Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Oxcarbazepine

Generic name
Oxcarbazepine
Brand name
ATC Code
N03AF02

Pharmacokinetics in children

Little enzyme induction. Measurement of plasma concentration is possible for optimization of therapy in certain cases, but is not done routinely. There is no validated therapeutic range of the plasma concentration of the metabolite 10-hydroxycarbazepine. A range of 12-30 mg/l is recommended by Rademaker, but 7-35 mg/l (by NVZA) or even broader ranges are listed. The NVZA considers plasma concentrations > 50 mg / l as a toxic concentration.

Rey (2004) found the following mean kinetic parameters of the active 10-monohydroxymetabolite MHD in children from 2 to 12 years.

  2-5 years (n=13) 6-12 years (n-17)
t1/2 4,8-6,7 hours 7,2-9,3 hours
tmax 3-4 hours 3-4 hours

The clearance of MHD decreases as the body weight increases from 1,45 ml / min / kg (15 kg), to 1 ml / min / kg (35 kg) and 0,85 ml / min / kg (50 kg) in children from 3 years of age (Sugiyama 2015). An mean clearance of 1,18 ml / min / kg was found in children aged 2-42 months (Northam 2005).
Northam 2005 also found an mean volume of 1,45 L / kg.

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dose recommendation of formulary compared to licensed use (on-label versus off-label)

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Available formulations

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Dosages

Epilepsy
  • Oral
    • 1 month up to 6 years
      • Initial dose: 10 - 20 mg/kg/day in 2 doses. Max: 300 mg/dose.
      • Maintenance dose: if indicated increase dose approximately every week with max 10 mg/kg/day to 20 - 60 mg/kg/day in 2 - 3 doses. Max: 60 mg/kg/day.

      • Consider the lower starting dose for children <3 months of age and for children not on enzyme-inducing comedication to avoid toxicity.

    • 6 years up to 18 years
      • Initial dose: 8 - 10 mg/kg/day in 2 doses. Max: 300 mg/dose.
      • Maintenance dose: Increase dose if indicated approximately every week by 10 mg/kg/day to 10 - 46 mg/kg/day in 2 - 3 doses. Max: 46mg/kg/day, but not exceeding 2.4 g/day.

      • In exceptional cases, dosing can be higher based on plasma or serumlevels.
Epilepsy, focal seizures
  • Oral
    • 2 years up to 10 years
      • Dose after stopping carbamazepine 15 - 35 mg/kg/day in 2 - 3 doses.

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Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2
No need for dose adjustment
GFR 30-50 ml/min/1.73 m2
No need for dose adjustment
GFR 10-30 ml/min/1.73 m2
50% of initial daily dose, then increase slowly upon clinical efficacy.
GFR < 10 ml/min/1.73 m2
A general recommendation is not provided.
Clinical consequences

Half-life and AUC of the pharmacologically active monohydroxycarbazepine metabolite are increased in patients with impaired renal function. This increases the risk of side effects.
Side effects include tiredness, dizziness, headache, drowsiness, double vision, nausea and vomiting. Hyponatraemia may occur as a result of an ADH-like effect. It occurs in 10-25% of patients. It usually proceeds without symptoms, but in rare cases may be accompanied by vomiting, headache, confusion, neurological disorders and lethargy.

Patients on dialysis

It is unknown whether oxcarbazepine is removed by hemodialysis or peritoneal dialysis.

For intermittent hemodialysis / continuous venovenous hemodialysis / hemo (dia) filtration / peritoneal dialysis:
halve the initial dose, then gradually increase the dose based on plasma concentration levels up to the intended clinical effect.

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The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

In general, the safety profile is the same for children and adults.

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The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications in children

Do not use oxcarbazepine in generalized tonic-clonic seizures with myocloni or absences because they can have an adverse effect in these types of seizures.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Dermatological reactions

Very rarely, severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported in connection with oxcarbazepine use. Patients with severe skin reactions may require in-patient treatment because these conditions are life-threatening and can rarely lead to death. Severe skin reactions associated with oxcarbazepine have been observed in both children and adults.

Patients of Asian descent (other than Japanese or Korean descent) with HLA-B * 1502 appear to have a high risk of Stevens-Johnson syndrome.  Genotyping is recommended in this patient group before (or immediately after) the start of the medication.

Risk of exacerbation of seizures

In connection with the use of oxcarbazepine, a risk of exacerbation of seizures was reported. This risk affects children in particular. If there is an exacerbation of seizures, stop taking oxcarbazepine.

Hypothyroidism

Hypothyroidism is a side effect of oxcarbazepine. Given the importance of thyroid hormones for child development after birth, monitoring of thyroid function during treatment with oxcarbazepine is recommended for the paediatric age group.

A risk of worsening seizures has been reported with the use of Trileptal. The risk of seizure aggravation is mainly seen in children.

"Oxcarbazepine can aggravate Dravet syndrome [Wallace et al. (2016) and Guerrini et al (1998 and 1999)]

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Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

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Barbiturates and derivatives
N03AA02
N03AA03
Hydantoin derivatives
N03AB02
Succinimide derivatives
N03AD01
Benzodiazepine derivatives
N03AE01
Carboxamide derivatives
N03AF01
N03AF03
Fatty acid derivatives
N03AG01
N03AG04
Other antiepileptics
N03AX23
N03AX24
N03AX10
N03AX26
N03AX18
N03AX09
N03AX14
N03AX22
N03AX16
N03AX17
N03AX03
N03AX11
N03AX15

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References

  1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
  2. NVN Werkgroep Richtlijnen Epilepsie, Epilepsie. Richtlijnen voor diagnostiek en behandeling, Herziene, tweede versie, januari 2006
  3. Dura, SmPC Oxcarbazepin 150mg/300mg/600mg Filmtabletten (64607.00.00), 09/2017
  4. Online GL. Gelbe Liste Online, https://www.gelbe-liste.de/, Accessed July 2, 2018
  5. Novartis, SmPC Trileptal 150mg/300mg/600mg Filmtabletten (47357.00.00), 11/2018
  6. Norvatis, SmPC Trileptal 60mg/ml Suspension zum Einnehmen (51794.00.00), 04/2018
  7. Neuraxpharm, SmPC Oxcarbazepin 150mg/300mg/600mg Filmtabletten(88673.00.00), 05/2017
  8. Hexal, SmPC Oxcarbazepin 60mg/ml Suspension zum Einnehmen (78624.00.00), 12/2014
  9. Desitin, SmPc Timox extent 150mg/300mg/600mg Tabletten mit veränderter Wirkstofffreisetzung (65230.00.00), 03/2018
  10. Desitin, SmPc Apydan extent 150mg/300mg/600mg Tabletten mit veränderter Wirkstofffreisetzung (65225.00.00), 12/2018
  11. Pina-Garza, J. E. et al, Oxcarbazepine adjunctive therapy in infants and young children with partial seizures, Neurology, 2005, 65(9), 1370-5
  12. Guerreiro, M. M. et al., A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy., Epilepsy Res, 1997, 27(3), 205-13
  13. Glauser, T. A. et al., Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group., Neurology, 2000, 54(12), 2237-44
  14. Donati, F. et al., The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures., 2007, 16(8), 670-9
  15. Coppola, G. et al., Levetiracetam or oxcarbazepine as monotherapy in newly diagnosed benign epilepsy of childhood with centrotemporal spikes (BECTS): an open-label, parallel group trial., Brain Dev, 2007, 29(5), 281-4
  16. Novartis Pharma B.V., SmPC Trileptal (RVG 24750- 24752) 16-11-2018, www.geneesmiddeleninformatiebank.nl
  17. Nederlandse Vereniging voor ZiekenhuisApothekers, TDM monografie oxcarbazepine, 2014
  18. Nederlandse Vereniging voor Neurologie, Epilepsiesyndromen (bij kinderen) & anti-epileptica, 09 juli 2015
  19. Guerrini R. et al, Antileptic Drug-induced Worsening of Seizures in Children, Epilepsia, 1998, 39(suppl.3), SZ-SIO
  20. Wallace A. et al, Pharmacotherapy for Dravet syndrome, Pediatr. Drugs, 2016, Jun;18(3), 197-208
  21. Nederlandse Vereniging voor Neurologie, Epilepsiesyndromen (bij kinderen) & anti-epileptica, 09 juli 2015

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Changes

Changes