Dosage Recommendations for Anticonvulsants Employed in Neonatal Seizures
Jeffrey L. Segar, MD and Sarah B. Tierney, PharmD
Peer Review Status: Internally Peer Reviewed 3/13/12
|Drug||Recommended Dosage||Therapeutic Serum Level||Onset Duration||Toxicity/Remarks|
|Phenobarbitial||1Loading 15-20 mg/kg IV over 15 - 20 min.
2Maintenance: 3-5 mg/kg IV, IM , POq 12 - 24 hr. (first dose given 12 to 24 hours after loading)
|15-40 mg/L||IV: Within 5 minutes
PO: Within 20-60 minutes
Max IV effect within 30 minutes
Duration: 5-10 hours
|Sedation, respiratory arrest, hypotension, T1/2 96 h / increase 1st two wk of life; induces drug metabolism(interactions), sensitivity reactions
IV push < 1 mg/kg/min.
|3Phenytoin||Loading: 15 - 20 mg/kg IV *Maintenance: 5 - 8 mg/kg/d
q 8 - 12 hr IV (first maintenance dose 24 hours after loading)
|10-20 mg/L4||Large patient variability in onset and duration||Extravasation risk due to high pH. *If >1 week old, may need to increase dosage to ³ 8 mg/kg IV q12 h or q 8h to maintain therapeutic effect / levels
IV push < 0.5 mg/kg/min.
(prodrug of phenytoin)
|Dosing the same as for phenytoin; however, doses are expressed in phenytoin sodium equivalents (PEs). 1 PE = 1 mg phenytoin||Same as for phenytoin||Conversion of fosphenytoin to phenytoin is 7-15 minutes then phenytoin kinetics take over||Rapidly absorbed via IV and IM route. Can give intraosseously.
Fosphenytoin is preferred product for pediatrics.
|Loading dose5 10 mg/kg IV over 15 minutes. Up to 50 mg/kg loading dose has been used. PO can also be used.
Maintenance dose 10 – 30 mg/kg/dose q 24 hours in neonatal period and q12 hours in infancy.
However, not routinely monitored.
Max effects within 60 minutes. Duration: not specified
t1/2 = 9 hours
|Must dilute to a concentration of 5 mg/ml in D5W or NS prior to IV administration. No drug-drug interactions. PO rapidly and completely absorbed. IV:PO conversion is 1:1. Well-tolerated even at a loading dose of 50 mg/kg. Adverse effects reported are some sedation and irritability at 24 hours after initial dose.|
|Lorazepam||0.05 - 0.1 mg/kg/dose slow IV push over 2 - 3 min.||IV: Within 5 minutes
Duration: 3-24 hours.
|May increase phenobarbital level. May cause respiratory depression.|
|Diazepam||50.2 to 0.75 mg/kg slow IV push.
Give in maximum increments of 0.2 mg/kg q 2 min.
If seizures stop before completion of dosing, discontinue infusion.
Rectal dose: 0.5-1.0 mg/kg.
|0.15-0.3mcg/ml||IV: Within 1-3 minutes
Rectal: Within 2-10 minutes
|CNS depression, respiratory depression including apnea, phlebitis.
Doses may be repeated q 15 - 30 min. x 2 to 3 doses total
- If seizures are noted to continue after the initial phenobarbital loading dose, an additional 5 mg/kg bolus dose can be given every 15 - 30 minutes (total load dose should not exceed 35 mg/kg). Sedation occurs at serum concentrations above 40 mg/L. Respiratory depression may develop with larger loading doses (serum concentrations above 60 mg/L) or if given in conjunction with diazepam.
- Maintenance phenobarbital doses of 5 mg/kg/day may occasionally result in accumulation of serum levels to >30 mg/L in the neonate less than 1 week of age. Unless undue sedation occurs (monitoring of serum phenobarbital levels will be of assistance in identifying and managing such patients) little adverse consequences should be anticipated from the higher serum levels. Therapeutic levels may be > 45 mg/L and require very careful respiratory monitoring.
- Phenytoin is contraindicated in patients with heart block or sinus bradycardia. FDA Alert (11/24/08): Potential increased risk of serious skin reactions including Stevens Johnson syndrome and toxic epidermal necrolysis in Asian patients positive for HLA allele, HLA-B*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais.
- Maintenance doses of phenytoin are impossible to accurately establish because of marked individual variation. Frequent plasma phenytoin concentration measurements are essential, particularly in the rapidly changing period of the first 3 weeks of age. Drug is highly protein bound; free fraction of drug may be increased in patients with hypoalbuminemia and/or hyperbilirubinemia. If the therapeutic range is based on the premise that in the neonate there is a greater concentration of unbound phenytoin in plasma at any given total plasma concentration, then a total plasma phenytoin concentration of 6-14 mcg/ml will provide the same concentration of unbound phenytoin as a 10-20 mcg/ml total concentration in an adult (Loughnan et al, 1977). However, the actual relationship between serum levels and anticonvulsant activity of phenytoin (alone) has not been demonstrated in the neonate. The plasma level 8 hr. after dosing should be the most representative of the average phenytoin concentration.
- Levetiracetam can be used as monotherapy or adjunctive therapy for neonatal seizures. In a retrospective case review of 22 neonates ≥ 37 weeks (Khan et al 2011); 20 patients received a loading dose of 50 mg/kg, 1 patient a loading dose of 20 mg/kg, and 1 patient a loading dose of 10 mg/kg. The patients’ were then maintained on 25 mg/kg q 12 hours, 20 mg/kg q 12 hours, and 10 mg/kg q 12 hours, respectively. Of the 22 patients, 19 (86%) demonstrated immediate seizure cessation at 1 hour. Furthermore, 7/22 (32%) achieved complete seizure cessation after administration of the loading dose, 14 (64%) achieved seizure cessation by 24 hours, 19 (86%) by 48 hours, and all 22 (100%) by 72 hours. Outcomes were confirmed by electroencephalographic correlation. Follow-up at 6 months after initiation of therapy demonstrated no new adverse effects. When used as 2nd or 3rd line therapy phenobarbital and phenobarbital and phenytoin/fosphenytoin where the first-line agents, respectively.
- The total acute IV dose of diazepam necessary to control neonatal seizures has ranged from less than 0.1 mg/kg to 2.7 mg/kg. Based on the proposed therapeutic serum level of diazepam, a dose of 0.5 mg/kg should produce levels in excess of that ordinarily necessary. Only in very unusual circumstances should alternate routes of administration be considered. Evidence does exist to support the efficacy of rectal administration. The parenteral injection form is used in conjunction with a syringe and catheter inserted 5 cm into the rectum. It is important to note that there is no evident advantage in using diazepam instead of phenobarbital, but to maintain anticonvulsant effect, a longer acting anticonvulsant such as phenobarbital is generally used following diazepam or lorazepam (as this combination often produces respiratory depression, close monitoring of the patient is essential).
- Abend NS, Gutierrez-Colina AM, Monk, HM, et al. Levetiracetam for Treatment of Neonatal Seizures. J Child Neurol 2011; 26(4): 465-470.
- Khan O, Chang E, Cipriani C, et al. Use of Intravenous Levetiracetam for Management of Acute Seizures in Neonates. Pediatr Neurol 2011; 44: 265-269.
- Lexi-Comp, Inc. Pediatric Drug Information. Accessed online. Updated annually.
- Merhar SL, Schibler KR, Sherwin CM, et al. Pharmacokinetics of Levetiracetam in Neonates with Seizures. J Pediatr 2011; 159: 152-4.
- Thomas Reuters. Neofax. 23rd Edition. 2010.
- Warner A, Privitera M, Bates D. Standards of laboratory practice: antiepileptic drug monitoring. Clinical Chemistry 1998; 44: 1085-1095.