Professional Drug Information > Difenoxin Hydrochloride and Atropine Sulfate

Difenoxin and Atropine (Systemic)

VA CLASSIFICATION
Primary: GA208

Note: Controlled substance classification—

Note: Controlled substance classification


U.S.—Schedule IV
Commonly used brand name(s): Motofen.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antidiarrheal (antiperistaltic)—

Indications

Note: The efficacy of any antidiarrheal medication for treatment of most cases of nonspecific diarrhea is questionable, especially in children. ^{{14} {21}} Preferred treatment for acute, nonspecific diarrhea consists of fluid and electrolyte replacement, nutritional therapy, ^{{21} {25}} and, if possible, elimination of the underlying cause of the diarrhea.


Accepted

Diarrhea (treatment adjunct)—Difenoxin and atropine combination is indicated in adults, as an adjunct to fluid and electrolyte therapy, in the symptomatic treatment of acute nonspecific diarrhea and acute exacerbations of chronic functional diarrhea. ^{{01} {15}}

Unaccepted
Difenoxin and atropine combination is not recommended for treatment of diarrhea in children. ^{{16} {21}}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Atropine sulfate: 694.84
    Difenoxin: 424.54

Mechanism of action/Effect:

Difenoxin—Probably acts both locally and centrally to reduce intestinal motility. Antidiarrheal activity is about 5 times that of diphenoxylate. ^{{01} {02} {03}}

Atropine—Has anticholinergic activity. However, in this preparation atropine is included in doses below the therapeutic level in an attempt to prevent abuse by deliberate overdosage. ^{01}

Biotransformation:

Hepatic. ^{15}

Half-life:

Atropine—2.5 hours. ^{20}

Difenoxin—4.5 hours. ^{21}

Time to peak concentration:

Difenoxin—40 to 60 minutes. ^{{01} {15}}

Peak serum concentration:

Difenoxin—2-mg dose produces a serum concentration of 160 nanograms per mL. ^{15}

Elimination:
    Atropine—Renal; 30 to 50% excreted unchanged.
    Difenoxin—Renal/fecal. ^{{01} {15}}


Precautions to Consider

Carcinogenicity

Long-term studies in rats with difenoxin and atropine have not shown any evidence of carcinogenesis. ^{{01} {15}}

Mutagenicity

Studies to evaluate mutagenic potential of difenoxin and atropine have not been performed. ^{{01} {15}}

Pregnancy/Reproduction

Pregnancy—
Studies in humans have not been done. ^{15}

Reproduction studies in rats and rabbits have not shown evidence of teratogenicity with doses of difenoxin and atropine up to 75 times the human therapeutic dose. However, studies in rats have shown that difenoxin and atropine combination causes an increase in delivery time and a significant increase in the percent of stillbirths when given in doses of 20 times the maximum human dose. ^{01}

FDA Pregnancy Category C. ^{{01} {15}}

Breast-feeding

Problems in humans have not been documented. However, risk-benefit must considered since both difenoxin and atropine are distributed into breast milk and have the potential to cause serious adverse effects in the nursing infant. There is no information concerning the concentration of these drugs in breast milk.

Pediatrics

Difenoxin and atropine combination is not recommended for treatment of diarrhea in children. Recommended treatment consists of oral rehydration therapy to prevent loss of fluids and electrolytes, ^{{13} {14} {17}} nutritional therapy, and, if possible, elimination of the underlying cause of the diarrhea.

Infants and young children exhibit increased sensitivity to the toxic effects of atropine. ^{01} Children may also be more susceptible to the respiratory depressant effects of difenoxin. ^{04}


Geriatrics


No information is available on the relationship of age to the effects of difenoxin and atropine in geriatric patients. However, elderly patients may be more susceptible to the respiratory depressant effects of difenoxin, ^{04} and to the mild anticholinergic effects and confusion caused by atropine. ^{19}

In geriatric patients with diarrhea, caution is recommended because of the risk of fluid and electrolyte loss. ^{{07} {09}}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Addictive medications, other, especially central nervous system (CNS) depressants with habituating potential    (concurrent use with difenoxin may increase the risk of habituation; caution is recommended ^{{01} {04}})


» Alcohol or
» CNS depression–producing medications, other (See Appendix II )    (concurrent use with difenoxin may increase the CNS depressant effects of either difenoxin or these medications; also, when tricyclic antidepressants are used concurrently with atropine, their anticholinergic effects may be intensified; dosage adjustment may be required ^{{01} {15}})


» Anticholinergics or other medications with anticholinergic activity (See Appendix II )    (these medications may enhance the effects of atropine during concurrent use; significant interaction is unlikely with usual doses of difenoxin and atropine combination, but may occur with its abuse ^{01})


» Monoamine oxidase (MAO) inhibitors, including furazolidone and procarbazine    (concurrent use with difenoxin may precipitate hypertensive crisis; MAO inhibitors may block detoxification of atropine, thus potentiating its action ^{{01} {15}})


» Naltrexone^{04}    (administration of naltrexone to a patient physically dependent on opioid drugs, such as difenoxin, will precipitate withdrawal symptoms; symptoms may appear within 5 minutes of naltrexone administration, persist for up to 48 hours, and be difficult to reverse)

    (naltrexone blocks the therapeutic effects of opioids, including antidiarrheal effects; naltrexone therapy should not be initiated in patients receiving difenoxin; also, patients receiving naltrexone should be advised to use alternative antidiarrheals when necessary)


Opioid (narcotic) analgesics    (concurrent use with difenoxin may result in increased risk of severe constipation and additive CNS depressant effects ^{{04} {15}})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Phenolsulfonphthalein (PSP) excretion test    (atropine utilizes the same tubular mechanism of excretion as PSP, resulting in decreased urinary excretion of PSP; concurrent use of atropine is not recommended in patients receiving a PSP excretion test ^{04})

With physiology/laboratory test values
Amylase, serum    (values may be increased as a result of spasm of the sphincter of Oddi ^{04})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Colitis, severe    (patient may develop toxic megacolon ^{{01} {15}})


» Diarrhea associated with pseudomembranous colitis resulting from treatment with broad-spectrum antibiotics    (inhibition of peristalsis may delay the removal of toxin from the colon, thereby prolonging and/or worsening the diarrhea ^{{01} {15} {22}})


Risk-benefit should be considered when the following medical problems exist
Alcoholism, active or in remission or
Drug abuse or dependence, history of    (difenoxin content may increase chances of drug abuse in patient already predisposed to dependence ^{{01} {15}})


Cardiovascular instability    (possible increase in heart rate may be undesirable)


» Dehydration    (may predispose to delayed difenoxin intoxication; inhibition of peristalsis may result in fluid retention in colon and may further aggravate dehydration; discontinuation of medication and rehydration therapy is essential if symptoms of dehydration, such as dryness of mouth, excessive thirst, wrinkled skin, decreased urination, and dizziness or lightheadedness, are present; fluid loss may have serious consequences, such as circulatory collapse and renal failure ^{{01} {09} {15}})


Diarrhea caused by infectious organisms    (bacterial diarrhea may worsen due to the increased contact time between the mucosa and the penetrating microorganism; however, there is no evidence of this occurring in actual practice ^{{01} {06} {07} {15}})


» Diarrhea caused by poisoning, until toxic material has been eliminated from gastrointestinal tract
Down's syndrome    (atropine may cause abnormal increase in pupillary dilation and acceleration of heart rate ^{01})


» Dysentery, acute, characterized by bloody stools and elevated temperature    (sole treatment with antiperistaltic antidiarrheals may be inadequate; antibiotic therapy may be required ^{{01} {07} {09}})


Gallbladder disease or gallstones    (difenoxin may cause biliary tract spasm ^{01})


» Gastrointestinal tract obstruction    (use of atropine and difenoxin combination may result in pseudo-obstruction, or dilation of the large or small bowel ^{23})


Glaucoma, angle-closure    (although unlikely with usual doses of this combination, atropine may precipitate an acute attack of angle-closure glaucoma ^{18})


» Hepatic function impairment or jaundice    (difenoxin may precipitate hepatic coma; it is recommended that dosage be reduced in patients with impaired hepatic function ^{{01} {15}})


Hiatal hernia associated with reflux esophagitis or
Hypertension    (although unlikely with usual doses of this combination, atropine may aggravate these conditions ^{04})


Hyperthyroidism    (characterized by tachycardia, which may be increased by atropine ^{04})


Hypothyroidism    (difenoxin may increase risk of respiratory depression ^{04})


Incontinence, overflow    (secondary to constipation, but often mistaken for diarrhea; ^{{23} {24}} use of difenoxin and atropine may worsen constipation and/or result in pseudo-obstruction of the colon ^{23})


Intestinal atony in the elderly or debilitated    (although unlikely with usual doses of this combination, use of atropine may result in obstruction ^{18})


Myasthenia gravis    (although unlikely with usual doses of this combination, atropine may aggravate condition because of inhibition of acetylcholine action ^{18})


Prostatic hypertrophy or
Urethral stricture, acute or
Urinary retention    (reduction in tone of urinary bladder may aggravate or lead to complete urinary retention ^{18})


Renal function impairment^{01}{15}    (decreased elimination of atropine may increase the risk of side effects)


Respiratory disease or impairment    (increased risk of respiratory depression ^{04})


Sensitivity to atropine or difenoxin^{01}{15}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Hepatic function determinations    (recommended at periodic intervals during long-term therapy, especially for patients with hepatic function impairment ^{01})






Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Paralytic ileus or toxic megacolon (bloating; constipation; loss of appetite; severe stomach pain with nausea and vomiting)



Those indicating need for medical attention only if they continue, worsen, or are bothersome
Incidence less frequent or rare ^{15}
    
Anticholinergic effects, mild (blurred vision; difficult urination; dryness of skin and mouth; fever)
    
confusion
    
dizziness or lightheadedness
    
drowsiness
    
headache
    
trouble in sleeping
    
unusual tiredness or weakness

Note: Since atropine is present in a subtherapeutic dose, symptoms of mild anticholinergic effects probably indicate overdosage, although in children they may occur at therapeutic doses. ^{01}




Those indicating possible withdrawal and the need for medical attention if they occur after discontinuation of prolonged high-dose therapy
Incidence rare
    
Increased sweating
    
muscle cramps
    
nausea or vomiting
    
shivering or trembling
    
stomach cramps





Overdose
For specific information on the agents used in the management of difenoxin and atropine overdose, see:
   • Naloxone (Systemic) monograph.For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Anticholinergic effects, severe (continuing blurred vision or changes in near vision^{15}; fast heartbeat^{15}; severe drowsiness^{15}; severe dryness of mouth, nose, and throat^{15}; unusual warmth, dryness, and flushing of skin^{15})
    
coma^{15}
    
respiratory depression (severe shortness of breath or troubled breathing^{15})
    
unusual excitement, nervousness, restlessness, or irritability

Note: Respiratory depression may occur as late as 12 to 30 hours after ingestion. ^{{01} {15}}



Treatment of overdose
Treatment of overdose with difenoxin and atropine is the same as treatment for meperidine or morphine overdosage and involves the following: ^{01}



• To decrease absorption—Gastric lavage if vomiting has not occurred. ^{15}


• Specific treatment—Intravenous administration of 0.4 mg of naloxone, which may be repeated at 2- to 3-minute intervals, for respiratory depression. ^{{01} {15}}


• Monitoring—Prolonged and careful monitoring for 48 to 72 hours.


• Supportive care—Support of respiration. ^{15} Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Difenoxin and Atropine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to atropine or difenoxin

Pregnancy—Studies in rats show increased delivery time and stillbirth at doses 20 times maximum human dose





Breast-feeding—Difenoxin and atropine distributed into breast milk; potential for serious adverse effects in nursing infant





Use in children—Not recommended for use in children; increased susceptibility to toxic effects of atropine and respiratory depressant effects of difenoxin; risk of dehydration






Use in the elderly—Increased risk of respiratory depression; risk of dehydration
Other medications, especially other anticholinergics, CNS depressants, MAO inhibitors, or naltrexone
Other medical problems, especially acute dysentery; dehydration; diarrhea caused by antibiotics or poisoning; gastrointestinal tract obstruction; hepatic function impairment or jaundice; or severe colitis

Proper use of this medication
Taking with food or meals if gastric irritation occurs

» Importance of not taking more medication than the amount prescribed because of habit-forming potential

» Importance of maintaining adequate hydration and proper diet ^{{09} {11}}

» Proper dosing
Missed dose: If on scheduled dosing regimen—Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during prolonged therapy

» Consulting physician if diarrhea is not controlled within 48 hours and/or fever develops

» Avoiding use of alcohol or other CNS depressants during therapy

» Suspected overdose: Getting emergency help at once

Need to inform physician or dentist of use of medication if any kind of surgery (including dental surgery) or emergency treatment is required

» Caution if dizziness or drowsiness occurs


Side/adverse effects
Signs of potential side effects, especially paralytic ileus or toxic megacolon


General Dosing Information
If clinical improvement is not observed within 48 hours, treatment with difenoxin and atropine should be discontinued. ^{{01} {15}}

Inhibition of peristalsis may produce fluid retention in the bowel, which may aggravate dehydration and depletion of electrolytes, and may also increase variability of response to the medication. If dehydration or electrolyte imbalance occurs, difenoxin and atropine therapy should be withheld until appropriate corrective therapy has begun. ^{01}

To prevent development of toxic megacolon in patients with acute ulcerative colitis, treatment with difenoxin and atropine should be discontinued promptly if abdominal pain or distention or other specific gastrointestinal symptoms such as anorexia, bloating, constipation, nausea, or vomiting occur. ^{01}

Prolonged use of larger-than-usual therapeutic doses may result in physical dependence. ^{{01} {15}}

Tolerance to the antidiarrheal effects of difenoxin and atropine may develop with prolonged use. ^{04}

This medication may suppress respiration, especially in the elderly, the very ill, and patients with respiratory problems. Lower doses may be required for these patients.


Oral Dosage Forms

DIFENOXIN HYDROCHLORIDE AND ATROPINE SULFATE TABLETS

Usual adult and adolescent dose
Antidiarrheal (antiperistaltic)
Oral, the equivalent of difenoxin hydrochloride, 2 mg initially, then 1 mg after each loose stool or every three or four hours as needed. ^{{01} {15}}


Usual adult prescribing limits
Up to the equivalent of 8 mg of difenoxin hydrochloride daily. ^{01}

Usual pediatric dose
Use is not recommended.

Usual geriatric dose
See Usual adult and adolescent dose.

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.


Strength(s) usually available
U.S.—


1 mg of difenoxin hydrochloride and 25 mcg (0.025 mg) of atropine sulfate (Rx) [Motofen (scored) (calcium stearate) (cellulose) (lactose) (corn starch)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • Keep out of reach of children.
   • May be habit-forming.

Note: Controlled substance in the U.S.

Revised: 07/15/1994

References

1. Motofen package insert (Carnrick—US), Rev 1/88, Rec 8/88.
   

2. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 517.
   

3. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 27th ed. London: The Pharmaceutical Press, 1972: 1749.
   

4. USP-DI 1989, Atropine mono; Opioid mono.
   

5. Pharmindex, New Products; March 1989: 4-5.
   

6. Awouters F, Niemegeers CJ, Janssen PA. Pharmacology of antidiarrheal drugs. Ann Rev Pharmacol Toxicol 1983; 23: 279-301.
   

7. DuPont HL. Using OTC drugs for acute diarrhea. Drug Therapy Feb 1983; 127-36.
   

8. Longe LR. Antidiarrheal and other gastrointestinal products. In: Handbook of Non-prescription Drugs 8th ed. Washington, D.C.: American Pharmaceutical Association, 1986; 59-74.
   

9. Brownlee HJ. Family practitioner's guide to patient self-treatment of acute diarrhea. Am J Med 1990; 88 (Suppl 6A): 27S-29S.
   

10. AMA Drug evaluations. 6th ed. Chicago: American Medical Association, September 1986: 963.
    

11. Rains CP, Shajeen MZ. Problems with antidiarrhoeals. Pharm J 1990; 245: 172.
    

12. Lomotil package insert (Searle—US), Rev 6/84, Rec 12/88.
    

13. Balistreri WF. Oral rehydration in acute infantile diarrhea. Am J Med 1990; 88 (Suppl 6A): 30S.
    

14. Kenyon J, Caldwell M, editors. Oral rehydration is the cornerstone of diarrhoea therapy in children. Drugs and Therapy Perspectives 1993; 1: 15-6.
    

15. Motofen (Carnrick). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 781-2.
    

16. Pediatrics Advisory Panel Meeting, 10/30/93.
    

17. Bezerra JA, Stathos TH, Duncan B, et al. Treatment of infants with acute diarrhea: what's recommended and what's practiced. Pediatrics 1992; 90: 1-4.
    

18. Valpin 50 product information (Dupont—US), Rev 8/85, Rec 10/88.
    

19. Panel comment, 5/94.
    

20. Olin BR, editor. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc, 1987: 298-300b.
    

21. Diarrhoeal Disease Control Programme. Guide for improving diarrhoea treatment practices of pharmacists and licensed drug sellers. Geneva: World Health Organization, 1993: 7-11.
    

22. Koda-Kimble MA, Young LY, editors. Applied therapeutics. The clinical use of drugs. 5th ed. Vancouver, WA: Applied Therapeutics, Inc., 1992: 40-1.
    

23. Panel comment, 5/94.
    

24. Abrams WB, Berkow R, editors. The Merck manual of geriatrics. Rahway, NJ: Merck Sharp & Dohme Research Laboratories, 1990: 508.
    

25. International Health Advisory Panel Meeting, 6/10/94.
    

26. Binder HJ. Net fluid and electrolyte secretion: the pathophysiologic basis of diarrhea. In: Binder HJ, editor. Mechanism of intestinal secretion. New York: Alan R Liss Inc., 1979: 1-15.
    

27. Brownlee HJ, editor. Proceedings of a symposium: Management of acute nonspecific diarrhea. Am J Med 1990; 88 (Suppl 6A).
    

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