Label: DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE tablet

Each diphenoxylate hydrochloride and atropine sulfate tablet, USP contains:

2.5 mg of diphenoxylate hydrochloride, USP (equivalent to 2.3 mg of diphenoxylate) and 0.025 mg of atropine sulfate, USP (equivalent to 0.01 mg of atropine)

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

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

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

Inactive ingredients of diphenoxylate hydrochloride and atropine sulfate tablets include colloidal silicon dioxide, lactose monohydrate, microcrystalline cellulose, pregelatinized starch and stearic acid.

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

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.

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 tablets 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 tablets 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 tablets 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 Hydrocholoride

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.

Atropinism

Since a subtherapeutic dose of atropine has been added to diphenoxylate hydrochloride and atropine sulfate tablets, consideration should be given to the development of adverse reactions associated with of atropine (see WARNINGS). Diphenoxylate hydrochloride and atropine sulfate tablets have caused atropinism (hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes) particularly in pediatric patients with Down’s syndrome. Diphenoxylate hydrochloride and atropine sulfate tablets are not indicated for use in pediatric patients (see CONTRAINDICATIONS and WARNINGS). Monitor patients for signs of atropinism.

The following serious adverse reactions are described elsewhere in labeling:

• Respiratory and/or CNS depression (see WARNINGS)
• Anticholinergic and opioid-toxicities, including atroponism (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.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088 OR LEADING PHARMA, LLC AT 1-844-740-7500.

Controlled Substance: Diphenoxylate hydrochloride and atropine sulfate tablets are classified as a Schedule V controlled substance by federal regulation. Diphenoxylate hydrochloride is chemically related to the narcotic analgesic meperidine.

Drug Abuse and Dependence: In doses used for the treatment of diarrhea, whether acute or chronic, diphenoxylate has not produced addiction.

Diphenoxylate hydrochloride is devoid of morphine-like subjective effects at therapeutic doses. At high doses it exhibits codeine-like subjective effects. The dose which produces antidiarrheal action is widely separated from the dose which causes central nervous system effects. The insolubility of diphenoxylate hydrochloride in commonly available aqueous media precludes intravenous self- administration. A dose of 100 to 300 mg/day, which is equivalent to 40 to 120 tablets, administered to humans for 40 to 70 days, produced opiate withdrawal symptoms. Since addiction to diphenoxylate hydrochloride is possible at high doses, the recommended dosage should not be exceeded.

Diagnosis:

Overdosage can be life-threatening. Symptoms of overdosage may include opioid and/or anticholinergic effects including respiratory depression, coma, delirium, lethargy, dryness of the skin and mucous membranes, mydriasis or miosis, flushing, hyperthermia, tachycardia, hypotonia, tachypnea, toxic encephalopathy, seizures and incoherent speech.

Respiratory depression has been reported up to 30 hours after ingestion and may recur despite an initial response to narcotic antagonists.

Treat all possible diphenoxylate hydrochloride and atropine sulfate overdosages as serious and maintain medical observation/hospitalization until patients become asymptomatic without naloxone use.

Treatment:

A pure narcotic antagonist (e.g., naloxone) should be used in the treatment of respiratory depression caused by diphenoxylate hydrochloride and atropine sulfate tablets. Refer to the prescribing information for naloxone. Consider diphenoxylate hydrochloride and atropine sulfate toxicity even in settings of negative toxicology tests.

Following initial improvement of respiratory function, repeated doses of naloxone hydrochloride may be required to counteract recurrent respiratory depression.

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

Management of Diarrhea in Patients 13 Years of Age and Older

Diphenoxylate hydrochloride and atropine sulfate tablets are recommended as adjunctive therapy for the management of diarrhea in patients 13 years of age and older. Consider the nutritional status and degree of dehydration in patients prior to initiating therapy with diphenoxylate hydrochloride and atropine sulfate tablets. 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, do not administer diphenoxylate hydrochloride and atropine sulfate tablets until appropriate corrective therapy has been indicated (see WARNINGS).

Initial and Maximum Recommended Dosage in Patients 13 Years of Age and Older

The initial adult dosage is 2 diphenoxylate hydrochloride and atropine sulfate tablets four times daily (maximum total daily dose of 20 mg per day of diphenoxylate hydrochloride). Most patients will require this dosage until initial control of diarrhea has been achieved. Clinical improvement of acute diarrhea is usually observed within 48 hours.

Dosage after Initial Control of Diarrhea

After initial control has been achieved, the diphenoxylate hydrochloride and atropine sulfate tablet dosage may be reduced to meet individual requirements. Control may often be maintained with as little as two diphenoxylate hydrochloride and atropine sulfate tablets daily.

Duration of Treatment

If clinical improvement of chronic diarrhea after treatment with the maximum recommended daily dosage is not observed within 10 days, discontinue diphenoxylate hydrochloride and atropine sulfate tablets as symptoms are unlikely to be controlled by further administration.

Product: 50090-5589

NDC: 50090-5589-0 15 TABLET in a BOTTLE

NDC: 50090-5589-1 20 TABLET in a BOTTLE

NDC: 50090-5589-2 30 TABLET in a BOTTLE