Difenoxin is a 4-phenylpiperidine which is closely related to the opioid analgesic meperidine. Difenoxin alone is a USA Schedule I controlled drug, as it may be habit forming. However, it is listed as a Schedule IV controlled drug if combined with atropine, which is added to decrease deliberate misuse. Motofen(R) is a brand mixture which combines atropine sulfate and difenoxin hydrochloride. It is approved by the FDA to treat acute and chronic diarrhea. Difenoxin is an active metabolite of the anti-diarrheal drug, diphenoxylate, which is also used in combination with atropine in the brand mixture Lomotil(R). It works mostly in the periphery and activates opioid receptors in the intestine rather than the central nervous system (CNS). Difenoxin is also closely related to loperamide, but unlike loperamide it is still capable of crossing the blood brain barrier to produce weak sedative and analgesic effects. However, the antidiarrheal potency of difenoxin is much greater than its CNS effects, which makes it an attractive alternative to other opioids.

Motofen(R) is a combination of atropine, an anticholinergic drug, and difenoxin, an antidiarrheal drug. It has been used in many countries for many years as a second line opioid-agonist antidiarrheal, which exists an intermediate between loperamide and paragoric. Diarrhea which is a result of cyclic or diarrhea predominant Inflammatory Bowel Syndrome may not be treated effectively with difenoxin, diphenoxylate, or loperamide. As such, diarrhea and cramping which does not respond to non-centrally acting derivatives or belladonna derivatives such as atropine are often treated with conservative doses of codeine. In patients with acute ulcerative colitis, as induction of toxic megacolon is possible, and thus use of Motofen(R) is cautioned. Motofen(R) has been assigned pregnancy category C by the FDA, and is to be used only when the potential benefits outweigh the potential risk to the fetus. The safety of use during lactation is unknown and thus not recommended. Each five-sided dye free MOTOFEN tablet contains: 1 mg of difenoxin (equivalent to 1.09 mg of difenoxin hydrochloride) and 0.025 mg of atropine sulfate (equivalent to 0.01 mg of atropine). Difenoxin acts as an antidiarrheal by activating peripheral opioid receptors in the small intestine and thereby inhibiting peristalsis. However, research has suggested that non-opioid receptor pathways exist. This would explain the potent antidiarrheal effects of difenoxin despite only limited opioid action.

Difenoxin:
https://drugs.ncats.io/drug/VQZ63K01IW

Motofen - Difenoxin and Atropine
Difenoxin and atropine combination medicine is used along with other measures to treat severe diarrhea in adults. Difenoxin helps stop diarrhea by slowing down the movements of the intestines.

Since difenoxin is chemically related to some narcotics, it may be habit-forming if taken in doses that are larger than prescribed. To help prevent possible abuse, atropine (an anticholinergic) has been added. If higher-than-normal doses of the combination are taken, the atropine will cause unpleasant effects, making it unlikely that such doses will be taken again.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that slow down the nervous system, possibly causing drowsiness). This medicine may cause some people to become dizzy, drowsy, or less alert than they are normally. Even if taken at bedtime, it may cause some people to feel drowsy or less alert on arising.

Pediatric:

This medicine should not be used in children.

Children, especially very young children, are very sensitive to the effects of difenoxin and atropine. This may increase the chance of side effects during treatment. Also, the fluid loss caused by diarrhea may result in a severe condition. For this reason, it is very important that a sufficient amount of liquids be given to replace the fluid lost by the body. If you have any questions about this, check with your health care professional.

Geriatric:
Shortness of breath or difficulty in breathing may be more likely to occur in elderly patients, who are usually more sensitive than younger adults to the effects of difenoxin. Also, the fluid loss caused by diarrhea may result in a severe condition. For this reason, elderly persons should not take this medicine without first checking with their doctor.

It is also very important that a sufficient amount of liquids be taken to replace the fluid lost by the body.

If you have any questions about this, check with your health care professional.

Other Medical Problems:
Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse (or history of)
• Drug abuse (history of) - There is a greater chance that this medicine may become habit-forming

• Colitis (severe) - A more serious problem of the colon may develop if you use this medicine

• Down's syndrome - Side effects may be more likely and severe in these patients

• Dysentery - This condition may get worse; a different kind of treatment may be needed

• Emphysema, asthma, bronchitis, or other chronic lung disease - There is a greater chance that this medicine may cause breathing problems in patients who have any of these conditions

• Enlarged prostate
• Urinary tract blockage or difficult urination - Problems with urination may develop with the use of this medicine

• Gallbladder disease or gallstones - Use of this medicine may cause spasms of the biliary tract and make the condition worse

• Glaucoma - Severe pain in the eye may occur with the use of this medicine; however, the chance of this happening is low

• Heart disease - This medicine may have some effects on the heart, which may make the condition worse

• Hiatal hernia - The atropine in this medicine may make this condition worse; however, the chance of this happening is low

• High blood pressure (hypertension) - The atropine in this medicine may cause an increase in blood pressure; however, the chance of this happening is low

• Intestinal blockage - This medicine may make the condition worse

• Kidney disease - The atropine in this medicine may build up in the body and cause side effects

• Liver disease - The chance of central nervous system (CNS) side effects, including coma, may be greater in patients who have this condition

• Myasthenia gravis - This medicine may make the condition worse

• Overactive or underactive thyroid - Unwanted effects on breathing and heart rate may occur

• Overflow incontinence - This medicine may make the condition worse

Difenoxin And Atropine (Oral Route) (Motofen):
https://www.mayoclinic.org/drugs-supplements/difenoxin-and-atropine-oral-route/description/drg-20061718

FDA Motofen (PDF 5 pages):
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017744s026lbl.pdf

Kaiser Permanente Motofen:
https://healthy.kaiserpermanente.org/health-wellness/drug-encyclopedia/drug.motofen-1-mg-0-025-mg-tablet.201582

PillPack Medication Guide (PDF):
https://www.pillpack.com/medication/atropine-difenoxin-oral-tablets.pdf

Walgreens Motofen Drug Information:
https://images.walgreens.com/pharmacy/marketing/library/finddrug/druginfodrugdetails.jsp?drugId=647144

Motofen (difenoxin and atropine)

Side Effects:
Drowsiness, dizziness, headache, tiredness, blurred vision, dry mouth, and loss of appetite may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.
RxList
Motofen (difenoxin and atropine): https://www.rxlist.com/motofen-drug/consumer-uses.htm
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Tell your doctor immediately if any of these unlikely but serious side effects occur: stomach/abdominal pain or swelling, severe nausea, vomiting, mental/mood changes (e.g., confusion, depression), restlessness, numbness/tingling of arms/legs.
Get medical help right away if you have any very serious side effects, including: eye pain/swelling/redness, vision changes (such as seeing rainbows around lights at night, blurred vision).
A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Motofen (atropine sulfate / difenoxin hydrochloride)

Maximum Dosage:
Prescribers Digital Reference
Motofen - Drug Summary: https://www.pdr.net/drug-summary/Motofen-atropine-sulfate-difenoxin-hydrochloride-2988
Adults:	8 mg/24 hours PO.
Geriatric:	8 mg/24 hours PO.
Adolescents:	8 mg/24 hours PO.
Children:	12 years: 8 mg/24 hours PO.
Children:	2-11 years: Safety and efficacy have not been established.
Children:	< 2 years: Contraindicated.
Infants:	Contraindicated.
Neonates:	Contraindicated.

(PDF 2 pages):
http://www.motofen.com/wp-content/uploads/2017/05/MotofenDDWClinicalHandout.pdf

https://en.wikipedia.org/wiki/Motofen

Difenoxin:
It was first approved in the US in 1978. An opioid drug. Difenoxin crosses the blood brain barrier and induces some euphoria; it is often sold with or administered with atropine to reduce the potential for abuse and overdose. Difenoxin is a Schedule I drug by itself in the US; the combination with atropine is in the less-restrictive category Schedule IV on account of the adulterant (the practice of making opioids more easily available by including an abuse-deterring adulterating agent is standard practice in the United States).