Prescription Drug Information: Diphenoxylate Hydrochloride and Atropine Sulfate

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE- diphenoxylate hydrochloride and atropine sulfate solution
Atlantic Biologicals Corps

Rx only

DESCRIPTION

Each 5 mL oral solution contains:

Diphenoxylate Hydrochloride …………………………………………………………….. 2.5 mg

Atropine Sulfate ……………………………………………………………………………. 0.025 mg

Alcohol ……………………………………………………………………………………………….. 15%

Inactive Ingredients:

The oral solution contains: alcohol, citric acid (anhydrous), FD&C Red No. 40, FD&C Yellow No. 6, glycerin, maltol, potassium sorbate, purified water, sorbitol solution and wild cherry flavor.

Diphenoxylate hydrochloride, an antidiarrheal, is ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisoni-pecotate monohydrochloride and has the following structural formula:

Diphenoxylate structural formula

C30H32N2O2 · HCl M.W 489.05

Atropine sulfate, an anticholinergic, is endo-(±)-α-(hydroxymethyl) benzeneacetic acid 8-methyl-8-azabicyclo[3.2.1] oct-3-yl ester sulfate (2:1) (salt) monohydrate and has the following structural formula:

Atropine Sulfate structural formula

(C17 H23 NO3 )2 · H2 SO4 · H2O M.W. 694.83

A subtherapeutic amount of atropine sulfate is present to discourage deliberate overdosage.

CLINICAL PHARMACOLOGY

Diphenoxylate is rapidly and extensively metabolized in man by ester hydrolysis to diphenoxylic acid (difenoxine), which is biologically active and the major metabolite in the blood. After a 5 mg oral dose of carbon-14 labeled diphenoxylate hydrochloride in ethanolic solution was given to three healthy volunteers, an average of 14% of the drug plus its metabolites was excreted in the urine and 49% in the feces over a four-day period. Urinary excretion of the unmetabolized drug constituted less than 1% of the dose, and diphenoxylic acid plus its glucuronide conjugate constituted about 6% of the dose. In a 16-subject crossover bioavailability study, a linear relationship in the dose range of 2.5 to 10 mg was found between the dose of diphenoxylate hydrochloride (given as liquid) and the peak plasma concentration, the area under the plasma concentration-time curve, and the amount of diphenoxylic acid excreted in the urine. In the same study the bioavailability of the tablet compared with an equal dose of the liquid was approximately 90%. The average peak plasma concentration of diphenoxylic acid following ingestion of four 2.5 mg tablets was 163 ng/mL at about 2 hours, and the elimination half-life of diphenoxylic acid was approximately 12 to 14 hours.

In dogs, diphenoxylate hydrochloride has a direct effect on circular smooth muscle of the bowel that conceivably results in segmentation and prolongation of gastrointestinal transit time. The clinical antidiarrheal action of diphenoxylate hydrochloride may thus be a consequence of enhanced segmentation that allows increased contact of the intraluminal contents with the intestinal mucosa.

INDICATIONS AND USAGE

Diphenoxylate hydrochloride and atropine sulfate is effective as adjunctive therapy in the management of diarrhea.

CONTRAINDICATIONS

Diphenoxylate hydrochloride and atropine sulfate is contraindicated in patients with:

1.
Known hypersensitivity to diphenoxylate or atropine.
2.
Obstructive jaundice.
3.
Diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria.

WARNINGS

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE IS NOT AN INNOCUOUS DRUG AND DOSAGE RECOMMENDATIONS SHOULD BE STRICTLY ADHERED TO, ESPECIALLY IN CHILDREN. DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE IS NOT RECOMMENDED FOR CHILDREN UNDER 2 YEARS OF AGE. OVERDOSAGE MAY RESULT IN SEVERE RESPIRATORY DEPRESSION AND COMA, POSSIBLY LEADING TO PERMANENT BRAIN DAMAGE OR DEATH (SEE OVERDOSAGE). THEREFORE, KEEP THIS MEDICATION OUT OF THE REACH OF CHILDREN.

THE USE OF DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE SHOULD BE ACCOMPANIED BY APPROPRIATE FLUID AND ELECTROLYTE THERAPY, WHEN INDICATED. IF SEVERE DEHYDRATION OR ELECTROLYTE IMBALANCE IS PRESENT, DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE SHOULD BE WITHHELD UNTIL APPROPRIATE CORRECTIVE THERAPY HAS BEEN INITIATED. DRUG-INDUCED INHIBITION OF PERISTALSIS MAY RESULT IN FLUID RETENTION IN THE INTESTINE, WHICH MAY FURTHER AGGRAVATE DEHYDRATION AND ELECTROLYTE IMBALANCE.

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE SHOULD BE USED WITH SPECIAL CAUTION IN YOUNG CHILDREN BECAUSE THIS AGE GROUP MAY BE PREDISPOSED TO DELAYED DIPHENOXYLATE TOXICITY AND BECAUSE OF THE GREATER VARIABILITY OF RESPONSE IN THIS AGE GROUP.

Antiperistaltic agents may prolong and/or worsen diarrhea associated with organisms that penetrate the intestinal mucosa (toxigenic E. coli, Salmonella, Shigella), and pseudomembranous enterocolitis associated with broad-spectrum antibiotics. Antiperistaltic agents should not be used in these conditions.

In some patients with acute ulcerative colitis, agents that inhibit motility or prolong intestinal transit time have been reported to induce toxic megacolon. Consequently, patients with acute ulcerative colitis should be carefully observed and diphenoxylate hydrochloride and atropine sulfate therapy should be discontinued promptly if abdominal distention occurs or if other untoward symptoms develop.

Since the chemical structure of diphenoxylate hydrochloride is similar to that of meperidine hydrochloride, the concurrent use of diphenoxylate hydrochloride and atropine sulfate with monoamine oxidase (MAO) inhibitors may, in theory, precipitate hypertensive crisis.

Diphenoxylate hydrochloride and atropine sulfate should be used with extreme caution in patients with advanced hepatorenal disease and in all patients with abnormal liver function since hepatic coma may be precipitated.

Diphenoxylate hydrochloride may potentiate the action of barbiturates, tranquilizers and alcohol. Therefore, the patient should be closely observed when any of these are used concomitantly.

PRECAUTIONS

General

Since a subtherapeutic dose of atropine has been added to the diphenoxylate hydrochloride, consideration should be given to the precautions relating to the use of atropine. In children, diphenoxylate hydrochloride and atropine sulfate should be used with caution since signs of atropinism may occur even with recommended doses, particularly in patients with Down’s syndrome.

Information for Patients

INFORM THE PATIENT (PARENT OR GUARDIAN) NOT TO EXCEED THE RECOMMENDED DOSAGE AND TO KEEP DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE OUT OF THE REACH OF CHILDREN AND IN A CHILD-RESISTANT CONTAINER. INFORM THE PATIENT OF THE CONSEQUENCES OF OVERDOSAGE, INCLUDING SEVERE RESPIRATORY DEPRESSION AND COMA, POSSIBLY LEADING TO PERMANENT BRAIN DAMAGE OR DEATH. Diphenoxylate hydrochloride and atropine sulfate may produce drowsiness or dizziness. The patient should be cautioned regarding activities requiring mental alertness, such as driving or operating dangerous machinery. Potentiation of the action of alcohol, barbiturates, and tranquilizers with concomitant use of diphenoxylate hydrochloride and atropine sulfate should be explained to the patient. The physician should also provide the patient with other information in this labeling, as appropriate.

Drug Interactions

Known drug interactions include barbiturates, tranquilizers, and alcohol. Diphenoxylate hydrochloride and atropine sulfate may interact with MAO inhibitors (see WARNINGS).

In studies with male rats, diphenoxylate hydrochloride was found to inhibit the hepatic microsomal enzyme system at a dose of 2 mg/kg/day. Therefore, diphenoxylate has the potential to prolong the biological half-lives of drugs for which the rate of elimination is dependent on the microsomal drug metabolizing enzyme system.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term study in animals has been performed to evaluate carcinogenic potential. Diphenoxylate hydrochloride was administered to male and female rats in their diets to provide dose levels of 4 and 20 mg/kg/day throughout a three-litter reproduction study. At 50 times the human dose (20 mg/kg/day), female weight gain was reduced and there was a marked effect on fertility as only 4 of 27 females became pregnant in three test breedings. The relevance of this finding to usage of diphenoxylate hydrochloride and atropine sulfate in humans in unknown.

Pregnancy

Pregnancy Category C

Diphenoxylate hydrochloride has been shown to have an effect on fertility in rats when given in doses 50 times the human dose (see above discussion). Other findings in this study include a decrease in maternal weight gain of 30% at 20 mg/kg/day and of 10% at 4 mg/kg/day. At 10 times the human dose (4 mg/kg/day), average litter size was slightly reduced.

Teratology studies were conducted in rats, rabbits, and mice with diphenoxylate hydrochloride at oral doses of 0.4 to 20 mg/kg/day. Due to experimental design and small numbers of litters, embryotoxic, fetotoxic, or teratogenic effects cannot be adequately assessed. However, examination of the available fetuses did not reveal any indication of tetratogenicity.

There are no adequate and well-controlled studies in pregnant women. Diphenoxylate hydrochloride and atropine sulfate should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.

Nursing Mothers

Caution should be exercised when diphenoxylate hydrochloride and atropine sulfate is administered to a nursing woman, since the physicochemical characteristics of the major metabolite, diphenoxylic acid, are such that it may be excreted in breast milk and since it is known that atropine is excreted in breast milk.

Pediatric Use

Diphenoxylate hydrochloride and atropine sulfate may be used as an adjunct to the treatment of diarrhea but should be accompanied by appropriate fluid and electrolyte therapy, if needed. DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE IS NOT RECOMMENDED FOR CHILDREN UNDER 2 YEARS OF AGE. Diphenoxylate hydrochloride and atropine sulfate should be used with special caution in young children because of the greater variability of response in this age group. See WARNINGS and DOSAGE AND ADMINISTRATION. In case of accidental ingestion by children, see OVERDOSAGE for recommended treatment.

ADVERSE REACTIONS

At therapeutic doses, the following have been reported; they are listed in decreasing order of severity, but not of frequency:

Nervous system: numbness of extremities, euphoria, depression, malaise/lethargy, confusion, sedation/drowsiness, dizziness, restlessness, headache.

Allergic: anaphylaxis, angioneurotic edema, urticaria, swelling of the gums, pruritus.

Gastrointestinal system: toxic megacolon, paralytic ileus, pancreatitis, vomiting, nausea, anorexia, abdominal discomfort.

The following atropine sulfate effects are listed in decreasing order of severity, but not of frequency: hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes. These effects may occur, especially in children.

THIS MEDICATION SHOULD BE KEPT IN A CHILD-RESISTANT CONTAINER AND OUT OF THE REACH OF CHILDREN SINCE AN OVERDOSAGE MAY RESULT IN SEVERE RESPIRATORY DEPRESSION AND COMA, POSSIBLY LEADING TO PERMANENT BRAIN DAMAGE OR DEATH.

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