Side Effects of Keppra (Levetiracetam)
Keppra is generally well-tolerated with the most common side effects being somnolence, weakness, dizziness, and infection, while the most serious adverse effects are behavioral disturbances including aggression, irritability, and mood changes, particularly in children and patients with prior psychiatric history. 1
Most Common Side Effects in Adults
The FDA-approved labeling identifies the following most frequent adverse events in adults with partial-onset seizures 1:
- Somnolence (15% vs 8% placebo) 1
- Weakness/Asthenia (15% vs 9% placebo) 1
- Dizziness (9% vs 4% placebo) 1
- Infection (13% vs 8% placebo) 1
Additional common effects include headache, pharyngitis, pain, rhinitis, and anorexia 1, 2. These adverse effects typically occur predominantly during the first 4 weeks of treatment 1.
Most Common Side Effects in Children
Pediatric patients experience a somewhat different profile 1:
- Hostility (12% vs 6% placebo) 1
- Nervousness (10% vs 2% placebo) 1
- Somnolence 1
- Accidental injury 1
- Irritability 1
Meta-analysis demonstrates children using levetiracetam have a statistically significant relative risk of 2.18 for behavioral side effects compared to placebo 3.
Serious Behavioral and Psychiatric Effects
The most clinically significant adverse effects are neuropsychiatric in nature 1, 4:
- Mood and behavior changes: aggression, agitation, anger, anxiety, apathy, mood swings, depression, hostility, and irritability 1
- Psychotic symptoms: hallucinations, delusions, and unusual behavior 1
- Risk factors: These effects are more common in learning-disabled individuals, those with prior psychiatric history, and those with symptomatic generalized epilepsy, with an overall estimated risk of 12-15% 4
- Chronotype influence: Morning chronotypes are significantly more susceptible to mood-related adverse effects, with 86.1% of intolerant patients being morning chronotypes versus only 13.9% intermediate types 5
Behavioral side effects have become the most common reason for drug discontinuation in clinical practice, despite being less prominent than somnolence in controlled trials 4.
Cardiovascular and Respiratory Effects
When administered intravenously, particularly at high doses (≥3000 mg) 6:
- Hypotension occurs in 9.2% of patients receiving high-dose IV push administration 6
- Tachycardia in 3.6% 6
- Arrhythmia in 1.8% 6
Levetiracetam demonstrates significantly lower rates of hypotension (0.7%) compared to fosphenytoin (3.2%) in status epilepticus treatment 7. It also results in lower need for endotracheal intubation (20%) versus fosphenytoin (26.4%) 7. In neonates, levetiracetam shows significantly fewer adverse events than phenobarbital, particularly lower risks of hypotension (RR = 3.90) and respiratory depression (RR = 2.06) 8.
Other Notable Adverse Effects
Additional side effects reported in at least 1% of patients include 1, 2:
- Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain 1, 2
- Neurological: ataxia, vertigo, amnesia, tremor, diplopia 1, 2
- Dermatological: rash, pruritus 9, 1
- Hematological: slight trends toward lower white and red blood cell counts, though no significant laboratory abnormalities 4
Injection site reactions occur in only 0.7% of patients 6.
Comparative Safety Profile
Levetiracetam offers significant safety advantages over traditional antiepileptic drugs 9, 7:
- Does not require hepatic level monitoring, unlike phenytoin and valproate 7
- Lower risk of hypotension and respiratory depression compared to phenobarbital 9
- Can be administered more rapidly than phenytoin/fosphenytoin with fewer adverse effects 9, 7
- No significant drug interactions due to metabolism independent of cytochrome P450 system 4
- No organ toxicity described with patient exposures exceeding 500,000 4
Time Course and Management
Most adverse effects appear early after initiation and generally resolve without medication withdrawal 10. The FDA labeling notes these side effects can happen at any time but occur more often within the first 4 weeks of treatment, except for infection 1. In geriatric patients, somnolence, dizziness, and mental confusion are frequent; initiating therapy at low doses and titrating slowly mitigates these neuropsychiatric effects 7.
Special Populations
Pregnancy and breastfeeding: Levetiracetam crosses into breast milk and may harm the baby; patients should not both breastfeed and take Keppra 1. Postpartum dose adjustments are necessary as physiological changes reverse, with empiric tapering protocols showing good tolerability 11.
Pediatric emergency use: In pediatric convulsive status epilepticus, levetiracetam demonstrates faster seizure cessation and shorter ICU stays compared to phenytoin, though with increased risk of agitation (RR = 3.90) 12.
Contraindications and Warnings
The FDA labeling emphasizes patients should 1:
- Not drive or operate machinery until they know how Keppra affects them, as it may cause dizziness or sleepiness 1
- Report immediately: extreme sleepiness, tiredness, weakness, or problems with muscle coordination 1
- Inform healthcare providers of any history of depression, mood problems, suicidal thoughts, or kidney problems 1