Levetiracetam
| Evidence Level: L5 | Predicted Indications: 1 |
Table of Contents
Levetiracetam: Beta-ketothiolase deficiency
One-Sentence Summary
Levetiracetam is an antiseizure medication, originally used to treat partial epilepsy.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Beta-ketothiolase deficiency |
| TxGNN Prediction Score | 0.9990 |
| Evidence Level | L5 |
| Canada Market Status | Marketed (marketed DINs on record: at least 18; cancelled: 2) |
| Number of DINs | at least 20 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data were not available in the data compiled for this report. Based on the literature retrieved, levetiracetam binds synaptic vesicle protein 2A (SV2A) and modulates presynaptic neurotransmitter release. This reduces neuronal hyperexcitability and explains its established activity against partial seizures.
Partial epilepsy and status epilepticus are closely related. Status epilepticus is a prolonged seizure state in which the normal mechanisms that stop a seizure fail. A drug that dampens excessive neurotransmitter release can plausibly help stop such seizures, particularly when benzodiazepines have not worked.
This is supported by direct trial evidence. In the ESETT trial, levetiracetam, fosphenytoin and valproate showed comparable efficacy in benzodiazepine-refractory status epilepticus. Levetiracetam is therefore an equivalent option rather than a superior one.
The other predictions are weaker:
- Startle epilepsy: small add-on clinical studies and case reports (L3).
- Audiogenic seizures: animal models and one veterinary randomized trial in cats (L4).
- Visual, micturition-induced, eating, thinking and reading seizures: only indirect or keyword-matched literature (L4).
- Orgasm-induced seizures and beta-ketothiolase deficiency: prediction only, with no trials or literature (L5).
Clinical Trial Evidence
Trials for status epilepticus (up to 10 most relevant shown):
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01960075 | Phase 3 | Completed | 478 | ESETT: blinded comparison of fosphenytoin, valproic acid and levetiracetam in benzodiazepine-refractory status epilepticus |
| NCT01150331 | Phase 3 | Completed | 203 | Pre-hospital IV levetiracetam plus clonazepam vs clonazepam alone in generalised tonic-clonic status epilepticus |
| NCT02920060 | Phase 2 | Completed | 80 | Levetiracetam vs sodium valproate in children with refractory generalised convulsive status epilepticus |
| NCT04926844 | Phase 2 | Completed | 144 | Levetiracetam plus midazolam in children with generalised convulsive status epilepticus |
| NCT07046611 | Phase 2/3 | Recruiting | 124 | Ketamine plus levetiracetam vs levetiracetam alone as second-line therapy in children |
| NCT06907173 | Phase 3 | Recruiting | 770 | KESETT: ketamine add-on to levetiracetam vs levetiracetam alone in established status epilepticus |
| NCT06403150 | Phase 4 | Completed | 62 | Open-label levetiracetam vs fosphenytoin in convulsive status epilepticus |
| NCT07052136 | Not applicable | Completed | 138 | Levetiracetam vs valproic acid in paediatric status epilepticus |
| NCT07098728 | Not applicable | Recruiting | 180 | IV levetiracetam vs phenobarbital in children with prolonged seizures unresponsive to benzodiazepines |
| NCT00362141 | Phase 2 | Unknown | 12 | Safety and tolerability of add-on levetiracetam in status epilepticus |
No clinical trials are registered for the other predicted indications.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31774955 | 2019 | RCT | N Engl J Med | Three anticonvulsants compared for benzodiazepine-refractory status epilepticus |
| 32203691 | 2020 | RCT secondary analysis | Lancet | ESETT results by age group for levetiracetam, fosphenytoin and valproate |
| 33190679 | 2020 | RCT | Health Technol Assess | EcLiPSE: levetiracetam as an alternative to phenytoin in children with convulsive status epilepticus |
| 38580318 | 2024 | Review | Semin Neurol | Phenytoin, valproic acid and levetiracetam appear to have similar safety and efficacy in urgent-phase status epilepticus |
| 35963261 | 2022 | Phase 3 RCT | Lancet Neurol | PEACH: prophylactic levetiracetam after intracerebral haemorrhage (seizure prevention) |
| 32385134 | 2020 | RCT | Pediatrics | Levetiracetam vs phenobarbital for neonatal seizures |
| 18486495 | 2008 | Clinical study | Seizure | Add-on levetiracetam in startle epilepsy: efficacy and tolerability |
| 17401745 | 2007 | Clinical study | J Neurol | Effect of levetiracetam in startle disease |
| 26690830 | 2017 | Veterinary RCT | J Feline Med Surg | Levetiracetam vs phenobarbital in cats with audiogenic reflex seizures |
| 22386591 | 2012 | Case series | Epilepsy Behav | Good response to levetiracetam in reading epilepsy (three patients) |
Canada Market Information
Dosage form and approved indication text were not available. Five main authorizations:
| DIN | Product Name |
|---|---|
| 02504561 | JAMP LEVETIRACETAM TABLETS |
| 02296136 | PMS-LEVETIRACETAM |
| 02285924 | APO-LEVETIRACETAM |
| 02461986 | SANDOZ LEVETIRACETAM |
| 02442388 | MINT-LEVETIRACETAM |
Safety Considerations
Package insert warnings and contraindications were not available. Please refer to the package insert for safety information.
- Disease-level cautions from the knowledge graph (not label text): kidney disease, liver disease, gallbladder disease, anxiety and related disorders, psychotic and other mental disorders, and blood-count abnormalities (neutropenia, agranulocytosis, leukopenia, pancytopenia).
- Drug interactions: 100 interactions were found. The seven rated Moderate involve morphine (including liposomal), opium, dronabinol, nabilone, metoclopramide and sibutramine. Others, such as pantoprazole, metformin and vancomycin, are rated Unknown.
- Literature-reported adverse effects: seizure aggravation, hyponatremia, gingival hyperplasia and irritability have been reported.
Conclusion and Next Steps
Decision: Proceed with Guardrails (for status epilepticus)
Rationale:
- Two Phase 3 randomized trials, including the large ESETT trial, support levetiracetam in status epilepticus.
- Levetiracetam performed comparably to alternatives rather than better, and it is widely marketed in Canada (20 DINs).
- Results may vary by age and cause.
- Startle epilepsy and audiogenic seizures could be treated as research questions. The remaining predictions should be on Hold.
To proceed, the following is needed:
- Health Canada package insert warnings and contraindications
- Mechanism of action data from DrugBank
- Confirmation of whether status epilepticus is already covered by the Canadian labelled indications, and the approved dosage forms and routes (particularly IV)
- Dosing and monitoring guidance by age group and cause, following local guidelines
- Direct human evidence for reflex-seizure predictions before further consideration
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.