Drug class: Antidiarrhea Agents
CAS number: 3810-80-8

Medically reviewed by Drugs.com on Mar 22, 2024. Written by ASHP.

Introduction

Antiperistaltic antidiarrhea agent; synthetic phenylpiperidine-derivative opiate agonist.

Uses for Diphenoxylate

Diarrhea

Adjunctive therapy in the management of diarrhea.

Symptomatic treatment of mild or uncomplicated travelers’ diarrhea, including that occurring in adult travelers with HIV infection. Should not be used in travelers with severe diarrhea or with high fever or blood in the stools; these travelers may benefit from short-term treatment with an anti-infective (e.g., a fluoroquinolone).

Ineffective for prevention of travelers’ diarrhea; may increase incidence of travelers’ diarrhea.

Diphenoxylate Dosage and Administration

Administration

Oral Administration

In children 2–12 years of age, administer as oral solution using only the calibrated measuring device provided by the manufacturer.

Do not administer in children <2 years of age because of the narrow range between therapeutic and toxic doses in this age group.

Discontinue if symptoms of travelers’ diarrhea persist >48 hours or worsen.

Dosage

Available as diphenoxylate hydrochloride; dosage expressed in terms of the salt. Commercially available only in combination with atropine sulfate (in subtherapeutic quantity to discourage deliberate overdosage).

Pediatric Patients

Diarrhea

Oral

Children 2–12 years of age: Initially, 0.3–0.4 mg/kg daily, given in 4 divided doses.

Children 13–16 years of age: Initially, 5 mg 3 times daily.

Pediatric dosage schedules are approximations of an average dosage recommendation; adjust dosage downward according to overall nutritional status and degree of dehydration.

Continue dosage at initial levels until symptoms are controlled and then reduce for maintenance as required; not likely to be effective if no response occurs within 48 hours.

Maintenance dosages may be as low as one-fourth the initial daily dosage.

Adults

Diarrhea

Oral

Initially, 5 mg 4 times daily.

Continue dosage at initial level until symptoms are controlled and then reduce for maintenance as required; not likely to be effective for treatment of acute diarrhea if no response occurs within 48 hours.

Maintenance dosage may be as low as one-fourth (e.g., 5 mg daily) the initial daily dosage.

If clinical improvement of chronic diarrhea after treatment with a maximum daily dosage of 20 mg is not observed within 10 days, symptoms are unlikely to be controlled by further administration.

Prescribing Limits

Do not exceed recommended dosage.

Pediatric Patients

Diarrhea

Oral

Children 2–12 years of age: 0.4 mg/kg daily in divided doses.

Children 13–16 years of age: 5 mg 3 times daily.

Adults

Diarrhea

Oral

20 mg daily in divided doses.

Cautions for Diphenoxylate

Contraindications

• Known hypersensitivity to diphenoxylate or atropine.

• Obstructive jaundice.

• Diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria.

Warnings/Precautions

Warnings

Do not use in patients with diarrhea caused by poisoning until the toxic material is eliminated from the GI tract by gastric lavage or cathartics.

Do not use in patients with high fever or blood in stools.

Acute Toxicity

Overdosage may result in severe respiratory depression and coma, possibly leading to permanent brain damage or death. Adhere strictly to dosage recommendations.

Respiratory depression is possible up to 30 hours after ingestion and may recur despite initial response to an opiate antagonist.

MAO Inhibitors

Because diphenoxylate is structurally similar to meperidine, consider the possibility of hypertensive crisis if diphenoxylate and MAO inhibitors are used concomitantly.

Fluid and Electrolyte Replacement Therapy

Appropriate fluid and electrolyte replacement therapy is recommended, when indicated. If severe dehydration or electrolyte imbalance is present, withhold diphenoxylate 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; may mask fluid and electrolyte depletion in treatment of acute enteritis, especially in young children.

Infectious Diarrhea and Pseudomembranous Enterocolitis

Antiperistaltic agents may prolong and/or worsen diarrhea resulting from some infections (e.g., those caused by Shigella, Salmonella, toxigenic Escherichia coli) and from pseudomembranous enterocolitis associated with broad spectrum antibiotics; do not use in these conditions.

Ulcerative Colitis

Toxic megacolon reported with agents that inhibit intestinal motility or prolong intestinal transit time in some patients with acute ulcerative colitis. Carefully observe patients with acute ulcerative colitis; discontinue promptly if abdominal distention occurs or other adverse symptoms develop.

Hepatic Effects

Hepatic coma reported in patients with cirrhosis. Use with extreme caution in patients with cirrhosis, advanced hepatorenal disease, or abnormal liver function tests results. Contraindicated in patients with jaundice.

General Precautions

Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling of Lomotil (fixed combination of diphenoxylate hydrochloride and atropine sulfate) and Lamictal (lamotrigine, an anticonvulsant agent) may result in errors.

Fixed Combination

Commercially available only in combination with atropine sulfate. Consider the cautions, precautions, and contraindications associated with atropine.

Abuse Potential

Evidence of physical dependence not reported with recommended dosages. Possibility of dependence when given in high dosage.

Specific Populations

Pregnancy

Category C.

Lactation

Active metabolite (diphenoxylic acid) may be distributed into milk; atropine is distributed into milk. Drug effects may occur in breast-fed infants. Caution advised if used in nursing women.

Pediatric Use

Not recommended for children <2 years of age. Use particular caution in young children due to greater variability of responses to the drug. Consider nutritional status and degree of dehydration. (See Fluid and Electrolyte Replacement Therapy under Cautions.)

Not recommended for treatment of travelers’ diarrhea in infants, children, or adolescents with HIV infection.

Consider precautions related to use of atropine in children; use with caution since signs of atropinism may occur even at recommended dosages, particularly in patients with Down’s syndrome.

Hepatic Impairment

Use with extreme caution in patients with cirrhosis, advanced hepatorenal disease, or abnormal liver function test results, since hepatic coma may be precipitated. Contraindicated in patients with jaundice.

Common Adverse Effects

Nausea, vomiting, abdominal discomfort or distention, sedation, dizziness, pruritus, anorexia, restlessness or insomnia, confusion, headache.

Drug Interactions

Inhibits hepatic microsomal CYP isoenzymes at a dosage of 2 mg/kg daily.

Drugs Metabolized by Hepatic Microsomal Enzymes

Possible pharmacokinetic interaction (increased plasma concentrations of enzyme substrate).

Specific Drugs

Diphenoxylate Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration attained within approximately 2 hours following oral administration.

Bioavailability of Lomotil tablets is approximately 90% that of the oral solution.

Onset

45 minutes to 1 hour.

Duration

3–4 hours.

Distribution

Extent

Active metabolite (diphenoxylic acid) may be distributed into milk.

Elimination

Metabolism

Rapidly and extensively metabolized to diphenoxylic acid (active metabolite); also metabolized to hydroxydiphenoxylic acid.

Elimination Route

Metabolites and their conjugates are excreted slowly, principally in feces via bile; lesser amounts are excreted in urine (<1% as unchanged drug).

Half-life

Diphenoxylate: About 2.5 hours.

Diphenoxylic acid: 3–14 hours.

Stability

Storage

Oral

Tablets

Well-closed, light-resistant containers at 15–30°C.

Solution

Tight, light-resistant containers at 15–30°C; avoid freezing.

Actions

• Acts on smooth muscle of the intestinal tract in a manner similar to that of morphine, inhibiting GI motility and excessive GI propulsion.

• Exhibits little or no analgesic activity.

• Single doses in the usual therapeutic range produce little or no opiate effect. High doses (40–60 mg) may produce euphoria, suppression of the opiate abstinence syndrome, and physical dependence after chronic administration.

Advice to Patients

• Importance of not exceeding recommended dosage.

• Consequences of overdosage may include severe respiratory depression and coma that may lead to permanent brain damage or death. Keep out of reach of children and in a child-resistant container.

• Risk of drowsiness or dizziness; use caution when driving or operating dangerous machinery.

• Importance of avoiding CNS depressants (e.g., alcohol, barbiturates, tranquilizers) during therapy.

• Importance of seeking medical attention if diarrhea is associated with high fever, chills, or severe cramps, or is persistent or associated with severe fluid loss.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Diphenoxylate hydrochloride preparations containing not more than 2.5 mg of the drug combined with not less than 0.025 mg of atropine sulfate are subject to control under the Federal Controlled Substances Act of 1970 as schedule V (C-V) drugs.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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