Label: CHLORDIAZEPOXIDE HYDROCHLORIDE AND CLIDINIUM BROMIDE capsule

Chlordiazepoxide hydrochloride and clidinium bromide capsules, USP are a fixed-combination of chlordiazepoxide hydrochloride, a benzodiazepine, and clidinium bromide, an anticholinergic.

Each chlordiazepoxide hydrochloride and clidinium bromide capsule USP contains the active ingredients 5 mg chlordiazepoxide hydrochloride USP and 2.5 mg clidinium bromide USP. Each capsule also contains the inactive ingredients: corn starch, lactose monohydrate and talc. The capsule shell contains D&C yellow - 10, FD&C blue - 1, gelatin, sodium lauryl sulfate and titanium dioxide. The capsules are imprinted with black ink containing black iron oxide, potassium hydroxide and shellac.

Chlordiazepoxide hydrochloride USP is 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide hydrochloride. A white to slightly yellow crystalline powder, it is freely soluble in water, sparingly soluble in ethanol and insoluble in hexane. 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:

Clidinium bromide USP is a synthetic anticholinergic agent which has been shown in experimental and clinical studies to have antispasmodic and antisecretory effects on the gastrointestinal tract. Structurally clidinium bromide is:

Meets USP Dissolution Test 2.

Effects on Reproduction

Reproduction studies in rats fed chlordiazepoxide hydrochloride, 10, 20 and 80 mg/kg daily (2.4, 4.8 and 19.4 times, respectively, the maximum recommended clinical dose of 40 mg/day, based on body surface area), and bred through one or two matings showed no congenital anomalies, nor were there adverse effects on 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 (24.2 times the maximum recommended human dose of 40 mg/day, based on body surface area) exhibited major skeletal defects.

Two series of reproduction experiments with clidinium bromide were carried out in rats, employing dosages of 2.5 and 10 mg/kg daily (1.2 and 4.9 times, respectively, the maximum recommended clinical dose of 20 mg/day, based on body surface area) in each experiment. In the first experiment, clidinium bromide was administered for a 9-week interval prior to mating; no untoward effect on fertilization or gestation was noted. The offspring were taken by caesarean section and did not show a significant incidence of congenital anomalies when compared to control animals. In the second experiment, adult animals were given clidinium bromide for 10 days prior to and through two mating cycles. No significant effects were observed on fertility, gestation, viability of offspring or lactation, as compared to control animals, nor was there a significant incidence of congenital anomalies in the offspring derived from these experiments.

A reproduction study was carried out in rats through two successive matings with administration of oral daily doses of 2.5 mg/kg chlordiazepoxide hydrochloride and 1.25 mg/kg clidinium bromide (0.6 times the maximum recommended clinical dose for both drugs, based on body surface area) or 25 mg/kg chlordiazepoxide hydrochloride and 12.5 mg/kg clidinium bromide (6.1 times the maximum recommended clinical dose for both drugs, based on body surface area). In the first mating, no significant differences were noted between the control or the treated groups, with the exception of a slight decrease in the number of animals surviving during lactation among those receiving the high dosage. In the second mating, similar results were obtained except for a slight decrease in the number of pregnant females and in the percentage of offspring surviving until weaning. No congenital anomalies were observed in both matings in either the control or treated groups.

Chlordiazepoxide hydrochloride and clidinium bromide capsules are indicated to control emotional and somatic factors in gastrointestinal disorders. Chlordiazepoxide hydrochloride and clidinium bromide capsules may also be used as adjunctive therapy in the treatment of peptic ulcer and in the treatment of the irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis.

Chlordiazepoxide hydrochloride and clidinium bromide capsules are contraindicated in the presence of glaucoma (since the anticholinergic component may produce some degree of mydriasis) and in patients with prostatic hypertrophy and benign bladder neck obstruction. It is contraindicated in patients with known hypersensitivity to chlordiazepoxide hydrochloride and/or clidinium bromide.

Risks From Concomitant Use with Opioids

Concomitant use of benzodiazepines, including chlordiazepoxide hydrochloride and clidinium bromide, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs - 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 hydrochloride and clidinium bromide 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. Advise both patients and caregivers about the risks of respiratory depression and sedation when chlordiazepoxide hydrochloride and clidinium bromide are used with opioids (see PRECAUTIONS).

Abuse, Misuse, and Addiction

The use of benzodiazepines, including chlordiazepoxide hydrochloride, a component of chlordiazepoxide hydrochloride and clidinium bromide capsules, 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).

Before prescribing chlordiazepoxide hydrochloride and clidinium bromide capsules and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of chlordiazepoxide hydrochloride and clidinium bromide, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of chlordiazepoxide hydrochloride and clidinium bromide 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.

CNS Adverse Reactions

In geriatric or debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia, oversedation or confusion (not more than 2 chlordiazepoxide hydrochloride and clidinium bromide capsules per day initially, to be increased gradually as needed and tolerated). In general, the concomitant administration of chlordiazepoxide hydrochloride and clidinium bromide 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 to chlordiazepoxide hydrochloride, e.g., excitement, stimulation and acute rage, have been reported in psychiatric patients and should be watched for during chlordiazepoxide hydrochloride and clidinium bromide therapy. The usual precautions are indicated when chlordiazepoxide hydrochloride 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.

No side effects or manifestations not seen with either compound alone have been reported with the administration of chlordiazepoxide hydrochloride and clidinium bromide. However, since chlordiazepoxide hydrochloride and clidinium bromide capsules contain chlordiazepoxide hydrochloride and clidinium bromide, the possibility of untoward effects which may be seen with either of these two compounds cannot be excluded.

When chlordiazepoxide hydrochloride has been used alone 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 with chlordiazepoxide hydrochloride 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 hydrochloride treatment.

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

Adverse effects reported with use of chlordiazepoxide hydrochloride and clidinium bromide are those typical of anticholinergic agents, i.e., dryness of the mouth, blurring of vision, urinary hesitancy and constipation. Constipation has occurred most often when chlordiazepoxide hydrochloride and clidinium bromide therapy has been combined with other spasmolytic agents and/or a low residue diet.

To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Overdosage of chlordiazepoxide hydrochloride and clidinium bromide, which contains a benzodiazepine (chlordiazepoxide hydrochloride) and an anticholinergic (clidinium bromide) may manifest signs and symptoms related to either of its components, although some effects such as altered levels of consciousness may be synergistic.

Overdosage of benzodiazepines, such as chlordiazepoxide hydrochloride, 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.

Signs and symptoms of anticholinergic overdosage are related to excessive anti-muscarinic anticholinergic activity. Peripheral signs and symptoms may include dry mucous membranes and skin, flushing, tachycardia, hypertension, ileus, urinary retention, and mydriasis. Garbled speech is often pathognomonic. Central signs and symptoms may include agitation and delirium, seizures, and hyperthermia. Benzodiazepines are considered a first-line treatment for anticholinergic toxicity acting to treat mild to moderate agitation and prevent seizures.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS, Dependence and Withdrawal Reactions). 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. Anticholinergic drugs usually increase heart rate and blood pressure. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids, and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage. Use of flumazenil may increase the risk of seizures in mixed overdosage with drugs that may precipitate seizures, including anticholinergic medications. Benzodiazepines are used to treat agitated delirium from anticholinergic toxicity. Therefore flumazenil administration may worsen the anticholinergic delirium and should generally be avoided.

Anticholinesterase inhibitors may reverse severe agitated delirium that is not controlled by benzodiazepines. They may also improve the airway and breathing in CNS depressed patients. Caution is warranted especially in mixed drug overdoses.

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

Recommended Dosage

Because of the varied individual responses to tranquilizers and anticholinergics, the optimum dosage of chlordiazepoxide hydrochloride and clidinium bromide capsules varies with the diagnosis and response of the individual patient. The dosage, therefore, should be individualized for maximum beneficial effects. The usual maintenance dose is 1 or 2 capsules, 3 or 4 times a day administered before meals and at bedtime.

Recommended Geriatric Dosage

Dosage should be limited to the smallest effective amount to preclude the development of ataxia, oversedation or confusion. The initial dose should not exceed 2 chlordiazepoxide hydrochloride and clidinium bromide capsules per day, to be increased gradually as needed and tolerated. Elderly patients have an increased risk of dose-related adverse reactions (see PRECAUTIONS).

Discontinuation or Dosage Reduction of Chlordiazepoxide Hydrochloride and Clidinium Bromide Capsules

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue chlordiazepoxide hydrochloride and clidinium bromide capsules or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS and DRUG ABUSE AND DEPENDENCE).

Chlordiazepoxide Hydrochloride and Clidinium Bromide Capsules USP, 5 mg/2.5 mg are available in green cap and green body hard gelatin capsule shells, imprinted with ‘CH/CB’ on cap, ‘5/2.5’ on body with black ink filled with white to off-white granular powder. They are supplied as follows:

Bottles of 100            NDC 59651-524-01

Store at 20o to 25○C (68○ to 77○F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Keep out of reach of children.

Dispense in tight, light-resistant container as defined in USP/NF.

Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides.

Distributed by:
Aurobindo Pharma USA, Inc.
279 Princeton-Hightstown Road
East Windsor, NJ 08520

Manufactured by:
Aurobindo Pharma Limited
Hyderabad-500 032, India

Issued: June 2023

Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Issued: June 2023

NDC 59651-524-01

Chlordiazepoxide
Hydrochloride and Clidinium
Bromide Capsules, USP
5 mg/2.5 mg

PHARMACIST: Dispense the Medication
Guide provided separately to each patient.

Rx only                                 100 Capsules

AUROBINDO