Phenobarbital is a barbiturate that may be used as an antiepileptic to control partial and generalised tonic-clonic seizures. It is also used as part of the emergency management of acute seizures including status epilepticus.
The dose should be adjusted to the needs of the individual patient to achieve adequate control of seizures; this usually requires plasma concentrations of 15 to 40 micrograms/mL or around 60 to 180 micromoles/litre. In the UK, the usual oral dose is 60 to 180 mg daily, taken at night. In the United States of America (US and USA), total daily doses of up to 300 mg have been given.
Phenobarbital sodium may be given parenterally as part of the emergency management of acute seizures including status epilepticus. Doses of 200 mg have been given by intramuscular injection, repeated after 6 hours if necessary. Doubts have been expressed about the efficacy of the intramuscular route owing to the delay in achieving adequate blood concentrations, and the subcutaneous route may cause tissue necrosis. In the UK, for the control of status epilepticus, doses of 10 mg/kg to a maximum of 1 g may be given intravenously. The BNF recommends that an intravenous injection solution containing 200 mg/mL should be diluted 1 in 10 and given at a rate not exceeding 100 mg/minute.
For doses in children, see below. As with other antiepileptics, withdrawal of phenobarbital therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients.
Phenobarbital has also been used as a hypnotic and sedative but drugs such as the benzodiazepines are preferred.
Phenobarbital stimulates the enzymes in hepatic microsomes responsible for the metabolism of some drugs and normal body constituents including bilirubin, and for this reason it has been used to reduce hyperbilirubinaemia in neonatal jaundice. Phenobarbital magnesium and phenobarbital diethylamine have also been used.
Tetrabamate is a complex of phenobarbital, difebarbamate, and febarbamate but its use has been associated with the development of hepatitis.
Administration in children. Phenobarbital may be used in children as an antiepileptic to control partial and generalised tonic-clonic seizures. It is also used as part of the emergency management of status epilepticus. The doses given below for all indications are those recommended by the BNFC in the UK. For treatment of epilepsy, the following doses are given orally, unless stated otherwise, according to age:
- neonates: an initial dose of 20 mg/kg by slow intravenous injection, then 2.5 to 5 mg/kg once daily by slow intravenous injection or orally, adjusted according to response
- 1 month to 12 years: an initial dose of 1 to 1.5 mg/kg twice daily, increased by 2 mg/kg daily if necessary to a usual maintenance dose of 2.5 to 4 mg/kg once or twice daily
- 12 to 18 years: 60 to 180 mg daily
For status epilepticus, an intravenous injection solution containing 200 mg/mL should be diluted 1 in 10 and given by intravenous injection over 20 minutes, at a rate not exceeding 1 mg/kg per minute, in the following doses according to age:
- neonate to 12 years: an initial dose of 20 mg/kg, followed by 2.5 to 5 mg/kg once or twice daily
- 12 to 18 years: an initial dose of 20 mg/kg (to a maximum of 1 g), followed by 300 mg twice daily
Alcohol withdrawal syndrome. Phenobarbital is used in some centres for the management of alcohol withdrawal syndrome (), but has a lower safety profile than benzodiazepines (the treatment of choice) and creates the potential for multiple drug interactions. Additionally, a lack of well-defined studies make its role difficult to assess.
Cerebral malaria. Phenobarbital has been used to prevent convulsions in patients with cerebral malaria () but a systematic review concluded that, although it was an effective anticonvulsant, it should not be given routinely to patients with cerebral malaria as it might increase mortality. The optimal dose, particularly in children, has yet to be confirmed. In an early study a single intramuscular injection of phenobarbital sodium 3.5 mg/kg, or 200 mg in patients over 60 kg was effective. A dose of 10 to 15 mg/kg was later suggested. Although a single intramuscular dose of phenobarbital 20 mg/kg markedly reduced seizure frequency in young children with cerebral malaria, it was also associated with a doubling of mortality The frequency of respiratory arrest was higher in the phenobarbital group than in controls given placebo, and mortality was greatly increased in those given phenobarbital who required 3 or more doses of diazepam. Intravenous use has also been tried, and a study suggested giving a loading dose of phenobarbital 15 mg/kg by intravenous infusion followed by 2.5 mg/kg 24 and 48 hours later. WHO recommends that a dose of 20 mg/kg should not be given without respiratory support but states that it is unknown whether ventilation would prevent the increase in mortality; it is also unknown whether lower doses are effective and safer.
Epilepsy. Phenobarbital is used in the treatment of epilepsy () for partial seizures with or without secondary generalisation and for primary generalised tonic-clonic seizures. It may also be tried for atypical absence, atonic, and tonic seizures but is not effective in absence seizures. However, the usefulness of phenobarbital is limited by problems of sedation in adults and paradoxical excitement in children. There is also concern about its effects on behaviour and cognition in children. Phenobarbital is therefore usually reserved for use in cases unresponsive to other antiepileptics, although some have suggested that its low cost and broad efficacy make it a suitable first-line drug in developing countries.
Febrile convulsions. Phenobarbital has been used prophylactically in children thought to be at risk of recurrence of febrile convulsions (), but routine use of antiepileptics is no longer recommended.
Neonatal abstinence syndrome. For reference to the use of phenobarbital for the treatment of neonates with opioid abstinence syndrome.
Neonatal intraventricular haemorrhage. Phenobarbital is one of several drugs that has been tried to prevent the development of neonatal intraventricular haemorrhage (). Initial studies of antenatal use in the mother were promising, but a larger randomised study in 610 women failed to show any effect of antenatal phenobarbital on incidence or severity of intraventricular haemorrhage. An assessment of surviving infants that could be traced at about 20 months of age also found that antenatal phenobarbital had no apparent effect on neurodevelopmental outcome. A systematic review of these and other studies concluded that giving phenobarbital before preterm birth cannot be recommended for routine clinical practice; strategies for future studies were suggested to improve methodology. Studies of use in neonates have also shown inconsistent results. A systematic review of studies of phenobarbital for prophylaxis of intraventricular haemorrhage in preterm neonates concluded that postnatal use cannot be recommended either, and is associated with an increased need for mechanical ventilation.
Neonatal seizures. Some consider phenobarbital to be the mainstay of treatment for all types of neonatal seizures (). In a study in 120 neonates with clinical seizure activity of varying aetiology, 48 were controlled by an initial intravenous loading dose of phenobarbital 15 to 20 mg/kg over 10 to 15 minutes, and a further 37 were controlled by sequential bolus doses of phenobarbital 5 to 10 mg/kg every 20 to 30 minutes up to a serum concentration of 40 micrograms/mL. Of the remaining 35 neonates only 7 responded when the serum-phenobarbital concentration was increased to 100 micrograms/mL, 13 required addition of a second antiepileptic (phenytoin or lorazepam) and 4 were controlled by addition of a third drug. Phenobarbital alone can effectively control seizures in the majority of neonates with recurrent seizure activity.
Phenobarbital given prophylactically as a single dose of about 40 mg/kg intravenously over one hour has also been shown to be effective in reducing the incidence of seizures in 15 infants with severe perinatal asphyxia compared with a control group who only received phenobarbital if there was clinical evidence of seizures. Subsequent follow-up over 3 years suggested that prophylactic phenobarbital might also improve later neurological outcome. However, a later retrospective cohort study found no significant difference in the rate of seizure recurrence and developmental outcome between infants who were discharged with prophylactic phenobarbital (33 patients) and those who were discharged without any antiepileptics (99).
Status epilepticus. Phenobarbital given intravenously is an alternative to intravenous phenytoin in the management of status epilepticus (). It should not be used in patients who have recently received oral phenobarbital or primidone. Although one study suggested that phenobarbital might be at least as effective, safe, and practical as diazepam with phenytoin for the initial treatment of convulsive status epilepticus, it tends to be reserved for patients who do not respond to benzodiazepines or phenytoin.
British Pharmacopoeia 2008; Paediatric Phenobarbital Oral Solution; Phenobarbital Elixir; Phenobarbital Injection; Phenobarbital Sodium Tablets; Phenobarbital Tablets;
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Phenobarbital Elixir; Phenobarbital Sodium for Injection; Phenobarbital Sodium Injection; Phenobarbital Tablets;
Theophylline, Ephedrine Hydrochloride, and Phenobarbital Tablets.
Argentina: Alepsal; Gardenal; Luminal; Luminaletas; Neurogabaf;
Brazil: Barbitron; Carbital; Edhanol; Fenocris; Garbital; Gardenal; Unifenobarb;
Czech Republic: Gardenal †; Luminal; Phenaemal; Phenaemaletten;
France: Aparoxal; Gardenal; Kaneuron;
Germany: Luminal; Luminaletten;
Greece: Gardenal; Kaneuron; Lumidrops †;
Hungary: Sevenal; Sevenaletta;
India: Gardenal; Luminal; Luminalettes †; Phenetone;
Israel: Luminal †;
Italy: Comizial †; Gardenale; Luminale; Luminalette; Neurobiol †;
Mexico: Alepsal; Fenabbott; Sevenal †;
New Zealand: Gardenal †;
Portugal: Bialminal; Luminal; Luminaletas;
South Africa: Gardenal †; Lethyl;
Spain: Gardenal; Gratusminal; Luminal; Luminaletas;
Switzerland: AphenyIbarbit; Luminal;
Thailand: Gardenal; Menobarb; Phenobarb †; Phenotal;
Turkey: Luminal; Luminaletten;
United Kingdom (UK): Gardenal †;
United States of America (US and USA): Luminal;
Argentina: Cumatil L; Lotoquis; Trixol †;
Belgium: Epipropane; Vethoine;
Brazil: Espasmalgon †; Garnibetal Complex; Vagostesyl;
Chile: Abalgin; Baldmin; Bellergal Retardado †; Belupan †; Bufacyl; Dispasmol †; Ergobelan; Immediat †; Sinpasmon; Valpin;
Czech Republic: Alnagon; Bel-laspon †; Contraspan †; Sanepil; Spasmoveralgin Neo †;
Hungary: Atrium †; Germicid-C; Meristin; Radipon; Troparinum;
India: Alergin; Asmapax; Asthmino †; Broncofol †; Cadiphylate; Dilantin with Phenobarbital; Epilan; Garoin;
Indonesia: Bellapheen; Ditalin; Piptal;
Israel: Pacetal; Philinal; Philinet;
Italy: Gamibetal Complex; Metinal-ldantoina L;
Mexico: Alepsal Compuesto; Gamibetal Complex; Paliatil;
Poland: Bellergot; Milocardin;
Portugal: Anti-Asmatico; Cosmaxil †; Hidantina Composta †; Prelus †;
Russia: Pentalgin-N (); Sedal-M (); Sedalgin-Neo ();
South Africa: Adco-Phenobarbitone Vitalet; Analgen-SA †; Don natal; Millerspas; Natrophylline Compound; Propain Forte;
Spain: Epilantin †; Equidan; Redutona;
Thailand: Bellergal †; Benera; Donnatal †; Neuramizone;
Turkey: Bellergal; Para-Nox; Pedimat;
United Arab Emirates (UAE); Alinal †;
United States of America (US and USA): Alkabel; Antispasmodic Elixir; Barbidonna † Bel-Phen-Ergot S; Bellacane; Bellamine; Bellatal; Bellergal-S; Donnatal; Folergot-DF; Hyosophen; Lufyllin-EPG †; Phenerbel-S; Quadrinal; Susano; Tedrigen; Theoclrine;
Venezuela: Ervostal; Fedratal †; Fenopol †; Frevag †; Metilfedrin †; Teofedril †; Traveget; Tropifen-F.
The symbol † denotes a preparation no longer actively marketed
Selections from the book: “Martindale: The Complete Drug Reference. Thirty-sixth edition”. Pharmaceutical Press. 2009
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