Phenobarbital Sodium Injection

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. As with secobarbital sodium and pentobarbital sodium, other barbiturates might be expected to lose their effectiveness for inducing and maintaining sleep after about 2 weeks. 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-hypnotic doses.

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.

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. 

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

    Anticonvulsion: 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% procaine solution into the affected area.

Intraarterial injection of any barbiturate must be avoided. The accidental intraarterial injection of a small amount of the solution may cause spasm and severe pain along the course of the artery. The injection should be terminated if the patient complains of pain or if other indications of accidental intraarterial injection occur, such as a white hand with cyanosed skin or patches of discolored skin and delayed onset of hypnosis.

The consequences of intraarterial injection of phenobarbital can vary from transient pain to gangrene. It is not possible to formulate strict rules for management of such accidents. The following procedures have been suggested: 1) release of the tourniquet or restrictive garments to permit dilution of injected drug, 2) relief of arterial spasm by injecting 10 mL of a 1% procaine solution into the artery and, if considered necessary, brachial plexus block, 3) prevention of thrombosis by early anticoagulant therapy and 4) supportive treatment.

Anticonvulsant Use

A therapeutic anticonvulsant level of phenobarbital in the serum is 10 to 25 µg/mL. To achieve the blood levels considered therapeutic in children, higher per-kilogram dosages are generally necessary for phenobarbital and most other anticonvulsants. In children and infants, phenobarbital at loading doses of 15 to 20 mg/kg produces blood levels of about 20 µg/mL shortly after administration.

In status epilepticus, it is imperative to achieve therapeutic blood levels of a barbiturate (or other anticonvulsants) as rapidly as possible. When administered intravenously, phenobarbital sodium may require 15 minutes or more to attain peak concentrations in the brain. If phenobarbital sodium is injected continuously until the convulsions stop, the brain concentration will continue to rise and can eventually exceed that required to control the seizures. Because a barbiturate-induced depression may occur along with a postictal depression once the seizures are controlled, it is important, therefore, to use the minimal amount required and to wait for the anticonvulsant effect to develop before administering a second dose.

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.

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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Phenobarbital Sodium Injection, USP is available in the following:

    65 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0476-25)

    130 mg/mL, 1 mL vials packaged in 25s (NDC 0641-0477-25)

Storage

Store at 20°-25°C (68°-77°F), 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 West-Ward Pharmaceutical Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

For Product Inquiry call 1-877-845-0689.

Manufactured by:

WEST-WARD
PHARMACEUTICALS
Eatontown, NJ 07724 USA

Revised June 2011

462-353-01

Phenobarbital Sodium Injection, USP
65 mg/mL
1 mL Vial
NDC 0641-0476-21

Phenobarbital Sodium Injection, USP
65 mg/mL
25 x 1 mL Vials
NDC 0641-0476-25