ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. At therapeutic doses, the following have been reported: they are listed in decreasing order of severity, but not of frequency:Nervous system: Numbnessof 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.Thefollowing atropine sulfate effects are listed in decreasing order ofseverity, but not of frequency: hyperthermia, tachycardia, urinaryretention, flushing, dryness of the skin and mucous membranes. Theseeffects may occur especially in children.THIS MEDICATION SHOULDBE KEPT IN CHILD-RESISTANT CONTAINER AND OUT OF THE REACH OF CHILDRENSINCE AN OVERDOSAGE MAY RESULT IN SEVERE RESPIRATORY DEPRESSION ANDCOMA, POSSIBLY LEADING TO PERMANENT BRAIN DAMAGE OR DEATH.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Diphenoxylate is rapidly and extensively metabolizedin man by ester hydrolysis to diphenoxylic acid (difenoxine), which isbiologically active and the major metabolite in the blood. After 5 mgoral dose of carbon-14 labeled diphenoxylate hydrochloride in ethanolicsolution was given to three healthy volunteers, an average of 14% ofthe drug plus its metabolites was excreted in the urine and 49% in thefeces over 4-day period. Urinary excretion of the unmetabolized drugconstituted less than 1% of the dose, and diphenoxylic acid plus itsglucuronide conjugate constituted about 6% of the dose. In 16 subjectcross-over bioavailability study, linear relationship in the doserange of 2.5 mg to 10 mg was found between the dose of diphenoxylatehydrochloride (given as Diphenoxylate Hydrochloride and AtropineSulfate Oral Solution) and the peak plasma concentration, the areaunder the plasma concentration-time curve, and the amount ofdiphenoxylic acid excreted in the urine. In the same study thebioavailability of the tablet compared with an equal dose of the liquidwas approximately 90%. The average peak plasma concentration ofdiphenoxylic acid following ingestion of four 2.5 mg tablets was 163ng/mL at about hours, and the elimination half-life of diphenoxylicacid was approximately 12 to 14 hours.In dogs, diphenoxylatehydrochloride has direct effect on circular smooth muscle of thebowel, that conceivably results in segmentation and prolongation ofgastrointestinal transit time. The clinical antidiarrheal action ofdiphenoxylate hydrochloride may thus be consequence of enhancedsegmentation that allows increased contact of the intraluminal contentswith the intestinal mucosa.

DESCRIPTION SECTION.

DESCRIPTION. Each tablet for oral administration contains:diphenoxylatehydrochloride, USP 2.5 mg(Warning May be habit forming)atropinesulfate, USP 0.025 mgDiphenoxylatehydrochloride, an antidiarrheal, is ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-isonipecotate monohydrochloride and has thefollowing structure:Atropinesulfate, 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 structure:A subtherapeutic amount of atropine sulfate is present to discourage deliberate overdosage.Eachtablet for oral administration contains the following inactiveingredients: colloidal silicon dioxide, microcrystalline cellulose,pregelatinized starch and stearic acid.. Diphenoxylate Hydrochloride Structural Formula. Atropine Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. DO NOT EXCEED RECOMMENDED DOSAGE.. Adults. The recommended initial dosage is two tablets fourtimes daily (20 mg per day). Most patients will require this dosageuntil initial control has been achieved, after which the dosage may bereduced to meet individual requirements. Control may often bemaintained with as little as mg (two tablets) daily.Clinicalimprovement of acute diarrhea is usually observed within 48 hours. Ifclinical improvement of chronic diarrhea after treatment with maximumdaily dose of 20 mg of diphenoxylate hydrochloride is not observedwithin 10 days, symptoms are unlikely to be controlled by furtheradministration.. Children. Diphenoxylate hydrochloride andatropine sulfate is not recommended in children under years of ageand should be used with special caution in young children (see WARNINGS and PRECAUTIONS).The nutritional status and degree of dehydration must be considered. Inchildren under 13 years of age, use oral solution. Do not use tabletsfor this age group.KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Diphenoxylate Hydrochloride and Atropine SulfateTablets, USP are available containing 2.5 mg of diphenoxylatehydrochloride, USP (Warning: May be habit forming) and 0.025 mg ofatropine sulfate, USP. The tablets are white round, unscored tabletsdebossed with over 15 on one side of the tablet and blank on the other side. They are available as follows:NDC 66336-0437-15bottles of 15 tabletsNDC 66336-0437-20bottles of 20 tabletsStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Protect from light.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.Pharmacist: Dispense with child-resistant closure only.Manufacture: Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED NOVEMBER 2009DPXAS:R12.

OVERDOSAGE SECTION.

OVERDOSAGE. RECOMMENDED DOSAGE SCHEDULES SHOULD BE STRICTLY FOLLOWED. THISMEDICATION SHOULD BE KEPT IN CHILD-RESISTANT CONTAINER AND OUT OF THEREACH OF CHILDREN, SINCE AN OVERDOSAGE MAY RESULT IN SEVERE, EVENFATAL, RESPIRATORY DEPRESSION.. Diagnosis. Initial signs of overdosage may include dryness of the skin and mucousmembranes, mydriasis, restlessness, flushing, hyperthermia, andtachycardia followed by lethargy or coma, hypotonic reflexes,nystagmus, pinpoint pupils, and respiratory depression. Respiratorydepression may be evidenced as late as 30 hours after ingestion and mayrecur in spite of an initial response to narcotic antagonists. TREATALL POSSIBLE OVERDOSAGES AS SERIOUS AND MAINTAIN MEDICAL OBSERVATIONFOR AT LEAST 48 HOURS, PREFERABLY UNDER CONTINUOUS HOSPITAL CARE.. Treatment. In the event of overdose, induction of vomiting,gastric lavage, establishment of patent airway, and possiblymechanically assisted respiration are advised. In vitroand animal studies indicate that activated charcoal may significantlydecrease the bioavailability of diphenoxylate. In non-comatosepatients, slurry of 100 of activated charcoal can be administeredimmediately after the induction of vomiting or gastric lavage.Apure narcotic antagonist (e.g., naloxone) should be used in thetreatment of respiratory depression caused by diphenoxylatehydrochloride and atropine sulfate. When narcotic antagonist isadministered intravenously, the onset of action is generally apparentwithin minutes. It may also be administered subcutaneously orintramuscularly, providing slightly less rapid onset of action but amore prolonged effect.To counteract respiratory depressioncaused by diphenoxylate/atropine overdosage, the following dosageschedule for the narcotic antagonist naloxone hydrochloride should befollowed:Adult Dosage: The usualinitial adult dose of naloxone hydrochloride is 0.4 mg administeredintravenously. If respiratory function does not adequately improveafter the initial-dose, the same IV dose may be repeated at to 3minute intervals.Children: The usualinitial dose of naloxone hydrochloride for children is 0.01 mg/kg ofbody weight administered intravenously and repeated at to minuteintervals if necessary.Following initial improvement ofrespiratory function, repeated doses of naloxone hydrochloride may berequired to counteract recurrent respiratory depression. Supplementalintramuscular doses of naloxone hydrochloride may be utilized toproduce longer-lasting effect.Since the duration of action ofdiphenoxylate hydrochloride is longer than that of naloxonehydrochloride, improvement of respiration following administration maybe followed by recurrent respiratory depression. Consequently,continued observation is necessary until the effect of diphenoxylatehydrochloride on respiration has passed. This effect may persist formany hours. The period of observation should extend over at least 48hours, preferably under continuous hospital care. Although signs ofoverdosage and respiratory depression may not be evident soon afteringestion of diphenoxylate hydrochloride, respiratory depression mayoccur from 12 to 30 hours later.

SPL UNCLASSIFIED SECTION.

Diagnosis. Initial signs of overdosage may include dryness of the skin and mucousmembranes, mydriasis, restlessness, flushing, hyperthermia, andtachycardia followed by lethargy or coma, hypotonic reflexes,nystagmus, pinpoint pupils, and respiratory depression. Respiratorydepression may be evidenced as late as 30 hours after ingestion and mayrecur in spite of an initial response to narcotic antagonists. TREATALL POSSIBLE OVERDOSAGES AS SERIOUS AND MAINTAIN MEDICAL OBSERVATIONFOR AT LEAST 48 HOURS, PREFERABLY UNDER CONTINUOUS HOSPITAL CARE.

WARNINGS SECTION.

WARNINGS. THIS IS NOT AN INNOCUOUS DRUG ANDDOSAGE RECOMMENDATIONS SHOULD BE STRICTLY ADHERED TO, ESPECIALLY INCHILDREN. DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE IS NOTRECOMMENDED FOR CHILDREN UNDER YEARS OF AGE. OVERDOSAGE MAY RESULT INSEVERE RESPIRATORY DEPRESSION AND COMA, POSSIBLY LEADING TO PERMANENTBRAIN DAMAGE OR DEATH (See OVERDOSAGE). THEREFORE, KEEP THIS MEDICATION OUT OF THE REACH OF CHILDREN.THE USE OF DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE SHOULD BEACCOMPANIED BY APPROPRIATE FLUID AND ELECTROLYTE THERAPY, WHENINDICATED. IF SEVERE DEHYDRATION OR ELECTROLYTE IMBALANCE IS PRESENT,THIS PRODUCT SHOULD BE WITHHELD UNTIL APPROPRIATE CORRECTIVE THERAPYHAS BEEN INITIATED. DRUG-INDUCED INHIBITION OF PERISTALSIS MAY RESULTIN FLUID RETENTION IN THE INTESTINE, WHICH MAY FURTHER AGGRAVATEDEHYDRATION AND ELECTROLYTE IMBALANCE.DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE SHOULD BE USED WITHSPECIAL CAUTION IN YOUNG CHILDREN BECAUSE THIS AGE GROUP MAY BEPREDISPOSED TO DELAYED DIPHENOXYLATE TOXICITY AND BECAUSE OF THEGREATER VARIABILITY OF RESPONSE IN THIS AGE GROUP.Antiperistalticagents may prolong and/or worsen diarrhea associated with organismsthat penetrate the intestinal mucosa (toxigenic E. coli, Salmonella, Shigella),and pseudomembranous enterocolitis associated with broad-spectrumantibiotics. Antiperistaltic agents should not be used in theseconditions.In some patients with acute ulcerative colitis,agents that inhibit intestinal motility or prolong intestinal transittime have been reported to induce toxic megacolon. Consequently,patients with acute ulcerative colitis should be carefully observed andtherapy should be discontinued promptly if abdominal distention occursor if other untoward symptoms develop.Since the chemicalstructure of diphenoxylate hydrochloride is similar to that ofmeperidine hydrochloride, the concurrent use of this product withmonoamine oxidase (MAO) inhibitors may, in theory, precipitatehypertensive crisis.This product should be used with extremecaution in patients with advanced hepatorenal disease and in allpatients with abnormal liver function since hepatic coma may beprecipitated.Diphenoxylate hydrochloride may potentiate theaction of barbiturates, tranquilizers, and alcohol. Therefore, thepatient should be closely observed when any of these are usedconcomitantly.