Side Effects, and Precautions

Dosing Recommendations

Adults with Partial-Onset Seizures

Start levetiracetam at 1000 mg/day divided into 500 mg twice daily (BID), then increase by 1000 mg/day every 2 weeks up to a maximum of 3000 mg/day. 1 Doses above 3000 mg/day provide no additional benefit despite being used in open-label studies. 1

Pediatric Dosing (Ages 4-16 Years)

• Initiate at 20 mg/kg/day in two divided doses (10 mg/kg BID) 1
• Increase by 20 mg/kg every 2 weeks to the target dose of 60 mg/kg/day (30 mg/kg BID) 1
• If 60 mg/kg/day is not tolerated, reduce the dose; the mean effective dose in clinical trials was 52 mg/kg 1
• Children ≤20 kg must use oral solution; those >20 kg may use tablets or solution 1

Myoclonic Seizures (Age ≥12 Years)

Begin with 1000 mg/day (500 mg BID), increase by 1000 mg/day every 2 weeks to 3000 mg/day. Lower doses have not been adequately studied for this indication. 1

Primary Generalized Tonic-Clonic Seizures

• Adults ≥16 years: 1000 mg/day (500 mg BID), titrate by 1000 mg/day every 2 weeks to 3000 mg/day 1
• Children 6-16 years: 20 mg/kg/day (10 mg/kg BID), increase by 20 mg/kg every 2 weeks to 60 mg/kg/day 1

Critical Dosing Adjustments for Renal Impairment

Levetiracetam is 66% renally excreted unchanged, making dose adjustment mandatory in renal dysfunction. 2, 3 Total body clearance decreases proportionally with declining creatinine clearance. 3

Adult Renal Dosing Algorithm 1

Creatinine Clearance	Dose Range	Frequency
>80 mL/min (Normal)	500-1500 mg	Every 12 hours
50-80 mL/min (Mild)	500-1000 mg	Every 12 hours
30-50 mL/min (Moderate)	250-750 mg	Every 12 hours
<30 mL/min (Severe)	250-500 mg	Every 12 hours
ESRD on dialysis	500-1000 mg*	Every 24 hours

*Give a 250-500 mg supplemental dose after dialysis 1

Calculate creatinine clearance using the Cockcroft-Gault equation before initiating therapy and monitor regularly, especially in elderly patients where serum creatinine may be misleadingly normal despite significant renal impairment. 1

Augmented Renal Clearance (ARC) in Critically Ill Patients

In critically ill patients with ARC (creatinine clearance >130 mL/min), standard dosing of 500 mg BID is inadequate. 4 Levetiracetam clearance can reach 6.5 L/h in ARC patients (versus 3.8 L/h in healthy individuals), resulting in subtherapeutic levels. 4 Start with at least 1500 mg BID in patients with documented ARC to achieve therapeutic exposure. 4

Pharmacokinetic Profile

• Bioavailability: >95% with rapid absorption; peak concentration at 1.3 hours 2
• Food effect: Slows absorption rate but not extent 2
• Protein binding: Minimal—not bound to plasma proteins 2, 3
• Volume of distribution: 0.5-0.7 L/kg 2
• Steady state: Achieved within 24-48 hours 2
• Half-life: 6-8 hours in adults, 5-7 hours in children, 10-11 hours in elderly 2
• Metabolism: 34% metabolized (primarily by blood hydrolysis, NOT hepatic cytochrome P450), 66% excreted unchanged in urine 2, 3

Side Effects and Adverse Reactions

Common Side Effects

• Somnolence (most frequent—reported in 16.7% of elderly patients) 5
• Dizziness (9.0% in elderly) 5
• Headache, fatigue, and behavioral changes 2

Serious Adverse Effects Requiring Immediate Attention

Acute interstitial nephritis and renal failure have been reported, typically occurring within 10 days of starting therapy. 6 Screen any child or adult presenting with abdominal pain, malaise, vomiting, oliguria, rash, or urticaria for potential renal complications. 6 Complete recovery occurs rapidly after discontinuation and corticosteroid administration. 6

Tolerability in Elderly (≥65 Years)

In patients ≥65 years, 42.3% reported one or more adverse events, with 19.2% discontinuing due to adverse effects. 5 Despite concomitant medications being common in this population, levetiracetam was generally well tolerated. 5

Drug Interactions

Levetiracetam has minimal drug interactions due to lack of hepatic cytochrome P450 metabolism and minimal protein binding. 2, 3 No clinically relevant pharmacokinetic interactions have been identified with other antiepileptic drugs, digoxin, warfarin, or oral contraceptives. 2 However, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. 2

Special Populations

Elderly Patients

No dose adjustment is required based solely on age, but renal function must be assessed as creatinine clearance declines with age. 2 The elimination half-life increases to 10-11 hours in elderly volunteers compared to 6-8 hours in younger adults. 2 Monitor closely for somnolence and dizziness, which are more common in this population. 5

Hepatic Impairment

No dose adjustment is necessary in hepatic impairment because levetiracetam metabolism is not hepatic. 3 The drug undergoes hydrolysis primarily in blood, not liver. 2

Pregnancy and Lactation

The FDA label does not provide specific pregnancy category information, but levetiracetam's lack of hepatic enzyme induction and minimal protein binding make it a favorable option compared to traditional antiepileptic drugs. 3

Administration Guidelines

• May be taken with or without food 1
• For oral solution in pediatrics: Use a calibrated measuring device, not household spoons 1
• Tablets: Administer only whole tablets; do not crush or split 1
• Dialysis patients: Administer supplemental dose after dialysis to facilitate directly observed therapy and avoid premature drug removal 1

Common Pitfalls to Avoid

1. Do not rely on serum creatinine alone in elderly patients—always calculate creatinine clearance or eGFR, as low muscle mass can mask significant renal impairment 1
2. Do not use standard dosing in critically ill patients with ARC—these patients require at least 1500 mg BID to achieve therapeutic levels 4
3. Do not overlook renal adverse effects—screen patients presenting with abdominal pain, rash, or oliguria for interstitial nephritis 6
4. Do not assume doses >3000 mg/day provide additional benefit—no evidence supports higher doses in adults 1
5. Do not forget supplemental dosing after dialysis—give 250-500 mg post-dialysis to maintain therapeutic levels 1