Pharmacokinetics in children

In (premature) neonates (30-41 weeks gestation age, 3-31 days postnatal) the following ranges of pharmacokinetic parameters were reported after a single dose of 7.5-50 mg / kg (Brachet-Liermain et al 1977, Gal et al. 1988, Irvine-Meek et al. 1982):

	n=
t½	30	9-67 hours
Cl	8	5.5-28 ml/hour/kg
Vd	8	0.28-0.47 l/kg

The following mean pharmacokinetic parameters have been found after oral administration of valproic acid in 437 children aged 1 month to 18 years (Cloyd et al. 1983, Kriel et al. 1986, Panomvana Na Ayudhya, et al 2006, Rodrigues et al. 2018, Serrano et al. al. 1999):

Tmax	1.3-4 uur
t½	6.4-13 uur
Cl	9-27 ml/uur/kg
Vd	0.16-0.4 l/kg

Clearance is highest in children between 1 and 2 years old (approx. 20 ml / hour / kg). As children get older, the clearance decreases, up to the age of 12, then adult values are found (Ding et al. 2015, Serrano et al. 1999, Taylor et al. 2007). In addition, clearance also increases with increasing dose (Kriel et al. 1986).

Parameters after oral administration are similar to the pharmacokinetic parameters after intravenous administration (Cook et al. 2016, Taylor et al. 2007).

 

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

Epilepsy, primary generalized and focal attacks

Oral 1 month up to 18 years [17] [22] [34] Initial dose: Sodium valproate: 7 - 10 mg/kg/day in 1 - 3 doses. Maintenance dose: Increase the initial dose weekly based on effect with dose increment of 5-10 mg/kg/day to 10 - 40 mg/kg/day in 1 - 3 doses. Max: 60 mg/kg/day. Directions for administration: Administer during meals. Do not combine with carbonated drinks. Give the slow-release tablet (Depakine Chrono) in 1-2 doses/day. (doses at higher end of range in 2 times daily) Higher doses of valproic acid may be required in highly treatment-resistant forms of epilepsy. In the literature, doses up to 100 mg / kg / day have been used safely and effectively (Hurst 1987, Ohtsuka et al. 1992). Slowly phase out, usually in at least 2-3 months (expert opinion NVN) Rectal 1 month up to 18 years Valproic acid: The rectal dose is equivalent to the oral dose Intravenous 1 month up to 18 years [3] Initial dose: Sodium valproate: 7 - 10 mg/kg/dose, bolus. Maintenance dose: titrate upon effect 10 - 40 mg/kg/day in 2 - 3 doses. Max: 2.500 mg/day. Alternatively as continuous infusion: 1-2 mg/kg/hour. Children who already use oral valproic acid: IV dose is the same as the oral dose.

Bipolar depression

Oral 12 years up to 18 years [15] [16] [29] [31] [35] [39] [43] [46] Initial dose: Sodium valproate: 10 mg/kg/day in 1 - 2 doses. Max: 500 mg/day. Maintenance dose: Increase the starting dose based on bloodlevels every 3 days to max 35 mg/kg/day in 1 - 2 doses. Max: 1.000 mg/day. Directions for administration: Administer during meals. Do not combine with carbonated drinks. Therapeutic Drug Monitoring: acute episode 80-120 mg/l,  in maintenance phase: 60-80 mg/L (NVZA 2019) The effectiveness of valproic acid in the treatment of bipolar depression has not been demonstrated compared to placebo. An effect has been seen in comparison with risperidone or other similar medicines. In individual cases, valproic acid can be effective in bipolar depression.   For the treatment of bipolar depression, valproic acid should be prescribed by a specialist in child and adolescent psychiatry. The dose should be determined individually, the lowest effective dose should be used.

Persistent status epilepticus
Intravenous 1 month up to 18 years [5] [8] [12] [23] [38] [40] [44] [45] Sodium valproate: 20 mg/kg/dose allow to run in over 4 minutes. Repeat if indicated

Migraine prophylaxis

Oral 5 years up to 18 years [10] [11] [13] [21] [25] [26] [30] [32] [42] Initial dose: Sodium valproate: 5 - 10 mg/kg/day in 1 - 2 doses. Maintenance dose: Increase initial dose weekly based on effect with dose increments of 5-10 mg/kg/day to max 30 mg/kg/day in 1 - 2 doses. The studies by (Apostol et al. 2008, Apostol et al. 2009) show that valproic acid is not more effective in migraine prophylaxis than placebo. Nevertheless, valproic acid can be considered in individual cases.

CAVE: PREGNANCY PREVENTION PROGRAMM FOR THIS DRUG
Route of administration not applicable 9 years up to 18 years [17] [28] See the warnings and precautions section.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Dose adjustment not needed

GFR 30-50 ml/min/1.73 m2

A lower dose may be required; valproic acid is adjusted based on its effect and side effects.

GFR 10-30 ml/min/1.73 m2

A lower dose may be required; valproic acid is adjusted based on its effect and side effects.

GFR < 10 ml/min/1.73 m2

A general recommendation is not provided

Clinical consequences

After severe overdose, coma with muscle hypotonia, hyporeflexia, miosis, metabolic acidosis and respiratory disorders have been reported. Very high plasma concentration can lead to convulsions and can be fatal.

Patients on dialysis

Hemodialysis / CVVH and peritoneal dialysis: dosing according to the effect, the side effects and the plasma concentration; for intermittent hemodialysis, administer a single dose after dialysis.

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

Sometimes affects hair growth, bodyweight and thrombocytes (e.g. thrombocytopenia, thrombocytopathia). In polytherapy, there have been rare (and potentially fatal) liver abnormalities.

Children under 3 years of age (particularly patients with intellectual disabilities) have a greater risk of severely impaired hepatic function, which can involve hyperammonaemia and somnolence

Psychiatric diseases as aggression, agitation, attention disorders and abnormal behaviour, psychomotor hyperactivity, learning disability were mainly observed in children.(SmPC Ergenyl)

Very rare occured Enuresis nocturna in children. (SmPC Orfiril)

 

 

 

 

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

Gastro-resistant tablets should preferably be used because there may be gastrointestinal complaints at the start of the therapy. For doses higher than 40 mg/kg/day, check blood count and liver function regularly. 

The risk of hepatotoxicity is greater when combined with other antiepileptic drugs and with salicylates, in particular in children aged less than three. For that reason, monotherapy is recommended in children aged < 3 years and the use of salicylates is not recommended. If epilepsy in this age group involves cerebral abnormalities, psychological retardation, genetic degeneration or known metabolic disorders and/or impaired hepatic function, the risk of hepatotoxicity is greatest above all during the first six months of treatment. Be aware of the possibility of drowsiness and episodes during the first 6 months.

The occurrence of severe pancreatitis, which can be fatal, has been reported very rarely. The risk of a fatal outcome is highest in young children and decreases with age. Possible risk factors for the development of severe pancreatitis are severe forms of seizures or severe neurological disorders with simultaneous anticonvulsant combination therapy (SmPC Convulex).

Be cautious with use of valproic acid in liver diseases, possible coagulation disorders, suspected metabolic disease and in children under 2 years of age due to the risk of Reye syndrome.

First signs of overdose: tremors, drowsiness.

For women of childbearing age, at least one reliable contraceptive method must be used. Valproate has a high teratogenic potential. Children exposed to valproate in the womb are at high risk of congenital malformations and neurological developmental disorders. (SmPC Orfiril/Ergenyl)

Interactions

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

Barbiturates and derivatives
	Phenobarbital Related Medicines Menu">	N03AA02

Hydantoin derivatives
	Phenytoin Related Medicines Menu">	N03AB02

Succinimide derivatives
	Ethosuximide Related Medicines Menu">	N03AD01

Carboxamide derivatives
	Carbamazepine Related Medicines Menu">	N03AF01

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

References

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