LOMOTIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for LOMOTIL (LOMOTIL).

How it works

Diphenoxylate is a meperidine congener that acts as an opioid receptor agonist, inhibiting gastrointestinal motility and prolonging transit time; atropine is added to discourage abuse at high doses.

What the body does with it

Metabolism	Diphenoxylate is metabolized primarily by the liver to diphenoxylic acid (active metabolite); CYP enzymes involved (mainly CYP3A4).
Excretion	Primarily renal (50-70% as metabolites, <5% unchanged) and fecal (30-50% via biliary excretion).
Half-life	Diphenoxylate: 2.5-3.5 hours; Difenoxin (active metabolite): 12-24 hours. Clinically, antidiarrheal effect is prolonged due to metabolite accumulation.
Protein binding	90% (diphenoxylate) and 80% (difenoxin) bound primarily to albumin.
Volume of Distribution	Diphenoxylate: 3.0-5.0 L/kg; difenoxin: 2.5-4.0 L/kg. Indicates extensive tissue distribution.
Bioavailability	Oral: approximately 90% (first-pass metabolism to difenoxin).
Onset of Action	Oral: 30-60 minutes for clinical effect.
Duration of Action	Oral: 3-4 hours for diphenoxylate; up to 24 hours for metabolite effects. Clinical notes: Duration is extended with repeated dosing due to active metabolite.

Classification & Brands

Brand Substitutes

Phenotil Tablet

Dosing & administration

Adults: 2 tablets (2.5 mg diphenoxylate/0.025 mg atropine) orally four times daily until control of diarrhea is achieved; maintenance dose is 2 tablets once or twice daily. Maximum dose: 8 tablets (20 mg diphenoxylate) per day.

Dosage form	TABLET
Renal impairment	Not studied. Use with caution due to potential accumulation of active metabolites. No specific GFR-based dosing recommendations; avoid in severe renal impairment.
Liver impairment	Child-Pugh A: No adjustment; dose cautiously. Child-Pugh B: Reduce dose by 50% or avoid. Child-Pugh C: Do not use.
Pediatric use	Children 2-12 years: Use oral solution (0.25 mg diphenoxylate/mL). Dose: 0.3-0.4 mg/kg of diphenoxylate orally per day in 4 divided doses. Maximum: 4 mL (1 mg diphenoxylate) per dose for 2-5 years; 6 mL (1.5 mg) per dose for 5-8 years; 8 mL (2 mg) per dose for 8-12 years. Not recommended for children <2 years.
Geriatric use	Initiate at lower doses (e.g., 2 tablets once daily) due to increased sensitivity to anticholinergic effects (atropine), risk of dehydration, and potential for central nervous system toxicity. Titrate cautiously; avoid prolonged use.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for LOMOTIL (LOMOTIL).

Breastfeeding	Atropine is excreted in breast milk in small amounts; diphenoxylate presence is unknown. M/P ratio not established. Potential for anticholinergic effects in infant, including gastrointestinal disturbances. Avoid use during breastfeeding unless essential.
Teratogenic Risk	First trimester: Limited data; diphenoxylate and atropine are not associated with major malformations in animal studies, but human data are insufficient. Second and third trimesters: No evidence of fetal harm, but prolonged use may cause neonatal withdrawal or anticholinergic effects. Use only if benefit outweighs risk.

Warnings & precautions

■ FDA Black Box Warning

Risk of respiratory depression, especially in children; not recommended in children younger than 6 years. Concomitant use with alcohol or CNS depressants may increase risk.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to diphenoxylate or atropine","Children under 6 years of age","Obstructive jaundice","Diarrhea associated with pseudomembranous enterocolitis or enterotoxin-producing bacteria","Patients with acute ulcerative colitis pending exclusion of toxic megacolon"]

Clinical Precautions

Precautions

["May cause respiratory depression, particularly at high doses or in children","Risk of anticholinergic effects from atropine component","Potential for abuse and dependence","Use with caution in patients with hepatic impairment","May precipitate toxic megacolon in patients with acute colitis","Discontinue if ileus or abdominal distention develops"]

Clinical Tips & Counseling

Drug interactions

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LOMOTIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for LOMOTIL (LOMOTIL).

How it works

Diphenoxylate is a meperidine congener that acts as an opioid receptor agonist, inhibiting gastrointestinal motility and prolonging transit time; atropine is added to discourage abuse at high doses.

What the body does with it

Metabolism	Diphenoxylate is metabolized primarily by the liver to diphenoxylic acid (active metabolite); CYP enzymes involved (mainly CYP3A4).
Excretion	Primarily renal (50-70% as metabolites, <5% unchanged) and fecal (30-50% via biliary excretion).
Half-life	Diphenoxylate: 2.5-3.5 hours; Difenoxin (active metabolite): 12-24 hours. Clinically, antidiarrheal effect is prolonged due to metabolite accumulation.
Protein binding	90% (diphenoxylate) and 80% (difenoxin) bound primarily to albumin.
Volume of Distribution	Diphenoxylate: 3.0-5.0 L/kg; difenoxin: 2.5-4.0 L/kg. Indicates extensive tissue distribution.
Bioavailability	Oral: approximately 90% (first-pass metabolism to difenoxin).
Onset of Action	Oral: 30-60 minutes for clinical effect.
Duration of Action	Oral: 3-4 hours for diphenoxylate; up to 24 hours for metabolite effects. Clinical notes: Duration is extended with repeated dosing due to active metabolite.

Classification & Brands

Brand Substitutes

Phenotil Tablet

Dosing & administration

Dosage form	TABLET
Renal impairment	Not studied. Use with caution due to potential accumulation of active metabolites. No specific GFR-based dosing recommendations; avoid in severe renal impairment.
Liver impairment	Child-Pugh A: No adjustment; dose cautiously. Child-Pugh B: Reduce dose by 50% or avoid. Child-Pugh C: Do not use.
Pediatric use	Children 2-12 years: Use oral solution (0.25 mg diphenoxylate/mL). Dose: 0.3-0.4 mg/kg of diphenoxylate orally per day in 4 divided doses. Maximum: 4 mL (1 mg diphenoxylate) per dose for 2-5 years; 6 mL (1.5 mg) per dose for 5-8 years; 8 mL (2 mg) per dose for 8-12 years. Not recommended for children <2 years.
Geriatric use	Initiate at lower doses (e.g., 2 tablets once daily) due to increased sensitivity to anticholinergic effects (atropine), risk of dehydration, and potential for central nervous system toxicity. Titrate cautiously; avoid prolonged use.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for LOMOTIL (LOMOTIL).

Breastfeeding	Atropine is excreted in breast milk in small amounts; diphenoxylate presence is unknown. M/P ratio not established. Potential for anticholinergic effects in infant, including gastrointestinal disturbances. Avoid use during breastfeeding unless essential.
Teratogenic Risk	First trimester: Limited data; diphenoxylate and atropine are not associated with major malformations in animal studies, but human data are insufficient. Second and third trimesters: No evidence of fetal harm, but prolonged use may cause neonatal withdrawal or anticholinergic effects. Use only if benefit outweighs risk.

Warnings & precautions

■ FDA Black Box Warning

Risk of respiratory depression, especially in children; not recommended in children younger than 6 years. Concomitant use with alcohol or CNS depressants may increase risk.