Diphenoxylate hydrochloride and atropine sulfate

Diphenoxylate hydrochloride and atropine sulfate
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

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Overview

Diphenoxylate hydrochloride and atropine sulfate is a anti motility that is FDA approved for the treatment of adjunctive therapy in the management of diarrhea. Common adverse reactions include anaphylaxis, angioneurotic edema, urticaria, swelling of the gums, pruritus, toxic megacolon, paralytic ileus, pancreatitis.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Diphenoxylate hydrochloride and atropine sulfate tablets are effective as adjunctive therapy in the management of diarrhea.
• 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 5 mg (two tablets) daily.
• Clinical improvement of acute diarrhea is usually observed within 48 hours. If clinical improvement of chronic diarrhea after treatment with a maximum daily dose of 20 mg of diphenoxylate hydrochloride is not observed within 10 days, symptoms are unlikely to be controlled by further administration

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Diphenoxylate hydrochloride and atropine sulfate in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Diphenoxylate hydrochloride and atropine sulfate in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Diphenoxylate hydrochloride and atropine sulfate in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Diphenoxylate hydrochloride and atropine sulfate in pediatric patients.

Contraindications

• Diphenoxylate hydrochloride and atropine sulfate tablets are contraindicated in patients with

• Known hypersensitivity to diphenoxylate or atropine, obstructive jaundice,
• Diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria.

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 2 YEARS OF AGE. OVERDOSAGE MAY RESULT IN SEVERE RESPIRATORY DEPRESSION AND COMA, POSSIBLY LEADING TO PERMANENT BRAIN DAMAGE OR DEATH. 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.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Clinical Trials Experience in the drug label.

Postmarketing Experience

• 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 A 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.

Drug Interactions

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

• Diphenoxylate hydrochloride has been shown to have an effect on fertility in rats when given in doses 50 times the human dose.
• Other findings in this study include a decrease in maternal weight gain of 30% at 20 mg/kg/day and of 10% at 4 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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Diphenoxylate hydrochloride and atropine sulfate in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Diphenoxylate hydrochloride and atropine sulfate during labor and delivery.

Nursing Mothers

• Caution should be exercised when this product is administered to a 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 2 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.

Geriatic Use

There is no FDA guidance on the use of Diphenoxylate hydrochloride and atropine sulfate in geriatric settings.

Gender

There is no FDA guidance on the use of Diphenoxylate hydrochloride and atropine sulfate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Diphenoxylate hydrochloride and atropine sulfate with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Diphenoxylate hydrochloride and atropine sulfate in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Diphenoxylate hydrochloride and atropine sulfate in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Diphenoxylate hydrochloride and atropine sulfate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Diphenoxylate hydrochloride and atropine sulfate in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

Monitoring

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Diphenoxylate hydrochloride and atropine sulfate and IV administrations.

Overdosage

• RECOMMENDED DOSAGE SCHEDULES SHOULD BE STRICTLY FOLLOWED. THIS MEDICATION SHOULD BE KEPT IN A 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 a 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, a slurry of 100 g 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 a narcotic antagonist is administered intravenously, the onset of action is generally apparent within 2 minutes. It may also be administered subcutaneously or intramuscularly, providing a slightly less rapid onset of action but a 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 2 to 3 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 2 to 3 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 a 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.

Pharmacology

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Mechanism of Action in the drug label.

Structure

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Structure in the drug label.

Pharmacodynamics

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Pharmacodynamics in the drug label.

Pharmacokinetics

• 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 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 a 16 subject cross-over bioavailability study, a 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 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.

Nonclinical Toxicology

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Clinical Studies in the drug label.

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 M over 15 on one side of the tablet and blank on the other side. They are available as follows:
• NDC 0378-0415-77 bottles of 90 tablets
• NDC 0378-0415-01 bottles of 100 tablets
• NDC 0378-0415-10 bottles of 1000 tablets

Storage

• Store at 20° to 25°C (68° to 77°F).

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Diphenoxylate hydrochloride and atropine sulfate Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Diphenoxylate hydrochloride and atropine sulfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• LOMOTIL®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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