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Combination of
DiphenoxylateMu opiate receptor agonist
AtropineMuscarinic acetylcholine receptors antagonist
Trade namesLomotil
Other namesCo-phenotrope
Clinical data
Main usesDiarrhea.[1]
Side effectsNausea, abdominal pain, sleepiness, itchiness, confusion, headache[1]
Routes of
By mouth
Defined daily doseNot established[2]
External links
Legal status
  • DE: Prescription only (Anlage II for higher doses) if combined with atropine sulphate
  • UK: POM (Prescription only)
  • US: Schedule V (alone) and V (with atropine)

Diphenoxylate/atropine, also known as co-phenotrope, is a combination of the medications diphenoxylate and atropine, used to treat diarrhea.[3] It may be used for mild travelers' diarrhea but is not recommended for severe disease or if blood is present.[1] It should not be used in those in whom Clostridioides difficile infection is a concern.[4] It is taken by mouth.[3] Benefits begin within an hour and last for up to 4 hours.[1]

Common side effects include nausea, abdominal pain, sleepiness, itchiness, confusion, and headache.[1] It may worsen disease in those with certain infections.[1] There are concerns of abuse and respiratory depression with high doses.[1] It is unclear if use in pregnancy is safe and use when breastfeeding it may result in side effects in the baby.[5] It is an opioid that acts on the intestines to decrease contractions.[1] The atropine is present to decrease the risk of misuse.[1]

Diphenoxylate was first made in 1956.[6] The combination was approved for medical use in the United States in 1960.[7] It is available as a generic medication and over the counter.[3] In the United States the wholesale cost per is dose is US$0.31.[8] In 2017, it was the 353rd most commonly prescribed medication in the United States, with more than 700 thousand prescriptions.[9] It is sold under the brand name Lomotil among others.[3] The medication is in Schedule V in the United States.[4]

Medical uses

Diphenoxylate is used to treat diarrhea in adults; it is only available as a combination drug with a subtherapeutic dose of atropine to prevent abuse.[10]

It should not be used in children due to the risk of respiratory depression.[10] It does not appear harmful to a fetus but the risks have not been fully explored.[10]

It should not be taken with other central depressants like alcohol, as they can increase its risks.[10]

It should not be used for people with diarrhea caused by an infection, for example with Clostridium difficile infection, since the slowing of peristalsis can prevent clearing of the infectious organism.[10]


In adults if is started with 4 pills, after which 3 pill may be taken every 6 hours.[11]

The defined daily dose is not established.[2]


Absolute contraindications are:

Side effects

The drug label has warnings with regard to the risk of respiratory depression, anticholinergic toxicity and opioid overdose, the risk of dehydration and electrolyte imbalance that people with severe diarrhea always run, and toxic megacolon in people with ulcerative colitis.[10]

Other adverse effects include numbness in the hands and feet, euphoria, depression, lethargy, confusion, drowsiness, dizziness, restlessness, headache, hallucinations, edema, hives, swollen gums, itchiness, vomiting, nausea, loss of appetite, and stomach pain.[10]


Interactions with other drugs:

Diarrhea that is caused by some antibiotics such as cefaclor, erythromycin or tetracycline can worsen.[citation needed]


It may cause serious health problems when overdosed. Effects may include any of the following: convulsions, respiratory depression (slow or stopped breathing), dilated eye pupils, nystagmus (rapid side-to-side eye movements), erythema (flushed skin), gastrointestinal constipation, nausea, vomiting, paralytic ileus, tachycardia (rapid pulse), drowsiness and hallucinations. Symptoms of toxicity may take up to 12 hours to appear.

Treatment of overdose must be initiated immediately after diagnosis and may include the following: ingestion of activated charcoal, laxative and a counteracting medication (narcotic antagonist).

Mechanism of action

Diphenoxylate is anti-diarrheal and atropine is anticholinergic. A subtherapeutic amount of atropine sulfate is present to discourage deliberate overdosage. Atropine has no anti-diarrheal properties, but will cause tachycardia when overused. The medication diphenoxylate works by slowing down the movement of the intestines. In some cases it has been shown to ease symptoms of opiate withdrawal.

Diphenoxylate is an opioid and acts by slowing intestinal contractions; the atropine is present to prevent drug abuse and overdose.

Diphenoxylate is rapidly metabolized to difenoxin; it is eliminated mostly in feces but also in urine.[10]

Like other opioids, diphenoxylate acts by slowing intestinal contractions, allowing the body to consolidate intestinal contents and prolong transit time, thus allowing the intestines to draw moisture out of them at a normal or higher rate and therefore stop the formation of loose and liquid stools; the atropine is an anticholinergic and is present to prevent drug abuse and overdose.[13]


Diphenoxylate is made by combining a precursor of normethadone with norpethidine. Loperamide (Imodium) and bezitramide are analogs. [14] Like loperamide, it has a methadone-like structure and a piperidine moiety.[15]

Society and culture


In the U.S. the wholesale cost per is dose is US$0.31.[8] In 2017, it was the 353rd most commonly prescribed medication in the United States, with more than 700 thousand prescriptions.[9]


The UK BAN generic name for diphenoxylate and atropine is co-phenotrope.[citation needed]

As of 2018, the combination drug is marketed in the US and some other countries under the following brands: Atridol, Atrolate, Atrotil, Co-Phenotrope, Dhamotil, Dimotil, Intard, Logen, Lomanate, Lomotil, Lonox, and Reasec.[16]

Legal status

In the United States, it is classified as a Schedule V controlled substance by federal law, and is available only for a medical purpose.[17]

In the United States, drugs containing diphenoxylate combined with atropine salts are classified as Schedule V controlled substances.[18][10] (Diphenoxlate by itself is a Schedule II controlled substance.)

It is on Schedule III of the Single Convention on Narcotic Drugs, only in forms that contain, according to the Yellow List: "not more than 2.5 milligrams of diphenoxylate calculated as base and a quantity of atropine sulfate equivalent to at least 1 per cent of the dose of diphenoxylate".[19]


  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Diphenoxylate Monograph for Professionals". Drugs.com. Archived from the original on 22 March 2019. Retrieved 26 December 2021.
  2. 2.0 2.1 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 1 July 2021. Retrieved 10 September 2020.
  3. 3.0 3.1 3.2 3.3 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 66. ISBN 9780857113382.
  4. 4.0 4.1 "Diphenoxylate hydrochloride and atropine sulfate solution". Dailymed. Archived from the original on 10 September 2015. Retrieved 22 March 2019.
  5. "Atropine / diphenoxylate Pregnancy and Breastfeeding Warnings". Drugs.com. Archived from the original on 22 March 2019. Retrieved 3 March 2019.
  6. Florey K (1991). Profiles of Drug Substances, Excipients and Related Methodology, Volume 19. Academic Press. p. 342. ISBN 9780080861142. Archived from the original on 2021-08-28. Retrieved 2021-12-26.
  7. "Diphenoxylate and Atropine (Professional Patient Advice)". Drugs.com. Archived from the original on 22 March 2019. Retrieved 22 March 2019.
  8. 8.0 8.1 "NADAC as of 2019-02-27". Centers for Medicare and Medicaid Services. Archived from the original on 2019-03-06. Retrieved 3 March 2019.
  9. 9.0 9.1 "Atropine Sulfate; Diphenoxylate Hydrochloride - Drug Usage Statistics". ClinCalc. Archived from the original on 2 July 2020. Retrieved 11 April 2020.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 "US label: Diphenoxylate hydrochloride and atropine sulfate tablets" (PDF). FDA. 12 February 2018. Archived (PDF) from the original on 16 April 2021. Retrieved 26 December 2021. For label updates see FDA index page for NDA 012462 Archived 2021-03-24 at the Wayback Machine
  11. BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 71. ISBN 978-0857114105.
  12. 12.0 12.1 12.2 "Diphenoxylate and atropine drug information". UpToDate. Archived from the original on 22 March 2019. Retrieved 14 February 2017.
  13. Stern J, Ippoliti C (November 2003). "Management of acute cancer treatment-induced diarrhea". Seminars in Oncology Nursing. 19 (4 Suppl 3): 11–6. doi:10.1053/j.soncn.2003.09.009. PMID 14702928.
  14. Casy AF, Parfitt RT (2013). Opioid Analgesics: Chemistry and Receptors. Springer Science & Business Media. p. 312. ISBN 9781489905857. Archived from the original on 2021-08-28. Retrieved 2021-12-26.
  15. Patrick GL (2013). An Introduction to Medicinal Chemistry. OUP Oxford. p. 644. ISBN 9780199697397. Archived from the original on 2021-08-28. Retrieved 2021-12-26.
  16. "Diphenoxylate international brands". Drugs.com. Archived from the original on 22 March 2019. Retrieved 11 May 2018.
  17. "DEA, Title 21, Section 829". Archived from the original on 2009-05-31. Retrieved 2007-07-16.
  18. "Diphenoxylate". MedlinePlus. 15 April 2018. Archived from the original on 11 May 2018. Retrieved 10 May 2018.
  19. "Yellow List: List of Narcotic Drugs Under International Control, 50th Edition" (PDF). International Narcotics Control Board. 2011. p. 8. Archived (PDF) from the original on 22 December 2014. Retrieved 10 May 2018.

External links