Librium Information

Pharmacology

Anxiolytic

Chlordiazepoxide possesses sedative, hypnotic, anxiolytic and muscle relaxant properties. These effects appear to be mediated through facilitation of the actions of gamma aminobutyric acid (GABA) in the CNS. Chlordiazepoxide acts selectively on polysynaptic neuronal pathways and may inhibit or augment transmission, depending on the endogenous function of GABA. It does not produce ganglionic blockade or reduce affective responses at therapeutic dosage as do phenothiazine drugs and reserpine. Amine oxidase inhibition has not been demonstrated with chlordiazepoxide.

Following oral administration, the drug appears in the blood stream in 0.5 to 1 hour; peak blood levels occur in 2 to 4 hours. After i.m. administration effects of the drug appear in 15 to 30 minutes, and following i.v. administration, within 3 to 30 minutes. Following administration of radioactive chlordiazepoxide to rats, distribution of the drug or its metabolites has been shown to be fairly even throughout all body tissues. Chlordiazepoxide readily passes the placental barrier, with the concentration of the drug in the fetal circulation approaching or equaling that in maternal circulation. Chlordiazepoxide has a volume of distribution of 0.3 L/kg and is 96% protein bound. The plasma half-life of a single dose of chlordiazepoxide in healthy subjects has been reported to range from 5 to 30 hours. Pharmacologically active metabolites of chlordiazepoxide include desmethylchlordiazepoxide, demoxepam, desmethyldiazepam and oxazepam. Less than 1% is excreted in the urine unchanged.

Indications

Symptomatic relief of mild anxiety and tension and for reduction of tension states that may accompany muscle spasm. As an adjunct in tension states associated with insomnia, pre and postoperative apprehension, tension headache, premenstrual tension and stress, and functional gastrointestinal, cardiovascular, gynecological, and dermatological disorders with an emotional overlay. May be useful in the alleviation of alcohol withdrawal syndromes, although drug dependence may result, substituting for alcohol dependence. May also reduce anxiety associated with psychosis, but is not a specific management of psychosis.

I.V. chlordiazepoxide is indicated for the relief of acute agitation and hyperactivity (e.g., alcoholism, anxiety, hysterical and panic states, drug withdrawal symptoms) when rapid action is required or oral administration is not feasible.

Contraindications

Myasthenia gravis, known hypersensitivity to benzodiazepines.

Warnings

Do not administer to patients in shock or coma. Do not add to parenteral fluids or further dilute or mix with other drugs. Inject slowly into a large lumen vein.

Precautions

Administer chlordiazepoxide with caution to patients with a history of blood dyscrasias or hepatic or renal disease.

Caution should be exercised and the minimal effective dosage that does not cause ataxia or over-sedation should be maintained in elderly or debilitated patients. Dosage should be increased gradually as needed and tolerated.

Occupational Hazards:

Caution patients about engaging in activities requiring mental alertness, judgment and physical coordination, such as driving an automobile or operating dangerous machinery.

Though generally not recommended, if combination therapy with other psychotropics seems indicated, carefully consider individual pharmacologic effects, particularly the use of potentiating drugs such as MAO inhibitors and phenothiazines. Patients should also be warned against the ingestion of alcohol, since tolerance may be decreased and effects enhanced.

Since it has not been found of particular value in psychotic patients, chlordiazepoxide should not be used in place of appropriate treatment.

Periodic blood counts and liver function tests are recommended if the medication is administered over a protracted period of time.

Pregnancy and Lactation:

Several studies have suggested an increased risk of congenital malformations associated with the use of diazepam, chlordiazepoxide and meprobamate during the first trimester of pregnancy. Therefore, the administration of chlordiazepoxide is rarely justified in women of childbearing potential. If the drug is prescribed for a woman of childbearing potential, she should be warned to contact her physician regarding discontinuation of the drug if she intends to become or suspects that she is pregnant. Use in lactation should be avoided.

Employ the usual precautions in treatment of anxiety states with evidence of impending depression; suicidal tendencies may be present and protective measures necessary.

Variable effects on blood coagulation have been reported very rarely in patients receiving the drug and oral anticoagulants; a causal relationship has not been established clinically.

Parenteral chlordiazepoxide should be administered with caution to patients in whom a drop in blood pressure might lead to cardiac complications.

Physical and psychological dependence:

Physical and psychological dependence have rarely been reported in persons taking recommended doses of chlordiazepoxide. Withdrawal symptoms following abrupt discontinuation of chlordiazepoxide have been reported in patients receiving treatment over extended periods of time. These symptoms may resemble those seen with barbiturate withdrawal. The more severe withdrawal reactions have usually been limited to those patients having taken excessive doses over extended periods. Consequently abrupt discontinuation after long-term use should generally be avoided and a gradual tapering of dose followed.

Chlordiazepoxide must be administered with caution to addiction-prone individuals or to those whose history suggests possible abuse.

Adverse Effects

Drowsiness, ataxia and confusion may occur, especially in the elderly and debilitated. These are reversible in most instances by proper dosage adjustment, but are also occasionally observed at the lower dosage ranges. In a few instances, syncope has been reported. Also encountered are isolated instances of skin eruptions, edema, minor menstrual irregularities, nausea and constipation, extrapyramidal symptoms, increased and decreased libido, all infrequent and generally controlled with dosage reduction; changes in EEG patterns (low voltage fast activity) may appear during and after treatment; blood dyscrasias (including leukopenia and rare cases of agranulocytosis), jaundice and hepatic dysfunction have been reported occasionally. Paradoxical reactions, such as excitement, stimulation, elevation of mood and rage, have been reported in psychotic patients and hyperactive aggressive children. These reactions may be secondary to the relief of anxiety symptoms and should be watched for particularly in the early phase of medication.

In clinical use, parenteral administration has occasionally produced mild, transitory fluctuations in blood pressure. These reactions have not presented a clinical problem and have not required supportive therapy. Following injection, some patients may become drowsy or unsteady. For these reasons, ambulatory patients should be kept under observation, preferably in bed, after treatment.

Overdose

Symptoms:

Drowsiness, ataxia, coma, confusion, diminished reflexes. Depression of the cardiovascular and respiratory centers may occur.

Treatment:

Gastric lavage; or, in children, induce emesis and if there is no immediate response, use gastric lavage. Management consists of supportive measures, close supervision and monitoring. I.V. fluids should be administered if required and an adequate airway maintained. Cardiovascular and CNS stimulants may be used if necessary. Dialysis appears to be of limited value. There have been occasional reports of excitation in patients following chlordiazepoxide 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.

Dosage

Optimum dosage varies with diagnosis and patient response; therefore, individual adjustment of dose is important, with minimum effective dose being used.

Oral:

Adults:

Usually 10 to 40 mg daily in divided doses. In severe cases, 25 mg 3 or 4 times a day may be given.

Elderly or debilitated patients:

5 mg 2 to 4 times daily.

Preoperative apprehension:

5 to 10 mg, 3 to 4 times daily on days prior to surgery.

Obstetrics:

25 to 50 mg on admission.

Children:

Initiate therapy with 10 mg daily in divided doses, increasing if necessary to 30 mg daily in 2 to 3 divided doses.

Parenteral:

Injections should be prepared immediately before administration. Chlordiazepoxide for i.m. injection is prepared by adding 2 mL of the i.m. diluent to 100 mg of drug and agitating gently until a clear solution is obtained. (The diluent should not be used if it is opalescent or hazy.) Injection should be made into the deltoid or deep into the upper outer quadrant of the gluteal muscle. A solution suitable for i.v. injection may be prepared by adding 5 mL of isotonic sodium chloride injection or sterile water for injection to 100 mg of chlordiazepoxide and agitating gently. Do not add to parenteral fluids or further dilute or mix with other drugs. The appropriate i.v. dose may be injected directly into a large lumen vein slowly over a one minute period.

Alcoholism:

50 to 100 mg i.m. or i.v. initially; repeat in 2 to 4 hours if necessary.

Acute anxiety:

50 to 100 mg i.m. or i.v. initially; then 25 to 50 mg 3 or 4 times daily, if necessary.

Acute phobia or panic reaction:

50 to 100 mg i.m. or i.v. initially; repeat in 4 to 6 hours, if necessary.

Acute psychotic agitation:

50 to 100 mg i.m. or i.v. initially; repeat in 4 to 6 hours, if necessary.

Preoperative anxiety:

50 to 100 mg i.m. 1 hour prior to surgery.

Acute drug withdrawal:

100 mg i.m. or i.v. initially; then 50 to 100 mg in 4 to 6 hours, if necessary. Lower doses (usually 25 to 50 mg) should be used for elderly or debilitated patients and for children.

Maximum recommended parenteral dose:

300 mg daily in divided doses. In most cases, acute symptoms may be rapidly controlled by parenteral administration so that subsequent treatment, if necessary, may be given orally.

Supplied

Capsules:

5 mg:

Each yellow, opaque body and green, opaque cap, No. 4 hard gelatin capsule, imprinted in black ink {ROCHEoverC} and {LIBRIUMover5} alternating between cap and body contains: Chlordiazepoxide HCl 5 mg. Nonmedicinal ingredients: Cornstarch, fast green FCF, gelatin, lactose, methylparaben, potassium sorbate, propylparaben, quinoline yellow WS, silicon dioxide, sodium lauryl sulfate, sunset yellow FCF, talc and titanium dioxide. Energy: 2.1 kJ (0.5 kcal). Gluten-free, paraben-free, sodium-free, sulfite-free and tartrazine-free. Bottles of 100.

10 mg:

Each green, opaque body and black, opaque cap, No. 4 hard gelatin capsule, imprinted in white ink ROCHE and {LIBRIUMover10} alternating on cap and body contains: Chlordiazepoxide HCl 10 mg. Nonmedicinal ingredients: Allura red AC, brilliant blue FCF sodium salt, cornstarch, fast green FCF, gelatin, lactose, methylparaben, potassium sorbate, propylparaben, quinoline yellow WS, silicon dioxide, sodium lauryl sulfate, sunset yellow FCF, talc and titanium dioxide. Energy: 2.0 kJ (0.5 kcal). Gluten-free, paraben-free, sodium-free, sulfite and tartrazine-free. Bottles of 100.

25 mg:

Each white, opaque body and green, opaque cap, No. 4 hard gelatin capsule, imprinted in black ink ROCHE and {LIBRIUMover25} alternating on cap and body contains: Chlordiazepoxide HCl 25 mg. Nonmedicinal ingredients: Cornstarch, fast green FCF, gelatin, lactose, methylparaben, potassium sorbate, propylparaben, quinoline yellow WS, silicon dioxide, sodium lauryl sulfate, talc and titanium dioxide. Energy: 1.8 kJ (0.4 kcal). Gluten-free, paraben-free, sodium-free, sulfite-free and tartrazine-free. Bottles of 100.

Store at 15 to 30°C. Store in a tightly closed, light-resistant container.

Injectable:

Duplex pack consisting of 1 ampul 100 mg dry chlordiazepoxide HCl and 1 ampul 2 mL special diluent for i.m. injection only. Each mL of sterile special diluent contains: Benzyl alcohol 15 mg as preservative, 40 mg polysorbate 80 and propylene glycol 207 mg in an aqueous solution buffered with maleic acid and sodium hydroxide. Sodium: <1 mmol (3 mg/mL) and pH is 3.0. Paraben-free and sulfite-free. Duplex packages of 10.

Protect from light. Prepare immediately before use; discard unused solution. Store special diluent at 2 to 8°C and do not use if opalescent or hazy. Dry substance may be stored at 15 to 30°C. Do not freeze

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