1. Carbamazepine overdosage despite low residual plasma concentration?
S. Thümmler1,*
1University Department of Child and Adolescent Psychiatry, Nice Children’s Hospitals CHU-Lenval, Nice, France
*Corresponding author:
Introduction:
Carbamazepine (CBZ) is an anti-epileptic drug frequently used in the treatment of partial epilepsy and the rapid-release CBZ oral suspension is regularly used in the pediatric population.
Case description:
4,5-year old boy
Partial epilepsy since the age of 12 months :
Episodes of clinical absences with pallor and staring,
accompanied by rhythmic theta EEG activity in the left central
temporal region.
EEG otherwise normal, normal MRI.
Normal perinatal history, non-consanguineous parents
Normal psychomotor and language development
Patient’s father also presents partial epilepsy.
Before CBZ treatment:
Valproïc acid inefficient (age months)
Levetiracetam (age 1,5-2 years) with complet seizure controll
Levetiracetam complicated by progressive behavioral troubles as irritability and choleric attacks
CBZ treatment (recommended dose mg/kg/d):
CBZ oral suspension
CBZ (9mg/kg/d) since the age of 24 months:
1. Complete regression of behavioral abnormalities
2. Complete seizure control for 1 year despite low residual
CBZ level of 2.3 mg/l (normal therapeutic value 4-10 mg/l),
Seizures and increase of CBZ dose at the age of 3
CBZ 14 mg/kg/d: residual plasma level 2.9 mg/l
CBZ 15 mg/kg/d (100mgx2): fatigue and general alteration 2 hours after the morning CBZ dose, for about 10 days,
totally reversible after decreasing CBZ dose,
therefore suggestive of CBZ overdosage
-= CBZ oral suspension only partial seizure control with side
effects upon dose increase
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Fig. 2. CBZ dose, galenic formulation and residual CBZ plasma levels. The patient presented clinical symptoms suggestive of overdosage during CBZ oral suspension treatment 15mg/kg/d despite low residual plasma level. Epilepsy has been controlled by high-dose CBZ extended-release (XP) tablets, without any side effects.
CBZ tablets
No symptoms suggestive of overdosage
Increased up to 22 mg/kg/j
Low therapeutic plasma level of 4.2 mg/l (N 4-12)
Persistence of some seizures
CBZ XP tablets (extented-released)
Complete seizure control at the same dose as CBZ tablets for 10 months
Residual plasma concentration of 4.8 mg/l.
Necessity of dose increase at 4,5 years (seizures)
28 mg/kg/d
Residual plasma level 6,7 mg/l
Discussion:
Partial epilepsy controlled by extended-release CBZ
Despite high-dose CBZ, residual plasma level in the lower therapeutic range suggesting rapid or ultra-rapid metabolism
Symptoms of CBZ overdosage 2 hours after administration of rapid-release oral suspension, but not with CBZ tablets
Case description consistent with the observation of peak CBZ plasma concentrations 2 hours after the administration of oral suspension, 12 hours after tablets and 24 hours after extended-release CBZ tablets [1]
Conclusion:
In contrast to CBZ oral solution, CBZ tablets at the same dose might be efficient for seizure control. In addition, symptoms of CBZ overdosage might be observed despite low residual CBZ plasma level during oral solution treatment as the consequence of very rapid metabolisation. Nevertheless, the galenic formulation of tablets is not recommended for the use in small children and patients with swallow difficulties, and there is currently no extended-release formulation available for this population.
Fig. 1. CBZ treatment between the age 2 to 4,5 years. Dose, galenic formulation, residual CBZ plasma level, seizure episodes. Despite high-dose CBZ, residual plasma concentration are only moderately elevated (therapeutic range 4-12 mg/l).
REFERENCES: [1] Vidal 2014, 89th edition, ISBN 13: , 2014.