Antiseizure medications with indications according to the US Food and Drug Administration package inserts are listed below. Of note, these may be different from the European Medicines Agency. Some off-label use is discussed.
Brivaracetam. Brivaracetam (Briviact®) was initially approved in 2016 for patients 16 years and older; in 2021, it was approved for the treatment of partial-onset seizures as adjunctive or monotherapy in patients 1 month of age and older. Most of the limited literature in pediatrics suggests better efficacy in focal epilepsy or drug-resistant epilepsy, with more limited and less promising studies in generalized epilepsies and epileptic syndromes (34; 25).
Brivaracetam binds to SVA2 glycoprotein with a 10 to 30 times higher affinity than levetiracetam and, in rodent models, higher blood-brain permeability (34; 25).
Although there is a lack of clinical studies directly comparing the effectiveness of brivaracetam to other antiseizure medications, the literature suggests that it is more favorable than levetiracetam in regard to behavioral side effects, and some patients may benefit from switching to brivaracetam (34). “Behavioral and cognitive functioning scores were stable/slightly improved in pediatric patients during long-term adjunctive brivaracetam therapy” in an open-label extended follow-up study (16). Side effects may include somnolence, dizziness, or fatigue.
Brivaracetam is available as an oral solution, tablet, and intravenous injection, and a maintenance dose is given twice daily; dosing is in mg/kg depending on weight category (Brivaracetam package insert, U.S. FDA, revised August 2021).
Cannabidiol. Cannabidiol (Epidiolex®) is the only FDA-approved drug that is derived from cannabis. In 2018, cannabidiol was approved for treating seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older. In 2020, the age was expanded to those 1 year of age and older, and it was approved for the treatment of seizures associated with tuberous sclerosis complex (Cannabidol oral solution package insert, US FDA, revised July 2020).
Since then, the expanded access program data suggest efficacy also in patients with other treatment-resistant epilepsies (09).
Key side effects include somnolence and elevation of liver enzyme levels. It is recommended to assess baseline serum transaminases (ALT and AST) and total bilirubin levels before initiation. Available as an oral solution only, dosing starts at 2.5 mg/kg/dose twice daily and increases at weekly intervals (no faster than every other day) by 2.5 mg/kg/dose twice daily to the recommended maintenance dose of 12.5 mg/kg/dose twice daily. The maximum dose has been suggested to be 20 to 25 mg/kg/day.
Cannabidiol is extensively metabolized by CYP450 enzymes in the liver and can inhibit other enzymes, leading to potential pharmacologic interactions with other drugs. Particularly, there can be an increase in the N-desmethylclobazam level and clinical side effects of sedation. In addition to sedation, side effects include fatigue, weight loss, and thrombocytopenia. The potential hepatotoxicity from cannabidiol and valproate has also been noted.
Carbamazepine. Carbamazepine (Tegretol®) is approved in the United States with no minimum age for:
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(1) Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types. |
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(2) Generalized tonic-clonic seizures (grand mal). |
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(3) Mixed seizure patterns that include the above or other partial or generalized seizures. |
Of note, carbamazepine is not effective in absence, myoclonic, or akinetic seizures; carbamazepine administration may increase the frequency of seizures in patients with these types of seizures.
Known as a first-generation antiseizure medication, carbamazepine remains a first-line treatment for focal epilepsy in many situations as it is one of the few antiseizure medications on the WHO Model List of Essential Medications.
Side effects include those typical for a sodium channel blocker, such as idiosyncratic (rash), sedation, headache, ataxia, nystagmus, diplopia, tremor, impotence, hyponatremia, and cardiac arrhythmia, in addition to the U.S. Box Warning for serious dermatologic reactions, the HLA-B*1502 allele, aplastic anemia, and agranulocytosis.
Carbamazepine is available as oral suspension, tablet, chewable tablet, and 12-hour extended-release. It is recommended to increase dosing in weekly intervals.
Cenobamate. Cenobamate (Xcopri®) is currently only approved for adults with focal onset seizures, not for pediatric patients.
Cenobamate is one of the newer generation antiseizure medications, and several small studies in pediatric patients (mostly adolescents) have shown promising similar rates of seizure freedom up to 20% (18; 33).
In the alkyl carbamate family (similar to felbamate), cenobamate selectively decreases sodium currents. Studies have demonstrated that cenobamate interacts adversely with certain antiseizure medications, namely, phenytoin, phenobarbital, and clobazam (26).
Side effects include sleepiness, dizziness, double vision, and headache.
With slow titration starting at 12.5 mg once daily and increasing every 2 weeks, no cases of Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms have been reported (these were notable concerns reported in initial studies) (27).
Clobazam. In the United States, Clobazam (Onfi®) is currently approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older.
Clobazam is used more widely in the European Union with a broad indication as adjunct treatment for epilepsy, and off-label in the United States, widely for the treatment of developmental and epileptic encephalopathies.
A 1,5 benzodiazepine medication, clobazam is highly selective for the GABAA subunit that is associated with antiseizure activity (a2) with less affinity towards subunit a1, which is known to contribute to sedation (02).
International consensus guidelines suggest that clobazam or valproate could be considered first-line medications for seizures in Dravet syndrome, though these medications are generally inadequate and require escalation of therapy (36).
Clobazam is available as oral film, oral suspension, and tablet, with dose escalation recommended no more than weekly. Common side effects include respiratory depression, somnolence, pyrexia, upper respiratory infections, lethargy, drooling, and constipation, with a U.S. Box Warning for risks from concomitant use of benzodiazepines and opioids, abuse, misuse, addiction, dependence, and withdrawal. In 2023, the FDA also warned of rare instances of drug reaction with eosinophilia and systemic symptoms.
Clonazepam. Clonazepam (Klonopin®) is approved in the United States for the treatment of intractable absence seizures, Lennox-Gastaut syndrome, and akinetic and myoclonic seizures. It is used off-label for rescue therapy of prolonged seizures and cluster seizures in children 4 months of age and older as a disintegrating tablet.
Clonazepam is nonselective for the benzodiazepine subunit a1 or a2. Some loss of effect may occur during the course of clonazepam treatment (Clonazepam package insert, US FDA, Revised February 2021).
Diazepam. Intravenous formulations are approved as treatment for status epilepticus in patients older than 30 days of age; rectal formulation is approved for status epilepticus in children 2 years of age and older.
Intranasal diazepam is approved for acute seizures or seizure clusters in children 6 years of age and older.
Divalproex sodium valproate. Divalproex sodium valproate (Depacon®, Depakote®) is approved as monotherapy and adjunctive therapy for complex partial seizures and simple and complex absence seizures, and adjunctive therapy in patients with multiple seizure types that include absence seizures (Divalproex sodium package insert, US FDA, revised May 2020).
Studies have shown that divalproex is effective for childhood absence epilepsy, with similar effectiveness as ethosuximide, but is associated with greater attentional dysfunction (12). Additionally, this is generally thought of as the first-choice drug in juvenile myoclonic epilepsy, though restricted in women of childbearing age (28). The American Epilepsy Society Guidelines also suggest that this is efficacious in the second phase treatment of status epilepticus in children and adults (13).
Divalproex sodium valproate is available as an intravenous or oral solution as well as immediate-release, sprinkle, delayed-release, or extended-release tablets. There is a U.S. Boxed warning for hepatoxicity, patients with mitochondrial disease, fetal risk, and pancreatitis.
Side effects include nausea, vomiting, dyspepsia, weight gain, tremor, hair loss, and hormonal issues in women.
Eslicarbazepine. Approved for children older than 4 years of age as monotherapy or adjunctive therapy for focal seizures (30; 17), eslicarbazepine is structurally similar to carbamazepine and oxcarbazepine, though more selective. Of note, this does not metabolize to 10-11 carbamazepine epoxide and, thus, is thought to have fewer side effects, such as hyponatremia (30). It is available in an oral once-daily formulation.
Side effects include idiosyncratic (rash), dizziness, somnolence, headache, ataxia, inattention, diplopia, tremor, nausea, vomiting, hyponatremia, and PR prolongation on ECG.
Ethosuximide. Ethosuximide blocks T-type calcium channels and is effective in preventing absence seizures. It is considered an optimal initial therapy for children with absence seizures, though it is not effective against other seizure types (01).
Side effects include idiosyncratic (rash), gastrointestinal disturbances, anorexia, weight loss, drowsiness, photophobia, and headache.
Everolimus. Everolimus is approved as adjunctive therapy in children 2 years of age or older for tuberous sclerosis complex-associated focal seizures and subependymal giant cell astrocytoma. This mTOR inhibitor requires therapeutic drug monitoring (04).
Side effects include delayed wound healing, tiredness, stomach pain, nausea, headache, and decreased appetite.
Felbamate. Felbamate is approved for monotherapy or adjunctive therapy in patients with focal seizures who are older than 14 years of age and patients with Lennox-Gastaut syndrome who are older than 2 years of age. With a U.S. box warning for aplastic anemia and hepatic failure, this medication is considered in refractory epilepsy where benefits exceed hematologic (aplastic anemia) and hepatotoxicity risks (24).
Fenfluramine. Fenfluramine is approved to treat seizures in children with Lennox-Gastaut syndrome and Dravet syndrome who are 2 years of age and older (32).
Side effects include diarrhea, sleepiness, and vomiting. With a U.S. warning for valvular heart disease, an echo is recommended before initiation.
Gabapentin. Gabapentin is approved as adjunctive therapy in focal seizures for children 3 years of age and older. Gabapentin is given three times daily.
Side effects include weight gain, sedation, and peripheral edema.
Ganaxolone. Ganaxolone is a synthetic neuroactive steroid that acts as a positive allosteric modulator of GABA-A receptors. It has been approved for seizures associated with CDKL5 deficiency disorder in children 2 years of age and older (14).
Side effects include somnolence, sedation, upper respiratory tract infection, fever, loss of voice, vision loss, and tachycardia.
Lacosamide. Lacosamide is approved for infants, children, and adolescents with focal seizures as monotherapy or adjunctive therapy, generalized tonic-clonic seizures as adjunctive therapy, refractory seizures, and refractory status epilepticus (available as an intravenous formulation).
Side effects include dizziness, headache, diplopia, nausea, vomiting, blurred vision, and PR prolongation on ECG.
Lamotrigine. Lamotrigine is approved for adjunctive therapy in patients 2 years of age or older with:
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• Partial seizures |
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• Primary generalized tonic-clonic seizures |
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• Generalized seizures of Lennox-Gastaut syndrome |
It is approved as monotherapy in patients 16 years of age or older, including conversion to lamotrigine as monotherapy in patients with partial seizures who are receiving treatment with carbamazepine, phenobarbital, phenytoin, primidone, or valproate.
Lamotrigine has suggested efficacy in other seizure types, including absence epilepsy; however, it is less effective than ethosuximide (01).
Common side effects include idiosyncratic (rash), tics, insomnia, dizziness, diplopia, headache, ataxia, and asthenia. Lamotrigine is known for interaction with other medications, and there is a U.S. FDA warning for serious skin rashes, including Stevens-Johnson syndrome.
Levetiracetam. Levetiracetam is approved for:
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• Adjunctive therapy for myoclonic seizures in juvenile myoclonic epilepsy in children 12 years of age and older. |
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• Focal onset seizures in infants and older. |
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• Adjunctive therapy for primary generalized tonic-clonic seizures in children 6 years of age and older. |
It is commonly used off-label for:
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• Generalized epilepsy in patients of childbearing potential (03). |
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• Seizure prophylaxis in traumatic brain injury (07). |
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• Individuals with brain tumors (03). |
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• Status epilepticus per American Epilepsy Society guidelines (13). |
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• Neonatal seizures (though current literature suggests that phenobarbital is more effective) (23). |
Levetiracetam has warnings for behavioral abnormalities, such as suicidal ideation, irritability, psychotic symptoms, and aggressive behavior; in 2023, the FDA also warned of rare instances of drug reaction with eosinophilia and systemic symptoms.
Lorazepam. Though lorazepam is not FDA-approved for seizures in children younger than 18 years of age, this benzodiazepine is frequently used to treat status epilepticus per current evidence-based American Epilepsy Society guidelines (13).
Midazolam. Similar to lorazepam, intravenous midazolam is approved in adults for status epilepticus and is often used off-label in the pediatric population (13).
The intranasal formulation is approved for the treatment of seizure clusters and acute seizures in those 12 years of age and older.
Oxcarbazepine. Oxcarbazepine is approved as monotherapy for focal seizures in children 4 years of age and older and as adjunctive therapy for focal seizures in children 2 years of age and older.
The main mechanism of action involves blocking sodium currents. It differs from carbamazepine in that it modulates different types of calcium channels and avoids the formation of the carbamazepine epoxide. Oxcarbazepine is thought to potentially have fewer side effects than carbamazepine, though this was not confirmed in a Cochrane review (15).
There is a safety note to test for HLA-B*1502 allele in patients at increased risk (such as those of Asian ancestry) for oxcarbazepine-associated Stevens-Johnson syndrome or toxic epidermal necrolysis.
Perampanel. Perampanel is approved as monotherapy or adjunctive therapy for treating focal seizures in children 4 years of age and older, as well as treatment for primary generalized tonic-clonic convulsions in those 12 years and older.
Of note, this AMPA receptor antagonist has a U.S. FDA Box warning for serious, life-threatening psychiatric and behavioral adverse reactions.
Phenobarbital. A barbiturate, phenobarbital is approved for status epilepticus and maintenance therapy in children, adolescents, and adults.
Phenobarbital is recommended as a first-line medication for neonatal seizures that require treatment per ILAE evidence-based and consensus guidelines (22).
Per American Epilepsy Society guidelines and current practice, phenobarbital is generally used in status epilepticus if the first- or second-line therapy medication options are not available (13).
There is a U.S. FDA warning for risks from concomitant use with opioids, dependence and withdrawal reactions after use for a longer duration than recommended, abuse, misuse, and addiction with unapproved use in adolescents and adults.
Phenytoin. Phenytoin is approved for status epilepticus and focal and generalized onset seizures in infants, children, and adolescents.
This voltage-gated sodium channel blocker has a U.S. FDA warning for cardiovascular risk associated with rapid infusion of the injection formulation.
Pregabalin. Pregabalin is approved for adjunctive therapy for focal seizures in infants and children.
This alpha delta-2 ligand has less evidence for efficacy than newer antiseizure medications, and side effects include dizziness, headache, and somnolence (06).
Primidone. A first-generation barbiturate with primary active metabolites of PEMA and phenobarbital, primidone is approved for focal, generalized tonic-clonic, and psychomotor seizures in infants and children.
Rufinamide. This triazole derivative drug is approved as adjunctive therapy in Lennox-Gastaut syndrome in children aged 1 year and older.
Available as oral suspension and tablet, this medication can be increased every other day. The primary contraindication is familial short QT syndrome, with more common adverse effects including somnolence, vomiting, headache, fatigue, dizziness, nausea, and, rarely, flu-like symptoms, nasopharyngitis, rash, ataxia, and diplopia.
Stiripentol. Stiripentol (Diacomit®) is approved in combination with clobazam for adjunctive treatment of seizures in Dravet syndrome (in addition to clobazam in the United States and clobazam + valproate internationally) for infants and children 6 months and older.
This agent likely enhances GABAergic inhibitory transmission, and the most common adverse events include drowsiness, appetite loss, weight loss, ataxia, and tremor.
Tiagabine. Tiagabine (Gabitril®) is approved as adjunctive therapy for focal seizures in children 12 years and older. It is thought to enhance the activity of GABA.
Rapid dose escalation should be avoided. Tiagabine is affected by enzyme-inducing medications. Side effects include dizziness, tremor, stupor or spike-wave stupor, and weakness.
Topiramate. Topiramate is approved as initial monotherapy for focal or primary generalized tonic-clonic seizures in children 2 years of age and older and as adjunctive therapy for focal seizures, primary tonic-clonic seizures, or seizures with Lennox-Gastaut syndrome.
There are reports of limited and mixed results for off-label use in neonates with refractory neonatal seizures and neonatal hypoxic ischemic encephalopathy (11; 38) and refractory infantile spasms (37).
Side effects include somnolence, anorexia, fatigue, nervousness, difficulty with concentration or attention, memory impairment, psychomotor slowing, metabolic acidosis, weight loss, language dysfunction, renal calculi, acute angle-closure glaucoma and other ocular abnormalities, and paresthesias.
Vigabatrin. Vigabatrin is approved as monotherapy in infants 1 month to 2 years of age with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss. It is also approved for treating refractory focal seizures in those 10 years or older.
For infants with tuberous sclerosis complex, vigabatrin is first-line therapy for infantile spasms. Based on limited studies, several centers’ protocols for first-line management of spasms include combination therapy or vigabatrin in conjunction with hormonal therapy (19).
The mechanism of action includes irreversible inactivation of GABA transaminase. Side effects include fatigue and weight gain, and there is a U.S. Boxed warning for permanent vision loss (bilateral concentric visual field constriction). Administration is available only through a Risk Evaluation and Mitigation Strategies program.
Zonisamide. In the United States, zonisamide is approved as adjunctive therapy in focal seizures in those over the age of 16 years. Double blind, placebo-controlled trials globally have shown efficacy and tolerability in pediatric patients with focal epilepsy (10).
Other studies have also shown effectiveness in other seizure types, such as absence seizures, myoclonic seizures, generalized tonic clonic, intractable childhood epilepsies, and infantile spasms (20; 10).
Zonisamide is considered an older, broad-spectrum antiseizure medication with multiple mechanisms of action, including blockade of sustained high-frequency repetitive firing of sodium-dependent action potentials, inhibition of low-threshold T-type calcium currents, a modulatory effect on GABA-mediated neuronal inhibition, inhibition of glutamate release, decreased nitric oxide levels, and weak inhibition of carbonic anhydrase. Adverse effect considerations include the sulfamoyl group, common adverse reactions (somnolence, anorexia, dizziness, ataxia, agitation or irritability, and difficulty with memory or concentration), renal calculi, and decreased appetite, sweating, and weight (10).
Available in the United States as a capsule and oral suspension, trough concentrations tend to correspond to clinical efficacy, and the long half-life (50 to 60 hours) may be ideal for once-daily dosing. CYP450 metabolism is subject to drug interactions between enzyme inducers and inhibitors (10).
