AHFS Class:

• Non-benzodiazepine Anxiolytics 28:24.12

Generic Name(s):

• Meprobamate

Meprobamate is an anxiolytic agent.

Anxiety

Meprobamate is used for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety.

Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of meprobamate for long-term use (i.e., longer than 4 months) has not been evaluated; the need for continued therapy should be reassessed periodically. 100 Meprobamate may be useful as an adjunct when anxiety complicates psychosis or the treatment of alcohol dependence. However, the additive CNS depressant effects of meprobamate and alcohol should be considered.

Sedation

Meprobamate has been used preoperatively to relieve anxiety and provide sedation†. Meprobamate is effective in promoting sleep in the anxious, tense patient. There is no convincing evidence that meprobamate has any advantage over other sedatives, including barbiturates, in relieving anxiety and tension.

Pain with Tension and Anxiety

Meprobamate in fixed combination with aspirin is used as an adjunct in the short-term (<10 days) treatment of pain accompanied by tension and/or anxiety in patients with musculoskeletal disease.101 The combination has been shown to be more effective than aspirin alone.101

Seizures

Meprobamate is ineffective as an anticonvulsant in the management of seizure disorders and may precipitate seizures. (See Cautions: Precautions and Contraindications.)

Administration

Meprobamate is administered orally. Prolonged administration of meprobamate should be avoided, because the drug may induce psychologic or physical dependence. However, if meprobamate has been administered chronically, the drug should be withdrawn slowly to avoid the possibility of precipitating withdrawal symptoms.

Dosage

Dosage of meprobamate must be individualized and the smallest effective dosage should be used (especially in geriatric or debilitated patients) to avoid oversedation.

The usual adult dosage of meprobamate as conventional tablets is 1.2-1.6 g daily in 3 or 4 divided doses. The maximum daily dose is 2.4 g. The usual adult hypnotic dose of meprobamate is 800 mg.

The usual sedative dosage of meprobamate as conventional tablets for children 6-12 years of age is 100-200 mg 2 or 3 times daily. Alternatively, children may be given 25 mg/kg daily or 700 mg/m² daily in 2 or 3 divided doses.

To relieve anxiety and provide sedation preoperatively†, adults have been given 400 mg and children have received 200 mg of meprobamate.

When meprobamate is used in fixed combination with aspirin for the short-term (10 days or less) treatment of pain accompanied by tension and/or anxiety in adults and children older than 12 years of age with musculoskeletal disease, the recommended dosage of meprobamate is 200 or 400 mg 3 or 4 times daily, as needed.101

Nervous System Effects

The most frequent adverse effects of meprobamate are drowsiness and ataxia. Other adverse CNS effects include dizziness, slurred speech, headache, vertigo, weakness, paresthesia, impaired visual accommodation, euphoria, and paradoxical CNS stimulation resulting in excitement and/or fast EEG activity.

Sensitivity Reactions

Mild to severe allergic or idiosyncratic reactions may occur, particularly in patients with a history of dermatologic or allergic conditions. In patients who have not received meprobamate previously, these reactions are usually evident by the time of the fourth dose of the drug. Mild reactions are characterized by pruritus, urticaria, and/or erythematous maculopapular rash which may be generalized or confined to the groin area. Other idiosyncratic reactions have included leukopenia, acute nonthrombocytopenic purpura, petechiae, ecchymoses, eosinophilia, adenopathy, peripheral edema, fever, and fixed drug eruptions with a cross-reaction to carisoprodol. Cross-sensitivity between meprobamate and mebutamate and/or carbromal also has occurred.

Rarely, severe hypersensitivity reactions manifested as hyperpyrexia, chills, angioedema, bronchospasm, anaphylaxis, stomatitis, proctitis, oliguria, or anuria may occur. Exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, and bullous dermatitis also have occurred. Bullous dermatitis resulting in death occurred in one patient following administration of meprobamate in combination with prednisolone.

Whenever allergic or idiosyncratic reactions occur, meprobamate should be discontinued and appropriate symptomatic therapy (e.g., administration of epinephrine, antihistamines, and/or corticosteroids) given if needed.

Hematologic Effects

Severe hematologic reactions have occurred rarely during meprobamate therapy and include agranulocytosis, aplastic anemia, thrombocytopenic purpura, erythroid hypoplasia, and at least one case of pancytopenia.

GI Effects

Adverse GI effects caused by meprobamate include anorexia, nausea, vomiting, and diarrhea.

Cardiovascular Effects

Adverse cardiovascular effects include palpitation, tachycardia, arrhythmias, transient ECG changes, syncope, and hypotension (including hypotensive crises) which has resulted in at least one fatality.

Precautions and Contraindications

When meprobamate is used in fixed combination with aspirin, the usual cautions, precautions, and contraindications associated with aspirin must be considered in addition to those associated with meprobamate.101

Because meprobamate is metabolized by the liver and excreted by the kidneys, the drug should be used with caution in patients with impaired hepatic or renal function. Meprobamate should be used with caution, if at all, in patients with seizure disorders, because the drug may occasionally precipitate seizures in these patients.

Patients should be warned that meprobamate may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Meprobamate should be used with caution and large quantities of the drug should not be prescribed for patients with suicidal tendencies or whose history indicates that they may increase dosage on their own initiative.

Patients should be instructed to report immediately to their physician symptoms such as sore throat, fever, easy bruising, or unusual bleeding which may be an indication of hematologic toxicity.

Meprobamate may exacerbate acute intermittent porphyria and is thus contraindicated in patients with a history of porphyria. The drug also is contraindicated in patients who have previously demonstrated allergic or idiosyncratic reactions to meprobamate or related compounds such as carisoprodol, mebutamate, or carbromal.

Pediatric Precautions

Because safety and efficacy of meprobamate in children younger than 6 years of age have not been established, the drug is not recommended for use in children in this age group.

Safety and efficacy of the fixed-combination tablets containing meprobamate and aspirin in children younger than 12 years of age have not been established.101

Geriatric Precautions

Clinical studies of meprobamate (with or without aspirin) did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.100,101 While other clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.100,101 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.100,101

Pregnancy and Lactation

Several studies have suggested an increased risk of congenital malformations associated with the use of anxiolytics (meprobamate, chlordiazepoxide, diazepam) during the first trimester of pregnancy. Since the use of anxiolytics is rarely urgent, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time therapy is initiated should be considered. Patients should be advised that if they become pregnant or intend to become pregnant during therapy, they should communicate with their physician about the desirability of discontinuing the drug.

The fact that meprobamate is distributed into milk in concentrations exceeding those in plasma should be considered when use of the drug is contemplated in lactating women.

CNS Depressants

Additive CNS depression may occur when meprobamate is administered concomitantly with other CNS depressants, including alcohol and psychotropic agents.100,101 If meprobamate is used concomitantly with other depressant drugs, including alcohol, caution should be used to avoid overdosage.

Oral Anticoagulants

Although animal studies indicated that meprobamate shortened the half-life of warfarin, subsequent human studies have shown that meprobamate does not have any clinically important effect on warfarin-induced hypoprothrombinemia.

Other Drugs

Although imipramine enhances the CNS effects of meprobamate in animals, no clinically important effect of this interaction has been documented in humans.

Laboratory Test Interferences

Meprobamate may cause falsely high urinary 17-ketosteroid and 17-ketogenicsteroid concentrations in the Zimmerman reaction and 17-hydroxycorticosteroid concentrations in the modified Glenn-Nelson technique.

Acute Toxicity

Manifestations

Meprobamate overdosage produces symptoms that are similar to those of barbiturate overdosage and may include drowsiness, lethargy, stupor, ataxia, coma, hypotension, shock, and respiratory depression. Death may result from respiratory failure or hypotension. Ingestion of 12 g of meprobamate has caused death, although some patients have survived the ingestion of as much as 40 g. Potentially lethal blood concentrations are those in excess of 100 mcg/mL. (See Pharmacokinetics: Absorption.)

Treatment

Treatment of meprobamate intoxication, like barbiturate intoxication, consists of general supportive therapy including maintenance of adequate airway, assisted respiration, and cautious administration of vasopressor agents if indicated. If the patient is comatose, having seizures, or lacks a gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. If the patient is fully conscious, emesis should be induced. Activated charcoal may be instilled after gastric lavage and/or emesis to adsorb any remaining drug, since relapse and death have been attributed to incomplete gastric emptying and delayed absorption. Urinary output should be monitored and overhydration avoided. Forced diuresis with an osmotic diuretic such as mannitol and/or peritoneal dialysis or hemodialysis may be beneficial in enhancing elimination of the drug. Preliminary in vitro studies have demonstrated a substantial increase in the removal of meprobamate when activated charcoal was added to dialysis fluid; however, clinical procedures to test the efficacy of adding activated charcoal to dialysis fluid have not been established.

Chronic Toxicity

Pathogenesis

Tolerance and psychologic and physical dependence may occur following prolonged use of high doses of meprobamate. Daily ingestion of 3.2 g of meprobamate for weeks or months has produced physical dependence and withdrawal symptoms when the drug was suddenly discontinued. Because of the drug's potential for inducing dependence, prolonged administration of meprobamate is not recommended.

Manifestations

Symptoms of meprobamate dependence are similar to those of barbiturate dependence or chronic alcoholism and may include drowsiness, ataxia, slurred speech, and vertigo. Sudden discontinuance of the drug in physically dependent patients may produce severe withdrawal symptoms within 12-48 hours including anxiety, anorexia, insomnia, vomiting, ataxia, tremors, muscle twitching, confusion, hallucinations, and seizures clinically indistinguishable from generalized tonic-clonic (grand mal) seizures. Seizures are most likely to occur in patients ingesting large amounts of the drug or patients who have CNS damage or a history of seizure disorders. Some fatalities have occurred following abrupt withdrawal of meprobamate. Withdrawal symptoms usually cease within 12-48 hours after they appear.

Treatment

Treatment of meprobamate physical dependence consists of cautious and gradual withdrawal of the drug over a period of 1-2 weeks. Alternatively, the patient may be stabilized on phenobarbital which is then withdrawn over 10-14 days. A 30-mg dose of phenobarbital is administered orally for each 400-800 mg of meprobamate that the patient has been taking daily. If the daily intake of meprobamate is not known, a test dose of pentobarbital may be given to assess the level of tolerance. The tolerated dose of pentobarbital is then converted to an equivalent amount of phenobarbital (30 mg phenobarbital is equivalent to 100-200 mg of pentobarbital). The total daily dose of phenobarbital is administered in 3 or 4 divided doses and is usually decreased by 30 mg/day. The patient should be closely monitored, preferably hospitalized, and general supportive therapy given as needed.

Pharmacology

Meprobamate has CNS depressant actions similar to those of the barbiturates. The mechanism of action of meprobamate is not known. The drug apparently acts at multiple sites in the CNS including the hypothalamus, thalamus, limbic system, and spinal cord, but not the medulla, the reticular activating system, or in the autonomic nervous system. Although there is some evidence that meprobamate relaxes skeletal muscle tension, the skeletal muscle relaxant effects of the drug are probably caused by its sedative effect. Very high doses of meprobamate may produce general anesthesia and concurrent depression of respiratory and vasomotor centers; death may result from respiratory failure and/or hypotension. (See Acute Toxicity: Manifestations.)

In animals, meprobamate antagonizes the convulsant effects of pentylenetetrazol, but meprobamate is of no clinical use for the management of epilepsy; in fact, the drug may aggravate generalized tonic-clonic (grand mal) seizures. Usual sedative doses of meprobamate have little or no effect on the EEG, but 800-mg doses produce increased fast activity, increased amplitude, and prominent beta waves. Like barbiturates, hypnotic doses of meprobamate substantially suppress rapid eye movement (REM) or dreaming stage of sleep. REM rebound has been reported to occur when the drug was withdrawn and thus could cause the patient to experience markedly increased dreaming, nightmares, and/or insomnia.

Pharmacokinetics

Absorption

Meprobamate is well absorbed from the GI tract following oral administration. Plasma concentrations of meprobamate required for sedative or hypnotic effects are not known. Oral administration of 400 mg of meprobamate produces peak plasma concentrations of 5-30 mcg/mL within 1-3 hours. Plasma concentrations of 30-100 mcg/mL are usually reached following mild overdosage and are associated with stupor or light coma. Plasma concentrations of 100-200 mcg/mL are associated with deep coma and are potentially lethal; fatalities frequently occur when plasma concentrations exceed 200 mcg/mL. The onset of sedative action is usually less than 1 hour following oral administration of meprobamate.

Distribution

Meprobamate appears to be uniformly distributed throughout the body. Meprobamate is distributed into the milk of lactating women in a concentration 2-4 times that in plasma. The drug crosses the placenta and is present in umbilical cord blood at or near maternal plasma concentrations. In vitro, about 20% of the drug appears to be bound to plasma proteins.

Elimination

The plasma half-life of meprobamate averages about 10-11 hours but may range from 6-16 hours.

Meprobamate is rapidly metabolized in the liver. Meprobamate can induce liver microsomal enzymes and thus may at least theoretically alter the metabolism of other drugs such as warfarin. (See Drug Interactions: Oral Anticoagulants.) There is some evidence that meprobamate may accelerate its own metabolism. Meprobamate metabolites are inactive and include 2β-hydroxymeprobamate, and glucosyluronide and glucuronide conjugates of meprobamate. These metabolites are excreted by the kidneys. About 10-12% of a dose of meprobamate is excreted in urine as unchanged drug within 24 hours. The remainder is excreted in urine as metabolites.

Chemistry and Stability

Chemistry

Meprobamate is an anxiolytic agent. The drug is a carbamate derivative which is structurally and pharmacologically related to mebutamate, carbromal, and carisoprodol. Meprobamate occurs as a white powder with a characteristic odor and a bitter taste. The drug is slightly soluble in water and freely soluble in alcohol and in polyethylene glycol 400. Meprobamate has a pK_a of about 14.

Stability

Meprobamate preparations generally should be stored in tight containers at a temperature less than 40°C, preferably at 15-30°C. However, USP states that the tablets can be stored in well-closed containers. The fixed-combination tablets of meprobamate and aspirin should be stored in tight, light-resistant containers at 20-25°C and protected from moisture.101 Following the date of manufacture, commercially available meprobamate oral products have expiration dates of 2-5 years, depending on dosage form and manufacturer.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

100. Watson Laboratories, Inc. Meprobamate tablets prescribing information. Corona, CA; 2004 Apr.

101. Leitner Pharmaceuticals. Equagesic^® (meprobamate 200 mg and aspirin 325 mg) tablets prescribing information. Bristol, TN; 2005 Feb.