Diphenoxylate Hydrochloride and Atropine Sulfate

DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE- diphenoxylate hydrochloride and atropine sulfate tablet
PD-Rx Pharmaceuticals, Inc.

Rx only

DESCRIPTION

Each diphenoxylate hydrochloride and atropine sulfate tablet, USP contains:

Diphenoxylate hydrochloride, USP2.5 mg (equivalent to 2.3 mg of diphenoxylate)
Atropine sulfate, USP0.025 mg (equivalent to 0.01 mg of atropine)

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

Chemical Structure
(click image for full-size original)

Atropine sulfate, USP 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:

Chemical Structure
(click image for full-size original)

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

Diphenoxylate hydrochloride and atropine sulfate tablets, USP contain the following inactive ingredients: colloidal silicon dioxide, microcrystalline stearate, pregelatinized starch and stearic acid.

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 diphenoxylate hydrochloride and atropine sulfate 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.

Diphenoxylate Hydrochloride and Atropine Sulfate Indications and Usage

Diphenoxylate hydrochloride and atropine sulfate tablets are indicated as adjunctive therapy in the management of diarrhea in patients 13 years of age and older.

CONTRAINDICATIONS

Diphenoxylate hydrochloride and atropine sulfate tablets are contraindicated in:

  • Pediatric patients less than 6 years of age due to the risks of respiratory and central nervous system (CNS) depression [see WARNINGS].
  • Patients with diarrhea associated with pseudomembranous enterocolitis ( Clostridium difficile) or other enterotoxin-producing bacteria due to the risk of gastrointestinal (GI) complications, including sepsis [see WARNINGS].
  • Patients with known hypersensitivity to diphenoxylate or atropine.
  • Patients with obstructive jaundice.

WARNINGS

Respiratory and/or CNS Depression in Pediatric Patients Less Than 6 Years of Age

Cases of severe respiratory depression and coma, leading to permanent brain damage or death have been reported in patients less than 6 years of age who received diphenoxylate hydrochloride and atropine sulfate . Diphenoxylate hydrochloride and atropine sulfate is contraindicated in patients less than 6 years of age due to these risks [see CONTRAINDICATIONS].

Anticholinergic and Opioid-Toxicities

Toxicities associated with the atropine and diphenoxylate components of diphenoxylate hydrochloride and atropine sulfate have been reported. The initial presenting symptoms may be delayed by up to 30 hours due to prolonged gastric emptying time induced by diphenoxylate hydrochloride. Clinical presentations vary in terms of which toxicity (anticholinergic vs. opioid) will present first or predominate; non-specific findings have been reported and include symptoms such as drowsiness [see OVERDOSAGE].

Dehydration and Electrolyte Imbalance

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.

Gastrointestinal Complications in Patients with Infectious Diarrhea

Diphenoxylate hydrochloride and atropine sulfate is contraindicated in patients with diarrhea associated with organisms that penetrate the GI mucosa (toxigenic E. coli, Salmonella, Shigella), and pseudomembranous enterocolitis ( Clostridium difficile) associated with broad-spectrum antibiotics [see CONTRAINDICATIONS]. Antiperistaltic agents, including diphenoxylate hydrochloride and atropine sulfate, slow gastrointestinal motility and may enhance bacterial overgrowth and the release of bacterial exotoxins. Diphenoxylate hydrochloride and atropine sulfate has been reported to result in serious GI complications in patients with infectious diarrhea, including sepsis, prolonged and/or worsened diarrhea. Prolonged fever and the delay in the resolution of stool pathogens were reported in study of Shigellosis in adults who used diphenoxylate hydrochloride and atropine sulfate vs. placebo.

Toxic Megacolon in Patients with Acute Ulcerative Colitis

In some patients with acute ulcerative colitis, agents that inhibit intestinal 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.

Interaction with Meperidine Hydrocholoride

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.

Hepatorenal Disease

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.

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