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Diphenoxylate and Atropine

Pronunciation

Pronunciation

(dye fen OKS i late & A troe peen)

Index Terms

  • Atropine and Diphenoxylate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Oral: Diphenoxylate hydrochloride 2.5 mg and atropine sulfate 0.025 mg per 5 mL (5 mL, 10 mL, 60 mL)

Lomotil: Diphenoxylate hydrochloride 2.5 mg and atropine sulfate 0.025 mg per 5 mL (60 mL) [contains alcohol 15%; cherry flavor] [DSC]

Tablet, Oral: Diphenoxylate hydrochloride 2.5 mg and atropine sulfate 0.025 mg

Lomotil: Diphenoxylate hydrochloride 2.5 mg and atropine sulfate 0.025 mg

Brand Names: U.S.

  • Lomotil

Pharmacologic Category

  • Antidiarrheal

Pharmacology

Diphenoxylate inhibits excessive GI motility and GI propulsion; commercial preparations contain a subtherapeutic amount of atropine to discourage abuse

Absorption

Diphenoxylate: Well absorbed

Metabolism

Diphenoxylate: Extensively hepatic via ester hydrolysis to diphenoxylic acid (active)

Excretion

Diphenoxylate: Primarily feces (49% as unchanged drug and metabolites); urine (~14%, [<1%] and metabolites)

Onset of Action

Within 45 to 60 minutes

Time to Peak

Diphenoxylate: Serum: ~2 hours

Half-Life Elimination

Diphenoxylate: 2.5 hours; Diphenoxylic acid: 12 to 14 hours

Use: Labeled Indications

Diarrhea: Adjunctive management of diarrhea

Contraindications

Hypersensitivity to diphenoxylate, atropine, or any component of the formulation; obstructive jaundice; diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria

Canadian labeling: Additional contraindications (not in US labeling): Jaundice

Dosing: Adult

Diarrhea: Oral: Note: If no improvement within 48 hours (acute symptoms) or 10 days at maximum dose (chronic symptoms) therapy is likely to be ineffective.

Initial: Diphenoxylate 5 mg (2 tablets) 3 or 4 times daily until control achieved (maximum: 20 mg/day), then reduce dose as needed; maintenance doses may be as low as 25% of initial daily dose required for control.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Diarrhea: Note: If no improvement within 48 hours (acute symptoms) therapy is likely to be ineffective.

US labeling: Children ≥2 years to <13 years (liquid only): Oral:

Initial: Diphenoxylate 0.3 to 0.4 mg/kg/day in 4 divided doses or alternatively:

2 years (11 to 14 kg): 1.5 to 3 mL 4 times daily

3 years (12 to 16 kg): 2 to 3 mL 4 times daily

4 years (14 to 20 kg): 2 to 4 mL 4 times daily

5 years (16 to 23 kg): 2.5 to 4.5 mL 4 times daily

6 to 8 years (17 to 32 kg): 2.5 to 5 mL 4 times daily

9 to 12 years (23 to 55 kg): 3.5 to 5 mL 4 times daily

Maintenance: Doses may be as low as 25% of initial daily dose; reduce dose as soon as possible after symptoms have been controlled

Canadian labeling: ≥4 years and Adolescents: Oral: Initial: Diphenoxylate 0.3 to 0.4 mg/kg/day in divided doses or alternatively:

4 to 8 years (20 to 27 kg): 2.5 mg 3 times daily

9 to 12 years (27 to 36 kg): 2.5 mg 4 times daily

≥13 years: 5 mg 4 times daily

Dosing: Renal Impairment

There are no specific dosage adjustments provided in the manufacturer’s labeling. Use with extreme caution in patients with advanced hepatorenal disease.

Dosing: Hepatic Impairment

There are no specific dosage adjustments provided in the manufacturer’s labeling. Use with extreme caution in patients with abnormal hepatic function and in advanced hepatorenal disease.

Administration

Use of the liquid preparation is recommended in children <13 years of age; use only plastic dropper provided when measuring liquid. Dropper has a 2 mL (1 mg) capacity and is calibrated in increments of 1/2 mL (0.25 mg).

Storage

Oral solution: Store at 20°C to 25°C (68°F to 77°F). Discard opened bottle after 90 days.

Tablet: Store at 20°C to 25°C (68°F to 77°F); protect from light.

Drug Interactions

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Analgesics (Opioid): Anticholinergic Agents may enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

EPHEDrine (Systemic): Atropine (Systemic) may enhance the therapeutic effect of EPHEDrine (Systemic). Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Avoid combination

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Frequency not defined.

Cardiovascular: Flushing, tachycardia

Central nervous system: Confusion, depression, dizziness, drowsiness, euphoria, headache, hyperthermia, lethargy, malaise, numbness, restlessness, sedation

Dermatologic: Pruritus, urticaria, xeroderma

Gastrointestinal: Abdominal distress, anorexia, gingival swelling, nausea, pancreatitis, paralytic ileus, toxic megacolon, vomiting, xerostomia

Genitourinary: Urinary retention

Hypersensitivity: Anaphylaxis, angioedema

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Dehydration/electrolyte imbalance: In case of severe dehydration or electrolyte imbalance, withhold diphenoxylate/atropine treatment until corrective therapy has been initiated. Use in conjunction with fluid and electrolyte therapy when appropriate. Inhibiting peristalsis may lead to fluid retention in the intestine aggravating dehydration and electrolyte imbalance.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

• Ulcerative colitis: Use with caution in patients with acute ulcerative colitis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: Use with caution in children; not recommended for use in children <2 years of age (US labeling) or <4 years (Canadian labeling). Younger children may be predisposed to delayed toxicity; signs of atropinism may occur even at recommended doses, especially in patients with Down syndrome.

Other warnings/precautions:

• Appropriate use: Do not exceed recommended dosage; overdose may result in severe respiratory depression, coma, and possible permanent brain damage or death. Clinical improvement of acute diarrhea is usually observed within 48 hours. If there is no response within 48 hours in children, diphenoxylate/atropine is unlikely to be effective and should be discontinued. If chronic diarrhea is not improved symptomatically within 10 days at maximum dosage, control is unlikely with further use. Reduction of intestinal motility may be deleterious in diarrhea resulting from Shigella, Salmonella, toxigenic strains of E. coli, and pseudomembranous enterocolitis associated with broad-spectrum antibiotics; use is not recommended.

• Dependence: Physical and psychological dependence have been reported with higher than recommended dosing.

Monitoring Parameters

Watch for signs of atropinism (dryness of skin and mucous membranes, tachycardia, thirst, flushing); monitor number and consistency of stools; observe for signs of toxicity, fluid and electrolyte loss, hypotension, and respiratory depression

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. Refer to individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, fatigue, dizziness, or headache. Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), difficulty breathing, slow breathing, shallow breathing, burning or numbness feeling, tachycardia, difficult urination, mood changes, vision changes, confusion, severe constipation, severe abdominal pain, or abdominal edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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