AHFS Class:

• Barbiturates 28:24.04

Generic Name(s):

• PHENobarbital

• PHENobarbital Sodium

Phenobarbital is a barbiturate anxiolytic and sedative.

Phenobarbital and phenobarbital sodium are used principally for routine sedation or to relieve anxiety and provide sedation preoperatively. Because several hours are required to achieve maximal effects, phenobarbital is not generally used orally as a hypnotic.

Phenobarbital may also be used to withdraw barbiturate or nonbarbiturate hypnotics in patients who are physically dependent on these drugs.

The drug is also used in the prophylactic management of epilepsy. (See Phenobarbital 28:12.04 and the Anticonvulsants General Statement 28:12.) The usefulness of parenteral phenobarbital sodium in terminating acute seizure episodes is limited by its relatively slow onset of action.

Studies indicate that phenobarbital is effective in the prevention and treatment of hyperbilirubinemia in neonates†. The drug has also been used to lower bilirubin concentrations in patients with congenital nonhemolytic unconjugated hyperbilirubinemia† or chronic intrahepatic cholestasis†. In limited studies, phenobarbital has been useful in the management of hyperlipemia associated with intrahepatic and extrahepatic cholestasis†.

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 patient 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.

Dosage

Dosage of phenobarbital must be individualized for each patient. Total daily dose should not exceed 600 mg. Following chronic administration, the drug should be withdrawn slowly to avoid the possibility of precipitating withdrawal symptoms if the patient is physically dependent on the drug.

Sedation and Hypnosis

When phenobarbital is used for sedation, the usual oral dosage for adults is 30-120 mg daily. Although the daily dosage is usually administered in 2 or 3 divided doses, there is no advantage in dividing the daily dosage because of the long half-life of phenobarbital. The sedative dose for children is 6 mg/kg daily or 180 mg/m² daily, administered orally in 3 equally divided doses.

The oral or parenteral hypnotic dose for adults is 100-320 mg. For the treatment of insomnia, the drug should not be administered for periods exceeding 2 weeks. To prevent rebound in rapid eye movement (REM) sleep, withdrawal of a single therapeutic dose over 5 or 6 days has been recommended when barbiturates are discontinued following prolonged use.

When phenobarbital sodium is used to allay preoperative anxiety and produce sedation, the usual dose is 100-200 mg for adults and 16-100 mg for children, administered IM 60-90 minutes before surgery. Alternatively, children may be given an oral or parenteral dose of 1-3 mg/kg preoperatively.

Drug Withdrawal

When phenobarbital is used to withdraw barbiturates or nonbarbiturate hypnotic drugs in physically dependent patients, a 30-mg dose of phenobarbital is administered orally for each 100- to 200-mg dose of the barbiturate or nonbarbiturate hypnotic that the patient has been taking daily. The total daily dose of phenobarbital is administered in 3 or 4 divided doses. If the patient shows signs of withdrawal on the first day, a loading dose of 100-200 mg of phenobarbital may be administered IM in addition to the oral dose. After stabilization on phenobarbital, the total daily dose of phenobarbital is decreased by 30 mg per day. Infants physically dependent on barbiturates may be given phenobarbital orally in a dosage of 3-10 mg/kg daily. After barbiturate withdrawal symptoms are relieved, the dosage of phenobarbital should be gradually decreased and the drug withdrawn completely over a 2-week period.

Other Uses

For the prevention and treatment of hyperbilirubinemia in neonates†, phenobarbital may be administered orally in a dosage of 7 mg/kg per day from the first to fifth day of life. Alternatively, phenobarbital sodium 5 mg/kg may be administered IM on the first day of life followed by 5 mg/kg orally on the second to seventh day of life.

To lower serum bilirubin or serum lipid concentrations in the management of chronic cholestasis†, adults have been given oral phenobarbital dosages of 90-180 mg daily in 2 or 3 divided doses, and children younger than 12 years of age have been given oral dosages of 3-12 mg/kg daily in 2 or 3 divided doses.

Precautions

Phenobarbital shares the toxic potentials of the barbiturates, and the usual precautions of barbiturate administration should be observed. (See Cautions in the Barbiturates General Statement 28:24.04.)

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.

Pharmacology

Phenobarbital shares the actions of the sedative-hypnotic barbiturates. In addition, the drug produces anticonvulsant effects in subhypnotic doses. The drug lowers serum bilirubin concentrations in neonates and patients with congenital nonhemolytic unconjugated hyperbilirubinemia and patients with chronic intrahepatic cholestasis, presumably by induction of glucuronyl transferase, the enzyme which conjugates bilirubin.

Pharmacokinetics

Absorption

About 70-90% of an oral dose of phenobarbital is absorbed slowly from the GI tract. The drug is readily absorbed following rectal administration. 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 unless a loading dose is given. Plasma phenobarbital concentrations of 10 mcg/mL produce sedation, and plasma concentrations of 40 mcg/mL produce sleep in most patients. Plasma phenobarbital concentrations 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 but may be 6-10 hours following hypnotic doses.

Distribution

In vitro, 20-45% of phenobarbital in the blood is bound to plasma proteins.

Elimination

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

Phenobarbital is hydroxylated by the liver 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 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. Phenobarbital occurs as white, odorless, glistening, small 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 pK_a of the drug is 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. Phenobarbital sodium 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

For further information on chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, chronic toxicity, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of phenobarbital, see the Barbiturates General Statement 28:24.04. See also the Anticonvulsants General Statement 28:12 and Phenobarbital 28:12.04. 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.