Pharmacokinetics in children

The following pharmacokinetic parameters in neonates are observed (Gonzalez 1993, Marsot 2014 en Touw 2000):

t½ (h)	114.2 ± 43 (1-10 days PNA) 73.19 ± 24.17 (11-30 days PNA) 41.23 ± 13.95 (31-70 days PNA)
Cl (ml/kg/h)	4.3 (2.1-6.4)
Vd (l/kg)	0.71 (0.34-1.24)

Hypothermia does not affect the pharmacokinetics of phenobarbital in neonates (van den Broek 2012, Filippi 2011, Shellhaas 2013 en Šíma 2015), although the severity of asphyxia seems to lead to a decrease in clearance of phenobarbital. (Pokorna et al. 2019).
Clearance of phenobarbital is increased in neonates and infants on ECMO (mediaan 6,5-8,1 ml/uur/kg resp.) (Pokorna et al. 2018).

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

Neonatal convulsions; status epilepticus

Intravenous Premature infants Gestational age < 36 weeks [22] [23] 20 mg/kg/dose, once only. Administer a second dose of 10 mg/kg after one hour if necessary. If the seizures persist: administer another dose of 10 mg/kg if necessary.. If the seizures persist: give midazolam Blood concentration: 10-40 mcg/ml Because of the risk of accumulation: determine the plasma concentration on Day 3 after starting. Titrate the dose depending on the clinical picture and the plasma concentration. Full-term neonates Gestational age ≥ 36 weeks [22] [23] 20 mg/kg/dose, once only. Administer a second dose of 10 mg/kg after one hour if necessary. If the seizures persist: administer another dose of 10 mg/kg if necessary.. If the seizures persist: give midazolam Blood concentration: 10-40 mcg/ml Because of the risk of accumulation: determine the plasma concentration on Day 3 after starting. Titrate the dose depending on the clinical picture and the plasma concentration. 1 month up to 18 years [1] [24] [25] 20 mg/kg/dose, as required repeat. Administer slowly over 15 min

Neonatal epileptic seizures

Intravenous Neugeborene Gestational age ≥ 36 weeks and ≥ 2.5 kg [2] [22] [23] 20 mg/kg/dose, once only. Bei wiederkehrenden Anfällen: 10 mg/kg/Dosis, bei Bedarf noch einmal wiederholen. Bei wiederkehrenden Anfällen: Midazolam verabreichen Blutspiegel: 20-40 mcg/ml In Verbindung mit dem Akkumulationsrisiko: Plasmakonzentration am 3. Tag nach Beginn bestimmen. Dosis je nach klinischem Bild und Plasmakonzentration titrieren

Epilepsy (all seizures), maintenance after neonatal convulsions /status epilepticus

Oral Premature infants Gestational age < 36 weeks [2] [14] [15] [18] [22] [23] Postnatal age 1 to 14 days: 2.5-5 mg/kg/day in 1 to 2 doses Postnatal age 14 to 28 days:  6 mg/kg/day in 1 to 2 doses Continuation of antiepileptic drugs after the acute phase (asphyxia) appears to be indicated where the MRI reveals structural abnormalities that may be epileptogenic Trough level 10-40 mcg/ml Neonates Gestational age ≥ 36 weeks and ≥ 2.5 kg [2] [14] [15] [18] [22] [23] With and without hypothermia: Postnatal age 1 to 14 days: 2.5-5 mg/kg/day in 1 to 2 doses Postnatal age 14 to 28 days:  6 mg/kg/day in 1 to 2 doses Continuation of antiepileptic drugs after the acute phase (asphyxia) appears to be indicated where the MRI reveals structural abnormalities that may be epileptogenic. Trough level: 10-40 mcg/ml 1 month up to 2 years [1] [3] 7 - 10 mg/kg/day in 1 - 2 doses. Trough level: 10-40 mcg/ml 2 years up to 10 years [1] [3] 3 - 7 mg/kg/day in 1 - 2 doses. Trough level: 10-40 mcg/ml 10 years up to 18 years [1] [3] 2 - 3 mg/kg/day in 1 - 2 doses. Trough level: 10-40 mcg/ml Intravenous Premature infants Gestational age < 36 weeks [14] [15] [18] [22] [23] Postnatal age 1 to 14 days: 2.5-5 mg/kg/day in 1 to 2 doses Postnatal age 14 to 28 days:  6 mg/kg/day in 1 to 2 doses Continuation of antiepileptic drugs after the acute phase (asphyxia) appears to be indicated where the MRI reveals structural abnormalities that may be epileptogenic Trough level 10-40 mcg/ml Neonates Gestational age ≥ 36 weeks and ≥ 2.5 kg [14] [15] [18] [22] [23] With and without hypothermia: Postnatal age 1 to 14 days: 2.5-5 mg/kg/day in 1 to 2 doses Postnatal age 14 to 28 days:  6 mg/kg/day in 1 to 2 doses Continuation of antiepileptic drugs after the acute phase (asphyxia) appears to be indicated where the MRI reveals structural abnormalities that may be epileptogenic. Trough level: 10-40 mcg/ml 1 month up to 2 years [1] [3] 7 - 10 mg/kg/day in 1 - 2 doses. Trough level: 10-40 mcg/ml 2 years up to 10 years [1] [3] 3 - 7 mg/kg/day in 1 - 2 doses. Trough level: 10-40 mcg/ml 10 years up to 18 years [1] [3] 2 - 3 mg/kg/day in 1 - 2 doses. Trough level: 10-40 mcg/ml

CAUTION:
Route of administration not applicable 0 years up to 18 years Therapeutic plasma concentration: 15-30 mg/l

Non-opioid-associated neonatal abstinence syndrome (NAS)

Intravenous Premature infants Gestational age < 37 weeks [21] [23] Initial dose 10 mg/kg/dose, as required repeat. Maintenance dose: depending on the Finnegan score: Finnegan Score Dose 8-10 6 mg/kg/day in 3 doses 11-13 8 mg/kg/day in 3 doses 14-16 10 mg/kg/day in 3 doses > 17 12 mg/kg/day in 3 doses Increase the dose if the FS has increased 3 consecutive times. Also increase the dose if the FS remains in the same range for 48 hours (i.e. does not decrease). If the FS drops to a lower range within 48 hours, reduce the dose. If the FS is < 8 for 48 hours, phase out the dose as follows: 6 mg/kg/24 hours in 3 doses 4 mg/kg/24 hours in 2 doses 2 mg/kg/24 hours in a single dose and then stop. . Full-term neonates Gestational age ≥ 37 weeks [21] [23] Initial dose 10 mg/kg/dose, as required repeat. Maintenance dose: depending on the Finnegan score: Finnegan Score Dose 8-10 6 mg/kg/day in 3 doses 11-13 8 mg/kg/day in 3 doses 14-16 10 mg/kg/day in 3 doses > 17 12 mg/kg/day in 3 doses Increase the dose if the FS has increased 3 consecutive times. Also increase the dose if the FS remains in the same range for 48 hours (i.e. does not decrease). If the FS drops to a lower range within 48 hours, reduce the dose. If the FS is < 8 for 48 hours, phase out the dose as follows: 6 mg/kg/24 hours in 3 doses 4 mg/kg/24 hours in 2 doses 2 mg/kg/24 hours in a single dose and then stop. .

Sedation

Intravenous Premature infants Gestational age < 37 weeks [23] 5 - 10 mg/kg/dose, once only. There is no support from the literature for this indication.  Phenobarbital is occasionally used for this indication when midazolam and morphine are less desirable (due to mucus formation and apnoea respectively). Full-term neonates Gestational age ≥ 37 weeks [23] 5 - 10 mg/kg/dose, once only. There is no support from the literature for this indication.  Phenobarbital is occasionally used for this indication when midazolam and morphine are less desirable (due to mucus formation and apnoea respectively).

Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

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

Highly sedative (does cause habituation). Behavioral disorders in the form of irritability, aggression, sleep disturbance and hyperactivity may occur.

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

Contra-indications in children

Hyperkinesia 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

IN CHILDREN AGED LESS THAN 5 YEARS:
The IV liquid contains propylene glycol and alcohol. There are no alternative products that either do not contain these additives or contain less of them. Be alert for possible propylene glycol intoxication in neonates and young children with unexplained metabolic acidosis. The strong liquid for injection of 10 mg/ml should not be used in neonates because of the extremely high propylene glycol load.

Check the hepatic and renal function at the start of therapy and if there are symptoms. Adjust the dose in liver function disorders.
Accumulation may occur at the start of maintenance dosing, especially in children under 1 year of age. The dosage should be titrated according to the clinical picture and the plasma concentration determination (Day 3 after starting)
First sign of overdose: sedation.

The solution is incompatible with PVC (e.g. feeding tubes). Clean the dosing injection for the solution with warm soapsuds, not water.

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.

Hydantoin derivatives
	Phenytoin Related Medicines Menu">	N03AB02

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. Waardenburg van DA, et al, Richtlijn status epilepticus kinderen ouder dan één maand, Nederlandse Vereniging voor Kindergeneeskunde, Augustus 2005
2. Smit LS et al, Richtlijnen voor behandeling van neonatale epileptische aanvallen, Nederlands Vlaamse Werkgroep Neonatale Neurologie van de sectie Neonatologie van de NVK en van de Nederlandse Vereniging voor Kinderneurologie, Nieuwe aangepaste versie juni 2012
3. Werkgroep Richtlijnen Epilepsie., Epilepsie. Richtlijnen voor diagnostiek en behandeling., Nederlandse Vereniging voor Neurologie en de Nederlandse Liga tegen Epilepsie, Herziene, tweede versie, januari 2006
4. AVOXA, ABDA-Datenbank Wirkstoffdossier Phenobarbital, 04/2011
5. Zuccotti, G.V. and V. Fabiano, Safety issues with ethanol as an excipient in drugs intended for pediatric use, Expert Opin Drug Saf, 2011, 10(4), 499-502
6. American Academy of Pediatrics, Ethanol in liquid preparations intended for children, Pediatrics, 1984, 73(3), 405-7
7. MacDonald, M.G., et al., Propylene glycol: increased incidence of seizures in low birth weight infants, Pediatrics, 1987, 79(4), 622-5
8. Glasgow, A.M., et al., Hyperosmolality in small infants due to propylene glycol, Pediatrics, 1983, 72(3), 353-5
9. Arulanantham, K. and M. Genel, Central nervous system toxicity associated with ingestion of propylene glycol, J Pediatr, 1978, 93(3), 515-6
10. neuraxpharm Arzneimittel , SmPC Phenobarbital-neuraxpharm® (3699.99.99/ 3699.98.99), 03/2015
11. DESITIN Arzneimittel , SmPC Luminal® Injektionslösung (6245807.00.00), 02/2015
12. DESITIN Arzneimittel , SmPC Luminal®/Luminaletten® (3699.98.99/ 3699.99.99), 12/2016
13. DESITIN Arzneimittel, SmPC Luminal®/Luminaletten® (3699.98.99/3699.99.99), 12/2016
14. Gonzalez AC et al. , Dosage programming of phenobarbital in neonatal seizures., J Clin Pharm Ther., 1993, Aug;18(4), 267-70
15. Marsot A et al. , Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach., Fundam Clin Pharmacol., 2014, Aug;28(4), 465-71
16. Touw DJ et al. , Clinical pharmacokinetics of phenobarbital in neonates., Eur J Pharm Sci., 2000, Dec;12(2), 111-6
17. van den Broek MPH et al. , Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach. , Clin Pharmacokinet., 2012, Oct 1;51(10), 671-9
18. Filippi L et al. , Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole body hypothermia., Epilepsia, 2011, Apr;52(4), 794-801
19. Shellhaas RA et al. , Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia.
20. Šíma M et al. , Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns. , Physiol Res., 2015, 64 Suppl 4, S513-9
21. Surran B et al. , Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial., J Perinatol., 2013, Dec;33(12), 954-9
22. Völler S et al. , Model-based clinical dose optimization for phenobarbital in neonates: An illustration of the importance of data sharing and external validation., Eur J Pharm Sci., 2017, Nov 15;109S, S90-S97
23. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie, Expert opinie dd 13 nov 2018
24. NICE, Epilepsies: diagnosis and management, www.nice.org.uk , 2012, January
25. Malamiri RA et al., Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial, Eur J Paediatr Neurol, 2012, 16 (5), 536-41
26. Pokorná et al, Severity of asphyxia is a covariate of phenobarbital clearance in newborns undergoing hypothermia., J Matern Fetal Neonatal Med, 2019, 32(14), 2302-2309
27. Pokorná et al, Phenobarbital pharmacokinetics in neonates and infants during extracorporeal membrane oxygenation, Perfusion, 2018, May 33 ( 1 suppl), 80-86

Changes

Therapeutic Drug Monitoring

Overdose