Phenobarbital Sodium

Description

DESCRIPTION The barbiturates are nonselective central nervous system (CNS) depressants which are primarily used as sedative hypnotics and also anticonvulsants in subhypnotic doses. The barbiturates and their sodium salts are subject to control under the Federal Controlled Substances Act (CIV). Barbiturates are substituted pyrimidine derivatives in which the basic structure common to these drugs is barbituric acid, a substance which has no central nervous system activity. CNS activity is obtained by substituting alkyl, alkenyl or aryl groups on the pyrimidine ring. Phenobarbital Sodium Injection, USP is a sterile solution for intramuscular or slow intravenous administration as a long-acting barbiturate. Each mL contains phenobarbital sodium either 65 mg or 130 mg, alcohol 0.1 mL, propylene glycol 0.678 mL and benzyl alcohol 0.015 mL in Water for Injection; hydrochloric acid added, if needed, for pH adjustment. The pH range is 9.2-10.2. Chemically, phenobarbital sodium is 2,4,6(1 H ,3 H ,5 H )-Pyrimidinetrione,5-ethyl-5-phenyl-, monosodium salt and has the following structural formula: C12 H 11 N 2 NaO 3 MW 254.22 The sodium salt of phenobarbital occurs as a white, slightly bitter powder, crystalline granules or flaky crystals; it is soluble in alcohol and practically insoluble in ether or chloroform.

What Is Phenobarbital Sodium Used For?

INDICATIONS AND USAGE Parenteral Sedative. Sedation is obtainable within an hour, and in adequate dosage, the duration of action is more than six hours. Included in the more common conditions in which the sedative action of this class of drugs is desired are anxiety-tension states, hyperthyroidism, essential hypertension, nausea and vomiting of functional origin, motion sickness, acute labyrinthitis, pylorospasm in infants, chorea and cardiac failure. Phenobarbital is also a useful adjunct in treatment of hemorrhage from the respiratory or gastrointestinal tract. Phenobarbital controls anxiety, decreases muscular activity and lessens nervous excitability in hyperthyroid patients. However, thyrotoxic individuals occasionally react poorly to barbiturates. Hypnotic, for the short-term treatment of insomnia, since it appears to lose its effectiveness for sleep induction and sleep maintenance after 2 weeks (see CLINICAL PHARMACOLOGY ). Preanesthetic. Long-term anticonvulsant, (phenobarbital, mephobarbital and metharbital) for the treatment of generalized tonic-clonic and cortical focal seizures. And, in the emergency control of certain acute convulsive episodes, e.g., those associated with status epilepticus, cholera, eclampsia, cerebral hemorrhage, meningitis, tetanus, and toxic reactions to strychnine or local anesthetics. Phenobarbital sodium may be administered intramuscularly or intravenously as an anticonvulsant for emergency use. When administered intravenously, it may require 15 or more minutes before reaching peak concentrations in the brain. Therefore, injecting phenobarbital sodium until the convulsions stop may cause the brain level to exceed that required to control the convulsions and lead to severe barbiturate-induced depression. Phenobarbital is indicated in pediatric patients as an anticonvulsant and as a sedative, including its preoperative and postoperative use.

Dosage and Administration

DOSAGE AND ADMINISTRATION Dosages of barbiturates must be individualized with full knowledge of their particular characteristics and recommended rates of administration. Factors to consider are the patient's age, weight and condition. Suggested doses of phenobarbital sodium for specific indications follow: Pediatric Dosage Recommended by the American Academy of Pediatrics (intended as a guide) Preoperative Sedation: 1 to 3 mg/kg IM or IV Anticonvulsant: 4 to 6 mg/kg/day for 7 to 10 days to blood level of 10 to 15 mcg/mL or 10 to 15 mg/kg/day IM or IV Status Epilepticus: 15 to 20 mg/kg over 10 to 15 minutes IV Adult Dosage (intended as a guide) Daytime Sedation: 30 to 120 mg daily in 2 to 3 divided doses IM or IV Bedtime Hypnosis: 100 to 320 mg IM or IV Preoperative Sedation: IM only — 100 to 200 mg 60 to 90 minutes before surgery Acute Convulsions: 20 to 320 mg IM or IV, repeated in 6 hours as necessary Parenteral routes should be used only when oral administration is impossible or impractical. Intramuscular injection of the sodium salts of barbiturates should be made deeply into a large muscle and a volume of 5 mL should not be exceeded at any one site because of possible tissue irritation. Injection into or near peripheral nerves may result in permanent neurological deficit. After intramuscular injection of a hypnotic dose, the patient's vital signs should be monitored. Subcutaneous administration is not recommended (see CONTRAINDICATIONS ). Intravenous Administration Intravenous injection is restricted to conditions in which other routes are not feasible, either because the patient is unconscious (as in cerebral hemorrhage, eclampsia or status epilepticus), or because the patient resists (as in delirium) or because prompt action is imperative. Slow IV injection is essential, and patients should be carefully observed during administration. This requires that blood pressure, respiration and cardiac function be maintained, vital signs be recorded and equipment for resuscitation and artificial ventilation be available. The rate of intravenous injection for adults should not exceed 60 mg/min for phenobarbital sodium. When given intravenously, do not use small veins, such as those on the dorsum of the hand or wrist. Preference should be given to a larger vein to minimize the risk of irritation with the possibility of resultant thrombosis. Avoid administration into varicose veins because circulation there is retarded. Inadvertent injection into or adjacent to an artery has resulted in gangrene requiring amputation of an extremity or a portion thereof. Careful technique, including aspiration, is necessary to avoid inadvertent intraarterial injection. (See below.) Treatment of Adverse Effects Due to Inadvertent Error in Administration Extravasation into subcutaneous tissues causes tissue irritation. This may vary from slight tenderness and redness to necrosis. Recommended treatment includes the application of moist heat and the injection of 0.5%...

Side Effects (Adverse Reactions)

ADVERSE REACTIONS The following adverse reactions and their incidence were compiled from surveillance of thousands of hospitalized patients. Because such patients may be less aware of certain of the milder adverse effects of barbiturates, the incidence of these reactions may be somewhat higher in fully ambulatory patients. Nervous System Somnolence, agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, thinking abnormality Respiratory System Hypoventilation, apnea Cardiovascular System Bradycardia, hypotension, syncope Digestive System Nausea, vomiting, constipation Dermatologic Reactions Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermic necrolysis. Other Reported Reactions Headache; injection site reactions; hypersensitivity reactions, including but not limited to angioedema and skin rashes; fever; liver damage and megaloblastic anemia following chronic phenobarbital use.

Drug Interactions

Drug Interactions Most reports of clinically significant drug interactions occuring 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 (bishydroxycoumarin) 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., warfarin, acenocoumarol, 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 thier 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, while 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 appear to decrease barbiturate metabolism; therefore, barbiturate blood levels should be monitored and appropriate dosage adjustments made as indicated. Central Nervous System Depressants The concomitant use of other central nervous system 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...

Contraindications

CONTRAINDICATIONS Barbiturates are contraindicated in patients with known barbiturate sensitivity. Barbiturates are also contraindicated in patients with a history of manifest or latent porphyria, marked impairment of liver functions or with severe respiratory distress where dyspnea or obstruction is evident. Large doses are contraindicated in nephritic subjects. Barbiturates should not be administered to persons with known previous addiction to the sedative-hypnotic group since ordinary doses may be ineffectual and may contribute to further addiction. Intraarterial administration is contraindicated. Its consequences vary from transient pain to gangrene. Subcutaneous administration produces tissue irritation, ranging from tenderness and redness to necrosis and is not recommended. (See DOSAGE AND ADMINISTRATION, Treatment of Adverse Effects Due to Inadvertent Error in Administration .)

Pregnancy and Breastfeeding

Pregnancy Teratogenic Effects-Pregnancy Category D Phenobarbital may cause major fetal malformations. (See WARNINGS, Use in Pregnancy .) Nonteratogenic Effects Reports of infants suffering from long-term barbiturate exposure in utero included the acute withdrawal syndrome of seizures and hyperirritability from birth to a delayed onset of up to 14 days. (See DRUG ABUSE AND DEPENDENCE . )

Nursing Mothers Caution should be exercised when a barbiturate is administered to a nursing woman since small amounts of barbiturates are excreted in the milk.

Overdosage

OVERDOSAGE The toxic dose of barbiturates varies considerably. Barbiturate intoxication may be confused with alcoholism, bromide intoxication and various neurological disorders. For sedation, therapeutic blood levels of phenobarbital range from 5-40 μg/mL; the lethal blood level is greater than 80 μg/mL and usually ranges from 100-200 μg/mL. Acute overdosage with barbiturates is manifested by CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning, they may show paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest and death) may occur. In extreme overdose, all electrical activity in the brain may cease, in which case a "flat" EEG normally equated with clinical death cannot be accepted. This effect is fully reversible unless hypoxic damage occurs. Consideration should be given to the possibility of barbiturate intoxication even in situations that appear to involve trauma. Complications such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure and renal failure may occur. Uremia may increase CNS sensitivity to barbiturates if renal function is impaired. Differential diagnosis should include hypoglycemia, head trauma, cerebrovascular accidents, convulsive states and diabetic coma. To obtain up-to-date information about the treatment of overdosage, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdose, interaction among drugs and the unusual drug kinetics in your patient. Treatment of overdosage is mainly supportive and consists of the following: Maintenance of an adequate airway, with assisted respiration and oxygen administration as...

How Supplied

HOW SUPPLIED Phenobarbital Sodium Injection, USP is available in the following: 65 mg/mL, 1 mL vials packaged in 25s (NDC 72162-1329-2) 65 mg/mL, 1 mL vials packaged in 3s (NDC 72162-1329-4) Storage Store at 20°-25°C (68°-77°), excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. Do not use if solution is discolored or contains a precipitate. To report SUSPECTED ADVERSE REACTIONS, contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504