Oral Adjunctive therapy in the management of diarrhoea
Adult: Available preparation:
Diphenoxylate hydrochloride 2.5 mg (equivalent to 2.3 mg of diphenoxylate) and
atropine sulfate 0.025 mg (equivalent to 0.01 mg of atropine)
Initially, 2 tabs 3-4 times daily. Maintenance: 2 tabs once daily as needed. Max: 8 tabs daily (diphenoxylate hydrochloride 20 mg and atropine sulfate 0.2 mg daily). Child: ≥13 years Same as adult dose. Dosage recommendations may vary among countries or individual products. Refer to specific product guidelines.
Administration
May be taken with or without food.
Contraindications
Jaundice, diarrhoea associated with pseudomembranous enterocolitis (Clostridium difficile) or other enterotoxin-producing bacteria, diarrhoea associated with inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease) and bacterial and amoebic colitis, intestinal obstruction, myasthenia gravis, paralytic ileus, pyloric stenosis, prostatic enlargement, raised intracranial pressure, head injury. Children <6 years of age.
Special Precautions
Patient with a history of drug addiction. Withhold treatment in patients with severe dehydration or electrolyte imbalance until corrective therapy has been initiated. Hepatic and renal impairment (including advanced hepatorenal disease and abnormal liver function). Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Atropinism, including hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes (particularly in children with Down syndrome), CNS depression (e.g. dizziness, drowsiness, mental depression, restlessness), gastrointestinal complications in patients with infectious diarrhoea, including sepsis, prolonged or worsened diarrhoea; physical and psychological dependence (with higher than recommended dose), toxic megacolon (in patients with acute ulcerative colitis). Gastrointestinal disorders: Paralytic ileus, pancreatitis, vomiting, nausea, abdominal discomfort, constipation. General disorders and administration site conditions: Lethargy or malaise. Immune system disorders: Hypersensitivity reactions (e.g. anaphylaxis, angioneurotic oedema, urticaria, swelling of the gums, pruritus). Metabolism and nutrition disorders: Anorexia. Nervous system disorders: Headache, numbness of extremities. Psychiatric disorders: Euphoria, confusion, hallucination. Potentially Fatal: Severe respiratory depression and coma (particularly in pediatric patients <6 years).
This drug may cause CNS depression, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor LFTs periodically during long-term therapy; number and consistency of stools; signs and symptoms of toxicity, fluid and electrolyte loss, hypotension, respiratory depression and atropinism (e.g. dryness of skin and mucous membranes, tachycardia, thirst, flushing).
Overdosage
Symptoms: Dry skin and mucous membranes, mydriasis or miosis, nystagmus, flushing, hyperthermia, tachycardia, lethargy, hypotonia, tachypnoea, toxic encephalopathy, incoherent speech, seizures, delirium, respiratory depression, coma. Management: Supportive treatment. Establish a patent airway and artificial ventilation if needed. May induce vomiting or gastric lavage, followed by administration of activated charcoal. Respiratory depression may be treated with a pure narcotic antagonist (e.g. naloxone).
Drug Interactions
Diphenoxylate: May potentiate the CNS depressant effects of barbiturates, benzodiazepines, opioids, anxiolytics, tranquillizers, general anaesthetics, antipsychotics, buspirone, antihistamines, and muscle relaxants. Concurrent use with MAOIs (e.g. selegiline, procarbazine, furazolidone) may precipitate a hypertensive crisis.
Atropine: May enhance the anticholinergic effect with anticholinergics or other medications with anticholinergic action (e.g. TCAs, some antihistamines, amantadine, phenothiazines, butyrophenones). May enhance the constipating effect of clozapine.
Food Interaction
Increased CNS depressant effects with alcohol.
Action
Description: Mechanism of Action: Diphenoxylate, a synthetic phenylpiperidine-derivative opiate agonist, is an antidiarrhoeal agent acting on the smooth muscle of the intestinal tract, inhibiting excessive gastrointestinal motility and propulsion.
Atropine, an antimuscarinic agent, is added in subtherapeutic amounts to discourage abuse.
Synonym: co-phenotrope. Onset: Within 45-60 minutes. Duration: 3-4 hours. Pharmacokinetics: Absorption: Diphenoxylate: Well absorbed from the gastrointestinal tract. Bioavailability: Approx 90%. Time to peak plasma concentration: Approx 2 hours.
Atropine: Rapid and well absorbed from the gastrointestinal tract. Distribution: Diphenoxylate: Enters breast milk.
Atropine: Distributed throughout the body. Crosses the placenta and blood-brain barrier and enters breast milk. Plasma protein binding: 14-44%. Metabolism: Diphenoxylate: Rapidly and extensively metabolised in the liver via ester hydrolysis to diphenoxylic acid (difenoxine), which is biologically active and the major metabolite in the blood.
Atropine: Incompletely metabolised in the liver via enzymatic hydrolysis. Excretion: Diphenoxylate: Mainly via faeces (49% as unchanged drug and metabolites); urine (approx 14%, as unchanged drug [<1%] and metabolites). Elimination half-life: Diphenoxylate: 2.5 hours (diphenoxylate); approx 12-14 hours (diphenoxylic acid).
Atropine: Via urine (13-50% as unchanged drug and metabolites). Elimination half-life: Approx 4 hours.
Chemical Structure
Diphenoxylate Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 13505, Diphenoxylate. https://pubchem.ncbi.nlm.nih.gov/compound/Diphenoxylate. Accessed Sept. 26, 2022.
Atropine Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 174174, Atropine. https://pubchem.ncbi.nlm.nih.gov/compound/Atropine. Accessed Sept. 26, 2022.
Anon. Atropine (Systemic). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 11/08/2022.Anon. Diphenoxylate and Atropine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 18/07/2022.Anon. Diphenoxylate Hydrochloride. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 18/07/2022.Beamotil Tablet (Duopharma Manufacturing [Bangi] Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 11/08/2022.Buckingham R (ed). Atropine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 18/07/2022.Buckingham R (ed). Diphenoxylate Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 18/07/2022.Joint Formulary Committee. Co-phenotrope. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 18/07/2022.Lomotil Tablet (Pfizer Laboratories Div Pfizer Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 18/07/2022.Pharmaniaga Diphenoxylate A (Pharmaniaga Manufacturing Berhad). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 11/08/2022.Spasil Tablet (IMEKS Pharma Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 11/08/2022.
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