Diphenoxylate Hydrochloride

Diarrhea

Diphenoxylate is used as adjunctive therapy in the treatment of diarrhea.

Antiperistaltic agents (e.g., diphenoxylate, loperamide) are used for symptomatic treatment of mild or uncomplicated travelers' diarrhea, including that occurring in adult travelers with human immunodeficiency virus (HIV) infection.100,102,103 The most important measure in the management of travelers' diarrhea is replacement of lost fluids and electrolytes.102 In addition, the possibility that reduction of intestinal motility may be deleterious in diarrheas resulting from certain organisms (see below) should be considered. Antiperistaltic agents should be discontinued if symptoms of diarrhea persist beyond 48 hours or if they worsen.100,102 Diphenoxylate or loperamide should not be used in travelers with severe diarrhea or with high fever or blood in the stools.100,102 In addition, antiperistaltic agents are not recommended for treatment of travelers' diarrhea in infants, children, or adolescents with HIV infection.102 Individuals in whom diarrhea is associated with high fever, chills, or severe cramps and those with persistent diarrhea and severe fluid loss should seek medical attention; these individuals may benefit from short-term treatment with an anti-infective agent (e.g., a fluoroquinolone).101,102,103

Antiperistaltic agents (e.g., diphenoxylate, loperamide) are not effective in preventing travelers' diarrhea.102 Data from controlled studies indicate that prophylactic use of difenoxylic acid (an active metabolite of diphenoxylate) increases the incidence of travelers' diarrhea and results in adverse effects.102

Diphenoxylate preparations should not be used in patients with diarrhea caused by poisoning until the toxic material is eliminated from the GI tract by gastric lavage or cathartics. Reduction of intestinal motility may be deleterious in diarrhea resulting from some infections (e.g., those caused by Shigella, Salmonella, and certain toxigenic strains of Escherichia coli ) in which expulsion of intestinal contents may be a protective mechanism and from antibiotic-associated pseudomembranous colitis; diphenoxylate preparations should not be used in these conditions. In addition, the possibility should be considered that inhibition of peristalsis may cause fluid retention in the intestine great enough to mask depletion of extracellular fluid and electrolytes in the treatment of acute enteritis, especially in young children. Diphenoxylate preparations should not be administered to children younger than 2 years of age because of the narrow range between therapeutic and toxic doses in this age group. (See Cautions: Pediatric Precautions.)

Dosage and Administration ⬆ ⬇

[Section Outline]

Administration
Dosage

Administration

Diphenoxylate hydrochloride is administered orally. Children 2-12 years of age should be given the drug as the oral solution rather than tablets, using only the calibrated measuring device provided by the manufacturer for measuring doses.

Dosage

Dosage of diphenoxylate preparations is expressed in terms of diphenoxylate hydrochloride. In antidiarrheal efficacy, 2.5 mg of the drug is equivalent to about 5 mL of paregoric.

The initial adult dosage of diphenoxylate hydrochloride for treatment of diarrhea is 5 mg 4 times daily. The initial dosage of diphenoxylate hydrochloride in children 13-16 years of age is 5 mg 3 times daily. The initial dosage in children 2-12 years of age is 0.3-0.4 mg/kg daily, given in 4 divided doses. Approximate initial dosages for children 2-12 years of age based on patient weight are as follows:

Age	Approximate Weight	Dosage of diphenoxylate hydrochloride in mg (mL of oral solution)
2 years	11-14 kg	0.75-1.5 mg (1.5-3 mL) 4 times daily
3 years	12-16 kg	1-1.5 mg (2-3 mL) 4 times daily
4 years	14-20 kg	1-2 mg (2-4 mL) 4 times daily
5 years	16-23 kg	1.25-2.25 mg (2.5-4.5 mL) 4 times daily
6-8 years	17-32 kg	1.25-2.5 mg (2.5-5 mL) 4 times daily
9-12 years	23-55 kg	1.75-2.5 mg (3.5-5 mL) 4 times daily

Pediatric dosage schedules are approximations of an average dosage recommendation and should be adjusted downward according to overall nutritional status and degree of dehydration. Use in children younger than 2 years of age is not recommended. (See Cautions: Pediatric Precautions.)

Recommended adult and pediatric dosages of diphenoxylate hydrochloride should not be exceeded. Dosage should be continued at initial levels until symptoms are controlled and then reduced for maintenance as required. Maintenance dosage may be as low as one-fourth (e.g., 5 mg daily in adults) the initial daily dosage. If no clinical improvement of acute diarrhea in adult or pediatric patients occurs within 48 hours, the drug is not likely to be effective. If no clinical improvement of chronic diarrhea occurs following treatment for 10 days with a maximum dosage of 20 mg daily in adults, symptoms are unlikely to be controlled by further administration of the drug.

Cautions ⬆ ⬇

[Section Outline]

Adverse Effects
Precautions and Contraindications
Pediatric Precautions
Pregnancy and Lactation

Adverse Effects

Adverse effects of diphenoxylate may include nausea, vomiting, abdominal discomfort or distention, paralytic ileus, toxic megacolon, pancreatitis, sedation, dizziness, pruritus, angioedema, giant urticaria, lethargy, anorexia, and restlessness or insomnia. Headache, tachycardia, numbness of the extremities, blurred vision, dryness of the mouth, swelling of the gums, euphoria, mental depression, weakness, general malaise, respiratory depression, and coma have also been reported. Atropine sulfate in commercially available diphenoxylate preparations may produce dryness of skin and mucous membranes, thirst, hyperthermia, tachycardia, urinary retention, and flushing, especially in children. Cautions applicable to atropine should be observed.

Precautions and Contraindications

Although evidence of physical dependence has not been reported clinically in patients receiving therapeutic doses of diphenoxylate, symptoms of opiate withdrawal occurred after individuals had been given 100-300 mg of the drug for 40-70 days. The possibility of dependence should be considered, particularly when the drug is given in high dosage. Diphenoxylate should be used with caution in patients receiving drugs capable of producing physical dependence, patients with a history of physical dependence, or patients who may increase dosage on their own initiative.

Hepatic coma has been reported following administration of diphenoxylate to patients with cirrhosis. The drug should be used with extreme caution in the presence of cirrhosis or advanced hepatorenal disease and in all patients with abnormal liver function test results, since hepatic coma may be precipitated; diphenoxylate is contraindicated in patients with obstructive jaundice. Because diphenoxylate may potentiate the effects of other CNS depressants including barbiturates, tranquilizers, and alcohol, diphenoxylate should be used with caution when administered in conjunction with such drugs. Since diphenoxylate is structurally similar to meperidine hydrochloride, the possibility of hypertensive crisis should be considered when diphenoxylate and monoamine oxidase inhibitors are used concomitantly.

Diphenoxylate should be used with caution in patients with acute ulcerative colitis, since drugs which inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon in some patients with this condition. Patients with acute ulcerative colitis should be closely observed and diphenoxylate therapy discontinued immediately if abdominal distention or other adverse symptoms occur. Diphenoxylate is contraindicated in the treatment of diarrhea associated with some infections (e.g., those caused by enterotoxin-producing bacteria) (see Uses) or with antibiotic-associated pseudomembranous colitis. Diphenoxylate preparations also are contraindicated in patients with known hypersensitivity to the drug or atropine.

Because of similarity in spelling between Lomotil^® (a trade name for the fixed combination of diphenoxylate hydrochloride and atropine sulfate) and Lamictal^® (the trade name for lamotrigine, an anticonvulsant agent), several dispensing errors have been reported to the manufacturer of Lamictal^® (GlaxoSmithKline).106,107 These medication errors may be associated with serious adverse events either due to lack of appropriate therapy for seizures (e.g., in patients not receiving the prescribed anticonvulsant, lamotrigine, which may lead to status epilepticus) or, alternatively, to the risk of developing adverse effects (e.g., serious rash) associated with the use of lamotrigine in patients for whom the drug was not prescribed and consequently was not properly titrated.106,107 Therefore, the manufacturer of Lamictal^® (GlaxoSmithKline) cautions that extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Lamictal^® and Lomotil^®.106,107 The manufacturer also recommends that when appropriate, clinicians might consider including the intended use of the particular drug on the prescription in addition to alerting patients to carefully check the drug they receive and promptly bring any question or concern to the attention of the dispensing pharmacist.106 The manufacturer also recommends that pharmacists assess the measures of avoiding dispensing errors and implement them as appropriate (e.g., placing drugs with similar names apart from one another in product storage areas, patient counseling).107

Pediatric Precautions

Diphenoxylate should be used with particular caution in young children since they exhibit variable responses to the drug. Use of diphenoxylate does not preclude appropriate fluid and electrolyte therapy; dehydration, especially in young children, may additionally influence the variability of response to the drug and may predispose to delayed diphenoxylate intoxication. Drug-induced inhibition of peristalsis may result in fluid retention in the intestine and thereby further aggravate dehydration and electrolyte imbalance. If severe dehydration or electrolyte imbalance occurs, diphenoxylate should be withheld until appropriate corrective therapy has been started. In addition, children, particularly those with Down's syndrome, may develop signs of atropinism even with the recommended dosage.

Diphenoxylate preparations are not recommended in children younger than 2 years of age because of the narrow range between therapeutic and toxic doses in this age group.

Some experts state that diphenoxylate is not recommended for the treatment of travelers' diarrhea in HIV-infected infants, children, or adolescents.100,102

Pregnancy and Lactation

Pregnancy

The effect of diphenoxylate hydrochloride on the human fetus is not known, and the drug should not be administered to pregnant women or to women of childbearing age who might become pregnant, unless the potential benefits to the patient outweigh the possible risk to the fetus.

Lactation

Atropine and, possibly, diphenoxylic acid (an active metabolite of diphenoxylate hydrochloride) are distributed into milk.105 Caution is advised if fixed combinations of diphenoxylate and atropine are administered in nursing women.105

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Metabolized by Hepatic Microsomal Enzymes
CNS Depressants
Monoamine Oxidase (MAO) Inhibitors

Drugs Metabolized by Hepatic Microsomal Enzymes

Diphenoxylate may prolong the half-life of drugs that are metabolized by hepatic microsomal enzymes.105 Animal studies indicate that diphenoxylate hydrochloride inhibits hepatic microsomal enzymes at a dosage of 2 mg/kg daily in rats. 105

CNS Depressants

Diphenoxylate hydrochloride may potentiate the action of CNS depressants (e.g., alcohol, barbiturates, tranquilizers).105 Patients should be monitored closely if these drugs are used concomitantly.105

Monoamine Oxidase (MAO) Inhibitors

Because the chemical structure of diphenoxylate hydrochloride is similar to that of meperidine hydrochloride, concomitant use of diphenoxylate with MAO inhibitors theoretically may precipitate hypertensive crisis.105

Other Information ⬆ ⬇

[Section Outline]

Manifestations
Treatment
Absorption
Distribution
Elimination
Chemistry
Stability

Acute Toxicity

Manifestations

Overdosage of the commercially available preparations containing diphenoxylate hydrochloride and atropine sulfate produces reactions similar to those of acute toxicity from opiate analgesics. In addition, symptoms of atropinism (e.g., dryness of the skin and mucous membranes, tachycardia) (see Acute Toxicity in the Antimuscarinics/Antispasmodics General Statement 12:08.08) have occurred in approximately 50% of reported acute toxicity cases. Children are particularly susceptible to toxic effects of these drugs, and fatalities have resulted from accidental ingestion of relatively small amounts (e.g., 5 Lomotil^® tablets in a 22-month-old infant).

Acute toxicity is usually manifested by drowsiness, miosis, hypotonia, loss of tendon reflexes, nystagmus, and seizures followed by respiratory depression and total apnea which may not become apparent until 12-30 hours after ingestion of the drug. In some patients, these symptoms have been preceded by atropinism manifested by high fever, generalized flushing, and tachypnea which may result from individual patient sensitivity to atropine and may persist for 2-3 hours.

Treatment

In the treatment of diphenoxylate overdosage, the patient should be hospitalized and closely observed for at least 48 hours. The stomach should be emptied immediately by inducing emesis or by gastric lavage. If the patient is comatose, lacks the gag reflex, or is having seizures, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Gastric lavage may be effective even several hours after drug ingestion, since pylorospasm and decreased GI motility produced by diphenoxylate may cause much of the drug to be retained in the stomach for an extended period of time. If respiratory depression occurs, primary attention should be given to reestablishment of adequate respiratory exchange by maintenance of adequate airway, control of respiration, and oxygen administration. The possibility of late onset of respiratory depression must be considered, and facilities for resuscitation should be readily available.

An opiate antagonist (i.e., naloxone hydrochloride) may be required for treatment of severe respiratory depression. It has been suggested that adults receive an initial IV naloxone hydrochloride dose of 0.4-2 mg.105 If improvement in respiratory functions is not satisfactory, such dose may be repeated in 2- to 3-minute intervals up to a total naloxone hydrochloride dosage of 10 mg.105 If no response is observed after a total of 10 mg of naloxone hydrochloride, the diagnosis of opiate agonist- or partial agonist-induced toxicity should be reevaluated since the depressive condition may be caused by a drug or disease process not responsive to naloxone.105 When IV access cannot be established, naloxone hydrochloride may be administered intramuscularly or subcutaneously.105 Children may receive an initial IV dose of 0.01 mg/kg; if this dose does not produce the desired degree of response, a subsequent dose of 0.1 mg/kg may be administered.105 When IV access cannot be established in such children, naloxone hydrochloride may be administered intramuscularly or subcutaneously in divided doses; naloxone hydrochloride may be diluted in sterile water if needed.105 (See Dosage and Administration: Administration in Naloxone Hydrochloride 28:10.) Since the duration of action of naloxone is shorter than that of diphenoxylate, additional doses of the opiate antagonist should be administered when necessary. Catheterization of the bladder has been recommended, since urinary retention may occur. IV infusion of fluids may also be required. Careful monitoring and control of temperature may be useful to prevent seizures.

Pharmacology

Diphenoxylate acts on smooth muscle of the intestinal tract in a manner similar to that of morphine, inhibiting GI motility and excessive GI propulsion. The drug has little or no analgesic activity. Although 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. Administration of opiate antagonists may precipitate withdrawal symptoms in patients following chronic administration of high doses of diphenoxylate hydrochloride; however, evidence of physical dependence to diphenoxylate has not been reported with recommended dosage. Commercial preparations of diphenoxylate contain a subtherapeutic quantity of atropine sulfate to discourage deliberate overdosage. The amount of atropine is too small to interfere with the constipating effect of diphenoxylate except, possibly, when the product is administered in very high dosage. Overdosage of diphenoxylate preparations may produce atropinism in some patients. (See Acute Toxicity.)

Pharmacokinetics

Absorption

In one study in fasting individuals, diphenoxylate hydrochloride was well absorbed from the GI tract following oral administration of an alcoholic solution of the drug without atropine sulfate. Peak plasma diphenoxylate concentrations occurred about 2 hours following administration of the drug. In a crossover bioavailability study of Lomotil^® tablets and oral solution, the bioavailability of the tablets was approximately 90% that of the solution; following an oral dose of four 2.5-mg tablets, an average peak plasma concentration of diphenoxylic acid (an active metabolite of diphenoxylate) of 163 ng/mL occurred within about 2 hours. Diphenoxylate has an onset of action within 45 minutes to 1 hour and a duration of action of 3-4 hours.

Distribution

Diphenoxylate is distributed into milk.

Elimination

Diphenoxylate has a plasma half-life of about 2.5 hours. Diphenoxylic acid, an active metabolite of diphenoxylate, reportedly has an elimination half-life of 3-14 hours.

Diphenoxylate is rapidly and extensively metabolized to diphenoxylic acid (difenoxine), an active metabolite. The drug is also metabolized to hydroxydiphenoxylic acid. Diphenoxylate metabolites and their conjugates are slowly excreted, principally in feces via bile; lesser amounts are excreted in urine. Less than 1% is excreted unchanged in urine.

Chemistry and Stability

Chemistry

Diphenoxylate hydrochloride is a synthetic phenylpiperidine-derivative opiate agonist that is structurally related to anileridine and meperidine. Diphenoxylate hydrochloride occurs as a white, odorless, crystalline powder and is slightly soluble in water and sparingly soluble in alcohol. The drug is commercially available only in combination with atropine sulfate. (See Pharmacology.)

Stability

Diphenoxylate hydrochloride and atropine sulfate tablets should be stored in well-closed, light-resistant containers at a temperature less than 40°C, preferably at 15-30°C. Diphenoxylate hydrochloride and atropine sulfate oral solution should be stored in tight, light-resistant containers at a temperature less than 40°C, preferably at 15-30°C; freezing should be avoided.

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.