Animal Pharmacology

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 HCl revealed a “taming” action with the elimination of fear and aggression. The taming effect of chlordiazepoxide HCl 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 50of 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.

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including chlordiazepoxide, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe chlordiazepoxide concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of chlordiazepoxide than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking chlordiazepoxide, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when chlordiazepoxide is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see DRUG INTERACTIONS).

Abuse, Misuse, and Addiction

The use of benzodiazepines, including chlordiazepoxide, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse) .

Before prescribing chlordiazepoxide and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of chlordiazepoxide, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of chlordiazepoxide along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

Dependence and Withdrawal Reactions

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue chlordiazepoxide or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of chlordiazepoxide).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions

The continued use of benzodiazepines, including chlordiazepoxide, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of chlordiazepoxide after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence) .

Protracted Withdrawal Syndrome

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE: Dependence).

Chlordiazepoxide HCl 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.

Neonatal Sedation and Withdrawal Syndrome

Use of chlordiazepoxide HCl late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see  PRECAUTIONS, Pregnancy) .Monitor neonates exposed to chlordiazepoxide HCl during pregnancy or labor for signs of sedation and monitor neonates exposed to chlordiazepoxide HCl during pregnancy for signs of withdrawal; manage these neonates accordingly.

Pediatric Use

Because of the varied response of pediatric patients to CNS-acting drugs, therapy should be initiated with the lowest dose and increased as required (see DOSAGE AND ADMINISTRATION). Since clinical experience with chlordiazepoxide HCl in pediatric patients under 6 years of age is limited, use in this age group is not recommended. Hyperactive aggressive pediatric patients should be monitored for paradoxical reactions to chlordiazepoxide HCl (see PRECAUTIONS).

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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Risks from Concomitant Use with Opioids

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when chlordiazepoxide is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use with Opioids and PRECAUTIONS: Drug Interactions).

Abuse, Misuse, and Addiction

Inform patients that the use of chlordiazepoxide, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see WARNINGS: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE).

Withdrawal Reactions

Inform patients that the continued use of chlordiazepoxide may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of chlordiazepoxide may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of chlordiazepoxide may require a slow taper (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE).

Pregnancy

Advise pregnant females that use of chlordiazepoxide HCl late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see  Warnings, Neonatal Sedation and Withdrawal Syndromeand Precautions, Pregnancy). Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to chlordiazepoxide HCl during pregnancy (see  Precautions, Pregnancy) .

Nursing

Advise patients that breastfeeding is not recommended during treatment with chlordiazepoxide HCl (see Precautions, Nursing Mothers).

Drug Interactions

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA Asites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.

Pregnancy:

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including chlordiazepoxide HCl, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at
1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS, Neonatal Sedation and Withdrawal Syndrome, and Clinical Considerations) .Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. Monitor neonates exposed to chlordiazepoxide HCl during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to chlordiazepoxide HCl during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS, Neonatal Sedation and Withdrawal Syndrome) .

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Nursing:

Risk Summary

There are no data on the presence of chlordiazepoxide in human milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. Because of chlordiazepoxide’s long half-life, the potential for chlordiazepoxide to accumulate in breast milk and the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with chlordiazepoxide HCl.

Controlled Substance

Chlordiazepoxide is a Schedule IV controlled substance.

Abuse

Chlordiazepoxide is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse may lead to addiction.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction).

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

Dependence

Physical Dependence

Chlordiazepoxide may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions).

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue chlordiazepoxide or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Chlordiazepoxide and WARNINGS: Dependence and Withdrawal Reactions).

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to Chlordiazepoxide may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of chlordiazepoxide may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Overdosage

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS:Abuse, Misuse, and Addiction). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

Consider contacting a poison center (1-800-222-1222), poisoncontrol.org, or medical toxicologist for additional overdosage management recommendations.

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.

For the relief of withdrawal symptoms of acute alcoholism, the parenteral form is usually used initially. If the drug is administered orally, the suggested initial dose is 50 to 100 mg, to be followed by repeated doses as needed until agitation is controlled up to 300 mg per day. Dosage should then be reduced to maintenance levels.

*See package insert for Sterile Chlordiazepoxide Hydrochloride.

Discontinuation or Dosage Reduction of Chlordiazepoxide

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue chlordiazepoxide or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increase the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence).