Diphenoxylate hydrochloride/Atropine sulfate

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# Overview
Diphenoxylate hydrochloride/Atropine sulfate is an antimuscarinic, anticholinergic and antidiarrheal agent that is FDA approved for the prophylaxis of management of diarrhea.   Common adverse reactions include abdominal discomfort, nausea, vomiting, dizziness, sedation, somnolence, euphoria and malaise.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Diarrhea
- Dosing information
- DO NOT EXCEED RECOMMENDED DOSAGE.
- Recommended initial dosage: two diphenoxylate hydrochloride tablets four times daily . 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-Atropine sulfate in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Diphenoxylate hydrochloride-Atropine sulfate in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### Diarrhea
- Dosing information
- Diphenoxylate hydrochloride is not recommended in children under 2 years of age and should be used with special caution in young children. The nutritional status and degree of dehydration must be considered. Do not use diphenoxylate hydrochloride tablets for children under 13 years of age .
- Keep this and all medications out of the reach of children.

## Off-Label Use and Dosage (Pediatric)

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

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Diphenoxylate hydrochloride-Atropine sulfate in pediatric patients.

# Contraindications
Diphenoxylate hydrochloride is contraindicated in patients with:
1. Known hypersensitivity to diphenoxylate or atropine.
2. Obstructive jaundice.
3. Diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria.

# Warnings
Diphenoxylate hydrochloride is not an innocuous drug and dosage recommendations should be strictly adhered to, especially in children. Diphenoxylate hydrochloride 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 should be accompanied by appropriate fluid and electrolyte therapy, when indicated. If severe dehydration or electrolyte imbalance is present, diphenoxylate hydrochloride 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 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 diphenoxylate hydrochloride 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 diphenoxylate hydrochloride with monoamine oxidase inhibitors (MAO) may, in theory, precipitate hypertensive crisis.
Diphenoxylate hydrochloride 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.
PRECAUTIONS
General
Since a 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 should be used with caution since signs of atropinism may occur even with recommended doses, particularly in patients with Down's syndrome.

# Adverse Reactions

## Clinical Trials 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.

## Postmarketing Experience
FDA Package Insert for Diphenoxylate hydrochloride-Atropine sulfate contains no information regarding Postmarketing experience.

# Drug Interactions
Known drug interactions include barbiturates, tranquilizers, and alcohol. Diphenoxylate hydrochloride may interact with MAO inhibitors.
In studies with male rats, diphenoxylate hydrochloride was found to inhibit the hepatic microsomal enzyme system at a dose of 2 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.

# 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. Diphenoxylate hydrochloride 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/Atropine sulfate in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Diphenoxylate hydrochloride/Atropine sulfate during labor and delivery.

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

### Pediatric Use
Diphenoxylate hydrochloride 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 is not recommended for children under 2 years of age. Diphenoxylate hydrochloride 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.

### Geriatic Use
There is no FDA guidance on the use of Diphenoxylate hydrochloride/Atropine sulfate in geriatric settings.

### Gender
There is no FDA guidance on the use of Diphenoxylate hydrochloride/Atropine sulfate with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Diphenoxylate hydrochloride/Atropine sulfate with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Diphenoxylate hydrochloride/Atropine sulfate in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Diphenoxylate hydrochloride/Atropine sulfate in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Diphenoxylate hydrochloride/Atropine sulfate in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Diphenoxylate hydrochloride/Atropine sulfate in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Oral

### Monitoring
FDA Package Insert for Diphenoxylate hydrochloride-Atropine sulfate contains no information regarding Drug Monitoring.

# IV Compatibility
There is limited information about the IV compatibility.

# 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.

# Pharmacology
There is limited information regarding Diphenoxylate hydrochloride/Atropine sulfate Pharmacology in the drug label.

## Mechanism of Action
There is limited information regarding Diphenoxylate hydrochloride/Atropine sulfate Mechanism of Action in the drug label.

## Structure
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-()--(hydroxymethyl) benzeneacetic acid 8-methyl-8-azabicyclo 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 tablets include acacia, corn starch, magnesium stearate, sorbitol, sucrose, and talc.

## Pharmacodynamics
FDA Package Insert for Diphenoxylate hydrochloride-Atropine sulfate contains no information regarding Pharmacodynamics.

## 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 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 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.

## Nonclinical Toxicology
FDA Package Insert for Diphenoxylate hydrochloride-Atropine sulfate contains no information regarding Nonclinical toxicology.

# Clinical Studies
FDA Package Insert for Diphenoxylate hydrochloride-Atropine sulfate contains no information regarding Nonclinical toxicology.

# How Supplied
Tablets  round, white, with SEARLE debossed on one side and 61 on the other side and containing 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate, supplied as:

## Storage
There is limited information regarding Diphenoxylate hydrochloride/Atropine sulfate Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Inform the patient (parent or guardian) not to exceed the recommended dosage and to keep diphenoxylate hydrochloride out of the reach of children and in a 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 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 diphenoxylate hydrochloride should be explained to the patient. The physician should also provide the patient with other information in this labeling, as appropriate.

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

# Brand Names
- Lomocot
- Lomotil
- Lonox
- Vi-Atro

# Look-Alike Drug Names
There is limited information regarding Diphenoxylate hydrochloride/Atropine sulfate Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price