Pharmacokinetics in children

The following pharmacokinetic parameters are reported (Smit 1999 en Al Za’abi 2006)

Age	n=	Cmax (mg/l)	Vd (l/kg)	Cl (ml/min/kg)	t1/2 (hour)
4-12 year	10	6,23-13,87	0,60-1,07 (mean 0,88)	-	-
1-123 days PNA (23-42,2 weeks GA)	83	-	0,33-2,14 (mean 1,03)	0.03-2.32 (mean 0,38)	2,54-205 (mean 32,8)

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

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Persistent status epilepticus
Intravenous 1 month up to 18 years [2] [5] [9] 20 mg/kg/dose, bolus in 20 min. Max single dose: 1.500 mg/dose. Directions for administration: Can cause arrhythmia and must therefore be administered while monitoring the heart rate. An additional loading dose of 10 mg/kg in 10 min can be considered.

Epilepsy: partial attacks, generalized tonic-clonic episodes, maintenance after status epilepticus
Oral 1 month up to 2 years [1] [6] [7] [8] 10 - 15 mg/kg/day in 2 - 3 doses. 2 years up to 10 years [1] [6] [7] [8] 6 - 10 mg/kg/day in 2 - 3 doses. 10 years up to 18 years [1] [6] [7] [8] 4 - 5 mg/kg/day in 2 - 3 doses.

Neuropathic pain
Oral 1 month up to 18 years [4] 4 - 7 mg/kg/day in 2 doses.

Arrhythmias

Oral 1 month up to 2 years [1] Initial dose: 15 mg/kg/day in 3 doses. Maintenance dose: Depending on the levels 8 - 12 mg/kg/day in 2 - 3 doses. Treatment by or after consultations with a paediatric specialist (paediatric cardiologist) who has experience using phenytoin for this indication. 2 years up to 18 years [1] [10] [11] Initial dose: 15 mg/kg/day in 2 - 3 doses. Maintenance dose: 4 - 6 mg/kg/day in 2 - 3 doses. Treatment by or after consultations with a paediatric specialist (paediatric cardiologist) who has experience using phenytoin for this indication. Intravenous 1 month up to 18 years Loading 1.25 mg/kg/dose, bolus in 5 min. repeat to cumulative maximum of 15 mg/kg (= loading dose in 1 hour).. Treatment by or after consultations with a paediatric specialist (paediatric cardiologist) who has experience using phenytoin for this indication.

Renal impaiment in children > 3 months

Plasma protein binding may decrease with renal impairment. With reduced protein binding, the free fraction increases (decrease in the total concentration while the free concentration remains the same). With a normal total concentration, intoxication symptoms may nevertheless occur.

Creatinine clearance less than 30 ml / min:
dose based on the free phenytoin concentration

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

Concentration-dependent side effects: nystagmus, ataxia, sedation. Side effects in chronic use: skin abnormalities, gingival hyperplasia, can reduce cognition. [Rademaker 2007]

Especially in children: Impairment of thyroid function [SmPC Phenhydan].

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

Contra-indications

No information available on specific contra indications in children.

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

Do not combine with products that contain calcium, including via feeding tubes. Watch out for poor bioavailability in neonates after oral administration. First signs of overdose: Ataxia, nystagmus, behavioural disorders.[Rademaker 2007]

Non-linear kinetics: increase dose in smaller and smaller steps.
Therapeutic plasma concentration Epilepsy: 10-20 mg/l; Non-protein bound concentration: 1-2 mg/l.
Therapeutic plasma concentration Arrhythmia: 8-18 mg/l, Non-protein bound concentration: 0.8-1.8 mg/l [Rademaker 2007].

Phenytoin may exacerbate Dravet's syndrome [NVN 2017].

The occurrence of serious adverse events may involve abnormal drug metabolism. CYP2C9 may determine the variation in response. Genotyping may be considered.

Patients with HLA-B*1502 appear to be at high risk for Stevens-Johnson syndrome and toxic epidermal necrolysis. Do not use in this group unless there are no alternatives.

Interactions

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

• NERVOUS SYSTEM
• ANTIEPILEPTICS

ANTIEPILEPTICS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

Barbiturates and derivatives
	Phenobarbital Related Medicines Menu">	N03AA02

Succinimide derivatives
	Ethosuximide Related Medicines Menu">	N03AD01

Carboxamide derivatives
	Carbamazepine Related Medicines Menu">	N03AF01

Fatty acid derivatives
	Valproic acid (sodiumvalproate) Related Medicines Menu">	N03AG01

Other antiepileptics
	Lamotrigine Related Medicines Menu">	N03AX09
	Levetiracetam Related Medicines Menu">	N03AX14

References

1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
2. Waardenburg van DA, et al., Richtlijn status epilepticus kinderen ouder dan één maand., Nederlandse Vereniging voor Kindergeneeskunde, Augustus 2005
3. Apotex Europe BV, SPC Diphantoine (RVG 02975/08050/08051/02976) 28-06-2017, www.geneesmiddeleninformatiebank.nl
4. Kamps WA et al, Werkboek ondersteundende behandeling kinderoncologie, VU Uitgeverij, 2005
5. Kruiff de CC. et al, Richtlijn Epileptische aanvallen/status epilepticus > 1 maand., Nederlandse Vereniging voor Kindergeneeskunde , 2012
6. Thilothammal N, et al, Comparison of phenobarbitone, phenytoin with sodium valproate: randomized, double-blind study, Indian Pediatr, 1996, 33, 549-55
7. Pal DK, et al, Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India, Lancet, 1998, 351, 19-23
8. Canadian Study Group for Childhood Epilepsy., Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy, Epilepsia, 1998, 39, 952-9
9. Agarwal P, et al, Randomized study of intravenous valproate and phenytoin in status epilepticus, Seizure, 2007, 16, 527-32
10. Garson A Jr, et al, Control of late postoperative ventricular arrhythmias with phenytoin in young patients, Am J Cardiol, 1980, 46, 290-4
11. Kavey RE, et al, Phenytoin therapy for ventricular arrhythmias occurring late after surgery for congenital heart disease, Am Heart J, 1982, 104, 794-8
12. Smit A, et al, Practical management of therapeutic diphenylhydantoin concentrations in children, S Afr Med J, 1999, 89, 1092-7
13. Al Za’abi M, et al, Application of routine monitoring data for determination of the population pharmacokinetics and enteral bioavailability of phenytoin in neonates and infants with seizures, Ther Drug Monit, 2006, 28, 793-9
14. NVN, Richtlijn epilepsie; Status epilepticus; bij kinderen; Flowchart kinderen, 2017

Changes

Therapeutic Drug Monitoring

Overdose