Loperamide (Oral-Local)


VA CLASSIFICATION
Primary: GA208

Commonly used brand name(s): Apo-Loperamide; Diarr-Eze; Imodium; Imodium A-D; Imodium A-D Caplets; Kaopectate II; Loperacap; Maalox Anti-Diarrheal; Nu-Loperamide; PMS-Loperamide; Pepto Diarrhea Control; Rho-Loperamide.

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



Category:


Antidiarrheal{39}

Indications

Note: Bracketed information in the Indications section refers to uses that not included in U.S. product labeling.

Note: The efficacy of any antidiarrheal medication for treatment of most cases of nonspecific diarrhea is questionable. Preferred treatment consists of fluid and electrolyte replacement, {10} {13} nutritional therapy, and, if possible, elimination of the underlying cause of the diarrhea. {16} {26} {33}


Accepted

Diarrhea (treatment)—Loperamide is indicated in adults for the control and symptomatic relief of acute nonspecific diarrhea {36} {45} {46} and of chronic diarrhea associated with inflammatory bowel disease {45} {46}. Loperamide is also indicated to reduce the volume of discharge from ileostomies, {01} {14} {20} {22} {25} {29} {30} {45} colostomies, and other intestinal resections. {05} {45} {46}
—[Loperamide may be used in children to treat diarrhea caused by rapid transit when the anatomy of the bowel has been altered by disease or by surgical procedures.]1{28} {40} {41}

Traveler's diarrhea (treatment)—Loperamide is indicated for symptomatic relief of secretory diarrhea produced by bacteria, viruses, and parasites. {10} {13} {31}

Unaccepted
Loperamide is not recommended for use in children up to 6 years of age {04} {05} {25} {29} {30} unless directed by a physician. {34} Loperamide is also not recommended for routine use or as the first line of therapy for treatment of diarrhea resulting from infection or food allergy in otherwise healthy, older children. {26} {27} {28}

Loperamide should not be used if diarrhea is accompanied by fever or if there is blood or mucus in the stool. {04} {10} {31} {36}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    513.51 {01} {05} {14} {25} {29} {30} {36}

pKa—
    8.6

Mechanism of action/Effect:

Loperamide acts on receptors along the small intestine to decrease circular and longitudinal muscle activity. {43} {44} Loperamide exerts its antidiarrheal action by slowing intestinal transit and increasing contact time, and perhaps also by directly inhibiting fluid and electrolyte secretion and/or stimulating salt and water absorption. {04} {06} {12} {13} {14} {15} {18} {23} {25} {29} {30} {43}


Other actions/effects:

High doses may inhibit gastric acid secretion. {32}

Absorption:

Not well absorbed from gastrointestinal tract {01} {07} {09} {35} {36}.

Protein binding:

Very high (97%).

Biotransformation:

Hepatic. {01} {36}

Half-life:

9.1 to 14.4 (average 10.8) hours. {01} {09} {13} {25} {29} {30}

Time to peak concentration:

Capsules—5 hours. {14} {25} {29} {30}

Oral solution—2.5 hours. {07} {14} {25} {29} {30} {36}

Duration of action:

Up to 24 hours. {11} {17}

Elimination:
    Fecal/renal. {25} {29} {30} {36}


Precautions to Consider

Carcinogenicity

Carcinogenic potential was not documented in a study using rats administered doses up to 133 times the maximum human dose. {01} {14} {25} {29} {30}

Pregnancy/Reproduction
Fertility—
Reproduction studies in rats and rabbits have shown that loperamide administered in doses up to 30 times the human therapeutic dose does not interfere with fertility. {05}

Pregnancy—
Adequate and well-controlled studies have not been done in humans. {25} {29} {30}

Reproduction studies in rats and rabbits have shown that loperamide administered in doses up to 30 times the human therapeutic dose did not cause harm to the offspring, {05} {36} or produce teratogenic effects. Higher doses, however, impaired maternal and neonate survival. {01} {25} {29} {30} {36}

FDA Pregnancy Category B. {14} {29} {30}

Breast-feeding

It is not known whether loperamide is distributed into breast milk. {14} {25} {29} {30} However, in a pre- and post-natal study, loperamide administered to female nursing rats at a dose of 40 mg per kg of body weight caused a decrease in pup survival. {01} {02}

Pediatrics

Loperamide is not recommended for use in children up to 6 years of age {04} {05} {25} {29} {30} unless directed by a physician, {34} or for routine use or as initial therapy in children older than 6 years of age. {28}

Oral rehydration therapy is the preferred treatment for children with diarrhea {10} {13} {16} {26} {33} because loperamide may mask dehydration and depletion of electrolytes. Dehydration may further increase the variability in the response to loperamide. {01} {03} {12} {14} {19} {21}

Children, especially those under 3 years of age, are more susceptible to the opiate-like effects (CNS effects) of loperamide. {01}


Geriatrics


In geriatric patients with diarrhea, caution is recommended because loperamide may mask dehydration and depletion of electrolytes. {10} {13} Dehydration may further increase the variability in the response to loperamide. {01}

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):

» Opioid (narcotic) analgesics    (concurrent use of loperamide with an opioid analgesic may increase the risk of severe constipation)


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} {05} {13} {14} {25} {29} {30})


» Diarrhea associated with Clostridium difficile resulting from treatment with broad-spectrum antibiotics    (loperamide may prolong transit time, causing a delay in the removal of toxins from the colon, thereby prolonging and/or worsening the diarrhea {01} {05} {13} {14} {25} {29} {30})


» Dysentery, acute, characterized by bloody stools and elevated temperature    (sole treatment with loperamide may be inadequate; antibiotic therapy may be required {01} {05} {10} {12} {14} {18} {25} {29})


» Previous allergic reaction to loperamide{01}{05}{14}{25}{29}{30}{31}{37}
Risk-benefit should be considered when the following medical problems exist
» Dehydration    (rehydration therapy is essential if signs or 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, especially in young children {01} {18})


Diarrhea caused by infectious organisms    (bacterial diarrhea may, on rare occasions, 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} {12})


Hepatic function impairment{04}{36}    (loperamide undergoes extensive first pass metabolism in the liver; therefore, patients with hepatic function impairment may have an increased risk of developing CNS toxicity {01} {05} {12} {14} {25} {29} {30} {31})




Side/Adverse Effects

Note: Adverse effects may be difficult to distinguish from the diarrheal syndrome itself and are usually self-limited. {05} {14} {17} {25} {29} {30}

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 rare {01} {08} {14} {17} {25} {29} {30}
    
Allergic reaction (skin rash)
    
toxic megacolon (bloating; constipation; loss of appetite; severe stomach pain with nausea and vomiting)



Those indicating need for medical attention only if they continue or are bothersome
Incidence rare {01} {09} {14} {25} {29} {30}
    
Dizziness or drowsiness
    
dryness of mouth





Overdose
For specific information on the agents used in the management of loperamide, see:
   • Charcoal, Activated (Oral-Local) monograph; and/or
   • 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
Although human data are inconclusive, animal pharmacological and toxicological data indicate that overdosage may result in CNS depression, constipation, and gastrointestinal irritation. {01} {14} {25} {29} {30} {36}

Treatment of overdose

Note: Treatment of loperamide overdose is similar to treatment for narcotic overdosage and involves the following: {01} {03} {04} {05} {14} {25} {29} {30} {36}

To decrease absorption—Administration of activated charcoal promptly after ingestion. If vomiting has occurred spontaneously after ingestion of loperamide overdose, a slurry of 100 grams of activated charcoal should be administered as soon as fluids can be retained. Gastric lavage if vomiting has not occurred.

Specific treatment—Use of narcotic antagonists (e.g., naloxone), if necessary.

Monitoring—Prolonged and careful monitoring.

Supportive care—Support of respiration. 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, Loperamide (Oral) .

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

Before using this medication
»   Conditions affecting use, especially:
Allergy to loperamide





Use in children—Not recommended for use in children unless directed by a physician; may mask symptoms of dehydration; variability in response to loperamide; increased susceptibility to CNS effects






Use in the elderly—May mask symptoms of dehydration; variability in response to loperamide
Other medical problems, especially acute dysentery, dehydration, diarrhea caused by antibiotics, or severe colitis

Proper use of this medication
» Not using if diarrhea is accompanied by fever or blood or mucus in the stool; contacting physician

» Importance of not taking more medication than the amount prescribed

Proper administration technique for oral solution

» Importance of maintaining adequate hydration and proper diet {10} {18} {25} {29} {30} {31} {36}

» Proper dosing
Missed dose: Not taking missed dose; not doubling doses {39}

» 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


Side/adverse effects
Signs of potential side effects, especially allergic reaction or toxic megacolon


General Dosing Information
Reduction of intestinal motility in patients with traveler's diarrhea may result in prolonged fever by slowing expulsion of infectious organisms that penetrate intestinal mucosa (for example, Shigella, Salmonella, and certain strains of Escherichia coli ).

Inhibition of peristalsis may produce fluid retention in the bowel, which may aggravate and mask dehydration and depletion of electrolytes, especially in young children, and may also increase variability in the response to the medication. If dehydration or electrolyte imbalance occurs, loperamide therapy should be withheld until appropriate corrective therapy has begun. {25} {29} {30}

In patients with acute ulcerative colitis, treatment with loperamide should be discontinued promptly in the event of abdominal distention or other symptoms that may indicate impending toxic megacolon. {17} {24} {25} {29} {30}

Neither tolerance to the antidiarrheal effects nor physical dependence on loperamide has been reported in humans, although a morphine-like dependence has occurred in monkeys receiving high doses. {14} {17} {25} {29} {30}

In acute diarrhea, treatment with loperamide should be discontinued after 48 hours if improvement does not occur. {04} {05} {13} {14} {25} {29} {30} {31} {36} In chronic diarrhea, if no improvement has occurred after at least 10 days of treatment with the maximum dose, loperamide is unlikely to be effective, although further administration may be the only alternative when diet and specific treatment are inadequate. {25} {29} {30}


Oral Dosage Forms

LOPERAMIDE HYDROCHLORIDE CAPSULES USP

Usual adult and adolescent dose
Acute diarrhea; or
Traveler's diarrhea
Oral, 4 mg after first loose bowel movement, followed by 2 mg after each subsequent loose bowel movement. {01} {05} {10} {13} {14} {25} {29} {30} {36}

Chronic diarrhea
Initial: Oral, 4 mg, followed by 2 mg after each subsequent loose bowel movement until diarrhea is controlled. {05} {14} {25} {29} {30}

Maintenance: Oral, 4 to 8 mg a day in divided daily doses as needed. {05} {14} {25} {29} {30}


Usual adult prescribing limits
16 mg per day. {05} {10} {13} {14} {25} {29} {30} {35}

Note: Maximum daily dosage for self-medication with loperamide using the over-the-counter product is 8 mg. {04} {31}


Usual pediatric dose

Note: Although loperamide is not recommended for routine use in children, the following pediatric doses have been used to treat diarrhea caused by specific motility disorders. {28}

Acute diarrhea; or
Traveler's diarrhea


Children up to 6 years of age:
Use is not recommended unless directed by a physician. {34}



Children 6 to 12 years of age:


Initial—
Oral, 80 to 240 mcg (0.08 to 0.24 mg) per kg of body weight a day in two or three divided doses; or, for

Children 6 to 8 years of age: Oral, 2 mg two times a day. {05} {14} {25} {29} {30}

Children 8 to 12 years of age: Oral, 2 mg three times a day. {05} {14} {25} {29} {30}



Maintenance—
Oral, 1 mg per 10 kg of body weight administered only after a loose stool. {14} {25} {29} {30}




Children older than 12 years of age:
See Usual adult and adolescent dose.


Chronic diarrhea
Dosage has not been established. {14} {25} {29} {30}


Note: In general, oral rehydration therapy and dietary treatment of diarrhea in children are preferred whenever possible.


Strength(s) usually available
U.S.—


2 mg (Rx) [Imodium (lactose)][Generic]

Canada—


2 mg (OTC) [Imodium (lactose)] [Loperacap]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), {14} {29} in a well-closed, light-resistant container, {25} {30} unless otherwise specified by manufacturer.


LOPERAMIDE HYDROCHLORIDE ORAL SOLUTION

Usual adult and adolescent dose
See Loperamide Hydrochloride Capsules USP.

Usual adult prescribing limits
8 mg per day {04} {31} for no more than two days. {36} {37}

Usual pediatric dose

Note: Although loperamide is not recommended for routine use in children, the following pediatric doses have been used to treat diarrhea caused by specific motility disorders. {28}

Acute diarrhea; or
Traveler's diarrhea


Children up to 2 years of age:
Use is not recommended unless directed by a physician. {34}



Children 2 to 11 years of age:


Initial—
Oral, 80 to 240 mcg (0.08 to 0.24 mg) per kg of body weight a day in two or three divided doses; or, for

Children 2 to 5 years of age: Oral, only under the direction of a physician, 1 mg after first loose bowel movement, followed by 1 mg after each subsequent loose bowel movement, not to exceed a total daily dose of 3 mg. {36}

Children 6 to 8 years of age: Oral, 2 mg after first loose bowel movement, followed by 1 mg after each subsequent loose bowel movement, not to exceed a total daily dose of 4 mg. {05} {14} {31} {36}

Children 9 to 11 years of age: Oral, 2 mg after first loose bowel movement, followed by 1 mg after each subsequent loose bowel movement, not to exceed a total daily dose of 6 mg. {14} {31} {36}



Maintenance—
Oral, 1 mg per 10 kg of body weight administered only after a loose stool. {34}




Children 12 years of age and older:
See Usual adult and adolescent dose.



Note: In general, oral rehydration therapy and dietary treatment of diarrhea in children are preferred whenever possible.


Strength(s) usually available
U.S.—


1 mg per 5 mL (OTC) [Imodium A-D (alcohol 5.25%)] [Maalox Anti-Diarrheal] [Pepto Diarrhea Control (alcohol 5.25%)][Generic]

Canada—


1 mg per 5 mL (OTC) [Diarr-Eze] [Imodium (alcohol 4.07%)] [PMS-Loperamide]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.


LOPERAMIDE HYDROCHLORIDE TABLETS USP

Usual adult and adolescent dose
See Loperamide Hydrochloride Capsules USP.

Usual adult prescribing limits
8 mg per day {04} {31} for no more than two days. {36} {37}

Usual pediatric dose

Note: Although loperamide is not recommended for routine use in children, the following pediatric doses have been used to treat diarrhea caused by specific motility disorders. {28}

Acute diarrhea; or
Traveler's diarrhea


Children up to 6 years of age:
Use is not recommended unless directed by a physician. {34}



Children 6 to 11 years of age:


Initial—
Oral, 80 to 240 mcg (0.08 to 0.24 mg) per kg of body weight a day in two or three divided doses; or, for

Children 6 to 8 years of age: Oral, 2 mg after first loose bowel movement, followed by 1 mg after each subsequent loose bowel movement, not to exceed a total daily dose of 4 mg. {31} {36}

Children 9 to 11 years of age: Oral, 2 mg after first loose bowel movement, followed by 1 mg after each subsequent loose bowel movement, not to exceed a total daily dose of 6 mg. {31} {36}



Maintenance—
Oral, 1 mg per 10 kg of body weight administered only after a loose stool {34}.




Children 12 years of age and older:
See Usual adult and adolescent dose.



Note: In general, oral rehydration therapy and dietary treatment of diarrhea in children are preferred whenever possible.


Strength(s) usually available
U.S.—


2 mg (OTC) [Imodium A-D Caplets (lactose)] [Kaopectate II (lactose)] [Maalox Anti-Diarrheal] [Pepto Diarrhea Control ( lactose)][Generic]

Canada—


2 mg (OTC) [Apo-Loperamide] [Diarr-Eze] [Imodium] [Nu-Loperamide] [PMS-Loperamide (scored)] [Rho-Loperamide][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed, light-resistant container {42} .



Revised: 09/29/2000



References
  1. Loperamide package inserts (US and Canada).
  1. Update on excretion of drugs in breast milk. Aust J Hosp Pharm 1988; 18: 161.
  1. Minton NA. Loperamide toxicity in a child after a single dose. Br Med J 1987; 294: 1383.
  1. Consumer Product Safety Commission. Requirements for child-resistant packaging; products containing loperamide. Fed Regist 1993; 58: 38961.
  1. Imodium product monograph (Janssen—Canada), Rev 9/23/93, Rec 4/26/94.
  1. Awouters F, Niemegeers CJ, Janssen PA. Pharmacology of antidiarrheal drugs. Ann Rev Pharmacol Toxicol 1983; 23: 279-301.
  1. Covington TR. Management of diarrhea. Facts Comp Drug Newsl 1988; 7: 1-2.
  1. Brown JW. Toxic megacolon associated with loperamide therapy. JAMA 1979; 241: 501-2.
  1. Diarrhoeal Disease Control Programme. Guide for improving diarrhoea treatment practices of pharmacists and licensed drug sellers. Geneva: World Health Organization, 1993: 17-22.
  1. Ericsson CD, DuPont HL. Travelers" diarrhea: approaches to prevention and treatment. Clin Infect Dis 1993; 16: 616-26.
  1. DuPont HL, Sanchez JF, Ericsson CD, et al. Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea. Am J Med 1990; 88(6A Suppl): 15S-19S.
  1. DuPont HL. Using OTC drugs for acute diarrhea. Drug Ther 1983: 127-36.
  1. Longe RL. Antidiarrheal products. In: Covington TR, Lawson LC, Young LL, editors. Handbook of nonprescription drugs. 10th ed. Washington, DC: American Pharmaceutical Association, 1993: 199-211.
  1. Imodium package insert (Janssen—US), Rev 1/93, Rec 6/1/93.
  1. Binder HJ. Pathophysiology of acute diarrhea. Am J Med 1990; 88(6A Suppl): 2S-4S.
  1. Balistreri WF. Oral rehydration in acute infantile diarrhea. Am J Med 1990; 88(6A Suppl): 30S.
  1. Ericsson CD, Johnson PC. Safety and efficacy of loperamide. Am J Med 1990; 88(6A Suppl): 10S-14S.
  1. Brownlee HJ. Family practitioner"s guide to patient self-treatment of acute diarrhea. Am J Med 1990; 88(6A Suppl): 27S-29S.
  1. Bhutta TL. Loperamide poisoning in children. Lancet 1990; 335: 363.
  1. Cann PA. Role of loperamide and placebo in management of irritable bowel syndrome. Dig Dis Sci 1984; 29: 239-47.
  1. Diarrhoeal Disease Study Group (UK). Loperamide in acute diarrhoea in childhood: results of a double blind, placebo controlled multicentre clinical trial. Br Med J 1984; 289: 1263-7.
  1. Lishman AH. The use of loperamide hydrochloride in the irritable bowel syndrome. Clin Res Rev 1982; 2: 45-9.
  1. Schiller LR, Santa Ana CA, Morawski SG, et al. Mechanism of the antidiarrheal effect of loperamide. Gastroenterology 1984; 86: 1475-83.
  1. Brown JW. Toxic megacolon associated with loperamide therapy. JAMA 1979; 241: 501-2.
  1. Loperamide package insert (Geneva—US), Rev 10/92, Rec 6/4/93.
  1. Kenyon J, Caldwell M, editors. Oral rehydration is the cornerstone of diarrhoea therapy in children. Drugs Ther Perspect 1993; 1: 15-6.
  1. Panel comments.
  1. Pediatrics Advisory Panel Meeting, 10/30/93.
  1. Loperamide package insert (Lemmon—US), Rev 6/90, Rec 6/2/93.
  1. Loperamide package insert (Mylan—US), Rev 10/92, Rec 9/22/93.
  1. Imodium A-D product labeling (McNeil—US), Rev 1992, Rec 6/24/94.
  1. Caldara R. Effect of loperamide and naloxone on gastric acid secretion in healthy man. Gut 1981; 22: 270-3.
  1. International Health Advisory Panel Meeting, 6/10/94.
  1. Reviewers" consensus on monograph revision of 8/94.
  1. 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: 507-8, 925.
  1. Imodium A-D product information (McNeil—US), Rec 8/30/94.
  1. Manufacturer comment, 9/94.
  1. Panel comment, 9/94.
  1. Reviewers" consensus on monograph revision of 10/94.
  1. Panel comment, 10/94.
  1. Panel comment, 10/94.
  1. The United States pharmacopeia. The national formulary. USP 23rd revision (January 1, 1995). NF 18th ed (January 1, 1995). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 901.
  1. PMS-Loperamide product monograph (Pharmascience—Canada), Rev 1/31/97, Rec 3/19/97.
  1. Loperacap product monograph (ICN—Canada), Rev 7/26/96, Rec 3/19/97.
  1. Nu-Loperamide product monograph (NuPharm—Canada), Rev 8/9/96, Rec 5/7/97.
  1. Apo-Loperamide product monograph (Apotex—Canada), Rev 2/1/96, Rec 3/10/97.
Hide
(web4)