PHENOBARBITAL

The barbiturates are nonselective central nervous system (CNS) depressants that are primarily used as sedative-hypnotics. In subhypnotic doses, they are also used as anticonvulsants. The barbiturates and their sodium salts are subject to control under the Federal Controlled Substances Act. Phenobarbital is a barbituric acid derivative and occurs as white, odorless, small crystals or crystalline powder that is very slightly soluble in water; soluble in alcohol, in ether, and in solutions of fixed alkali hydroxides and carbonates; sparingly soluble in chloroform. Phenobarbital is 5-ethyl-5-phenylbarbituric acid. Phenobarbital is a substituted pyrimidine derivative in which the basic structure is barbituric acid, a substance that has no CNS activity. CNS activity is obtained by substituting alkyl, alkenyl, or aryl groups on the pyrimidine ring. It has the following structural formula: Each phenobarbital tablet contains 16.2 mg, 32.4 mg, 64.8 mg or 97.2 mg of phenobarbital. In addition each tablet contains: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. This is the image of the structual formula for Phenobarbital.

Sedative Anticonvulsant – For the treatment of generalized and partial seizures.

The dose of phenobarbital must be individualized with full knowledge of its particular characteristics. Factors of consideration are the patient’s age, weight, and condition. Sedation: For sedation, the drug may be administered in single dose of 30 to 120 mg repeated at intervals: frequency will be determined by the patient’s response. It is generally considered that no more than 400 mg of phenobarbital should be administered during a 24-hour period. Adults: Daytime Sedation: 30 to 120 mg daily in 2 to 3 divided doses. Oral Hypnotic: 100 to 200 mg. Anticonvulsant Use – Clinical laboratory reference values should be used to determine the therapeutic anticonvulsant level of phenobarbital in the serum. To achieve the blood levels considered therapeutic in pediatric patients, higher per-kilogram dosages are generally necessary for phenobarbital and most other anticonvulsants. In children and infants, phenobarbital at a loading dose of 15 to 20 mg/kg produces blood levels of about 20 mcg/mL shortly after administration. Phenobarbital has been used in the treatment and prophylaxis of febrile seizures. However, it has not been established that prevention of febrile seizures influences the subsequent development of epilepsy. Adults: 60 to 200 mg/day. Pediatric Patients: 3 to 6 mg/kg/day. Special Patient Population – Dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. Dosage should be reduced for patients with impaired renal function or hepatic disease.

Phenobarbital is contraindicated in patients who are hypersensitive to barbiturates, in patients with a history of manifest or latent porphyria, and in patients with marked impairment of liver function or respiratory disease in which dyspnea or obstruction is evident.

The following adverse reactions have been reported: CNS Depression – Residual sedation or “hangover”, drowsiness, lethargy, and vertigo. Emotional disturbances and phobias may be accentuated. In some persons, barbiturates such as phenobarbital repeatedly produce excitement rather than depression, and the patient may appear to be inebriated. Irritability and hyperactivity can occur in children. Like other nonanalgesic hypnotic drugs, barbiturates such as phenobarbital, when given in the presence of pain, may cause restlessness, excitement, and even delirium. Rarely, the use of barbiturates results in localized or diffuse myalgic, neuralgic, or arthritic pain, especially in psychoneurotic patients with insomnia. The pain may appear in paroxysms, is most intense in the early morning hours, and is most frequently located in the region of the neck, shoulder girdle, and upper limbs. Symptoms may last for days after the drug is discontinued. Respiratory/Circulatory – Respiratory depression, apnea, circulatory collapse. Allergic – Acquired hypersensitivity to barbiturates consists chiefly in allergic reactions that occur especially in persons who tend to have asthma, urticaria, angioedema, and similar conditions. Hypersensitivity reactions in this category include localized swelling, particularly of the eyelids, cheeks, or lips, and erythematous dermatitis. Rarely, exfoliative dermatitis (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) may be caused by phenobarbital and can prove fatal. The skin eruption may be associated with fever, delirium, and marked degenerative changes in the liver and other parenchymatous organs. In a few cases, megaloblastic anemia has been associated with the chronic use of phenobarbital. Other – Nausea and vomiting; headache, osteomalacia. The following adverse reactions and their incidence were compiled from surveillance of thousands of hospitalized patients who received barbiturates. Because such patients may be less aware of the milder adverse effects of barbiturates, the incidence of these reactions may be somewhat higher in fully ambulatory patients. More than 1 in 100 Patients: The most common adverse reaction, estimated to occur at a rate of 1 to 3 patients per 100, is: Nervous System: Somnolence Less than 1 in 100 Patients: Adverse reactions estimated to occur at a rate of less than 1 in 100 patients are listed below, grouped by organ system and by decreasing order of occurrence: Nervous System: Agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, abnormality in thinking Respiratory System: Hypoventilation, apnea Cardiovascular System: Bradycardia, hypotension, syncope Digestive System: Nausea, vomiting, constipation Other Reported Reactions: Headache, injection site reactions, hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic phenobarbital use To report SUSPECTED ADVERSE REACTIONS, contact e5 Pharma, LLC at 1-561-288-4885, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital. However, the application of these data to other barbiturates appears valid and warrants serial blood level determinations of the relevant drugs when there are multiple therapies. Anticoagulants. Phenobarbital lowers the plasma levels of dicumarol and causes a decrease in anticoagulant activity as measured by the prothrombin time. Barbiturates can induce hepatic microsomal enzymes resulting in increased metabolism and decreased anticoagulant response of oral anticoagulants (e.g., acenocoumarol, warfarin, dicumarol, and phenprocoumon). Patients stabilized on anticoagulant therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. Corticosteroids. Barbiturates appear to enhance the metabolism of exogenous corticosteroids, probably through the induction of hepatic microsomal enzymes. Patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen. Griseofulvin. Phenobarbital appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. The effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. However, it would be preferable to avoid concomitant administration of these drugs. Doxycycline. Phenobarbital has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. This mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. If phenobarbital and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely. Phenytoin, Sodium Valproate, Valproic Acid. The effect of barbiturates on the metabolism of phenytoin appears to be variable. Some investigators report an accelerating effect, whereas others report no effect. Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid increase the phenobarbital serum levels; therefore, phenobarbital blood levels should be closely monitored and appropriate dosage adjustments made as clinically indicated. CNS Depressants. The concomitant use of other CNS depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects. Monoamine Oxidase Inhibitors (MAOIs). MAOIs prolong the effects of barbiturates, probably because metabolism of the barbiturate is inhibited. Estradiol, Estrone, Progesterone, and other Steroidal Hormones. Pretreatment with or concurrent administration of phenobarbital may decrease the effect of estradiol by increasing its metabolism. There have been reports of patients treated with antiepileptic drugs (e.g., phenobarbital) who become pregnant while taking oral contraceptives. An alternate contraceptive method might be suggested to women taking phenobarbital.