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Librium is a versatile therapeutic agent of proven value for the relief of anxiety and tension.
Librium is the first of a new class, unrelated chemically and pharmacologically to other types of tranquilizers. Librium promptly relieves anxiety and is among the safer of the effective psychopharmacologic compounds available.
Chlordiazepoxide HCl is 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide hydrochloride. A colorless, crystalline substance, it is soluble in water. It is unstable in solution and the powder must be protected from light. The molecular weight is 336.22. The structural formula of chlordiazepoxide HCl is as follows:
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The drug has been studied extensively in many species of animals and these studies are suggestive of action on the limbic system of the brain, which recent evidence indicates is involved in emotional responses.
Hostile monkeys were made tame by oral drug doses which did not cause sedation. Librium revealed a "taming" action with the elimination of fear and aggression. The taming effect of Librium was further demonstrated in rats made vicious by lesions in the septal area of the brain. The drug dosage which effectively blocked the vicious reaction was well below the dose which caused sedation in these animals.
The LD 50 of parenterally administered chlordiazepoxide HCl was determined in mice (72 hours) and rats (5 days), and calculated according to the method of Miller and Tainter, with the following results: mice, IV, 123 ± 12 mg/kg; mice, IM, 366 ± 7 mg/kg; rats, IV, 120 ± 7 mg/kg; rats, IM, >160 mg/kg.
Effects on Reproduction: Reproduction studies in rats fed 10, 20 and 80 mg/kg daily and bred through one or two matings showed no congenital anomalies, nor were there adverse effects on lactation of the dams or growth of the newborn. However, in another study at 100 mg/kg daily there was noted a significant decrease in the fertilization rate and a marked decrease in the viability and body weight of offspring which may be attributable to sedative activity, thus resulting in lack of interest in mating and lessened maternal nursing and care of the young. One neonate in each of the first and second matings in the rat reproduction study at the 100 mg/kg dose exhibited major skeletal defects. Further studies are in progress to determine the significance of these findings.
Injectable Librium is indicated for the management of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
Librium is contraindicated in patients with known hypersensitivity to the drug.
As in the case of other CNS-acting drugs, patients receiving Librium should be cautioned about possible combined effects with alcohol and other CNS depressants.
As is true of all preparations containing CNS-acting drugs, patients receiving Librium should be cautioned against hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle.
Usage in Pregnancy: An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.
Management of Overdosage: Manifestations of Librium overdosage include somnolence, confusion, coma and diminished reflexes. Respiration, pulse and blood pressure should be monitored, as in all cases of drug overdosage, although, in general, these effects have been minimal following Librium overdosage. General supportive measures should be employed, along with immediate gastric lavage.
Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of Levophed® (levarterenol) or Aramine (metaraminol). Dialysis is of limited value. There have been occasional reports of excitation in patients following Librium overdosage; if this occurs barbiturates should not be used. As with the management of intentional overdosage with any drug, it should be borne in mind that multiple agents may have been ingested.
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS , and PRECAUTIONS , should be consulted prior to use.
Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines. (See DRUG ABUSE AND DEPENDENCE section.)
Injectable Librium (intramuscular or intravenous) is indicated primarily in acute states, and patients receiving this form of therapy should be kept under observation, preferably in bed, for a period of up to 3 hours. Ambulatory patients should not be permitted to operate a vehicle following an injection. Injectable Librium should not be given to patients in shock or comatose states. Reduced dosage (usually 25 to 50 mg) should be used for elderly or debilitated patients. In general, the concomitant administration of Librium and other psychotropic agents is not recommended. If such combination therapy seems indicated, careful consideration should be given to the pharmacology of the agents to be employed--particularly when the known potentiating compounds such as the MAO inhibitors and phenothiazines are to be used. The usual precautions in treating patients with impaired renal or hepatic function should be observed.
Paradoxical reactions, eg, excitement, stimulation and acute rage, have been reported in psychiatric patients and in hyperactive aggressive pediatric patients, and should be watched for during Librium therapy. The usual precautions are indicated when Librium is used in the treatment of anxiety states where there is any evidence of impending depression; it should be borne in mind that suicidal tendencies may be present and protective measures may be necessary. Although clinical studies have not established a cause and effect relationship, physicians should be aware that variable effects on blood coagulation have been reported very rarely in patients receiving oral anticoagulants and Librium. In view of isolated reports associating chlordiazepoxide with exacerbation of porphyria, caution should be exercised in prescribing chlordiazepoxide to patients suffering from this disease.
Pediatric Use: Reduced dosage (usually 25 to 50 mg) should be used for pediatric patients age 12 years and older (see DOSAGE AND ADMINISTRATION). Since clinical experience in pediatric patients under 12 years of age is limited, the use of the drug in this age group is not recommended. Hyperactive aggressive pediatric patients should be monitored for paradoxical reactions to Librium (see PRECAUTIONS ).
The necessity of discontinuing therapy because of undesirable effects has been rare. Drowsiness, ataxia and confusion are more commonly seen in the elderly and debilitated.
Other adverse reactions reported during therapy include isolated instances of syncope, hypotension, tachycardia, skin eruptions, edema, minor menstrual irregularities, nausea and constipation, extrapyramidal symptoms, blurred vision, as well as increased and decreased libido. Such side effects have been infrequent and are generally controlled with reduction of dosage. Similarly, hypotension associated with spinal anesthesia has occurred. Pain following intramuscular injection has been reported. Changes in EEG patterns (low-voltage fast activity) have been observed in patients during and after Librium treatment.
Blood dyscrasias (including agranulocytosis), jaundice and hepatic dysfunction, have occasionally been reported during therapy. When Librium treatment is protracted, periodic blood counts and liver function tests are advisable.
Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuance of chlordiazepoxide. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving chlordiazepoxide or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
Solutions of Librium for intramuscular or intravenous use should be prepared aseptically. Sterilization by heating should not be attempted.
Intramuscular: Add 2 mL of Special Intramuscular Diluent to contents of 5-mL dry-filled amber ampul of Librium Sterile Powder (100 mg). Avoid excessive pressure in injecting this special diluent into the ampul containing the powder since bubbles will form on the surface of the solution. Agitate gently until completely dissolved. Solution should be prepared immediately before administration. Any unused solution should be discarded. Deep intramuscular injection should be given slowly into the upper outer quadrant of the gluteus muscle.
Caution: Librium solution made with the Special Intramuscular Diluent should not be given intravenously because of the air bubbles which form when the intramuscular diluent is added to the Librium powder. Do not use diluent solution if it is opalescent or hazy.
Intravenous: In most cases, intramuscular injection is the preferred route of administration of Injectable Librium since beneficial effects are usually seen within 15 to 30 minutes. When, in the judgment of the physician, even more rapid action is mandatory, Injectable Librium may be administered intravenously. A suitable solution for intravenous administration may be prepared as follows: Add 5 mL of sterile physiological saline or sterile water for injection to contents of 5-mL dry-filled amber ampul of Librium Sterile Powder (100 mg). Agitate gently until thoroughly dissolved. Solution should be prepared immediately before administration. Any unused portion should be discarded. Intravenous injection should be given slowly over a 1-minute period.
Caution: Librium solution made with physiological saline or sterile water for injection should not be given intramuscularly because of pain on injection.
Dosage should be individualized according to the diagnosis and the response of the patient. While 300 mg may be given during a 6-hour period, this dose should not be exceeded in any 24-hour period.
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In most cases, acute symptoms may be rapidly controlled by parenteral administration so that subsequent treatment, if necessary, may be given orally. (See package insert for Oral Librium.)
For Parenteral Administration: Ampuls--Duplex package consisting of a 5-mL dry-filled ampul containing 100 mg chlordiazepoxide HCl in dry crystalline form, and a 2-mL ampul of Special Intramuscular Diluent (for intramuscular administration) compounded with 1.5% benzyl alcohol, 4% polysorbate 80, 20% propylene glycol, 1.6% maleic acid and sodium hydroxide to adjust pH to approximately 3. Boxes of 10 (NDC 0187-3755-74).
Before preparing solution for intramuscular or intravenous administration, please read instructions for PREPARATION AND ADMINISTRATION OF SOLUTIONS.
Manufactured for ICN Pharmaceuticals, Inc, Costa Mesa, CA 92626 by Hoffmann-La Roche Inc., Nutley, NJ 07110
Revised: March 1999