Chapter 14: Phenobarbital and Primidone

PHENOBARBITAL

Phenobarbital is a barbituric acid derivative with hypnotic activity and central nervous system (CNS) depressant effects. Phenobarbital is one of the oldest anticonvulsant agents still used in clinical practice. It is FDA-approved for short-term sedation/hypnosis and treatment of generalized or partial onset seizures and provides an alternative to treat refractory status epilepticus. It is less commonly used as the first-line anticonvulsant due to disadvantages such as cognitive impairment, respiratory depression, sedation, and significant drug interactions. The anticonvulsant activity of phenobarbital is thought to be due to its effect on postsynaptic GABA receptors, which increases seizure threshold but the full mechanism is not completely understood.¹ Phenobarbital has also been used off-label to treat alcohol withdrawal, neonatal seizures, febrile seizures, neonate hyperbilirubinemia, and adults with congenital nonhemolytic unconjugated hyperbilirubinemia or chronic cholestasis.

DOSING

Phenobarbital is available in an injectable formulation, which can be given intravenously or intramuscularly, and oral formulation (tablets and solution) (see Table 14-1). In adult patients, the recommended dose for sedation and hypnosis is 30–100 mg/day and titrated upward slowly to 400 mg/day. For epilepsy management, dosing is usually weight-based where an adult maintenance dose of 2 mg/kg/day would result in a predicted steady-state concentration of 20 mg/L. A case report suggests that dosing should be with total body weight.² If immediate therapeutic concentrations are required a loading dose of 15–20 mg/kg can be administered intravenously or orally in three divided doses every 2 to 3 hours. When phenobar-bital is administered intravenously, a rate of no more than 50 mg/min is recommended to avoid toxicity with the propylene glycol diluent.³ Maintenance dosing in children (1–15 years old) is usually 3–5 mg/kg/day and for neonates (<2 weeks of age) is 2–4 mg/kg/day.⁴ Because phenobarbital has a long half-life, it can be dosed once daily; however, initially excessive sedation may limit the ability to use once-daily dosing. Excessive sedation can be minimized by gradually increasing the dose using the following schedule: Start with 25 percent of the final daily dose each evening for 5-–7 days and if tolerated the dose can then be increased to 50 percent of the final recommended dose for the next 5–7 days and then 75 percent of the final recommended dose for the next 5–7 days. The titration to the final dose should be completed by the fourth week of therapy. Steady-state serum concentrations should be checked about 3–4 weeks after achieving the total maintenance dose. A serum phenobarbital concentration targeting between 10–40 mg/L is considered within optimum range for therapeutic drug monitoring (TDM).⁵