Specific safety and tolerability considerations in the use of anticonvulsant medications in children

Figures & data

Table 1 Antiepileptic medications commonly used in children based on seizure type/electroclinical syndrome

Seizure type/electroclinical syndrome	Commonly used first-line AEDs
Generalized genetic or presumed genetic etiology
– Juvenile myoclonic epilepsy, juvenile absence epilepsy, epilepsy with generalized tonic clonic seizures alone	Valproic acid, lamotrigine, levetiracetam, topiramate, zonisamide, benzodiazepines
– Childhood absence epilepsy	Ethosuximide, valproic acid, lamotrigine
– Genetic epilepsy with febrile seizures plus	Levetiracetam, lamotrigine, valproic acid
Generalized, structural, or unknown etiologya
– Lennox–Gastaut, myoclonic atonic epilepsy	Valproic acid, lamotrigine, topiramate, clobazam, rufinamide
Focal, structural/metabolic, or unknown etiologyb	Carbamazepine, oxcarbazepine, levetiracetam, valproic acid
West syndrome	ACTH, high-dose prednisolone, vigabatrin
Epilepsy with continuous spike-wave in sleep or Landau–Kleffner Syndromec	Levetiracetam, high-dose diazepam, steroids
Dravet Syndrome	Valproic acid, benzodiazepines, topiramate, stiripentold

Notes:

a A ketogenic diet should be considered early if medication is ineffective;

b surgical therapy should be considered in patients with single presumed focus after two or more AEDs have failed for lack of efficacy;

c no randomized controlled trials; recommendations based on clinical experience only;

d compassionate use only in the US.

Abbreviations: AEDs, antiepileptic drugs; ACTH, adrenocorticotropic hormone.

Table 2 Common adverse effects of antiepileptic medications

Adverse effect	Class/type of antiepileptic drug most commonly implicated
Neurocognitive
– Sedation, fatigue, sleepiness	All, but more commonly benzodiazepines, phenobarbital, topiramate, zonisamide, felbamate, rufinamide, pregabalin, tiagabine
– Ataxia, vertigo, diplopia	Carbamazepine, oxcarbazepine, phenytoin, lacosamide
– Tremor	Valproic acid, carbamazepine, oxcarbazepine, phenytoin
– Slow thinking, word-finding problems	Topiramate, zonisamide, phenobarbital, benzodiazepines
– Insomnia	Felbamate, vigabatrin, levetiracetam
– Hyperactivity, inattention	Benzodiazepines, phenobarbital, levetiracetam, valproic acid
– Irritability, behavioral problems	Benzodiazepines, phenobarbital, levetiracetam, vigabatrin
– Mood changes, depression	Levetiracetam, phenobarbital, benzodiazepines, vigabatrin, topiramate, zonisamide
Gastrointestinal
– Nausea, vomiting	Felbamate, valproic acid, ethosuximide, oxcarbazepine, carbamazepine, lamotrigine, topiramate, zonisamide, rufinamide
– Anorexia	Topiramate, zonisamide, felbamate
– Increased appetite	Valproic acid, clobazam, pregabalin
Headache	Rufinamide, levetiracetam, lamotrigine, oxcarbazepine, lacosamide
Electrolyte disturbances
– Hyponatremia	Oxcarbazepine, carbamazepine
– Metabolic acidosis	Topiramate, zonisamide
Bone
– Reduced bone mineral density	Phenobarbital, primidone, phenytoin, carbamazepine, valproate, oxcarbazepine

Table 3 Rare, serious adverse effects of antiepileptic medications

Adverse effect	Antiepileptic drug
Skin
– Allergic rash/Stevens–Johnson syndrome	Lamotrigine, phenytoin, phenobarbital, carbamazepine, oxcarbazepine, rufinamide
Gastrointestinal
– Hepatic failure	Valproic acid, felbamate
– Pancreatitis	Valproic acid
Bone marrow
– Aplastic anemia	Felbamate, carbamazepine, phenytoin, phenobarbital, ethosuximide
Cardiac
– Arrhythmias	Rufinamide – shortened QT interval Lacosamide – prolonged PR interval
Kidney
– Nephrolithiasis	Topiramate, zonisamide
Eye
– Irreversible peripheral field loss	Vigabatrin
– Angle closure glaucoma	Topiramate
Psychiatric
– Suicide	Blackbox warning for all AEDs
Metabolic
– Worsening of rare inborn disorders of metabolism	Valproic acid
Reproductivea
– Polycystic ovarian syndrome	Valproic acid
– Teratogenicity (highest risk)	Valproic acid, phenytoin

Note:

a All AEDs have a potential risk of teratogenicity.

Abbreviation: AEDs, antiepileptic drugs.

Table 4 Pharmacokinetics by age

	Neonate (0–3 months)	Infant (3–12 months)	Toddler (1–3 years)	Child (3–18 years)
Gastric absorption	↓	↓	↓	↔
Protein binding	↓	↓	↔	↔
Hepatic CYP	↓	↑	↑	↑
metabolism UGT	↓	↓	↓/↑	↑
Renal clearance	↓	↓	↓/↔	↔

Abbreviations: CYP, cytochrome p450; UGT, uridine diphosphate glucuronosyltransferase.

Table 5 Pathways for the metabolism and excretion of antiepileptic medications

Primary pathway of metabolism and excretion
Renal	Gabapentin Pregabalin Vigabatrin
Hepatic – CYP	Carbamazepine Clobazam Phenytoin Midazolam
Hepatic – UGT	Lamotrigine Lorazepam
Hepatic – CYP and UGT	Tiagabine Valproic acid
Hepatic – Non CYP or UGT	Rufinamide
Combined renal and hepatic	Ethosuximide Felbamate Lacosamide Levetiracetam Oxcarbazepine Phenobarbital Topiramate Zonisamide

Abbreviations: CYP, cytochrome p450; UGT, uridine diphosphate glucuronosyltransferase.

Table 6 Indications for checking serum drug levels of antiepileptic medications

Indications for checking serum drug levels

To assess serum concentration at steady state of target dosing

In the setting of complex pharmacokinetics

To assess at various stages of development

To assure compliance

Table 7 Clinically significant interactions between antiepileptic medications

Drug	BZ	CBZ	ETH	FBM	GBP	GVG	LCS	LEV	LTG	OXC	PB	PGB	PHT	PRM	RUF	ST	TGB	TPM	VPA	ZNS
BZ		Dec BZ*			Dep						Dep	Dep	Dec BZ*, Dec PHT					Dep
CBZ			Dec ETH	Dec CBZ, Inc Epo, Dec FBM		Inc CBZ		Inc CBZ Tox	Dec LTG, Inc Epo	Dec MHD	Dec CBZ		Inc PHT, Dec CBZ	Dec CBZ, Dec PRM, Inc PB	Dec CBZ, Dec RUF	Dec ST	Dec TGB	Dec TPM	Dec VPA, Dec CBZ Inc Epo, Syn	Dec ZNS
ETH											Dec ETH		Dec ETH						Dec VPA, Inc ETH, Syn
FBM											Inc PB		Inc PHT, Dec FBM						Inc VPA
GBP											Dep	Dep						Dep
GVG													Dec PHT
LCS
LEV
LTG										Dec LTG	Dec LTG		Dec LTG	Dec LTG	Dec LTG				Inc LTG, Syn
OXC											Dec MHD		Inc PHT						Dec MHD
PB												Dep	Inc or Dec PHT		Inc PB, Dec RUF	Dec ST	Dec TGB	Dec TPM, Dep	Dec VPA, Inc PB	Dec ZNS
PGB																	Dep
PHT														Inc PB	Inc PHT, Dec RUF	Dec ST	Dec TGB	Dec TPM, Inc PHT	Dec VPA, Dec or Inc PHT	Dec ZNS
PRM															Dec RUF	Dec ST	Dec TGB		Dep	Dec ZNS
RUF																			Inc RUF
ST
TGB
TPM																			Dec TPM, VPA, Tox
VPA																				Inc ZNS t½
ZNS

Note:

* Clonazepam.

Abbreviations: BZ, benzodiazepine; CBZ, carbamazepine; Dec, decrease; Dep, CNS depressant effects; Epo, epoxide; ETH, ethosuximide; FBM, felbamate; GBP, gabapentin; GVG, vigabatrin; Inc, increase; LCS, lacosamide; LEV, levetiracetam; LTG, lamotrigine; MHD, monohydrate derivative; OXC, oxcarbazepine; PB, phenobarbital; PGB: pregabalin; PHT, phenytoin; PRM, primidone; RUF, rufinamide; ST, steroids; Syn, synergy; t½, half life; TGB, tiagabine; Tox, toxicity; TPM, topiramate; VPA, valproic acid; ZNS, zonisamide.