Phenobarbital

Pronunciation

(fee noe BAR bi tal)


U.S. Brand Names

Luminal® Sodium



Synonyms

Phenobarbital Sodium; Phenobarbitone; Phenylethylmalonylurea



Generic Available

Yes



Canadian Brand Names

PMS-Phenobarbital



Use

Management of generalized tonic-clonic (grand mal) and partial seizures; sedative



Use - Unlabeled/Investigational

Febrile seizures in children; may also be used for prevention and treatment of neonatal hyperbilirubinemia and lowering of bilirubin in chronic cholestasis; neonatal seizures; management of sedative/hypnotic withdrawal



Restrictions

C-IV



Pregnancy Risk Factor

D



Pregnancy Implications

Crosses the placenta. Cardiac defect reported; hemorrhagic disease of newborn due to fetal vitamin K depletion may occur; may induce maternal folic acid deficiency; withdrawal symptoms observed in infant following delivery. Epilepsy itself, number of medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy. Benefit:risk ratio usually favors continued use during pregnancy and breast-feeding.



Lactation

Enters breast milk/not recommended (AAP recommends use "with caution")



Contraindications

Hypersensitivity to barbiturates or any component of the formulation; marked hepatic impairment; dyspnea or airway obstruction; porphyria; pregnancy



Warnings/Precautions

Potential for drug dependency exists, abrupt cessation may precipitate withdrawal, including status epilepticus in epileptic patients. Do not administer to patients in acute pain. Use caution in elderly, debilitated, renally or hepatic dysfunction, and pediatric patients. May cause paradoxical responses, including agitation and hyperactivity, particularly in acute pain and pediatric patients. Use with caution in patients with depression or suicidal tendencies, or in patients with a history of drug abuse. Tolerance, psychological and physical dependence may occur with prolonged use. May cause CNS depression, which may impair physical or mental abilities. Patients must cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Effects with other sedative drugs or ethanol may be potentiated. May cause respiratory depression or hypotension, particularly when administered intravenously. Use with caution in hemodynamically unstable patients (hypovolemic shock, CHF) or patients with respiratory disease. Due to its long half-life and risk of dependence, phenobarbital is not recommended as a sedative in the elderly. Use has been associated with cognitive deficits in children. Use with caution in patients with hypoadrenalism.



Adverse Reactions

Frequency not defined.

Cardiovascular: Bradycardia, hypotension, syncope

Central nervous system: Drowsiness, lethargy, CNS excitation or depression, impaired judgment, "hangover" effect, confusion, somnolence, agitation, hyperkinesia, ataxia, nervousness, headache, insomnia, nightmares, hallucinations, anxiety, dizziness

Dermatologic: Rash, exfoliative dermatitis, Stevens-Johnson syndrome

Gastrointestinal: Nausea, vomiting, constipation

Hematologic: Agranulocytosis, thrombocytopenia, megaloblastic anemia

Local: Pain at injection site, thrombophlebitis with I.V. use

Renal: Oliguria

Respiratory: Laryngospasm, respiratory depression, apnea (especially with rapid I.V. use), hypoventilation

Miscellaneous: Gangrene with inadvertent intra-arterial injection

Overdosage/Toxicology

Symptoms of overdose include unsteady gait, slurred speech, confusion, jaundice, hypothermia, hypotension, respiratory depression, and coma. In severe overdose, charcoal hemoperfusion may accelerate removal. Treatment is symptom-directed and supportive.



Drug Interactions

of CYP2C8/9 (minor), 2C19 (major), 2E1 (minor); CYP1A2 (strong), 2A6 (strong), 2B6 (strong), 2C8/9 (strong), 3A4 (strong)

SubstrateInduces

Acetaminophen: Barbiturates may enhance the hepatotoxic potential of acetaminophen overdoses

Antiarrhythmics: Barbiturates may increase the metabolism of antiarrhythmics, decreasing their clinical effect; includes disopyramide, propafenone, and quinidine

Anticonvulsants: Barbiturates may increase the metabolism of anticonvulsants; includes ethosuximide, felbamate (possibly), lamotrigine, phenytoin, tiagabine, topiramate, and zonisamide; does not appear to affect gabapentin or levetiracetam

Antineoplastics: Limited evidence suggests that enzyme-inducing anticonvulsant therapy may reduce the effectiveness of some chemotherapy regimens (specifically in ALL); teniposide and methotrexate may be cleared more rapidly in these patients

Antipsychotics: Barbiturates may enhance the metabolism (decrease the efficacy) of antipsychotics; monitor for altered response; dose adjustment may be needed

Beta-blockers: Metabolism of beta-blockers may be increased and clinical effect decreased; atenolol and nadolol are unlikely to interact given their renal elimination

Calcium channel blockers: Barbiturates may enhance the metabolism of calcium channel blockers, decreasing their clinical effect

Chloramphenicol: Barbiturates may increase the metabolism of chloramphenicol and chloramphenicol may inhibit barbiturate metabolism; monitor for altered response

Cimetidine: Barbiturates may enhance the metabolism of cimetidine, decreasing its clinical effect

CNS depressants: Sedative effects and/or respiratory depression with barbiturates may be additive with other CNS depressants; monitor for increased effect; includes ethanol, sedatives, antidepressants, narcotic analgesics, and benzodiazepines

Corticosteroids: Barbiturates may enhance the metabolism of corticosteroids, decreasing their clinical effect

Cyclosporine: Levels may be decreased by barbiturates; monitor

CYP1A2 substrates: Phenobarbital may decrease the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, estrogens, fluvoxamine, mirtazapine, ropinirole, and theophylline.

CYP2A6 substrates: Phenobarbital may decrease the levels/effects of CYP2A6 substrates. Example substrates include ifosfamide and rifampin.

CYP2B6 substrates: Phenobarbital may decrease the levels/effects of CYP2B6 substrates. Example substrates include bupropion, efavirenz, promethazine, selegiline, and sertraline.

CYP2C8/9 substrates: Phenobarbital may decrease the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, losartan, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, sulfonamides, warfarin, and zafirlukast.

CYP2C19 inducers: May decrease the levels/effects of phenobarbital. Example inducers include aminoglutethimide, carbamazepine, phenytoin, and rifampin.

CYP2C19 inhibitors: May increase the levels/effects of phenobarbital. Example inhibitors include delavirdine, fluconazole, fluvoxamine, gemfibrozil, isoniazid, omeprazole, and ticlopidine.

CYP3A4 substrates: Phenobarbital may decrease the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, clarithromycin, cyclosporine, erythromycin, estrogens, mirtazapine, nateglinide, nefazodone, nevirapine, protease inhibitors, tacrolimus, and venlafaxine.

Doxycycline: Barbiturates may enhance the metabolism of doxycycline, decreasing its clinical effect; higher dosages may be required

Estrogens: Barbiturates may increase the metabolism of estrogens and reduce their efficacy

Felbamate may inhibit the metabolism of barbiturates and barbiturates may increase the metabolism of felbamate

Griseofulvin: Barbiturates may impair the absorption of griseofulvin, and griseofulvin metabolism may be increased by barbiturates, decreasing clinical effect

Guanfacine: Effect may be decreased by barbiturates

Immunosuppressants: Barbiturates may enhance the metabolism of immunosuppressants, decreasing its clinical effect; includes both cyclosporine and tacrolimus

Loop diuretics: Metabolism may be increased and clinical effects decreased; established for furosemide, effect with other loop diuretics not established

MAO inhibitors: Metabolism of barbiturates may be inhibited, increasing clinical effect or toxicity of the barbiturates

Methadone: Barbiturates may enhance the metabolism of methadone resulting in methadone withdrawal

Methoxyflurane: Barbiturates may enhance the nephrotoxic effects of methoxyflurane

Oral contraceptives: Barbiturates may enhance the metabolism of oral contraceptives, decreasing their clinical effect; an alternative method of contraception should be considered

Theophylline: Barbiturates may increase metabolism of theophylline derivatives and decrease their clinical effect

Tricyclic antidepressants: Barbiturates may increase metabolism of tricyclic antidepressants and decrease their clinical effect; sedative effects may be additive

Valproic acid: Metabolism of barbiturates may be inhibited by valproic acid; monitor for excessive sedation; a dose reduction may be needed

Warfarin: Barbiturates inhibit the hypoprothrombinemic effects of oral anticoagulants via increased metabolism; this combination should generally be avoided

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: May cause decrease in vitamin D and calcium.

Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased). Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Stability

Protect elixir from light; not stable in aqueous solutions; use only clear solutions; do not add to acidic solutions, precipitation may occur; I.V. form is with benzquinamide (in syringe), cephalothin, chlorpromazine, hydralazine, hydrocortisone, hydroxyzine, insulin, levorphanol, meperidine, methadone, morphine, norepinephrine, pentazocine, prochlorperazine, promazine, promethazine, ranitidine (in syringe), vancomycin

incompatible

Compatibility

Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D5/4NS, D5/2NS, D5NS, D5W, D10W, LR, /2NS, NS

111

Y-site administration: Compatible: Enalaprilat, fosphenytoin, gatifloxacin, levofloxacin, linezolid, meropenem, propofol, sufentanil. Incompatible: Amphotericin B cholesteryl sulfate complex, hydromorphone

Compatibility in syringe: Compatible: Heparin. Incompatible: Hydromorphone, pentazocine, ranitidine, sufentanil

Compatibility when admixed: Compatible: Amikacin, aminophylline, calcium chloride, calcium gluconate, colistimethate, dimenhydrinate, meropenem, polymyxin B sulfate, sodium bicarbonate, thiopental, verapamil. Incompatible: Chlorpromazine, cimetidine, clindamycin, dimenhydrinate, diphenhydramine, droperidol, ephedrine, hydralazine, hydrocortisone sodium succinate, hydroxyzine, insulin (regular), kanamycin, levorphanol, meperidine, morphine, norepinephrine, pancuronium, penicillin G, pentazocine, phenytoin, procaine, prochlorperazine edisylate, prochlorperazine mesylate, promazine, promethazine, streptomycin, succinylcholine, vancomycin. Variable (consult detailed reference): Isoproterenol, metaraminol, methyldopate, norepinephrine

Mechanism of Action

Short-acting barbiturate with sedative, hypnotic, and anticonvulsant properties. Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. In high doses, barbiturates exhibit anticonvulsant activity; barbiturates produce dose-dependent respiratory depression.



Pharmacodynamics/Kinetics

Onset of action: Oral: Hypnosis: 20-60 minutes; I.V.: ~5 minutes

Peak effect: I.V.: ~30 minutes

Duration: Oral: 6-10 hours; I.V.: 4-10 hours

Absorption: Oral: 70% to 90%

Protein binding: 20% to 45%; decreased in neonates

Metabolism: Hepatic via hydroxylation and glucuronide conjugation

Half-life elimination: Neonates: 45-500 hours; Infants: 20-133 hours; Children: 37-73 hours; Adults: 53-140 hours

Time to peak, serum: Oral: 1-6 hours

Excretion: Urine (20% to 50% as unchanged drug)

Dosage

Children:

Sedation: Oral: 2 mg/kg 3 times/day

Hypnotic: I.M., I.V., SubQ: 3-5 mg/kg at bedtime

Preoperative sedation: Oral, I.M., I.V.: 1-3 mg/kg 1-1.5 hours before procedure

Adults:

Sedation: Oral, I.M.: 30-120 mg/day in 2-3 divided doses

Hypnotic: Oral, I.M., I.V., SubQ: 100-320 mg at bedtime

Preoperative sedation: I.M.: 100-200 mg 1-1.5 hours before procedure

Anticonvulsant: Status epilepticus: Loading dose: I.V.:

Infants and Children: 10-20 mg/kg in a single or divided dose; in select patients may administer additional 5 mg/kg/dose every 15-30 minutes until seizure is controlled or a total dose of 40 mg/kg is reached

Adults: 300-800 mg initially followed by 120-240 mg/dose at 20-minute intervals until seizures are controlled or a total dose of 1-2 g

Anticonvulsant maintenance dose: Oral, I.V.:

Infants: 5-8 mg/kg/day in 1-2 divided doses

Children:

1-5 years: 6-8 mg/kg/day in 1-2 divided doses

5-12 years: 4-6 mg/kg/day in 1-2 divided doses

Children >12 years and Adults: 1-3 mg/kg/day in divided doses or 50-100 mg 2-3 times/day

Sedative/hypnotic withdrawal (unlabeled use): Initial daily requirement is determined by substituting phenobarbital 30 mg for every 100 mg pentobarbital used during tolerance testing; then daily requirement is decreased by 10% of initial dose

Dosing interval in renal impairment: Clcr<10 mL/minute: Administer every 12-16 hours

Hemodialysis: Moderately dialyzable (20% to 50%)

Dosing adjustment/comments in hepatic disease: Increased side effects may occur in severe liver disease; monitor plasma levels and adjust dose accordingly

Administration

Avoid rapid I.V. administration >50 mg/minute; avoid intra-arterial injection; parenteral solutions are highly alkaline; avoid extravasation



Monitoring Parameters

Phenobarbital serum concentrations, mental status, CBC, LFTs, seizure activity



Reference Range

Therapeutic:

Infants and children: 15-30 mcg/mL (SI: 65-129

mol/L)

Adults: 20-40 mcg/mL (SI: 86-172

mol/L)

Toxic: >40 mcg/mL (SI: >172

mol/L)

Toxic concentration: Slowness, ataxia, nystagmus: 35-80 mcg/mL (SI: 150-344

mol/L)

Coma with reflexes: 65-117 mcg/mL (SI: 279-502

mol/L)

Coma without reflexes: >100 mcg/mL (SI: >430

mol/L)

Test Interactions

Assay interference of LDH



Dietary Considerations

Vitamin D: Loss in vitamin D due to malabsorption; increase intake of foods rich in vitamin D. Supplementation of vitamin D and/or calcium may be necessary. Sodium content of injection (65 mg, 1 mL): 6 mg (0.3 mEq).



Patient Education

I.M./I.V.: Patient instructions and information are determined by patient condition and therapeutic purpose. If self-administered, use exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or loss of appetite (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or constipation (increased exercise, fluids, fruit, or fiber may help). Report skin rash or irritation; CNS changes (confusion, depression, increased sedation, excitation, headache, insomnia, or nightmares); respiratory difficulty or shortness of breath; changes in urinary pattern or menstrual pattern; muscle weakness or tremors; or difficulty swallowing or feeling of tightness in throat. Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Breast-feeding is not recommended.

Pregnancy/breast-feeding precautions:

Additional Information

Injectable solutions contain propylene glycol.



Anesthesia and Critical Care Concerns/Other Considerations

Phenobarbital 65 mg/mL and 130 mg/mL each contains propylene glycol 702.4 mg/mL (67.8% v/v).

Status Epilepticus: A randomized, double-blind trial (Treiman D, 1998) evaluated the efficacy of four treatments in overt status epilepticus. Treatment arms were designed based upon accepted practices of North American neurologists. The treatments were: 1) lorazepam 0.1 mg/kg, 2) diazepam 0.15 mg/kg followed by phenytoin 18 mg/kg, 3) phenytoin 18 mg/kg alone, and 4) phenobarbital 15 mg/kg. Treatment was considered successful if the seizures were terminated (clinically and by EEG) within 20 minutes of start of therapy without seizure recurrence within 60 minutes from the start of therapy. Patients who failed the first treatment received a second and a third, if necessary. Patients did not receive randomized treatments after the first one but the treating physician remained blinded. Treatment success: Lorazepam 64.9%, phenobarbital 58.2%, diazepam/phenytoin 55.8%, and phenytoin alone 43.6%. Using an "intention-to-treat" analysis, there was no statistical difference between the groups. Results of subsequent treatments in patients who failed the first therapy indicated that response rate significantly dropped regardless of treatment. Aggregate response rate to the second treatment was 7.0% and third treatment 2.3%.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported



Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions



Dosage Forms

Elixir: 20 mg/5 mL (5 mL, 7.5 mL, 15 mL, 473 mL, 946 mL, 4000 mL) [contains alcohol]

Injection, solution, as sodium: 60 mg/mL (1 mL); 130 mg/mL (1 mL) [contains alcohol]

Luminal® Sodium: 60 mg/mL (1 mL); 130 mg/mL (1 mL) [contains alcohol 10%]

Tablet: 15 mg, 30 mg, 32 mg, 60 mg, 65 mg, 100 mg

References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,"Pediatrics, 2001, 108(3):776-89.

Amitai Y and Degani Y, "Treatment of Phenobarbital Poisoning With Multiple Dose of Activated Charcoal in an Infant,"J Emerg Med, 1990, 8(4):449-50.

Bleck TB, Seizures, Stroke, and Other Neurologic Emergencies. In: Zimmerman JL, Roberts PR, eds. Multidisciplinary Critical Care Review, Des Plains, IL: Society of Critical Care Medicine; 2003:325-34.

Jacobsen D, Wiik-Larsen E, Dahl T, et al, "Pharmacokinetic Evaluation of Haemoperfusion in Phenobarbital Poisoning,"Eur J Clin Pharmacol, 1984, 26(1):109-12.

Lin JL and Jeng LB, "Critical, Acutely Poisoned Patients Treated With Continuous Arteriovenous Hemoperfusion in the Emergency Department,"Ann Emerg Med, 1995, 25(1):75-80.

Mockli G, Crowley M, Stern R, et al, "Massive Hepatic Necrosis in a Child After Administration of Phenobarbital,"Am J Gastroenterol, 1989, 84(7):820-2.

Pond SM, Olson KR, Osterloh JD, et al, "Randomized Study of the Treatment of Phenobarbital Overdose With Repeated Doses of Activated Charcoal,"JAMA, 1984, 251(23):3104-8.

Treiman DM, Meyers PD, Walton NY, et al, "A Comparison of Four Treatments for Generalized Convulsive Status Epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group,"N Engl J Med, 1998, 339(12):792-8.

International Brand Names

Alepsal® (AR, MX); Aparoxal® (FR); Aphenylbarbit® (CH); Bialminal® (PT); Calminal® (BE); Comizial® (IT); Edhanol® (BR); Fenemal Dak® (DK); Fenemal® (NO); Fenemal SAD® (DK); Fenobarbital Cevallos® (AR); Fenobarbital® (EC, RO); Fenobarbitale Sodico® (IT); Fenobarbital Fada® (AR); Fenobarbital FNA® (NL); Fenobarbital Lando® (AR); Fenobarbital Larjan® [inj.] (AR); Fenobarbital L.CH.® (CL); Fenobarbital Richmond® (AR); Fenobarbital Richmond® [inj.] (AR); Fenobarbital Sodico® (CL); Fenobarbiton® (YU); Fenocris® (BR); Gardenal® (AR, BE, BR, CZ, ES); Gardenale® [inj.] (IT); Gardenale® (IT); Gardenaletas® (AR); Gardénal® (FR); Gardenal® (HK, IN, LU, NZ); Gardénal® [inj.] (FR); Gardenal Sodium® (GB, TH, ZA); Gratusminal® (ES); Hysteps® (CZ); Lethyl® (ZA); Lumidrops® (GR); Luminal® (AR, CH, DE, ES, IN, TR); Luminale® [inj.] (IT); Luminale® (IT); Luminaletas® (AR, ES); Luminalette® (IT); Luminaletten® (DE, TR); Luminal® [inj.] (CZ, DE, IL); Luminalum® (PL); Menobarb® (TH); Pevalon® (CY); Phenaemal® (CZ); Phenaemaletten® (CZ, DE); Phenobarbital Atlantic® (TH); Phenobarbital® (GB, IL, RU); Phenobarbitone® (AU, IL, NZ); Phenobarbitone® [inj.] (AU, NZ); Phenobarbitone Sodium® (AU); Phenobarbiton® (HR, SI, YU); Phenobarbiton natrijum® (YU); Phenobarbiton natrium® (SI); Phenobarb® (TH); Phenoson® (BD); Phenotal® (TH); PMS-Phenobarbital (CA); Sevenaletta® (HU); Sevenal® (HU)



Review Date: 1969-12-31 Reviewed By: Keywords: ,
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