Chlordiazepoxide HCl/ Clidinium Bromide CAPSULES

to control emotional
and somatic factors
in gastrointestinal disorders

Chlordiazepoxide HCl/Clidinium Bromide combines in a single capsule formulation the antianxiety action of chlordiazepoxide hydrochloride and the anticholinergic/spasmolytic effects of clidinium bromide, both exclusive developments of Roche research.

Each Chlordiazepoxide HCl/Clidinium Bromide capsule contains 5 mg chlordiazepoxide hydrochloride and 2.5 mg clidinium bromide. Each capsule also contains corn starch, lactose and talc. Gelatin capsule shells may contain methyl and propyl parabens and potassium sorbate, with the following dye systems: D&C Yellow No. 10 and either FD&C Blue No. 1 or FD&C Green No. 3.

Chlordiazepoxide hydrochloride is a versatile, therapeutic agent of proven value for the relief of anxiety and tension. It is indicated when anxiety, tension or apprehension are significant components of the clinical profile. It is among the safer of the effective psychopharmacologic compounds.

Chlordiazepoxide hydrochloride is 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide hydrochloride. A colorless, 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:

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

Chlordiazepoxide hydrochloride 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 hydrochloride revealed a "taming" action with the elimination of fear and aggression. The taming effect of chlordiazepoxide hydrochloride 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 oral LD of single doses of chlordiazepoxide hydrochloride, calculated according to the method of Miller and Tainter, is 720 ± 51 mg/kg as determined in mice observed over a period of 5 days following dosage. ₅₀

Clidinium bromide is an effective anticholinergic agent with activity approximating that of atropine sulfate against acetylcholine-induced spasms in isolated intestinal strips. On oral administration in mice it proved an effective antisialagogue in preventing pilocarpine-induced salivation. Spontaneous intestinal motility in both rats and dogs is reduced following oral dosing with 0.1 to 0.25 mg/kg. Potent cholinergic ganglionic blocking effects (vagal) are produced with intravenous usage in anesthetized dogs.

Oral doses of 2.5 mg/kg to dogs produced signs of nasal dryness and slight pupillary dilation. In two other species, monkeys and rabbits, doses of 5 mg/kg, po, given three times daily for 5 days did not produce apparent secretory or visual changes.

The oral LD of single doses of clidinium bromide is 860 ± 57 mg/kg as determined in mice observed over a period of 5 days following dosage; the calculations were made according to the method of Miller and Tainter. ₅₀

Based on a review of this drug by the National Academy of Sciences — National Research Council and/or other information, FDA has classified the indications as follows:

"Possibly" effective: 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.

Final classification of the less-than-effective indications requires further investigation.

Chlordiazepoxide HCl/Clidinium Bromide is 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.

As in the case of other preparations containing CNS-acting drugs, patients receiving Chlordiazepoxide HCl/Clidinium Bromide should be cautioned about possible combined effects with alcohol and other CNS depressants. For the same reason, they should be cautioned against hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle.

Manifestations of chlordiazepoxide hydrochloride overdosage include somnolence, confusion, coma and diminished reflexes. 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 hydrochloride overdosage.

While the signs and symptoms of Chlordiazepoxide HCl/Clidinium Bromide overdosage may be produced by either of its components, usually such symptoms will be overshadowed by the anticholinergic actions of clidinium bromide. The symptoms of overdosage of clidinium bromide are excessive dryness of mouth, blurring of vision, urinary hesitancy and constipation.

General supportive measures should be employed, along with immediate gastric lavage. Administer physostigmine 0.5 to 2 mg at a rate of no more than 1 mg per minute. This may be repeated in 1 to 4 mg doses if arrhythmias, convulsions or deep coma recur. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of levarterenol or metaraminol. Methylphenidate or caffeine and sodium benzoate may be given to combat CNS-depressive effects. Dialysis is of limited value. Should excitation occur, 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.

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

In 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 HCl/Clidinium Bromide capsules per day initially, to be increased gradually as needed and tolerated). In general, the concomitant administration of Chlordiazepoxide HCl/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, eg, excitement, stimulation and acute rage, have been reported in psychiatric patients and should be watched for during Chlordiazepoxide HCl/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. 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 hydrochloride.

No side effects or manifestations not seen with either compound alone have been reported with the administration of Chlordiazepoxide HCl/Clidinium Bromide. However, 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 are those typical of anticolinergic agents, ie, dryness of the mouth, blurring of vision, urinary hesitancy and constipation. Constipation has occurred most often when Chlordiazepoxide HCl/Clidinium Bromide therapy has been combined with other spasmolytic agents and/or a low residue diet. Chlordiazepoxide HCl/Clidinium Bromide

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuance of chlordiazepoxide. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving chlordiazepoxide or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

Because of the varied individual responses to tranquilizers and anticholinergics, the optimum dosage of Chlordiazepoxide HCl/Clidinium Bromide 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.

NDC:68151-2500-1 in a PACKAGE of 1 CAPSULES

Manufactured in Canada by: Valeant Pharmaceuticals International, Inc. Steinbach, MB R5G 1Z7 Canada

Manufactured for: Oceanside Pharmaceuticals a division of Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA

LB0093-00 Rev. 03/13