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.

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 tablets .

Diphenoxylate hydrochloride and atropine sulfate tabelts are 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 tabelts 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 tablets should be accompanied by appropriate fluid and electrolyte therapy, when indicated.

If severe dehydration or electrolyte imbalance is present, diphenoxylate hydrochloride and atropine sulfate tablets 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 tabelets are 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 tablets, slow gastrointestinal motility and may enhance bacterial overgrowth and the release of bacterial exotoxins.

Diphenoxylate hydrochloride and atropine sulfate tablets have 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 tablets 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 tablets therapy should be discontinued promptly if abdominal distention occurs or if other untoward symptoms develop.

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

Hepatorenal Disease Diphenoxylate hydrochloride and atropine sulfate tablets 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.

Interaction with CNS Depressants Diphenoxylate hydrochloride may potentiate the action of other drugs that cause dizziness or drowsiness, including barbiturates, benzodiazepines and other sedatives/hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol.

Therefore, the patient should be closely observed when any of these are used concomitantly.

ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Respiratory and/or CNS depression (see WARNINGS ) Anticholinergic and opioid-toxicities, including atropinism (see WARNINGS and PRECAUTIONS ) Dehydration and electrolyte imbalance (see WARNINGS ) GI Complications in patients with infectious diarrhea (see WARNINGS ) Toxic megacolon in patients with acute ulcerative colitis (see WARNINGS ) At therapeutic doses of diphenoxylate hydrochloride and atropine sulfate tablets, the following other adverse reactions 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, hallucination Allergic: anaphylaxis, angioneurotic edema, urticaria, swelling of the gums, pruritus Gastrointestinal system: megacolon, paralytic ileus, pancreatitis, vomiting, nausea, anorexia, abdominal discomfort The following adverse reactions related to atropine sulfate are listed in decreasing order of severity, but not of frequency: hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes.

To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA) Inc.

at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.