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. |
| Molecular Weight | 489.09 |
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 | Avoid use; teratogenic risk in animal studies, human data limited. |
| 2nd trimester | Avoid use; potential fetal anticholinergic effects. |
| 3rd trimester | Avoid use; risk of neonatal anticholinergic toxicity and withdrawal. |
Clinical note
Comprehensive clinical and safety monograph for DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE (DIPHENOXYLATE HYDROCHLORIDE AND ATROPINE SULFATE).
| Placental transfer | Diphenoxylate crosses placenta; atropine also crosses. Evidence: positive detection in fetal blood. |
| Breastfeeding | Diphenoxylate excreted into breast milk; risk of anticholinergic effects in infant; avoid or use with caution. |
| Lactation Rating |
■ 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 atropineGlaucomaObstructive jaundiceSevere hepatic impairmentDiarrhea associated with pseudomembranous enterocolitis
| 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. |
| Food/Dietary | Avoid alcohol and grapefruit juice. Alcohol potentiates CNS depression. Grapefruit juice may alter metabolism. No other significant food interactions. |
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| 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. |
| 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. |
| Clinical Pearls | Diphenoxylate/atropine is a schedule V controlled substance due to diphenoxylate's opioid activity. Atropine is added at subtherapeutic doses to discourage abuse. Onset of action is 45-60 minutes; duration is 3-4 hours. Avoid in children <6 years due to risk of respiratory depression and atropine toxicity. Do not exceed recommended doses; high doses can cause opioid euphoria. Use with caution in patients with inflammatory bowel disease as it may precipitate toxic megacolon. Monitor for CNS depression, especially with concurrent CNS depressants. Discontinue if no response within 48 hours. |
| Patient Advice | Take exactly as prescribed; do not exceed the recommended dose or duration. · This medication may cause drowsiness, dizziness, or blurred vision; avoid driving or operating machinery until you know how it affects you. · Avoid alcohol and other central nervous system depressants (e.g., sedatives, tranquilizers) as they may increase drowsiness and risk of serious side effects. · Do not use for more than 2 days unless directed by your doctor; prolonged use can lead to dependence and opioid addiction. · If you have a fever or bloody diarrhea, stop taking this medication and contact your healthcare provider immediately. · Keep out of reach of children; accidental overdose can be fatal due to respiratory depression. · Store at room temperature away from moisture and heat. |