Chapter 7
Adverse Effects of Antiepileptic Drugs
CQ 7-1

What are the adverse effects of antiepileptic drugs?
Summary
Adverse effects of antiepileptic drugs comprise idiosyncratic drug reactions, dose-dependent adverse effects, andadverse effects after long-term usage.

Comment
Adverse effects of antiepileptic drugs are roughly divided into acute early idiosyncratic reactions to drugs associated withallergic mechanisms, dose-dependent inhibitory action on the nervous system, and chronic phase adverse effects seen after
long-term usage.
For idiosyncratic reactions to drugs, skin rash is a representative adverse effect occurring at a relatively high frequency.
Rare but serious adverse effects include Stevens-Johnson syndrome (SJS), drug-induced hypersensitivity syndrome (DIHS),
and toxic epidermal necrolysis (TEN). When these conditions are suspected, the suspected drug should be discontinued, anda dermatologist should be consulted. Pancytopenia, myelosuppression, and hepatic dysfunction may also be observed asadverse effects with allergic mechanisms. Most of the adverse effects due to these idiosyncratic reactions occur from 1‒2weeks to 2‒3 months after the start of treatment. Therefore, attention should be given during the early stage of administration.
Adverse effects due to suppression of the nervous system (neurotoxic side effects) include many adverse effects such asdizziness, nystagmus, diplopia, drowsiness, nausea, anorexia, cerebellar ataxia, and psychiatric symptoms. Many of theseadverse effects are dose-dependent.
Some adverse effects are accompanied by long-term use of antiepileptic drugs, such as weight gain, hypertrichosis or hairloss, urolithiasis, cerebellar atrophy, and gingival hyperplasia. Enzyme inducers (phenytoin, carbamazepine, phenobarbital,and primidone) and valproate are risk factors of osteoporosis.
To identify adverse effects of antiepileptic drugs, systematic adverse effect screening has been reported to be useful1).
Representative adverse effects of major antiepileptic drugs are summarized in Table 1.

▪ References
1) Gilliam FG, Fessler AJ, Baker G, et al. Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology.
2004; 62(1): 23-27.

▪ Search formula and secondary reference sources
PubMed search: June 26, 2015(((“Epilepsy/drug therapy” [Majr]) AND “adverse effects” [Subheading])) OR “Anticonvulsants/adverse effects” [Majr] Filters: Randomized
Controlled Trial; Publication date from 2008/01/01 to 2015/12/31; Humans; English; Japanese = 119
Ichushi search: June 29, 2015((((((epilepsy/TH or epilepsy/AL)) and (SH = drug therapy)) and (adverse effects/AB or adverse effects/TI)) and (DT = 2008:2015 and PT = excludingproceedings))) and (PT = Comment, review) = 94

Chapter 763

Table 1. Typical adverse effects of major antiepileptic drugs.
Drug

Idiosyncratic adverse effects

Carbamazepine

rash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS

Clobazamrare

Clonazepam

rare

Ethosuximide
Gabapentin
Lamotrigine

rash, pancytopenia
rarerash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS
rare
rash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS
rash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS

Levetiracetam
Phenobarbital

Phenytoin

Primidone

Valproaterash, liver injury, pancytopenia,
thrombocytopenia, SJS, TEN,
DIHS
pancreatitis, liver injury

Topiramate

rare

Zonisamide

rare

Rufinamide

drug-induced hypersensitivity
syndrome, SJS, status epilepticus,
aggressiveness, QT interval
shortening
attention deficit, hyperactivity
disorder, talkativeness,sleeping disorder, aggressiveness,prolonged QTrash, leukocytopenia, tachypnea,
paresthesia

Stiripentol

Sultiame

Dose-dependent adverse effects
diplopia, nystagmus, dizziness, ataxia,drowsiness, nausea, hyponatremia, cardiac
conduction disturbance or cardiac failure,
reduced cognitive function, hearing
abnormality
drowsiness, ataxia, behavioral disorder,
salvation
drowsiness, ataxia, behavioral disorder,
salvation
drowsiness, abnormal behavior
dizziness, ataxia, drowsiness, myoclonus
drowsiness, dizziness, diplopia, excitability

drowsiness, abnormal behavior, bad mooddizziness, ataxia, drowsiness, reduced
cognitive function

Adverse effects after
long-term use
osteoporosis

weight gain

osteoporosis

diplopia, nystagmus, dizziness, ataxia,drowsiness, peripheral neuropathy, cardiac
conduction disturbance or cardiac failure,
asterixis
dizziness, ataxia, drowsinesscerebellar atrophy,
hypertrichosis, gingival
hyperplasia, osteoporosis

thrombocytopenia, tremor, hyponatremia,
increased ammonia, Parkinson syndrome
anorexia, psychotic symptom, drowsiness,speech symptom, metabolic acidosis,
hypohidrosis
anorexia, psychotic symptom, drowsiness,speech symptom, metabolic acidosis,
hypohidrosis, reduced cognitive function
anorexia, drowsinessweight gain, hair loss,
osteoporosis
urolithiasis, weight loss

osteoporosis

urolithiasis

somnolence, insomnia, anorexia, ataxia

anorexia, drowsiness

SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, DIHS: drug-induced hypersensitivity syndrome[Before prescription, read the package inserts of individual drugs]

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Part IThe Clinical Practice Guidelines for Epilepsy 2018