What is the recommended first‑line monotherapy for a child or adolescent with epilepsy, including drug choices and dosing for focal and generalized seizures?

First-Line Monotherapy for Epilepsy in Children and Adolescents

Focal Onset Seizures

For children and adolescents with focal seizures, lamotrigine, levetiracetam, or carbamazepine are the recommended first-line monotherapy options, with lamotrigine showing the best overall profile for treatment retention and tolerability. 1, 2

Drug Selection and Dosing

• Lamotrigine is supported by high-certainty evidence demonstrating superior treatment retention compared to most other antiepileptic drugs, including carbamazepine 1

  • Start at low doses and titrate slowly over several weeks to minimize rash risk 1
  • Lamotrigine performs significantly better than carbamazepine for treatment failure due to adverse events (HR 1.26,95% CI 1.10–1.44) 1

• Levetiracetam shows equivalent efficacy to lamotrigine with minimal drug interactions and excellent tolerability 1, 2

  • No significant difference between lamotrigine and levetiracetam for treatment failure outcomes 1
  • Particularly advantageous in patients requiring multiple medications due to lack of cytochrome P450 interactions 3

• Carbamazepine remains an effective option but has higher treatment failure rates due to adverse events compared to lamotrigine 1, 2

  • Start at 10–15 mg/kg/day and increase by 5–10 mg/kg/week 4
  • Target daily doses typically below 60 mg/kg/day 4
  • More drug interactions than newer agents 3

Clinical Decision Algorithm

• First choice: Lamotrigine or levetiracetam for most children and adolescents with focal seizures 1, 2
• Alternative: Carbamazepine if lamotrigine or levetiracetam are contraindicated or not tolerated 2
• Avoid: Phenytoin and phenobarbitone as first-line due to inferior tolerability profiles 1, 3

Generalized Tonic-Clonic Seizures (With or Without Other Generalized Seizure Types)

Sodium valproate is the most effective first-line treatment for generalized tonic-clonic seizures, but lamotrigine or levetiracetam are the preferred alternatives, particularly in females of childbearing potential. 1, 2

Drug Selection and Dosing

• Sodium valproate demonstrates the best efficacy profile for generalized seizures 1, 2

  • Initial dose: 15 mg/kg/day, increasing at one-week intervals by 5–10 mg/kg/day 4
  • Maximum recommended dose: 60 mg/kg/day 4
  • Therapeutic serum concentrations: 50–100 μg/mL 4
  • Absolute contraindication in girls and women of childbearing age unless no alternative exists and strict pregnancy prevention measures are in place, due to high teratogenicity risk 1, 3, 2

• Lamotrigine is the preferred alternative when valproate is contraindicated 1, 2

  • No significant difference between sodium valproate and lamotrigine for treatment failure (HR 1.06,95% CI 0.81–1.37) 1
  • Suitable for all age groups and both sexes 2

• Levetiracetam is another suitable first-line alternative 1, 2

  • No significant difference between sodium valproate and levetiracetam for treatment failure (HR 1.13,95% CI 0.89–1.42) 1
  • Better safety profile in pregnancy compared to valproate 3

Clinical Decision Algorithm

• Males and prepubertal females: Sodium valproate as first choice 1, 2
• Females of childbearing potential: Lamotrigine or levetiracetam as first choice 1, 3, 2
• If valproate fails or is not tolerated: Switch to lamotrigine or levetiracetam 1, 2

Absence Seizures

Ethosuximide is the first-line treatment for absence seizures without generalized tonic-clonic seizures, while sodium valproate is preferred when both absence and tonic-clonic seizures are present. 5, 2

• Ethosuximide has level A evidence for absence seizures without tonic-clonic seizures 2
• Sodium valproate is effective for absence seizures and provides coverage for tonic-clonic seizures if present 5
• If valproate cannot be used, add ethosuximide or a benzodiazepine to control absence seizures when treating tonic-clonic seizures with other agents 5

Critical Pitfalls to Avoid

• Never use carbamazepine or phenytoin for generalized epilepsies, as they may worsen absence or myoclonic seizures 5
• Do not prescribe valproate to females of childbearing potential without exhausting all alternatives and implementing strict contraception 1, 3, 2
• Avoid phenobarbitone as first-line due to significant adverse effects including cognitive impairment and behavioral problems 1, 3
• Do not combine multiple drugs initially—optimize monotherapy first before considering combination therapy 6

Monitoring and Titration Principles

• Start at low doses and titrate gradually to minimize adverse effects 4, 6
• Target complete seizure freedom with minimal or no adverse effects 6
• If satisfactory response is not achieved at standard doses, measure plasma drug levels to ensure therapeutic range 4
• Maximum tolerated dose should be explored before declaring treatment failure 6
• Doses above 60 mg/kg/day for valproate carry increased thrombocytopenia risk (>110 μg/mL in females, >135 μg/mL in males) 4