AHFS Class:

• Barbiturates 28:12.04

Generic Name(s):

• PHENobarbital

• PHENobarbital Sodium

Phenobarbital is a barbiturate-derivative anticonvulsant.

As an anticonvulsant, phenobarbital is used principally in the management of tonic-clonic (grand mal) seizures and partial seizures. Phenobarbital may be used as the initial drug, particularly in infants and young children, but more often is administered concomitantly with phenytoin or other anticonvulsants. In infants and young children, phenobarbital is effective in the prevention of febrile seizures. Routine use of phenobarbital for long-term prophylactic treatment of febrile seizures in children is controversial; most clinicians recommend selective use of the drug in these children and a careful assessment of the potential risks versus benefits. Children with febrile seizures who may be at particular risk of future difficulties and for whom prophylactic therapy is probably indicated include those whose first febrile seizure occurs at an early age (i.e., at less than 18 months of age); those who exhibit substantial abnormalities in neurologic function at the time of the first febrile episode or who have a history of substantial developmental delays; those who have febrile seizures that are complex, persist for more than 15 minutes, have focal features, or occur in series with a combined duration of more than 30 minutes, including those in whom they occur as a recurrence; and those with a family (i.e., parents, siblings) history of afebrile seizures.

Although IV phenobarbital sodium is occasionally used as initial therapy, IV diazepam is generally considered the drug of choice for termination of status epilepticus; parenterally administered phenobarbital sodium may be useful to prevent seizure recurrence after seizures are initially terminated with other anticonvulsants (e.g., diazepam, phenytoin sodium) or for termination of status epilepticus that does not respond to initial therapy with other anticonvulsants. The usefulness of parenteral phenobarbital sodium in terminating acute seizure episodes is limited by the slow onset of action of the drug.

Administration

Phenobarbital is administered orally. Phenobarbital sodium is administered by IM or slow IV injection. Parenteral solutions prepared from sterile phenobarbital sodium powder, but not the commercially available injections, may also be injected subcutaneously. Subcutaneous injection or extravasation of the commercially available injections causes tissue irritation, which can result in local reactions varying in severity from slight redness and tenderness to necrosis. If such extravasation or inadvertent injection occurs, treatment that includes application of moist heat and injection of 0.5% procaine hydrochloride at the affected site has been recommended.

IV administration of the drug should be reserved for emergency treatment of acute seizure states; however, usefulness of the drug in these conditions is limited. (See Uses.) When the drug is administered IV, the patients should be hospitalized and under close supervision. The drug must be administered IV slowly at a rate not greater than 60 mg/minute. Inadvertent intra-arterial injection of commercially available phenobarbital sodium injections can cause spasm and severe pain along the affected artery, which can result in local reactions varying in severity from transient pain to gangrene. The injection should be stopped if the patient complains of pain or if signs of inadvertent intra-arterial injection occur, such as patches of discolored skin, a white hand with cyanosed skin, or delayed onset of action. The most appropriate therapy for such inadvertent injection has not been fully established, and the manufacturers' labeling should be consulted for current recommendations.

Patients who are currently receiving or beginning therapy with phenobarbital and/or any other anticonvulsant should be closely monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.100,101,102 (See Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12.)

Dosage

Dosage must be carefully and slowly adjusted according to individual requirements and response. When a patient is transferred to another anticonvulsant drug, the dosage of phenobarbital should be gradually reduced over a period of 1 week while, at the same time, therapy is instituted with a low dose of the replacement drug.

When phenobarbital is used in conjunction with mephobarbital, the dose of each drug should be one-half the full dose of the drug used alone. Phenobarbital should be withdrawn or dosage reduced slowly to avoid precipitating seizures or status epilepticus.

The usual oral dosage of phenobarbital for adults is 100-300 mg daily. The drug frequently is given at bedtime. There is no advantage in dividing the daily dosage because of the long half-life of phenobarbital. For children, the usual oral dosage is 3-5 mg/kg or 125 mg/m² daily. For the prevention of febrile seizures, maintenance dosage of 3-4 mg/kg daily has been effective. A period of 2-3 weeks of therapy may be required to achieve full anticonvulsant effects.

For management of status epilepticus and other acute seizure states, phenobarbital sodium is administered parenterally in doses of 200-600 mg for adults and 100-400 mg for children. Since up to 30 minutes may be required for maximum effect, it is important to allow the anticonvulsant effect to develop before administering additional doses, in order to prevent overdosage. Some clinicians administer phenobarbital sodium IV until seizures stop or a total dose of 20 mg/kg has been given. IV injections should be discontinued as soon as the desired effect is obtained.

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of phenobarbital, see the Anticonvulsants General Statement 28:12. See also the Barbiturates General Statement 28:24.04 and see Phenobarbital 28:24.04.

Phenobarbital shares the toxic potentials of the barbiturate-derivative anticonvulsants, and the usual precautions of anticonvulsant administration should be observed. (See Cautions in the Anticonvulsants General Statement 28:12. See also Cautions in the Barbiturates General Statement 28:24.04.)

Clinicians should inform patients, their families, and caregivers about the potential for an increased risk of suicidal thinking and behavior (suicidality) associated with antiepileptic therapy.100 For a complete discussion, see Cautions: CNS Effects and Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12.

Serious adverse effects rarely occur with phenobarbital. When the drug is administered orally in the management of epilepsy, the principal adverse effect is drowsiness or sedation; however, in children the drug may produce paradoxical excitement and hyperactivity or exacerbate existing hyperkinetic behavior, which is sometimes severe enough to necessitate a change to a different barbiturate derivative or another anticonvulsant. Geriatric patients frequently react to barbiturates with excitement, confusion, or depression. Phenobarbital causes some type of skin reaction in 1-3% of all patients; however, these reactions are usually mild maculopapular, morbilliform, or scarlatiniform rashes which resolve quickly when the drug is discontinued. Very rarely, exfoliative dermatitis, erythema multiforme, or Stevens-Johnson syndrome has occurred. Phenobarbital should be administered with extreme caution to patients with nephritis.

IV phenobarbital sodium may cause respiratory depression, particularly if the drug is administered too rapidly. The drug must be administered slowly at a rate not greater than 60 mg/minute, and personnel and equipment should be readily available for administration of artificial respiration.

Safe use of phenobarbital during pregnancy or lactation has not been established. Barbiturates can cause fetal harm when administered to pregnant women. (See Cautions: Pregnancy and Lactation, in the Anticonvulsants General Statement 28:12 and the Barbiturates General Statement 28:24.04.)

Pharmacology

Phenobarbital shares the actions of the barbiturate-derivative anticonvulsants and is effective in the management of epilepsy in subhypnotic doses.

Pharmacokinetics

Absorption

About 70-90% of an oral dose of phenobarbital is absorbed slowly from the GI tract. Following rectal administration of phenobarbital sodium, the drug is readily absorbed from the colon. Following oral administration of phenobarbital, peak blood concentrations are reached in 8-12 hours and peak brain concentrations in 10-15 hours. Because phenobarbital has a long plasma half-life, 3-4 weeks of therapy may be required to achieve steady-state plasma concentrations. Plasma phenobarbital concentrations of 10-40 mcg/mL produce anticonvulsant activity in most patients. Therapeutic plasma concentrations are usually attained after 2-3 weeks of therapy at a dosage of 100-200 mg daily. Plasma phenobarbital concentrations of greater than 50 mcg/mL may produce coma, and those in excess of 80 mcg/mL are potentially lethal.

When phenobarbital sodium is administered IV, the onset of action usually occurs within 5 minutes and maximum effects are achieved within 30 minutes. IM or subcutaneous administration of phenobarbital sodium results in a slightly slower onset of action. The duration of action of parenterally administered phenobarbital sodium is usually 4-6 hours.

Distribution

In vitro studies indicate that 20-45% of the drug in the blood is bound to plasma proteins.

Elimination

Phenobarbital has a long plasma half-life (2-6 days).

Phenobarbital is metabolized by the liver via oxidative hydroxylation to form p -hydroxyphenobarbital, an inactive metabolite. Phenobarbital is a potent inducer of the enzymes involved in the metabolism of other drugs, but there is no conclusive evidence that phenobarbital accelerates its own metabolism. Approximately 25% of a dose is excreted unchanged in urine and about 75% of the drug is excreted in urine as the p -hydroxy metabolite and its glucuronide and sulfate conjugates. Alkalinization of the urine and/or increasing the urinary flow rate substantially increases the rate of excretion of unchanged phenobarbital. Unmetabolized drug may accumulate in patients with oliguria or uremia.

Orally administered activated charcoal has been shown to enhance the elimination of phenobarbital. Following IV administration of phenobarbital in healthy adults, orally administered activated charcoal decreased the mean serum half-life of phenobarbital from 110 to 45 hours and increased mean total body and nonrenal clearances of the drug from 4.4 to 12 mL/kg per hour and from 52 to 80% of total body clearance, respectively. Multiple-dose, nasogastric administration of activated charcoal has been used effectively to treat phenobarbital overdose; activated charcoal enhances elimination of the drug and shortens the duration of coma.

Chemistry and Stability

Chemistry

Phenobarbital is a barbiturate-derivative anticonvulsant. Phenobarbital occurs as white crystals or a white, crystalline powder which may show polymorphism and is very slightly soluble in water, soluble in alcohol, and stable in air. The drug has a pK_a of 7.41, and its lipid solubility is low. Phenobarbital sodium occurs as flaky crystals; white, crystalline granules; or a white powder. The drug is odorless, has a bitter taste, and is hygroscopic. The sodium salt is very soluble in water, freely soluble in propylene glycol, and soluble in alcohol. Phenobarbital sodium injection has a pH of 8.5-10.5; to adjust the pH, phenobarbital may be substituted for the equivalent amount of the sodium salt.

Stability

Aqueous solutions of phenobarbital sodium are not generally stable. The drug is more stable in polyethylene glycol or propylene glycol. Propylene glycol is frequently used as a solvent in commercially available phenobarbital sodium injections. Solutions of phenobarbital sodium should not be added to acidic solutions because precipitation of phenobarbital may occur. Solutions for injection should not be used if they contain a precipitate. Commercially available phenobarbital sodium injection may be diluted with most IV infusion solutions (e.g., 0.45 or 0.9% sodium chloride, 5% dextrose, lactated Ringer's, Ringer's). Solutions of phenobarbital sodium are physically and/or chemically incompatible with many drugs. Specialized references should be consulted for specific compatibility information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

100. Food and Drug Administration. FDA Alert. Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website: http://web.archive.org/web/20090309235730/http://www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm.

101. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website: http://web.archive.org/web/20090402050418/http://www.fda.gov/bbs/topics/NEWS/2008/NEW01786.html.

102. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website: http://web.archive.org/web/20090220022701/http://www.fda.gov/CDER/Drug/infopage/antiepileptics/default.htm.