Phenobarbital Sodium Injection (CIV) 130 mg/mL

INDICATIONS AND USAGE Parenteral

1. 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.
2. Hypnotic, for the short-term treatment of insomnia, since it appears to lose its effectiveness for sleep induction and sleep maintenance after 2 weeks (seeCLINICAL PHARMACOLOGY).
3. Preanesthetic.
4. 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.
5. Phenobarbital is indicated in pediatric patients as an anticonvulsant and as a sedative, including its preoperative and postoperative use.

PRECAUTIONS

General

Untoward reactions may occur in the presence of fever, hyperthyroidism, diabetes mellitus and severe anemia. In cases of great debility, severely impaired liver function, pulmonary or cardiac disease, status asthmaticus, shock or uremia, phenobarbital sodium should be used with extreme caution. Intramuscular injection should be confined to a total volume of 5 mL and made in a large muscle in order to avoid possible tissue irritation.

Barbiturates may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (seeDRUG ABUSE AND DEPENDENCE). Barbiturates should be administered with caution, if at all, to patients who are mentally depressed, have suicidal tendencies or a history of drug abuse.

Elderly or debilitated patients may react to barbiturates with marked excitement, depression and confusion. In some persons, barbiturates repeatedly produce excitement rather than depression.

In patients with hepatic damage, barbiturates should be administered with caution and initially in reduced doses. Barbiturates should not be administered to patients showing the premonitory signs of hepatic coma.

Parenteral solutions of barbiturates are highly alkaline. Therefore, extreme care should be taken to avoid perivascular extravasation or intraarterial injection. Extravascular injection may cause local tissue damage with subsequent necrosis; consequences of intraarterial injection may vary from transient pain to gangrene of the limb. Any complaint of pain in the limb warrants stopping the injection.

Information for the Patient

Practitioners should give the following information and instructions to patients receiving barbiturates:

1. The use of barbiturates carries with it an associated risk of psychological and/or physical dependence. The patient should be warned against increasing the dose of the drug without consulting a physician.
2. Barbiturates may impair mental and/or physical abilities required for the performance of potentially hazardous tasks (e.g., driving, operating machinery, etc.).
3. Alcohol should not be consumed while taking barbiturates. Concurrent use of the barbiturates with other CNS depressants (e.g., alcohol, narcotics, tranquilizers and antihistamines) may result in additional CNS depressant effects.
4. If phenobarbital is used during pregnancy, the patient should be apprised of the potential hazard to the fetus (see WARNINGS).

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 its metabolism. There have been reports of patients treated with antiepileptic drugs (e.g., phenobarbital) who became pregnant while taking oral contraceptives. An alternate contraceptive method might be suggested to women taking phenobarbital.

Drug/Laboratory Test Interactions

Prolonged therapy with barbiturates should be accompanied by periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic systems (see PRECAUTIONS, Generaland ADVERSE REACTIONS).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal Data

Phenobarbital sodium is carcinogenic in mice and rats after lifetime administration. In mice, it produced benign and malignant liver-cell tumors. In rats, benign liver-cell tumors were observed very late in life.

Human Data

In an epidemiological study of 9,136 patients who were treated on an anticonvulsant protocol which included phenobarbital, results indicated a higher than normal incidence of hepatic carcinoma.

Previously, some of these patients were treated with thorotrast, a drug which is known to produce hepatic carcinomas. Thus, this study did not provide sufficient evidence that phenobarbital is carcinogenic in humans. A retrospective study of 84 children with brain tumors matched to 73 normal controls and 78 cancer controls (malignant disease other than brain tumors) suggested an association between exposure to barbiturates prenatally and an increased incidence of brain tumors.

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 uteroincluded the acute withdrawal syndrome of seizures and hyperirritability from birth to a delayed onset of up to 14 days. (SeeDRUG ABUSE AND DEPENDENCE****.)

Labor And Delivery

Hypnotic doses of barbiturates do not appear to significantly impair uterine activity during labor. Full anesthetic doses of barbiturates decrease the force and frequency of uterine contractions. Administration of sedative- hypnotic barbiturates to the mother during labor may result in respiratory depression in the newborn. Premature infants are particularly susceptible to the depressant effects of barbiturates. If barbiturates are used during labor and delivery, resuscitation equipment should be available.

Barbiturates are additive with other central nervous system depressants administered during labor and delivery. Data are currently not available to evaluate the effect of barbiturates when forceps delivery or other intervention is necessary or to determine the long-term effects of obstetrically administered barbiturates on the later growth, development and functional maturation of the child.

While barbiturates are usually reported to have a minimal effect on neonatal behavior, a delayed interest in breastfeeding and a depressed response to auditory and visual stimuli have been noted.

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.

WARNINGS

Phenobarbital Sodium Injection contains the preservative benzyl alcohol and is not recommended for use in neonates. There have been reports of fatal 'gasping syndrome' in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.

Habit Forming

Barbiturates may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (seeDRUG ABUSE AND DEPENDENCEand CLINICAL PHARMACOLOGY). Patients who are psychologically dependent on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. To minimize the possibility of overdosage or the development of dependence, the prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment. Abrupt cessation after prolonged use in the dependent person may result in withdrawal symptoms, including delirium, convulsions and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive dosage over long periods of time (seeDRUG ABUSE AND DEPENDENCE).

Dermatologic Reactions

Exfoliative dermatitis and Stevens-Johnson syndrome, possibly fatal, are rare hypersensitivity reactions to phenobarbital. Physicians should be alert to signs which may precede the onset of barbiturate- induced cutaneous lesions, and the drug should be discontinued whenever dermatological reactions occur.

Intravenous Administration

Too rapid administration may cause severe respiratory depression, apnea, laryngospasm, hypertension or vasodilation with fall in blood pressure.

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 brain levels to exceed that required to control the convulsions and lead to severe barbiturate-induced depression.

Acute or Chronic Pain

Caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. However, the use of barbiturates as sedatives in the postoperative surgical period and as adjuncts to cancer chemotherapy is well established.

Use in Pregnancy

Barbiturates can cause fetal harm when administered to a pregnant woman. Retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. Phenobarbital may cause major fetal malformations.

Following oral or parenteral administration, barbiturates readily cross the placental barrier and are distributed throughout fetal tissues with highest concentrations found in the placenta, fetal liver and brain. Fetal blood levels approach maternal blood levels following parenteral administration.

Withdrawal symptoms occur in infants born to mothers who receive barbiturates throughout the last trimester of pregnancy (seeDRUG ABUSE AND DEPENDENCE).

Phenobarbital should be used during pregnancy only when clearly indicated. If phenobarbital is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus.

Use in Children

Phenobarbital has been reported to be associated with cognitive defects in children taking it for complicated febrile seizures.

Synergistic Effects

The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects.

HOW SUPPLIED

Phenobarbital Sodium Injection, USP is available in the following:

• 130 mg/mL, 1 mL vials (NDC 72162-1330-6) packaged in 25s (NDC 72162-1330-4)
• 130 mg/mL, 1 mL vials (NDC 72162-1330-8) packaged in 3s (NDC 72162-1330-2)

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.

Repackaged/Relabeled by:
Bryant Ranch Prepack, Inc.
Burbank, CA 91504

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:

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.