Diphenoxylate
Diphenoxylate hydrochloride
Also known as: Co-phenotrope · Lofenoxal · Lomotil · Diphenoxylate hydrochloride
Reviewed by the VetSheet Veterinary TeamUpdated Apr 5, 2026Evidence-based veterinary reference
Dosing by species
Dosing data for this drug is not yet available in the VetSheet formulary. Every other section below is complete. Consult the current product label before prescribing.
Overview
Diphenoxylate is a synthetic opioid agonist used primarily as an antidiarrheal agent. It is typically formulated with a sub-therapeutic dose of atropine (as co-phenotrope) to discourage abuse.
Warning: Use with caution in infectious diarrhea or toxigenic infections, as decreasing GI motility can delay the clearance of pathogens and toxins.
Clinical Pearl: While historically used for acute diarrhea, modern veterinary medicine often prefers addressing the underlying cause or using probiotics/prebiotics, reserving motility modifiers for specific refractory cases.
Mechanism of action
Diphenoxylate acts locally and centrally on mu-opioid receptors in the gastrointestinal tract.
- Increases intestinal segmental smooth muscle tone.
- Decreases the propulsive activity (peristalsis) of smooth muscle.
- Decreases electrolyte and water secretion into the intestinal lumen. → The addition of atropine is at a sub-therapeutic dose to cause unpleasant anticholinergic side effects if overdosed, thereby discouraging abuse.
Safety & warnings
Contraindications
- Toxigenic diarrhea
- Infectious enteritis (e.g., Salmonella, Parvovirus)
- Obstructive GI disease
- Severe liver disease
- Cats (generally avoided due to CNS excitation/depression)
Adverse effects
- Constipation
- Sedation
- Bloating
- Paralytic ileus
- CNS depression (especially in cats)
- Anticholinergic effects at high doses (dry mouth, tachycardia)
Precautions
Caution: Do not use in cases of infectious diarrhea where pathogen clearance is necessary. Use with extreme caution in cats due to increased sensitivity to opioids. Monitor for signs of ileus or severe constipation.
Drug interactions
May cause severe hypertensive crisis
Additive CNS and respiratory depression
Additive anticholinergic effects and increased risk of severe ileus
Monitoring
- Fecal output and consistency
- Bowel sounds (auscultation for ileus)
- CNS status (sedation or excitation)
Pharmacokinetics
Half-life
Absorption
Well absorbed from the gastrointestinal tract.
Distribution
Widely distributed; crosses the blood-brain barrier.
Metabolism
Rapidly metabolized in the liver to diphenoxylic acid (difenoxine), which is the primary active metabolite.
Elimination
Excreted primarily in feces via bile, with a smaller amount excreted in urine.
Overdose
Overdose can lead to severe CNS depression, respiratory depression, and paralytic ileus. Due to the atropine component, anticholinergic signs (tachycardia, dry mucous membranes, mydriasis) may also occur.
Treatment: Naloxone can be used to reverse the opioid effects. Provide supportive care for anticholinergic toxicity and respiratory depression.
Available products
Formulations
- Oral: 2.5 mg diphenoxylate + 0.025 mg atropine tablet
Human-labeled
- Lomotil (2.5 mg diphenoxylate / 0.025 mg atropine tablets)
Regulatory status
Human approved products used off-label in veterinary medicine.
POM (Prescription Only Medicine)
POM (Prescription Only Medicine)
No regulatory data for: 🇭🇰 HK · 🇹🇼 TW · 🇯🇵 JP · 🇰🇷 KR · 🇦🇺 AU
Storage & stability
Store at room temperature in a tightly closed container, protected from light and moisture.
Client information
Diphenoxylate is used to treat severe diarrhea by slowing down gut movement.
- Do not give more than prescribed, as overdosing can cause serious side effects including extreme sleepiness and constipation.
- Ensure your pet has access to plenty of fresh water to prevent dehydration.
- Contact your veterinarian if the diarrhea persists for more than 48 hours, if your pet becomes lethargic, or if you notice blood in the stool.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturer’s current label.