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Anita Cheng
Brenda Banwell
Simon Levin
Jamie A Seabrook
David Freeman
Michael Rieder


Phenytoin, pharmacokinetics, drug safety, drug dosing



Historically, physicians have been reluctant to maintain infants on phenytoin (PHT) following initial stabilization with intravenous loading doses, as therapeutic blood levels are difficult to achieve with conventional oral doses, and there is concern that high doses will result in toxicity.



To determine the oral dose of PHT required to achieve therapeutic blood concentrations, without clinical toxicity, in the first weeks of life.



Eight infants with seizures were treated with phenytoin from 2 weeks to 3 months of age. Total and free phenytoin concentrations, and urine phenytoin metabolite (p-hydroxyphenytoin) were measured every 2 weeks. Parents were asked to note seizure frequency and complete a questionnaire about possible side effects every 2 weeks.



No infants had seizures and no clinical side effects were noted. Doses required to achieve therapeutic serum concentrations ranged from 10-20mg/kg/day, considerably higher than doses required in adults. Free phenytoin levels were 8-13% of total serum concentrations, similar to ratios reported in adults.



To achieve therapeutic serum phenytoin levels in infants, doses of 10-20 mg/kg/day are required. These higher doses can be safely administered without clinical toxicity.

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1. Rennie J, Boyland G. Neonatal Seizures and their Treatment. Curr Opin Neurol 2003;16:177–81.
2. Bassan H, Bental Y, Shany E, et al. Neonatal seizures: dilemmas in workup and management. Pediatr Neurol 2008 Jun;38(6):415-21.
3. Silverstein FS, Ferriero DM. Off-label use of antiepileptic drugs for the treatment of neonatal seizures. Pediatr Neurol 2008 Aug;39(2):77-9.
4. Rennie J, Boyland G. Treatment of Neonatal Seizures. Arch Dis Child Fetal Neonatal Ed 2007;92:F148–F150.
5. Carmo K, Barr P. Drug treatment of neonatal seizures by neonatologists and paediatric neurologists. J Paediatr Child Hlth 2005;41:313–6.
6. Barth A, Shen J, et al. Neonatal Seizures: Multicenter Variability in Current Treatment Practices. Pediatr Neurol 2007;37:85-90.
7. Herranz J, Armijo J, Arteaga R. Clinical Side Effects of Phenobarbital, Primidone, Phenytoin, Carbamazepine and Valproate during Monotherapy in Children. Epilepsia 1988;29:794-804.
8. Katzung B. Basic and Clinical Pharmacology, Third Edition. Appelton and Lange, Norwalk, Connecticut, 264-266, 1987.
9. Sicca F, Contaldo A, Rey E, Dula O. Phenytoin administration in the newborn and infant. Brain & Development 2000;22:35-40.
10. Neubauer D, Novosel-SeverM. Phenytoin treatment in the newborn and infant. Brain & Development Mar 2001;23(1):75.
11. Albani M, Wernicke I. Oral Phenytoin in Infancy: Dose requirement, Absorption, and Elimination. Pediatric Pharmacology 1983;3:229-236.
12. Albani M. An Effective Dose Schedule for Phenytoin Treatment of Status Epilepticus in Infancy and Childhood. Neuropaediatrics 1977;286- 292.
13. Painter MJ, Scher MS, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. New Engl J Med 1999 Aug 12;341(7):485-9.
14. Suzuki Y, Mimaki T, Cox S, Koepke J, Hayes J, Walson P. Phenytoin age-ose-concentration relationship in children. Therapeut Drug Monitor Apr 1994;16(2):145-50.
15. Loughan PM, Greenwald A, PurtonWW, Arandi J, Watters G, Neims A. Pharmacokinetic Observations of Phenytoin Disposition in the Newborn and Young Infant. Arch Dis Child 1977;52;302-9.
16. Rane A, Wilson J. Clinical Pharmacokinetics in Infants and Children. Clin Pharmacokinet 1976;1:2- 24.
17. Malik S, Painter M, Venkataramanan R, Alvin J. Phenytoin and Phenobarbital Stable Isotope Studies in Neonates. Pediatric Neurology 2003;29:376-80.
18. Merrit H, Putnam T. A New Series of Anticonvulsant Drugs Tested By Experiments on Animals. Arch Neurol Psychiat 1938;39:1003-15.
19. Borofsky L, Lois S, Kutt H. Diphenylhydantoin in Children. Pharmacology and Efficacy. Neurol 1973;23:967-72.
20. Chiba K, Ishizaki T, Miura H, Minagawa K. Michaelis-Menton Pharmacokinetics of Diphenylhydantoin and Application in the Pediatric Age Patient. J Pediat 1980;96(3),479-84.
21. Rane A, Lunde P, Jallings B, Yaffe S, Sjoqvist F. Plasma Protein Binding of Diphenylhydantoin in Normal and Hyperbilirubinemic Infants. J Pediat 1971;78(5):877-82.
22. Bauer L, Blouin R. Phenytoin Michaelis-Menton Pharmacokinetics in Caucasian Pediatric Patients. Clin Pharmacokinet 1983;8:545-9.
23. Bach B, Hansen J, Kampmann J. Disposition of Antipyrine and Phenytoin Correlated with Age and Liver Volume in Man. Clin Pharmacokinet 1981;6:389-96.
24. Blain P, Mucklow J, Bacon C, Rawlins M. Pharmacokinetics of Phenytoin in Children. Br J Clin Pharmac 1981;12:659-61.
25. Fredhom B, Rane A, Persson B. Diphenylhydantoin Binding to Proteins in Plasma and It’s Dependence on Free Fatty Acid and Bilirubin Concentration in Dogs and Newborn Infants. Pediat Res 1975;9:26- 30.
26. Al Za’abi M, Lanner A, Xiaonian X, Donovan T, Charles B. Application of Routine Monitoring Data for Determination of the Population Pharmacokinetics and Enteral Bioavailability of Phenytoin in Neonates and Infants With Seizures. Ther DrugMonit 2006;28:793–9.