PHENOBARBITAL SODIUM injection

Drug Details [pdf]

SPL UNCLASSIFIED SECTION

CIV
FOR IM OR SLOW IV ADMINISTRATION
DO NOT USE IF SOLUTION IS DISCOLORED OR CONTAINS A PRECIPITATE

Rx only
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(1H,3H,5H)-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.
CLINICAL PHARMACOLOGY

Barbiturates are capable of producing all levels of CNS mood alteration from excitation to mild sedation, to hypnosis, and deep coma. Overdosage can produce death. In high enough therapeutic doses, barbiturates induce anesthesia. Barbiturates depress the sensory cortex, decrease motor activity, alter cerebellar function and produce drowsiness, sedation and hypnosis.

Barbiturate-induced sleep differs from physiological sleep. Sleep laboratory studies have demonstrated that barbiturates reduce the amount of time spent in the rapid eye movement (REM) phase of sleep or dreaming stage. Also, Stages III and IV sleep are decreased. Following abrupt cessation of barbiturates used regularly, patients may experience markedly increased dreaming, nightmares and/or insomnia. Therefore, withdrawal of a single therapeutic dose over 5 or 6 days has been recommended to lessen the REM rebound and disturbed sleep which contribute to drug withdrawal syndrome (for example, decrease the dose from 3 to 2 doses a day for 1 week).

In studies, secobarbital sodium and pentobarbital sodium have been found to lose most of their effectiveness for both inducing and maintaining sleep by the end of 2 weeks of continued drug administration even with the use of multiple doses. The short-, intermediate- and to a lesser degree, long-acting barbiturates have been widely prescribed for treating insomnia. Although the clinical literature abounds with claims that the short-acting barbiturates are superior for producing sleep while the intermediate-acting compounds are more effective in maintaining sleep, controlled studies have failed to demonstrate these differential effects. Therefore, as sleep medications, the barbiturates are of limited value beyond short-term use.

Barbiturates have little analgesic action at subanesthetic doses. Rather, in subanesthetic doses these drugs may increase the reaction to painful stimuli. All barbiturates exhibit anticonvulsant activity in anesthetic doses.

Barbiturates are respiratory depressants by virtue of their direct effect on the medullary respiratory center. They diminish and, in high doses, may abolish the sensitivity of the respiratory center to its normal stimulus, carbon dioxide. The degree of respiratory depression is dependent upon dose. With hypnotic doses, respiratory depression produced by barbiturates is similar to that which occurs during physiologic sleep with slight decrease in blood pressure and heart rate.

Ordinary hypnotic doses of barbiturates have no significant effect on the cardiovascular system. The barbiturates tend to decrease the tonus of the gastrointestinal musculature. They have no direct injurious effect on the normal kidney. Severe oliguria or anuria may occur in acute barbiturate poisoning, largely as a result of the marked hypotension.

Hypnotic doses tend to reduce slightly the metabolic rate in man. Body temperature is reduced slightly, owing to lessened activity and to depression of the central temperature-regulatory mechanisms.

While anesthetic doses of all barbiturates exert an anticonvulsant effect, phenobarbital has a selective anticonvulsant activity independent of the degree of sedation produced. Phenobarbital limits the spread of seizures and raises the seizure threshold in grand mal (generalized tonic-clonic) epilepsy.

Studies in laboratory animals have shown that barbiturates cause reduction in the tone and contractility of the uterus, ureters and urinary bladder. However, concentrations of the drugs required to produce this effect in humans are not reached with sedative-hypnoticdoses.

Barbiturates do not impair normal hepatic function, but have been shown to induce liver microsomal enzymes, thus increasing and/or altering the metabolism of barbiturates and other drugs. (See PRECAUTIONS, Drug Interactions.)

Following IV administration, the onset of action is 5 minutes for phenobarbital sodium. For IM administration, the onset of action is slightly slower. Maximal CNS depression may not occur until 15 minutes or more after IV administration.

Duration of action, which is related to the rate at which the barbiturates are redistributed throughout the body, varies among persons and in the same person from time to time.

No studies have demonstrated that the different routes of administration are equivalent with respect to bioavailability.

Barbiturates are weak acids that are absorbed and rapidly distributed to all tissues and fluids with high concentrations in the brain, liver and kidneys. Lipid solubility of the barbiturates is the dominant factor in their distribution within the body. The more lipid soluble the barbiturate, the more rapidly it penetrates all tissues of the body. Barbiturates are bound to plasma and tissue proteins to a varying degree with the degree of binding increasing directly as a function of lipid solubility.

Phenobarbital has the lowest lipid solubility, lowest plasma binding, lowest brain protein binding, the longest delay in onset of activity and the longest duration of action. Its diffusion across the blood-brain barrier and its distribution into other tissues occurs more slowly than with other short-acting barbiturates. Fifteen minutes or more may be required for maximal central depression following intravenous administration of phenobarbital. However, with time, phenobarbital distributes into all tissues and fluids. Barbiturates are known to cross the placenta. Phenobarbital is 20-45% protein bound. In adults, the plasma half-life of phenobarbital is 53 to 118 hours (mean 79 hours) and in children/newborns, the plasma half-life is 60 to 180 hours (mean 110 hours).

Barbiturates are metabolized primarily by the hepatic microsomal enzyme system, and the metabolic products are excreted in the urine and, less commonly, in the feces. Approximately 25 to 50 percent of a dose of phenobarbital is eliminated unchanged in the urine, whereas the amount of other barbiturates excreted unchanged in the urine is negligible. Urinary pH and rate of urine flow affect the renal circulation of unchanged phenobarbital, a greater quantity being eliminated in alkaline urine and at increased flow rates. The excretion of unmetabolized barbiturate is one feature that distinguishes the long-acting category from those belonging to other categories which are almost entirely metabolized. The inactive metabolites of the barbiturates are excreted as conjugates of glucuronic acid.
INDICATIONS AND USAGE

Parenteral

a. 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.

b. 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).

c. Preanesthetic.

d. 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.

e. Phenobarbital is indicated in pediatric patients as an anticonvulsant and as a sedative, including its preoperative and postoperative use.

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 (see DRUG 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:

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.
Barbiturates may impair mental and/or physical abilities required for the performance of potentially hazardous tasks (e.g., driving, operating machinery, etc.).
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.
If phenobarbital is used during pregnancy, the patient should be apprised of the potential hazard to the fetus (see CONTRAINDICATIONS).

Drug Interactions

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 (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, General and 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 CONTRAINDICATIONS, 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.)

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.

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