CHLORDIAZEPOXIDE HYDROCHLORIDE

Chlordiazepoxide hydrochloride, is the prototype for the benzodiazepine compounds. It is a versatile therapeutic agent of proven value for the relief of anxiety. Chlordiazepoxide hydrochloride is among the safer of the effective psychopharmacologic compounds available, as demonstrated by extensive clinical evidence. Chlordiazepoxide hydrochloride is available as capsules containing 5 mg, 10 mg or 25 mg chlordiazepoxide hydrochloride. Each capsule also contains corn starch, lactose monohydrate and talc. Gelatin capsule shells may contain methyl and propyl parabens and potassium sorbate, with the following dye systems: 5-mg capsules – FD&C Yellow No. 6 plus D&C Yellow No. 10 and either FD&C Blue No. 1 or FD&C Green No. 3. 10-mg capsules – D&C Yellow No. 10 and either FD&C Blue No. 1 plus FD&C Red No. 3 or FD&C Green No. 3 plus FD&C Red No. 40. 25-mg capsules – D&C Yellow No. 10 and either FD&C Green No. 3 or FD&C Blue No. 1. Chlordiazepoxide hydrochloride is 7-chloro-2-(methylamino)-5-phenyl-3H-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 molecular weight is 336.22. The structural formula of chlordiazepoxide hydrochloride is as follows: structure-formula.jpg

Chlordiazepoxide hydrochloride capsules are 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. The effectiveness of chlordiazepoxide hydrochloride capsules in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

Because of the wide range of clinical indications for chlordiazepoxide, the optimum dosage varies with the diagnosis and response of the individual patient. The dosage, therefore, should be individualized for maximum beneficial effects. ADULTS USUAL DAILY DOSE Relief of Mild and Moderate Anxiety Disorders and Symptoms of Anxiety 5 mg or 10 mg, 3 or 4 times daily Relief of Severe Anxiety Disorders and Symptoms of Anxiety 20 mg or 25 mg, 3 or 4 times daily Geriatric Patients, or in the presence of debilitating disease 5 mg, 2 to 4 times daily 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 PEDIATRIC PATIENTS USUAL DAILY DOSE Because of the varied response of pediatric patients to CNS-acting drugs, therapy should be initiated with the lowest dose and increased as required. Since clinical experience in pediatric patients under 6 years of age is limited, the use of the drug in this age group is not recommended. 5 mg, 2 to 4 times daily (may be increased in some pediatric patients to 10 mg, 2 to 3 times daily) 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 Injectable 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 ).

Chlordiazepoxide hydrochloride capsules are contraindicated in patients with known hypersensitivity to the drug.

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 a 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. To report SUSPECTED ADVERSE REACTIONS, contact Epic Pharma, LLC at 1-888-374-2791 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 A sites 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 hydrochloride capsules, 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 hydrochloride capsules during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to chlordiazepoxide hydrochloride capsules 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 neonates and infants, advise patients that breastfeeding is not recommended during treatment with chlordiazepoxide hydrochloride capsules.