General Administration Information
For storage information, see the specific product information within the How Supplied section.
-May be given with food if needed.
Oral Liquid Formulations
-Administer undiluted, or mix with water, milk, or fruit juice and administer immediately.
-Oral solution contains 13.5% alcohol.
-Administer using a calibrated measuring device for accurate measurement of the dose.
Extemporaneous Alcohol-Free 10 mg/mL Phenobarbital Suspension :
-With a mortar and pestle, crush ten (10) 60-mg tablets into a fine powder.
-Mix 30 mL of Ora-Plus with 30 mL of either Ora-Sweet or Ora-Sweet SF and add a small amount to phenobarbital powder and triturate to make a paste. Add geometric amounts of the vehicle to the almost desired volume while mixing into a suspension.
-Transfer suspension to amber plastic bottle and fill to final volume of 60 mL with remaining Ora-Plus/Ora-Sweet mixture for a final concentration of 10 mg/mL.
-Storage: Suspension is stable for 115 days at room temperature when stored in plastic amber bottle.
-Suspension can be mixed with chocolate syrup (1:1) prior to administration to mask the bitter taste and improve palatability.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Phenobarbital may be diluted with at least an equal volume of compatible fluid (0.9% NaCl, 5% Dextrose, or Lactated Ringers).
-ISMP recommended standard concentrations for intermittent infusions in neonates: 10 or 65 mg/mL.
Intermittent Intravenous Administration
-Infuse over 10-15 minutes at a rate no greater than 2 mg/kg/minute, not to exceed 30 mg/minute in infants and children. The maximum infusion rate in adults is 60 mg/min, which may be appropriate for older adolescents in urgent situations.
-During injection, monitor blood pressure, respiration, and cardiac function; equipment for necessary for resuscitation and artifical ventilation should be readily available.
-Phenobarbital is an irritant; avoid small veins and extravasation. Do not administer intra-arterially.
-No dilution of the commercially available injection solution is required.
-Inject deeply into a large muscle.
-Do not inject more than 5 mL into any one site.
Antiepileptic drugs (AEDs) such as phenytoin increase the risk of suicidal ideation and behavior. Monitor all patients beginning treatment with AEDs or currently receiving such treatment closely for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. A pooled analysis of 199 placebo-controlled trials including 11 different AEDs showed that patients (>= 5 years of age) receiving AEDs had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), with an adjusted relative risk of 1.8 (95% CI 1.2-2.7). Four completed suicides occurred in patients treated with AEDs compared to none among controls. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor and risk was generally consistent among all AEDs examined. Suicidal ideation or behavior have occurred as early as 1 week after AED initiation and may occur any time during treatment.
Sedation (drowsiness) is the most common adverse effect of phenobarbital. Pronounced sedation can occur with high doses of phenobarbital used to stop seizure activity. A more subtle degree of sedation occurs with maintenance doses, but tolerance usually develops over time. Sedation, lethargy, nystagmus, and ataxia are usually not problematic with long-term use but may occur with higher dosage (blood concentrations > 30 mcg/ml). Concentrations > 40 mcg/ml may produce more serious CNS depression and result in coma, respiratory depression, or apnea depending on the concentration and the patient's sensitivity to phenobarbital's effects. Dizziness, lethargy, headache, vertigo, anxiety, and irritability, can also develop during therapy with phenobarbital. Hypnotic doses may produce residual sedation, mood distortions (emotional lability), and impaired cognition. Children may experience more CNS reactions than other populations. Some children respond with paradoxical CNS stimulation (e.g., adverse behavioral reactions, hyperactivity, nightmares, insomnia) or exacerbation of pre-existing hyperactivity. Impaired cognitive development has been reported in children treated chronically with phenobarbital when compared with placebo. When compared with other older antiepileptic drugs, cognitive effects have been worse with phenobarbital or the findings have been insignificant. However, not all studies demonstrate effects on long-term cognitive development with phenobarbital and cognitive changes appear to improve when therapy is discontinued.
Anticonvulsant hypersensitivity syndrome can occur with phenobarbital and can be very serious. A hypersensitivity syndrome may present as various organ system problems, including blood, liver, renal, and skin disorders and usually occurs 2 weeks to 3 months after therapy initiation. Discontinuation of the drug may not be sufficient to reverse progression of a serious hypersensitivity reaction because of the slow metabolism and excretion of phenobarbital. Patients who have experienced such reactions due to phenobarbital therapy should not be further exposed to the drug. Hypersensitivity reactions may first appear as cutaneous reactions, that include scarlatiniform or morbilliform maculopapular rash and urticaria. Because skin eruptions may be indicators of serious sensitivity reactions, they should be investigated promptly, with consideration of drug discontinuation. Angioedema, bullous rash, exfoliative dermatitis, lupus-like symptoms, photosensitivity, purpura, serum sickness, Stevens-Johnson syndrome, or toxic epidermal necrolysis are relatively rare but serious adverse effects. Although uncommon, phenobarbital has been reported to cause interstitial nephritis and drug-induced liver problems like hepatitis or jaundice (with accompanying elevated hepatic enzymes). Blood dyscrasias (e.g., agranulocytosis, aplastic anemia, neutropenia, or thrombocytopenia) can also occur rarely during therapy. Periodic blood tests (CBC) may be considered if phenobarbital is used for long-term therapy, but such tests are not considered mandatory. Symptoms such as unusual tiredness or weakness (asthenia), unusual bleeding or bruising (ecchymosis), and unexplained sore throat or fever should be investigated promptly.
GI effects, such as nausea, vomiting, and constipation, have been reported during therapy with phenobarbital but generally are not severe. Nausea and vomiting occurring with initial dosing is usually mild and attenuates with continued administration. Administration with food and/or sufficient fluid may alleviate some complaints.
Phenobarbital is associated with vitamin D deficiency and decreased bone mineral density and may induce osteopenia or osteomalacia with long-term use. This is particularly concerning in the pediatric population because bone development is critical during this time. Unusual bone pain or tenderness should be investigated. Mild macrocytosis has been reported with phenobarbital use in children; megaloblastic anemia has been reported rarely with chronic use. Phenobarbital, like other barbiturates, can exacerbate porphyria, causing a buildup of porphyrin precursors and enhancing porphyrin synthesis.
Respiratory depression, bronchospasm, hypotension, sinus bradycardia, and vasodilation leading to circulatory collapse may occur with rapid intravenous (IV) administration of phenobarbital. IV doses should be given slowly at recommended infusion rates and the patient monitored frequently. Resuscitation equipment should be readily available during IV therapy. An injection site reaction, such as phlebitis or pain, is also possible during parenteral therapy with phenobarbital. Severe local reactions from inadvertent intra-arterial administration of phenobarbital have included pain, arterial spasm, and tissue necrosis (gangrene). Injury to adjacent nerves may occur in some cases. Intramuscular (IM) injections should not be given repeatedly at the same site to minimize tissue damage. Parenteral preparations have a pH of 8.5-10.5 and are hyperosmolar, so extravasation should be avoided. Subcutaneous administration is also not recommended as localized adverse effects, that may range from slight erythema or irritation to serious reactions (tissue necrosis), may occur.
Prolonged use of barbiturates can produce physiological dependence with or without a psychological dependence based on the subjective effects of the drugs. Abrupt withdrawal can cause a variety of symptoms including: anxiety, muscle twitching, tremor of hands, progressive weakness, dizziness, distortion of vision, insomnia, nausea/vomiting, and postural hypotension. Major manifestations of withdrawal include hallucinations, delirium, and seizures. Sudden withdrawal of phenobarbital can precipitate status epilepticus. In order to maintain seizure control, phenobarbital should be withdrawn gradually whenever possible. In addition, consistent use of phenobarbital during the third trimester may cause physical dependence and respiratory depression in the neonate, and a neonatal abstinence syndrome has been reported.
Anticonvulsants may enhance the hepatic breakdown of vitamin D into inactive polar metabolites. Patients receiving phenobarbital for greater than 6 months should be monitored for vitamin D deficiency and receive supplementation when indicated by low serum concentrations. Anticonvulsants may also impair folate metabolism; patients should be monitored for folate deficiency and supplemented when necessary.
The use of phenobarbital is contraindicated in patients with a history of barbiturate hypersensitivity. Injectable solutions may also contain propylene glycol and should be avoided in patients with a hypersensitivity to propylene glycol. Phenobarbital is associated with the anticonvulsant hypersensitivity syndrome, which can cause severe and potentially fatal reactions that are preceded by skin eruptions. Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of adverse hematologic (i.e., agranulocytosis), hypersensitivity, or other adverse reactions to barbiturate or other anticonvulsants. Hypersensitivity reactions have been reported in patients who previously experienced hydantoin hypersensitivity (e.g., phenytoin) or carbamazepine hypersensitivity. Estimates of cross-sensitivity vary, but may range from 30-80%. Phenytoin, carbamazepine, and phenobarbital are all metabolized to hydroxylated aromatic compounds via the cytochrome P450 hepatic oxidative enzymes; arene oxide intermediates are formed during metabolism and are thought to be responsible for cross-sensitivity among these anticonvulsants in susceptible individuals. Some individuals may have a reduced ability to detoxify the intermediate toxic metabolites (e.g., arene oxides) of these anticonvulsants, which may be genetically mediated. However, studies of familial reactions have also shown that allergies to one anticonvulsant may not translate to allergies to others. There is no way to predict with certainty which patients will exhibit cross-sensitivity.
Use caution when administering phenobarbital to patients with acute or chronic pain, as the pain may be exacerbated. Paradoxical reactions, such as agitation and hyperactivity, may occur.
There is an increased risk of suicidal ideation and behavior in patients receiving antiepileptic drugs (AEDs). Suicidal ideation or behavior has occurred as early as 1 week after AED initiation and may occur any time during treatment. All patients beginning treatment with phenobarbital should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Inform patients, caregivers, and families of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. A pooled analysis of 199 placebo-controlled clinical studies (patients 5 years of age and older) with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups was conducted. There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor.
Intraarterial administration of phenobarbital is contraindicated; severe localized reactions such as pain, spasm or gangrene (tissue necrosis) may occur. Subcutaneous administration should also be avoided because localized injection reactions that may range from slight irritation to tissue necrosis can occur. Parenteral administration of barbiturates should be given cautiously to patients with hypertension, hypotension, cardiac disease, or other hemodynamically-unstable state (i.e., heart failure, shock). Intravenous administration of phenobarbital should generally be reserved for emergency settings or when enteral therapy is not possible; close supervision is necessary in a monitored unit. Do not exceed recommended IV infusion rates; too rapid administration may cause severe respiratory depression, apnea, laryngospasm, hypertension, or vasodilation with hypotension.
Phenobarbital is contraindicated in patients with pulmonary disease in which dyspnea or obstruction is evident. Phenobarbital can cause dose-dependent respiratory depression. Too rapid IV administration may result in bronchospasm, depressed respiration, hypotension, and vasodilation. Use with close supervision in patients with sleep apnea or other obstructive pulmonary condition.
Phenobarbital should be prescribed with caution to patients with a history of substance abuse because of the potential for psychological and/or physical dependence to the drug. Avoid abrupt discontinuation of phenobarbital after prolonged use to limit drug withdrawal. Sudden, abrupt discontinuation of phenobarbital in epileptic patients may precipitate acute seizures, other seizure disorder, or status epilepticus. When discontinuing therapy, a gradual dose reduction is recommended.
Phenobarbital may cause blurred vision, drowsiness, dizziness, or mental status changes, especially with initial use. Patients should use caution with activities requiring coordination and concentration (e.g., riding a bicycle, gymnastics, operating a vehicle) until they are aware of the effects of the drug. Ethanol ingestion or concomitant use of other sedating drugs can magnify CNS depression and should be avoided. The lethal dose of a barbiturate is significantly less if alcohol is also ingested. If the patient is of an age that alcohol use is a possibility, counsel the patient about the dangers of concomitant use.
Phenobarbital is contraindicated in patients with marked impairment of liver function (e.g., severe hepatic disease). Phenobarbital is extensively metabolized in the liver. Those with hepatic disease may be at increased risk for developing drug toxicity and may require lower dosage and slower dosage titration. Because barbiturates are sedating and also may impair the ability of the liver to metabolize ammonia, barbiturates are best avoided in patients with hepatic encephalopathy.
Barbiturates should be used cautiously in patients with renal impairment. Metabolites and unchanged drug are excreted in the kidneys. Renal failure or anuria can lead to phenobarbital toxicity because >= 25% of the drug is excreted unchanged in the urine. The chronic use of phenobarbital should generally be avoided in patients with renal failure; dosages need to be adjusted and administered less frequently. Close monitoring of concentrations is necessary in patients receiving dialysis because phenobarbital is removed by hemodialysis.
Phenobarbital, like other barbiturates, is contraindicated in patients with manifest or latent porphyria. Phenobarbital can exacerbate this disease. Barbiturates can stimulate the activity of enzymes like ALA synthetase, causing a buildup of porphyrin precursors and enhancing porphyrin synthesis.
Use phenobarbital with caution in children with low bone density. Phenobarbital is associated with loss of bone mineral density and there may be an increased risk of osteopenia/osteoporosis and osteomalacia with long-term therapy.
Phenobarbital injection contains the preservative benzyl alcohol and caution is advised when administering to neonates, including premature neonates. There have been reports of fatal 'gasping syndrome' in neonates following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms of this syndrome include sudden gasping respiration, hypotension, bradycardia, and cardiovascular collapse. Additionally, the oral solution contains a significant amount of alcohol and this should be considered when giving to neonates and young infants. An alcohol-free suspension can be extemporaneously compounded if alcohol content is a concern.
All neonates with a history of in utero exposure to phenobarbital should be monitored carefully. Consistent in utero exposure during the third trimester may cause physical dependence and respiratory depression in the neonate, and a neonatal abstinence syndrome has been reported. Acute symptoms of withdrawal and seizures may occur any time during the first 14 days of life. In addition, hypoprothrombinemia with hemorrhage has been observed within the first 24 hours in neonates and appears to result from drug-induced vitamin K deficiency in the fetus; administration of vitamin K to the neonate at birth is effective in treatment or prophylaxis of these problems.
Description: Phenobarbital is an oral and parenteral barbiturate with anticonvulsant and sedative-hypnotic properties. Phenobarbital is the oldest of the commonly used anticonvulsants, although its use is less common among non-neonatal populations. It is the longest-acting agent in the barbiturate group. In general, phenobarbital is effective in all seizure disorders except absence (petit mal). Historically, it was regularly prescribed to prevent febrile seizures but now is infrequently used for this due to side effects and lack of efficacy. The use of phenobarbital as an anticonvulsant in children and adolescents has gradually declined due to concerns over its effects on cognitive development. Phenobarbital is now used primarily for neonatal seizures, where it is a recommended first-line therapy. Phenobarbital is also used for neonatal abstinence syndrome in nonopiate- or polydrug-exposed infants. Although not reported with phenobarbital specifically, other anticonvulsants have been associated with an increased risk of suicidal ideation and depression and this is considered a class effect; close monitoring for emerging or worsening of suicidal thoughts/behavior or depression is recommended during therapy. Phenobarbital's label carries an indication for use in pediatric patients (exact age not specified) as an anticonvulsant.
General dosing information:
-Phenobarbital is the first-line therapy for neonatal seizures.
-Phenobarbital has a broad spectrum of activity for various seizure types; however, it has fallen out of favor as a first-line therapy for maintenance treatment of pediatric epilepsy due to adverse effects and the efficacy of newer antiepileptic agents.
-Long-term therapy with phenobarbital is not recommended for the prevention of simple febrile seizures.
For the treatment of status epilepticus:
Neonates: 15 to 20 mg/kg IV over 10 to 15 minutes as a single loading dose initially. Additional 5 to 10 mg/kg bolus doses may be given at 15- to 30-minute intervals for refractory seizures. A maximum total dose of 40 mg/kg has been recommended. Initiate maintenance dose 12 to 24 hours after the loading dose (see maintenance dosage information).
Infants, Children, and Adolescents: 15 to 20 mg/kg IV over 10 to 15 minutes as a single loading dose initially (Max: 1,000 mg/dose). Additional 5 to 10 mg/kg bolus doses may be given at 15- to 30-minute intervals for refractory seizures. A maximum total dose of 40 mg/kg has been recommended. In a case series (n = 50) and case reports (n = 3), very-high-dose phenobarbital (up to 120 mg/kg/day) was used for refractory status epilepticus without a predetermined maximum concentration or dose ; however, aggressive dosing such as this should only be attempted by highly qualified pediatric neurologists. Equipment necessary for resuscitation and artificial ventilation and trained personnel must be readily available. Initiate maintenance dose 12 to 24 hours after the loading dose (see maintenance dosage information).
For the maintenance treatment of seizures (including neonatal seizures, partial seizures, clonic seizures, myoclonic seizures, tonic seizures, or tonic-clonic seizures not responding to other anticonvulsants):
Oral, Intravenous, or Intramuscular dosage:
Neonates: 3 to 4 mg/kg PO or IV/IM once daily initially; titrate to an optimum dose based on patient response and therapeutic concentration. May increase to 5 mg/kg/day if patient response and/or serum concentrations are inadequate.
Infants and Children 6 years and younger: 4 to 8 mg/kg/day PO or IV/IM in 1 to 2 divided doses. Gradually titrate dosage based on patient response and serum concentrations. Dose requirements for phenobarbital decrease with increasing age and are highest in children around 1 year of age and those on concomitant antiepileptic drugs. Studies have shown that doses up to 10 mg/kg/day may be necessary in younger children, particularly those younger than 3 years, to achieve therapeutic concentrations.
Children and Adolescents 7 years and older: 3 to 6 mg/kg/day PO or IV/IM in 1 to 2 divided doses. Gradually titrate dosage based on patient response and serum concentrations.
For neonatal abstinence syndrome*:
Intravenous or Oral dosage:
Neonates: 16 mg/kg PO or IV as a loading dose, then begin maintenance dosing 24 hours later with 1 to 4 mg/kg/dose PO every 12 hours. Adjust maintenance dose to abstinence scores and phenobarbital serum concentration. Once the patient's condition has stabilized, decrease dose by 10% to 20% per day as tolerated until the drug can be discontinued. Phenobarbital is recommended for neonatal abstinence syndrome in nonopiate- or polydrug-exposed infants.
For the treatment of hyperbilirubinemia*:
-for hyperbilirubinemia in neonates:
Oral or Intravenous dosage:
Neonates: 5 mg/kg/day PO or IV in 1 to 2 divided doses for the first few days (3 to 6 days) after birth. A loading dose of 10 mg/kg prior to maintenance therapy has been suggested to achieve steady state faster and improve clinical benefit. A meta-analysis (3 studies) reported a reduction in serum bilirubin concentrations, a decrease in the duration and need for phototherapy, and a decrease in the need for exchange transfusions in preterm very low birth weight neonates who received phenobarbital.
-for the treatment of hyperbilirubinemia due to chronic cholestasis:
Infants, Children, and Adolescents: 3 to 10 mg/kg/day PO in 1 to 2 divided doses. Phenobarbital decreases serum bilirubin concentrations and increases bile acid clearance.
-for the treatment of hyperbilirubinemia due to type II Crigler-Najjar syndrome:
Neonates, Infants, Children, and Adolescents: 5 mg/kg/day PO in 1 to 2 divided doses. Long-term reduction in serum bilirubin concentrations may be necessary to decrease the risk of kernicterus.
For procedural sedation and relief of preoperative anxiety:
Intramuscular or Intravenous dosage:
Infants, Children, and Adolescents: 1 to 3 mg/kg/dose IM or IV 60 to 90 minutes before surgery (Max: 200 mg/dose).
For sedation maintenance, to relieve anxiety, tension, and apprehension:
Infants, Children, and Adolescents: 6 mg/kg/day PO given in 3 divided doses. Max: 120 mg/day.
Therapeutic Drug Monitoring:
Usual target serum concentration: 15-40 mcg/ml
-For the treatment of seizure disorders, blood phenobarbital concentrations should be used to help guide therapy in addition to the patient's clinical response. Most references suggest a therapeutic range of 10-40 mcg/ml; however, most patients require a minimum of 15 mcg/ml to become seizure-free. Some patients with refractory seizures may require blood concentrations above the usual therapeutic range; such cases should be directed/monitored by an experienced pediatric neurologist. Side effects (e.g., sedation) typically begin to appear when blood concentrations exceed 40 mcg/ml. Concentrations > 50 mcg/ml may produce respiratory depression and more pronounced CNS depression; concentrations > 80 mcg/ml may be potentially fatal. While minor sedation occurs initially at concentrations of roughly 5 mcg/ml, this is a transient effect.
-Due to phenobarbital's long half-life, a loading dose is required to achieve therapeutic blood concentrations quickly; in the absence of a loading dose, several weeks of therapy may be required before the appropriate maintenance dose and therapeutic serum concentrations are achieved. In addition, the full effect on a maintenance dose adjustment on blood concentrations will not be seen for several days after the adjustment.
Maximum Dosage Limits:
Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenobarbital concentrations and clinical parameters. For status epilepticus, single doses do not usually exceed 20 mg/kg IV; for anticonvulsant maintenance treatment, doses above 5 mg/kg/day are not usually necessary.
Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenobarbital concentrations and clinical parameters. For status epilepticus, single doses do not usually exceed 20 mg/kg IV; for anticonvulsant maintenance treatment, doses above 10 mg/kg/day are not usually necessary.
Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenobarbital concentrations and clinical parameters. For status epilepticus, single doses do not usually exceed 20 mg/kg IV (Max: 1000 mg/dose); for anticonvulsant maintenance treatment, doses above 8 (> 6 years) to 10 mg/kg/day (<= 6 years) are not usually necessary.
Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenobarbital concentrations and clinical parameters. For status epilepticus, single doses do not usually exceed 20 mg/kg IV (Max: 1000 mg/dose); for anticonvulsant maintenance treatment, doses above 6 mg/kg/day are not usually necessary.
Patients with Hepatic Impairment Dosing
Modify initial dose depending on degree of hepatic impairment; no quantitative recommendations are available. Initiate dose cautiously and adjust based on clinical response and serum concentrations.
Patients with Renal Impairment Dosing
CrCl >= 10 ml/min: No dosage adjustment needed.
CrCl < 10 ml/min: Decrease dose by 50% and administer every 24 hours.
Phenobarbital is efficiently removed by hemodialysis. Dosage schedules should be adjusted so that the timing of a normally administered dosage is given after the hemodialysis session.
Peritoneal dialysis (as CAPD) removes phenobarbital by roughly 40-50% (not as efficient as drug removal as hemodialysis); no quantitative recommendations for dose adjustment are available. Some references have suggested that 50% of a normal dose be given after a CAPD session.
Monograph content under development
Mechanism of Action: In general, barbiturates are non-selective CNS depressants with sedative-hypnotic actions. Only certain barbiturates, like phenobarbital, confer additional anticonvulsant actions. With phenobarbital, a relatively high therapeutic index has contributed to its wide use as an anticonvulsant versus other barbiturate drugs. Phenobarbital, like other barbiturates, may cause CNS depression in various degrees ranging from mild sedation (at normal doses) to general anesthesia or coma (such as with overdosage). With sufficient intoxication (i.e., overdose), all barbiturates can induce peripheral and central depression of respiratory drive, a fall in blood pressure, cardiovascular compromise and other effects.
-Anticonvulsant actions: Phenobarbital inhibits the spread of seizure activity in the cortex, thalamus, and limbic systems, and increases the threshold for electrical stimulation of the motor cortex. There is a decrease in both pre- and postsynaptic excitability. The inhibition of seizure activity occurs primarily at synapses where GABA and GABA-A receptors mediate neurotransmission. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes; GABA-A is the primary receptor subtype in the CNS. Barbiturates augment GABA responses by promoting the binding of GABA to the receptor and increasing the length of time that chloride channels are open. The mechanism is distinct from the benzodiazepines, which increase the frequency of channel openings. Phenobarbital also appears to reduce the effects of glutamate and also inhibits neurotransmitter release from nerve terminals, an effect that is mediated by depression of voltage-dependent calcium channels. All actions result in a hyperpolarized cell membrane that prevents further excitation of the cell. Compared to pentobarbital, phenobarbital is a less potent enhancer of GABA responses and a less potent inhibitor of calcium currents. The differences in pharmacology probably explain why phenobarbital displays anticonvulsant activity with minimal sedation versus pentobarbital, which produces marked sedation and CNS depression at anticonvulsant dosages.
-Hypnotic effects: Sedative-hypnotic effects of barbiturates are believed to be a result of activity on GABA in the polysynaptic midbrain reticular formation, which controls CNS arousal. In the presence of pain, the ability of the barbiturates to produce sedation may be reduced. During chronic administration, tolerance to sedative-hypnotic effects occurs quickly within a few days time and the effects may be significantly reduced within 2 weeks of use. The development of tolerance indicates that barbiturates should only be considered for short term relief for acute sedation.
-Other actions: Because it induces glucuronyl transferase and hepatic bilirubin-binding Y protein, phenobarbital has been used to lower serum bilirubin concentrations in neonates and patients with chronic cholestasis. Phenobarbital induces the activity of numerous hepatic enzymes, including those of the cytochrome P450 oxidases.
-Tolerance, abuse and dependence: Tolerance to barbiturates often confers tolerance to all CNS-depressant drugs (e.g., ethanol, others). As with other CNS-depressant drugs, selected individuals may abuse or become physically and psychologically dependent on barbiturates. Some patients may experience euphoria or paradoxic excitement with use. Tolerance generally develops to the effects on mood, sleep and sedation but not to anticonvulsant or lethal effects.
Pharmacokinetics: Phenobarbital is usually administered orally, or by intramuscular or intravenous injection. Bioavailability is similar for all routes of administration. Distribution of phenobarbital is less rapid than that of other barbiturates because it is less lipid-soluble, but the drug is found in all tissues and fluids, including adipose tissue and cerebrospinal fluid. Only unionized drug crosses the blood brain barrier; acidosis can increase the pharmacologic effect of phenobarbital by increasing the concentration of unionized drug. Phenobarbital has a biphasic distribution. Volume of distribution in children ranges from 0.6 to 1.2 L/kg. About 15% to 55% of phenobarbital is bound to plasma proteins, with protein binding increasing with age. Approximately 25% to 50% of phenobarbital is eliminated unchanged in the urine, but the excretion is pH-dependent. Increasing the urinary flow rate or alkalinizing the urine will increase the rate of excretion of unchanged phenobarbital. The remainder of the dose (roughly 50% to 75%) is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1. There is no clear evidence that phenobarbital accelerates its own metabolism. The metabolites are excreted as the p-hydroxy metabolite, the glucuronide, and sulfate conjugates.
Phenobarbital is the longest acting of all the commercially available barbiturates; the half-life in children ranges from 37 to 69 hours, which is shorter than that of adults (53 to 118 hours). In the absence of a loading dosage, several weeks of therapy may be required to achieve steady-state plasma concentrations. Therapeutic plasma concentrations (for anticonvulsant activity) are roughly 10 to 40 mcg/mL. Plasma concentrations greater than 50 mcg/mL may produce coma or respiratory depression; and concentrations above 80 mcg/mL are potentially fatal.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP2C19, CYP2E1, CYP1A2, CYP3A4, UGT1A1, other UGT enzymes, and P-glycoprotein (P-gp)
Phenobarbital is inactivated by the liver, primarily via CYP2C9, with minor metabolism by CYP2C19 and 2E1. Importantly, phenobarbital may accelerate the clearance of other drugs metabolized via hepatic microsomal enzymes (e.g., UGT (UDP-glucuronosyltransferase), CYP2C-family enzymes, CYP3A-family enzymes, and CYP1A2); coadministration may result in significant drug interactions. Phenobarbital is also a strong inducer of the P-glycoprotein (P-gp) drug transporter.
Onset of action after oral administration is at least 1 hour with a duration of action of 10 to 12 hours. Time to achieve peak concentration is 3 hours in infants and young children and 9 hours in neonates.
Onset of action after IV administration is approximately 5 minutes. Maximum CNS depression may not occur until 15 minutes or longer after administration.
Onset of action after IM administration is slower than after onset for IV administration. Maximum CNS depression may not occur until 15 minutes or longer after administration.
Higher plasma concentrations of phenobarbital are achieved after IM administration than after oral administration in neonates. Little difference has been reported for other pediatric populations. Absorption is delayed after oral administration in neonates with a Tmax of 9 hours. After IM administration, the Tmax ranges from 7 to 40 hours in premature neonates and 30 minutes to 27 hours in full term neonates. Protein binding is 25% to 50% less in neonates compared to older children and is even lower in hyperbilirubinemic neonates; this results in a higher phenobarbital free fraction. Volume of distribution in neonates is larger than in other populations (approximately 0.7 to 1.2 L/kg), and is not affected by gestational age or birthweight. The elimination half-life is highly variable and ranges from 45 to 409 hours.
Infants and Children
Peak concentrations are achieved 3 hours after oral administration and 45 minutes to 6 hours after IM administration in infants and children. The volume of distribution is approximately 0.6 to 0.9 L/kg in infants and 0.6 to 0.7 L/kg in children. The elimination half-life ranges from 47 to 63 hours in infants and 37 to 69 hours in children.