Levetiracetam
Modern antiepileptic drug for the treatment of epileptic seizures
Levetiracetam is a newer-generation antiepileptic drug that, since its European approval in 2000 (under the brand name Keppra), has become one of the most commonly prescribed seizure suppressants worldwide. The active ingredient is distinguished by a favourable pharmacokinetic profile, a broad spectrum of seizure types, and a comparatively low potential for interactions with other medications. Levetiracetam is available as tablets, modified-release tablets, oral solution, and infusion solution, allowing flexible dosing options both in outpatient and inpatient settings.
Levetiracetam is used both as monotherapy and as adjunctive therapy. The active ingredient has broad approval for focal seizures, myoclonic seizures in the context of juvenile myoclonic epilepsy, and primary generalised tonic-clonic seizures. In neurology, it has become a standard medication that is also administered intravenously in emergency departments in acute status epilepticus situations.
Mechanism of Action
The precise mechanism of action of levetiracetam differs fundamentally from that of classical antiepileptics. The active ingredient selectively and with high affinity binds to the synaptic vesicle protein SV2A (Synaptic Vesicle Protein 2A), located at the presynaptic membrane. This protein plays a key role in regulating neurotransmitter release, particularly in controlling the fusion process of synaptic vesicles with the plasma membrane.
By binding to SV2A, levetiracetam modulates presynaptic neurotransmitter release and reduces excessive synchronous neuronal discharge, without significantly impairing normal synaptic transmission. Levetiracetam shows no relevant interaction with classical ion channels (Na+, Ca2+) or GABA receptors at therapeutically relevant concentrations, which explains its unique activity profile and good tolerability.
Additionally, it has been observed that levetiracetam inhibits certain voltage-dependent N-type calcium channels and can modulate the action of GABA and glycine receptors. These mechanisms may contribute to the overall antiepileptic effect without, however, overshadowing the dominant SV2A mechanism.
Indications
- Focal seizures (with and without secondary generalisation): As mono- and adjunctive therapy in adults, adolescents, and children from 1 month of age
- Myoclonic seizures in juvenile myoclonic epilepsy: Adjunctive therapy in adolescents and adults from 12 years of age
- Primary generalised tonic-clonic seizures (grand mal): Adjunctive therapy in idiopathic generalised epilepsy from 12 years of age
- Status epilepticus: Intravenous administration in emergency medicine when benzodiazepines are insufficient or contraindicated
- Off-label applications: Prophylaxis during cranial irradiation, post-operative seizure prophylaxis after brain surgery, neuropathic pain (under investigation)
Dosage and Administration
Adults and adolescents above 50 kg: Starting dose 250 mg twice daily; increase after 2 weeks to 500 mg twice daily (standard dose). Depending on efficacy and tolerability, this can be increased to up to 1500 mg twice daily (maximum daily dose 3000 mg). Children (4 to 16 years): 10 mg/kg body weight twice daily as starting dose; increase to 20 to 30 mg/kg body weight twice daily possible. Infants and young children (1 month to 6 years): Use of oral solution (100 mg/ml), weight-adapted dosing according to the product information.
Levetiracetam can be taken independently of meals. Tablets should not be split or chewed, but swallowed with sufficient liquid. Modified-release tablets are taken once daily. In renal insufficiency, the dose must be adjusted, as levetiracetam is predominantly excreted renally. Levetiracetam should never be discontinued abruptly; gradual tapering over several weeks is required to avoid rebound seizures.
Side Effects
Very common (over 10%): Somnolence (drowsiness), nasopharyngitis, behavioural symptoms such as irritability, aggression, and mood swings. These neuropsychiatric side effects in particular represent the greatest clinical challenge and not infrequently lead to treatment discontinuation.
Common (1 to 10%): Headache, dizziness, tremor, balance disorders, diplopia (double vision), nausea, abdominal pain, diarrhoea, decreased appetite, depression, anxiety, insomnia.
Occasional to rare: Suicidal thoughts and suicidal behaviour (considered a class effect for all antiepileptics), hallucinations, confusion, pancreatitis, thrombocytopenia, leucopenia. Severe skin reactions (Stevens-Johnson syndrome) have been very rarely described.
Interactions
Levetiracetam has a very low pharmacokinetic interaction potential, as it is not metabolised via the cytochrome P450 system and has no clinically relevant protein binding. It therefore barely affects plasma levels of other antiepileptics or other medications.
Relevant interactions:
- Probenecid: Inhibits the renal excretion of the main metabolite ucb L057, which can lead to elevated plasma levels
- Carbamazepine: Combination can lead to increased somnolence and dizziness (pharmacodynamic interaction)
- Alcohol: Enhancement of sedative effects; concurrent consumption should be avoided
- Other CNS-depressant substances: Additive effects on sedation and reaction capacity are possible
Special Notes
Psychiatric monitoring: Due to the known frequency of neuropsychiatric side effects, patients and carers should be informed about these. In the event of suicidal thoughts, severe mood swings, or aggressive behaviour, immediate medical consultation is necessary.
Pregnancy: Levetiracetam crosses the placenta. Animal studies showed developmental toxic effects at high doses. In humans, no adequate controlled studies are available. As uncontrolled seizures during pregnancy carry significant risks, existing therapy should not be discontinued without medical advice. Pre-conception counselling by an epilepsy specialist is recommended.
Driving ability: At the start of treatment and with dose changes, the ability to participate in road traffic may be impaired. Patients should be informed accordingly.
Renal insufficiency: As levetiracetam is excreted approximately 60 percent unchanged renally, dose reduction is required with impaired renal function. Regular monitoring of renal function is recommended.
Frequently Asked Questions
How quickly does levetiracetam work?
Levetiracetam is rapidly and completely absorbed after oral ingestion; maximum plasma levels are reached after approximately one hour. A seizure-suppressive effect can occur after just a few days, although full efficacy usually develops after several days to weeks of intake at steady state.
Can levetiracetam change mood?
Yes, neuropsychiatric side effects such as irritability, aggression, or depressive moods are known and not infrequent effects of levetiracetam. These should be discussed with the treating physician if they occur; dose adjustment or a change of antiepileptic medication may be indicated.
Is levetiracetam a controlled substance?
No, levetiracetam is not subject to the German Narcotics Act (BtMG) and is neither an opioid nor a benzodiazepine. It is prescribed on a normal prescription.
References
- Product information Keppra (UCB Pharma), as of 2024
- S1 guideline Epilepsies in adults of the German Society for Neurology (DGN), 2023
- European Medicines Agency (EMA): Keppra EPAR
- Rogawski MA, Loscher W: The neurobiology of antiepileptic drugs. Nature Reviews Neuroscience, 2004
- Federal Institute for Drugs and Medical Devices (BfArM): Product monograph Levetiracetam