DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE (DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE).
Diphenoxylate is a synthetic opioid agonist that acts on mu-opioid receptors in the gastrointestinal tract to reduce peristalsis and prolong transit time. Atropine is added in subtherapeutic doses to discourage intentional overdose and provides anticholinergic effects.
| Metabolism | Diphenoxylate: primarily hepatic metabolism via ester hydrolysis to diphenoxylic acid (active metabolite); also metabolized by CYP3A4. Atropine: hepatic metabolism via glucuronidation and oxidative metabolism. |
| Excretion | Diphenoxylate is primarily excreted in feces via biliary elimination (approx. 50%) and renal excretion (approx. 50% as metabolites); atropine is mainly excreted renally (30-50% unchanged and metabolites). |
| Half-life | Diphenoxylate: 2.5-12 hours (parent drug); difenoxin (active metabolite): 12-14 hours. Atropine: 2-4 hours. Clinical context: extended half-life of difenoxin allows twice-daily dosing for antidiarrheal effect. |
| Protein binding | Diphenoxylate: >90% bound to plasma proteins (albumin). Atropine: 44% bound to albumin. |
| Volume of Distribution | Diphenoxylate: Vd approximately 5-10 L/kg (extensive tissue distribution). Atropine: Vd 1-2 L/kg. |
| Bioavailability | Oral: diphenoxylate bioavailability ~90%; atropine bioavailability ~30-50% due to first-pass metabolism. |
| Onset of Action | Oral: 45 minutes to 1 hour for diphenoxylate/atropine combination. |
| Duration of Action | 3-4 hours for antidiarrheal effect per dose; prolonged with repeated dosing due to active metabolite. |
Each tablet contains diphenoxylate HCl 2.5 mg and atropine sulfate 0.025 mg. Adults: 2 tablets orally 4 times daily until diarrhea controlled, then reduce dose. Maximum 8 tablets per day for 2 days.
| Dosage form | TABLET |
| Renal impairment | Avoid use in severe renal impairment (GFR < 30 mL/min); no specific dose adjustment guidelines available for mild-moderate impairment, use with caution. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C); in moderate impairment (Child-Pugh class B) use with caution, reduce initial dose by 50% and monitor closely. |
| Pediatric use | Not recommended in children < 2 years; age 2-5: 0.3-0.4 mg/kg/day diphenoxylate divided into 4 doses (max 2 mg/day); age 5-12: 2.5-5 mg diphenoxylate 3-4 times daily. |
| Geriatric use | Use with caution due to increased sensitivity to anticholinergic effects; initiate at lower doses (e.g., 1 tablet 2-3 times daily) and titrate slowly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE (DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE).
| Breastfeeding | Excreted in breast milk in low amounts; atropine may suppress lactation. M/P ratio not established. Avoid breastfeeding due to potential for infant anticholinergic effects and respiratory depression. |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: Limited human data; animal studies show fetal toxicity at high doses. Second/third trimesters: Use only if benefit outweighs risk; may cause neonatal withdrawal if maternal dependence. Avoid prolonged use near term; atropine may cause neonatal anticholinergic effects. |
■ FDA Black Box Warning
Concomitant use with opioids for cough control or tramadol may increase risk of respiratory depression, particularly in children. Not approved for pediatric use under 6 years of age due to risk of respiratory depression.
| Serious Effects |
Hypersensitivity to diphenoxylate or atropine; pediatric patients <6 years of age; obstructive jaundice; severe hepatic impairment; diarrhea associated with pseudomembranous colitis or enterotoxin-producing bacteria; concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuation
| Precautions | May cause respiratory depression in overdose, especially in children; monitor for signs of anticholinergic effects; use with caution in patients with hepatic disease, renal impairment, dehydration, electrolyte imbalances, or history of opioid dependence; discontinue if constipation or abdominal distension occurs; may exacerbate diarrhea secondary to antibiotic-associated colitis or toxic megacolon. |
Loading safety data…
| Fetal Monitoring | Monitor maternal respiratory function, heart rate, and signs of anticholinergic toxicity. Fetal: heart rate monitoring if used near term; assess neonatal for withdrawal symptoms post-delivery. |
| Fertility Effects | No significant data on human fertility impairment. At high doses, animal studies show reduced fertility; clinical relevance unknown. |