Phenobarbital: Package Insert and Label Information

PHENOBARBITAL- phenobarbital tablet
REMEDYREPACK INC.

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WARNING: MAY BE HABIT-FORMING

DESCRIPTION

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:

Chemical Structure

Each phenobarbital tablet contains 16.2 mg, 32.4 mg, 64.8 mg, or 97.2 mg of phenobarbital.

In addition, each tablet contains: magnesium stearate, microcrystalline cellulose, silicon dioxide, and sodium starch glycolate.

CLINICAL PHARMACOLOGY

Barbiturates are capable of producing all levels of CNS mood alteration, from excitation to mild sedation, 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 physiologic sleep. Sleep laboratory studies have demonstrated that barbiturates reduce the amount of time spent in the rapid eye movement (REM) phase of sleep or the 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 that contribute to the 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 (including amobarbital) 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 whereas 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; however, of the drugs in this class, only phenobarbital, mephobarbital, and metharbital are effective as oral anticonvulsants in subhypnotic doses.

Barbiturates are respiratory depressants, and the degree of respiratory depression is dependent upon the dose. With hypnotic doses, respiratory depression produced by barbiturates is similar to that which occurs during physiologic sleep and is accompanied by a slight decrease in blood pressure and heart rate.

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).

Pharmacokinetics

Barbiturates are absorbed in varying degrees following oral or parenteral administration. The salts are more rapidly absorbed than are the acids. The rate of absorption is increased if the sodium salt is ingested as a dilute solution or taken on an empty stomach.

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. Phenobarbital is classified as a long-acting barbiturate when taken orally. Its onset of action is 1 hour or longer, and its duration of action ranges from 10 to 12 hours.

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 activity, and the longest duration of action. The plasma half-life for phenobarbital in adults ranges between 53 and 118 hours with a mean of 79 hours. The plasma half-life for phenobarbital in children and newborns (less than 48 hours old) ranges between 60 to 180 hours with a mean of 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% of a dose of phenobarbital is eliminated unchanged in the urine. 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

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

CONTRAINDICATIONS

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.

WARNINGS

  1. Habit Forming. Phenobarbital may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (see DRUG ABUSE AND DEPENDENCE and Pharmacokinetics under CLINICAL PHARMACOLOGY). Patients who have psychologic dependence on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. In order 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 a person who is dependent on the drug may result in withdrawal symptoms, including delirium, convulsions, and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive doses over long periods of time (see DRUG ABUSE AND DEPENDENCE).
  2. 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.
  3. Usage in Pregnancy. Barbiturates can cause fetal damage 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. Barbiturates readily cross the placental barrier and are distributed throughout fetal tissues; the highest concentrations are 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 women who receive barbiturates throughout the last trimester of pregnancy (see DRUG ABUSE AND DEPENDENCE). If phenobarbital is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
  4. Usage in Pediatric Patients. Phenobarbital has been reported to be associated with cognitive deficits in children taking it for complicated febrile seizures.
  5. Synergistic Effects. The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects.

PRECAUTIONS

General

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 have a history of drug abuse.

Elderly or debilitated patients may react to barbiturates with marked excitement, depression, or confusion. In some persons, especially children, 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.

The systemic effects of exogenous and endogenous corticosteroids may be diminished by phenobarbital. Thus, this product should be administered with caution to patients with borderline hypoadrenal function, regardless of whether it is of pituitary or of primary adrenal origin.

Information for Patients

The following information and instructions should be given 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 the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly.
  3. Alcohol should not be consumed while taking barbiturates. The concurrent use of the barbiturates with other CNS depressants (e.g., alcohol, narcotics, tranquilizers, and antihistamines) may result in additional CNS-depressant effects.

Laboratory Tests

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

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.

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. CNS Depressants. The concomitant use of other CNS depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects.
  7. Monoamine Oxidase Inhibitors (MAOIs). MAOIs prolong the effects of barbiturates, probably because metabolism of the barbiturate is inhibited.
  8. 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.

Carcinogenesis

  1. 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.
  2. Human Data. In a 29-year epidemiological study of 9,136 patients who were treated on an anticonvulsant protocol that included phenobarbital, results indicated a higher than normal incidence of hepatic carcinoma. Previously, some of these patients had been treated with thorotrast, a drug which is known to produce hepatic carcinomas. Thus, this study did not provide sufficient evidence that phenobarbital sodium 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.

Usage in Pregnancy

  1. Teratogenic Effects. Pregnancy Category D – See Usage in Pregnancy under WARNINGS.
  2. 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 impair uterine activity significantly 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.

Data are not available to evaluate the effect of barbiturates when forceps delivery or other intervention is necessary or to determine the effect of barbiturates on the later growth, development, and functional maturation of the child.

Nursing Mothers

Caution should be exercised when phenobarbital is administered to a nursing woman, because small amounts of barbiturates are excreted in the milk.

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