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: 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 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 and 20 mg/kg/day throughout three litter reproduction study. At 50 times the human dose (20 mg/kg/day), female weight gain was reduced and there was marked effect on fertility as only of 27 females became pregnant in three test breedings. The relevance of this finding to usage of diphenoxylate hydrochloride and atropine sulfate in humans is unknown.

CLINICAL PHARMACOLOGY SECTION.

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 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 4-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 16 subject cross-over bioavailability study, linear relationship in the dose range of 2.5 mg to 10 mg was found between the dose of diphenoxylate hydrochloride (given as Diphenoxylate Hydrochloride and Atropine Sulfate Oral Solution) 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 hours, and the elimination half-life of diphenoxylic acid was approximately 12 to 14 hours.In dogs, diphenoxylate hydrochloride has 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 consequence of enhanced segmentation that allows increased contact of the intraluminal contents with the intestinal mucosa.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Diphenoxylate hydrochloride and atropine sulfate tablets are contraindicated in patients withKnown hypersensitivity to diphenoxylate or atropine,Obstructive jaundice,Diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria.. Known hypersensitivity to diphenoxylate or atropine,. Obstructive jaundice,. Diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria.

CONTROLLED SUBSTANCE SECTION.

Controlled Substance. Diphenoxylate hydrochloride and atropine sulfate tablets are classified as Schedule controlled substance. Diphenoxylate hydrochloride is chemically related to the narcotic analgesic meperidine.

DESCRIPTION SECTION.

DESCRIPTION. Each tablet for oral administration contains:diphenoxylatehydrochloride, USP 2.5 mg(Warning May be habit forming)atropinesulfate, USP 0.025 mgDiphenoxylate hydrochloride, an antidiarrheal, is ethyl 1-(3-cyano-3, 3-diphenylpropyl)-4-phenyl-isonipecotate monohydrochloride and has the following structure: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 structure:A subtherapeutic amount of atropine sulfate is present to discourage deliberate overdosage.Each tablet for oral administration contains the following inactive ingredients: 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 four times daily (20 mg per day). Most patients will require this dosage until initial control has been achieved, after which the dosage may be reduced to meet individual requirements. Control may often be maintained with as little as mg (two tablets) daily.Clinical improvement of acute diarrhea is usually observed within 48 hours. If clinical improvement of chronic diarrhea after treatment with maximum daily dose of 20 mg of diphenoxylate hydrochloride is not observed within 10 days, symptoms are unlikely to be controlled by further administration.. Children. Diphenoxylate hydrochloride and atropine sulfate is not recommended in children under years of age and should be used with special caution in young children (see WARNINGS and PRECAUTIONS). The nutritional status and degree of dehydration must be considered. In children under 13 years of age, use oral solution. Do not use tablets for this age group.KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. Controlled Substance. Diphenoxylate hydrochloride and atropine sulfate tablets are classified as Schedule controlled substance. 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. 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.

DRUG INTERACTIONS SECTION.

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 dose of 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.

GENERAL PRECAUTIONS SECTION.

General. Since 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 Downs syndrome.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Diphenoxylate Hydrochloride and Atropine Sulfate Tablets, USP are available containing 2.5 mg of diphenoxylate hydrochloride, USP (Warning: May be habit forming) and 0.025 mg of atropine sulfate, USP. The tablets are white round, unscored tablets debossed with over 15 on one side of the tablet and blank on the other side. They are available as follows:NDC 33261-0685-15bottles of 15 tabletsNDC 33261-0685-30bottles of 30 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.Mylan Pharmaceuticals Inc.Morgantown, WV 26505Repackaged By :Aidarex Pharmaceuticals LLC,Corona, CA 92880REVISED NOVEMBER 2009DPXAS:R12.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Diphenoxylate hydrochloride and atropine sulfate tablets are effective as adjunctive therapy in the management of diarrhea.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. INFORM THE PATIENT (PARENT OR GUARDIAN) NOT TO EXCEED THE RECOMMENDED DOSAGE AND TO KEEP THIS PRODUCT OUT OF THE REACH OF CHILDREN AND IN 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 this product should be explained to the patient. The physician should also provide the patient with other information in this labeling, as appropriate.

NURSING MOTHERS SECTION.

Nursing Mothers. Caution should be exercised when this product is administered to nursing woman, since the physicochemical characteristics of the major metabolite, diphenoxylic acid, are such that it may be secreted in breast milk and since it is known that atropine is secreted in breast milk.

OVERDOSAGE SECTION.

OVERDOSAGE. RECOMMENDED DOSAGE SCHEDULES SHOULD BE STRICTLY FOLLOWED. THIS MEDICATION SHOULD BE KEPT IN CHILD-RESISTANT CONTAINER AND OUT OF THE REACH OF CHILDREN, SINCE AN OVERDOSAGE MAY RESULT IN SEVERE, EVEN FATAL, RESPIRATORY DEPRESSION.. Diagnosis. Initial signs of overdosage may include dryness of the skin and mucous membranes, mydriasis, restlessness, flushing, hyperthermia, and tachycardia followed by lethargy or coma, hypotonic reflexes, nystagmus, pinpoint pupils, and respiratory depression. Respiratory depression may be evidenced as late as 30 hours after ingestion and may recur in spite of an initial response to narcotic antagonists. TREAT ALL POSSIBLE OVERDOSAGES AS SERIOUS AND MAINTAIN MEDICAL OBSERVATION FOR 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 possibly mechanically assisted respiration are advised. In vitro and animal studies indicate that activated charcoal may significantly decrease the bioavailability of diphenoxylate. In non-comatose patients, slurry of 100 of activated charcoal can be administered immediately after the induction of vomiting or gastric lavage.A pure narcotic antagonist (e.g., naloxone) should be used in the treatment of respiratory depression caused by diphenoxylate hydrochloride and atropine sulfate. When narcotic antagonist is administered intravenously, the onset of action is generally apparent within minutes. It may also be administered subcutaneously or intramuscularly, providing slightly less rapid onset of action but more prolonged effect.To counteract respiratory depression caused by diphenoxylate/atropine overdosage, the following dosage schedule for the narcotic antagonist naloxone hydrochloride should be followed:Adult Dosage: The usual initial adult dose of naloxone hydrochloride is 0.4 mg administered intravenously. If respiratory function does not adequately improve after the initial-dose, the same IV dose may be repeated at to minute intervals.Children: The usual initial dose of naloxone hydrochloride for children is 0.01 mg/kg of body weight administered intravenously and repeated at to minute intervals if necessary.Following initial improvement of respiratory function, repeated doses of naloxone hydrochloride may be required to counteract recurrent respiratory depression. Supplemental intramuscular doses of naloxone hydrochloride may be utilized to produce longer-lasting effect.Since the duration of action of diphenoxylate hydrochloride is longer than that of naloxone hydrochloride, improvement of respiration following administration may be followed by recurrent respiratory depression. Consequently, continued observation is necessary until the effect of diphenoxylate hydrochloride on respiration has passed. This effect may persist for many hours. The period of observation should extend over at least 48 hours, preferably under continuous hospital care. Although signs of overdosage and respiratory depression may not be evident soon after ingestion of diphenoxylate hydrochloride, respiratory depression may occur from 12 to 30 hours later.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 2.5 mg/0.025 mgNDC 33261-0685-30Diphenoxylate HCland Atropine SulfateTablets, USPCV2.5 mg/0.025 mgRx 30 TABLETSEach tablet contains:Diphenoxylate HCl, USP 2.5 mgAtropine Sulfate, USP 0.025 mgWARNING: May Be HabitFormingDispense in tight, light-resistant container as defined in the USP using child-resistant closure.Keep container tightly closed.Keep this and all medication out of the reach of children.Pharmacist: Dispense with child-resistant closure only.SPECIAL NOTE: Diphenoxylate HCl and Atropine Sulfate is not recommended for children under years of age.Usual Adult Dosage: Two tablets (5 mg) four times daily. For maintenance, less according to response. See insert. Children to 12 years: Use oral solution, tablets are not recommended for this age group.Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Protect from light.Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.www.mylan.comRM0415MM2. IMAGE LABEL.

PEDIATRIC USE SECTION.

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 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.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Since 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 Downs syndrome.. Information for Patients. INFORM THE PATIENT (PARENT OR GUARDIAN) NOT TO EXCEED THE RECOMMENDED DOSAGE AND TO KEEP THIS PRODUCT OUT OF THE REACH OF CHILDREN AND IN 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 this product 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 dose of 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 and 20 mg/kg/day throughout three litter reproduction study. At 50 times the human dose (20 mg/kg/day), female weight gain was reduced and there was marked effect on fertility as only of 27 females became pregnant in three test breedings. The relevance of this finding to usage of diphenoxylate hydrochloride and atropine sulfate in humans is 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 decrease in maternal weight gain of 30% at 20 mg/kg/day and of 10% at 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 teratogenicity.There are no adequate and well controlled studies in pregnant women. This product should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.. Nursing Mothers. Caution should be exercised when this product is administered to nursing woman, since the physicochemical characteristics of the major metabolite, diphenoxylic acid, are such that it may be secreted in breast milk and since it is known that atropine is secreted 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 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.

PREGNANCY SECTION.

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 decrease in maternal weight gain of 30% at 20 mg/kg/day and of 10% at 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 teratogenicity.There are no adequate and well controlled studies in pregnant women. This product should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.

SPL UNCLASSIFIED SECTION.

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 decrease in maternal weight gain of 30% at 20 mg/kg/day and of 10% at 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 teratogenicity.There are no adequate and well controlled studies in pregnant women. This product should be used during pregnancy only if the anticipated benefit justifies the potential risk to the fetus.

WARNINGS SECTION.

WARNINGS. THIS 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 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, THIS PRODUCT 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 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 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 this product with monoamine oxidase (MAO) inhibitors may, in theory, precipitate hypertensive crisis.This product 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.