Chlordiazepoxide

Chlordiazepoxide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

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Overview

Chlordiazepoxide is an antianxiety agent that is FDA approved for the {{{indicationType}}} of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety. Common adverse reactions include edema, constipation, nausea, ataxia, confusion, somnolence, and irregular periods.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Relief of Mild and Moderate Anxiety Disorders and Symptoms of Anxiety

• The usual daily dosage - 5 mg or 10 mg, 3 or 4 times daily.

Relief of Severe Anxiety Disorders and Symptoms of Anxiety

• The usual daily dosage - 20 mg or 25 mg, 3 or 4 times daily.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Chlordiazepoxide in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Chlordiazepoxide in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Preoperative Apprehension and Anxiety

• On days preceding surgery, 5 to 10 mg orally, 3 or 4 times daily. If used as preoperative medication, 50 to 100 mg IM* 1 hour prior to surgery.

• The usual daily dosage - 5 mg, 2 to 4 times daily (may be increased in some pediatric patients to 10 mg, 2 to 3 times daily)

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Chlordiazepoxide in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Chlordiazepoxide in pediatric patients.

Contraindications

• Chlordiazepoxide HCI Capsules are contraindicated in patients with known hypersensitivity to the drug.

Warnings

• Chlordiazepoxide may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a vehicle or operating machinery. Similarly, it may impair mental alertness in children. The concomitant use of alcohol or other central nervous system depressants may have an additive effect. PATIENTS SHOULD BE WARNED ACCORDINGLY.

• 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.

• Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines. (See DRUG ABUSE AND DEPENDENCE section.)

Precautions

• In elderly and debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (10 mg or less per day initially, to be increased gradually as needed and tolerated). In general, the concomitant administration of chlordiazepoxide HCI 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, e.g., excitement, stimulation and acute rage, have been reported in psychiatric patients and in hyperactive aggressive children, and should be watched for during chlordiazepoxide therapy. The usual precautions are indicated when chlordiazepoxide HCI capsules are 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 chlordiazepoxide. In view of isolated reports associating chlordiazepoxide with exacerbation of porphyria, caution should be exercised in prescribing chlordiazepoxide to patients suffering from this disease.

Adverse Reactions

Clinical Trials Experience

• The necessity of discontinuing therapy because of undesirable effects has been rare. Drowsiness, ataxia and confusion have been reported in some patients —particularly the elderly and debilitated. While these effects can be avoided in almost all instances by proper dosage adjustment, they have occasionally been observed at the lower dosage ranges. In few instances syncope has been reported.

• Other adverse reactions reported during therapy include isolated instances of skin eruptions, edema, minor menstrual irregularities, nausea and constipation, extrapyramidal symptoms, as well as increased and decreased libido. Such side effects have been infrequent and are generally controlled with reduction of dosage. Changes in EEG patterns (low-voltage fast activity) have been observed in patients during and after chlordiazepoxide treatment.

• Blood dyscrasias (including agranulocytosis), jaundice and hepatic dysfunction have occasionally been reported during therapy. When chlordiazepoxide treatment is protracted, periodic blood counts and liver function tests are advisable.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Chlordiazepoxide in the drug label.

Drug Interactions

There is limited information regarding Chlordiazepoxide Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Chlordiazepoxide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Chlordiazepoxide during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Chlordiazepoxide with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Chlordiazepoxide with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Chlordiazepoxide with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Chlordiazepoxide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Chlordiazepoxide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Chlordiazepoxide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Chlordiazepoxide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Chlordiazepoxide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Chlordiazepoxide in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

Monitoring

There is limited information regarding Monitoring of Chlordiazepoxide in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Chlordiazepoxide in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Manifestations of chlordiazepoxide overdosage includes somnolence, confusion, coma and diminished reflexes.

Management

• Respiration, pulse and blood pressure should be monitored, as in all cases of drug overdosage, although, in general, these effects have been minimal following chlordiazepoxide 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 norepinephrine or metaraminol. Dialysis is 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.

• 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, WARNINGS, and PRECAUTIONS should be consulted prior to use.

Chronic Overdose

There is limited information regarding Chronic Overdose of Chlordiazepoxide in the drug label.

Pharmacology

Chlordiazepoxide
Systematic (IUPAC) name
7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide
Identifiers
CAS number	58-25-3
ATC code	N05BA02
PubChem	2712
DrugBank	DB00475
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	299.75 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic
Half life	5–30 hours (Active metabolite desmethyldiazepam 36-200 hours: other active metabolites include oxazepam.)
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	D(US)
Legal status	Prescription Only (S4)(AU) ?(UK) Schedule IV(US)
Routes	oral intramuscular

Mechanism of Action

• Chlordiazepoxide HCI has antianxiety, sedative, appetite-stimulating and weak analgesic actions. The precise mechanism of action is not known. The drug blocks EEG arousal from stimulation of the brain stem reticular formation. It takes several hours for peak blood levels to be reached and the half-life of the drug is between 24 and 48 hours. After the drug is discontinued plasma levels decline slowly over a period of several days. Chlordiazepoxide is excreted in the urine, with 1 to 2% unchanged and 3 to 6% as a conjugate.

Structure

• Chlordiazepoxide hydrochloride is the prototype for the benzodiazepine compounds.

• Chlordiazepoxide hydrochloride is 7-chloro-2-(methylamino)-5-phenyl-3 H-1, 4-benzodiazepine 4-oxide hydrochloride. A white to practically white crystalline substance, it is soluble in water. It is unstable in solution and the powder must be protected from light. The structural formula of chlordiazepoxide hydrochloride is as follows:

This image is provided by the National Library of Medicine.

• Available as capsules for oral administration containing either 5 mg, 10 mg or 25 mg of chlordiazepoxide hydrochloride.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Chlordiazepoxide in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Chlordiazepoxide in the drug label.

Nonclinical Toxicology

• 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. Chlordiazepoxide revealed a “taming” action with the elimination of fear and aggression. The taming effect of chlordiazepoxide 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 LD50 of parenterally administered chlordiazepoxide HCI 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, I.V., 123 ± 12 mg/kg; mice, I.M., 336 ± 7 mg/kg; rats, I.V., 120 ± 7 mg/kg; rats, I.M., >160 mg/kg.

• Effects on Reproduction:

• Reproduction studies in rats fed 10, 20, and 80 mg/kg daily and bred through one or two mating 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.

Clinical Studies

There is limited information regarding Clinical Studies of Chlordiazepoxide in the drug label.

How Supplied

• Chlordiazepoxide Hydrochoride Capsules USP, 5 mg are available as a two-piece hard gelatin capsule with an aqua green opaque cap and a yellow opaque body filled with white powder, imprinted in black ink barr 158. They are available as follows:

• NDC 51079-374-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).

• Chlordiazepoxide Hydrochloride Capsules USP, 10 mg are available as a two-piece hard gelatin capsule with a black opaque cap and a green opaque body filled with white powder, imprinted in white ink barr 033. They are available as follows:

• NDC 51079-375-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).

• Chlordiazepoxide Hydrochloride Capsules USP, 25 mg are available as a two-piece hard gelatin capsule with an aqua green opaque cap and a white opaque body filled with white powder, imprinted in black ink barr 159. They are available as follows:

• NDC 51079-141-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).

• Store at 20° to 25°C (68° to 77°F) in a dry place.

• Protect from light.

Storage

There is limited information regarding Chlordiazepoxide Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

• To assure the safe and effective use of benzodiazepines, patients should be informed that, since benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their physician before either increasing the dose or abruptly discontinuing the drug.

Precautions with Alcohol

• Alcohol-Chlordiazepoxide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• CHLORDIAZEPOXIDE HYDROCHLORIDE®

Look-Alike Drug Names

• chlordiazePOXIDE® — chlorproMAZINE®

• chlordiazePOXIDE® — chlorproMAZINE hydrochloride®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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