Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 9 DOSAGE AND ADMINISTRATION 10 OVERDOSAGE 11 ACTION AND CLINICAL PHARMACOLOGY 12 STORAGE AND STABILITY 13 SPECIAL HANDLING INSTRUCTIONS 13 DOSAGE FORMS, COMPOSITION AND PACKAGING 13
PHARMACEUTICAL INFORMATION 15 CLINICAL TRIALS 15 DETAILED PHARMACOLOGY 19 TOXICOLOGY 21 REFERENCES 26
IMODIUM(r) Loperamide Hydrochloride
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Caplet/2mg Quick-Dissolve tablet/2mg oral solution 2 mg/15 mL | None For a complete listing see Dosage Forms, Composition and Packaging section. |
IMODIUM(r) (loperamide hydrochloride) is indicated: as an adjunct to rehydration therapy for the symptomatic control of acute non-specific diarrhea for chronic diarrhea associated with inflammatory bowel disease for reducing the volume of discharge for ileostomies, colostomies and other intestinal resections Treatment of diarrhea with IMODIUM(r) is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate (or when indicated). In acute diarrhea, if clinical improvement is not observed within 48 hours, the administration of IMODIUM(r) should be discontinued and patients should be advised to consult their physician.
Geriatrics (>65 years of age):
No dose adjustments are required for the elderly.
Pediatrics (2 to 12 years of age):
Loperamide should be used in children only on the advice of a physician. IMODIUM(r) caplets and Quick-Dissolve tablets are not suited for children under 6 years of age.
Children under 2 years of age:
The use of IMODIUM(r) in children under 2 years is contraindicated.
Renal Impairment:
No dosage adjustment necessary in renal impairment.
Hepatic Impairment:
Although no pharmacokinetic data are available in patients with hepatic impairment, IMODIUM(r) should be used with caution in such patients because of reduced first pass metabolism.
Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. IMODIUM(r) is contraindicated in those in whom constipation must be avoided. IMODIUM(r) should not be used in the following cases:
in patients with acute dysentery, which is characterized by blood in stools and elevated temperature,
in patients with acute ulcerative colitis,
in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter,
in patients with pseudomembranous colitis associated with the use of broad- spectrum antibiotics.
In patients who the inhibition of peristalsis is to be avoided. In such patients, agents which inhibit intestinal motility or delay intestinal transit time have increased the possible risk of significant sequelae including ileus, megacolon and toxic megacolon.
Must be discontinued promptly if abdominal distension occurs or if other untoward symptoms develop.
General
Since treatment of diarrhea with IMODIUM(r) is only symptomatic, diarrhea should be treated causally, whenever causal treatment is available. Fluid and electrolyte depletion may occur in patients who have diarrhea. The use of IMODIUM(r) does not preclude the administration of appropriate fluid and electrolyte therapy. IMODIUM(r) should be kept out of the reach of children. IMODIUM(r) caplets and Quick-Dissolve tablets are not suited for children under 6 years of age. Due to the particular ease with which IMODIUM(r) Quick-Dissolve tablets may be swallowed, special care should be taken when storing this product. In case of accidental ingestion of IMODIUM(r) by children see OVERDOSAGE. Tiredness, dizziness, or drowsiness may occur in the setting of diarrheal syndromes treated with IMODIUM(r). Therefore, it is advisable to use caution when driving a car or operating machinery.
Dependence/Tolerance
Physical dependence to IMODIUM(r) in humans has not been observed. However, studies in morphine-dependent monkeys demonstrated that loperamide hydrochloride at doses above those recommended for humans prevented signs of morphine withdrawal. However, in humans, the naloxone challenge pupil test, which when positive indicated opiate-like effects, performed after a single high dose, or after more than two years of therapeutic use of IMODIUM(r), was negative.
Hepatic/Biliary/Pancreatic
Patients with hepatic dysfunction should be monitored for signs of CNS toxicity due to the extensive first pass metabolism of loperamide in the liver.
Immune
Patients with AIDS treated with IMODIUM(r) for diarrhea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.
Neurologic
IMODIUM(r) should be used with special caution in young children and those with compromised blood brain barrier (e.g., meningitis) because of the greater variability of response in these groups. Dehydration, particularly in young children, may further influence the variability of response to IMODIUM(r).
Renal
Since the majority of the drug is metabolized, and metabolites or the unchanged drug is excreted in the feces, dose adjustments in patients with a kidney disorder are not required.
Special Populations
Safe use of IMODIUM(r) during pregnancy has not been established. Reproduction studies performed in the rat and the rabbit revealed no evidence of impaired fertility or harm to the fetus at dosage levels up to 30-fold, the therapeutic dose for man. Therefore, IMODIUM(r) should be used in pregnant women only when, in the opinion of the physician, the potential benefits outweigh the potential risks. Although there are no indications that loperamide hydrochloride possesses teratogenic or embryotoxic properties, the anticipated therapeutic benefits should be weighed against potential hazards before IMODIUM(r) is given during pregnancy, especially during the first trimester. The extent of exposure in pregnancy during clinical trials has not been established.
Small amounts of loperamide may appear in human breast milk. Therefore, IMODIUM(r) is not recommended during breast-feeding.
The use of IMODIUM(r) is not recommended for children under 12 years of age except on the advice of a physician (See DOSAGE AND ADMINISTRATION). IMODIUM(r) should be used with special caution in young children because of greater variability of response in this group. Dehydration, particularly in young children, may further influence the variability of response to IMODIUM(r). In patients with diarrhea, especially in children, fluid and electrolyte depletion may occur. In such cases administration of appropriate fluid and electrolyte replacement therapy is the most important measure. IMODIUM(r) should not be given to children under 6 years of age without medical prescription and supervision. The use of the IMODIUM(r) caplet or Quick-Dissolve tablet is not suitable for children under 6 years of age. The use of IMODIUM(r) is contraindicated for children under 2 years of age.
No dose adjustment is required for the elderly.
The standard for defining frequency terms will be based on the Council for International Organizations of Medical Science (CIOMS) convention. Specifically: Very common (> 1/10) Common (> 1/100, < 1/10) Uncommon (> 1/ 1,000, < 1/100) Rare (> 1/10,000, < 1/1,000) Very rare (< 1/10,000), including isolated reports
Adverse Drug Reaction Overview
The adverse effects reported in adults during clinical trials are difficult to distinguish from symptoms associated with the diarrheal syndrome. In adults, they were generally of a minor and self-limiting nature e.g., abdominal pain or discomfort; drowsiness or dizziness; tiredness; dry mouth; nausea and vomiting. Hypersensitivity reactions, such as skin rash and urticaria, and extremely rare cases of anaphylactic shock and bullous eruption including Toxic Epidermal Necrolysis, have also been reported. In the majority of these cases, the patients were on other medications which may have caused or contributed to the events. Constipation and/or abdominal distension have also been reported. In some very rare cases, particularly in which the treatment information had not been respected, these effects have been associated with ileus. Urinary retention has been reported rarely. Opiate-like effects (CNS) have been observed in young children (under 3 years of age). No adverse experiences were reported after prolonged use of loperamide. With the IMODIUM(r) Quick-Dissolve tablet formulation, some subjects have complained about a burning or prickling sensation on the tongue immediately following its use.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The frequency provided is a reflection of adverse experiences in clinical trials and does not represent true incidence or frequency as seen with epidemiologic studies. 1.) Common Adverse events in patients with acute diarrhea The following adverse events with an incidence of 1.0% or greater or classified as "common", which were more frequently reported in patients on loperamide hydrochloride than on placebo, are presented in the table below:
Table 1: Listing of Common Adverse Events in patients with acute diarrhea with an Incidence of 1.0% or greater as measured in Clinical Trials.
| Acute Diarrhea | ||
| Loperamide Hydrochloride | Placebo | |
| No. of treated patients | 231 | 236 |
| Gastrointestinal disorders% Constipation | 2.6% | 0.8% |
The adverse events with an incidence of 1.0% or greater or classified as "common", which were more frequently reported in patients on placebo than on loperamide hydrochloride, were: dry mouth, flatulence, abdominal cramp and colic. 2.) Common Adverse events in patients with chronic diarrhea The adverse events with an incidence of 1.0% or greater or classified as "common", which were more frequently reported in patients on loperamide hydrochloride than on placebo, are presented in the table below:
Table 2: Listing of common Adverse Events in patients with chronic diarrhea with an Incidence of 1.0% or greater as measured in Clinical Trials.
| Chronic Diarrhea | ||
| Loperamide Hydrochloride | Placebo | |
| No. of treated patients | 285 | 277 |
| Gastrointestinal disorders% Constipation | 5.3% | 0.0% |
| Nervous system disorders% Dizziness | 1.4% | 0.7% |
The adverse events with an incidence of 1.0% or greater or classified as "common", which were more frequently reported in patients on placebo than on loperamide hydrochloride were: nausea, vomiting, headache, meteorism, abdominal pain, abdominal cramp and colic. 3.) Common Adverse events from seventy-six controlled and uncontrolled studies in patients with acute or chronic diarrhea The following adverse events with an incidence of 1.0% or greater or classified as "common" in patients from all studies are given in the table below:
Table 3: Listing of common Adverse Events in patients with acute and chronic diarrhea with an Incidence of 1.0% or greater as measured in Clinical Trials.
| Acute Diarrhea | Chronic Diarrhea | All Studies a | |
| No. of treated patients | 1913 | 1371 | 3740 |
| Gastrointestinal disorders% Nausea Constipation Abdominal cramps | 0.7% 1.6% 0.5% | 3.2% 1.9% 3.0% | 1.8% 1.7% 1.4% |
a
All patients in all studies, including those in which it was not specified if the adverse events occurred in patients with acute or chronic diarrhea.
Post-Market Adverse Drug Reactions
Adverse events which may be causally related to the administration of IMODIUM(r) that have come to light as a result of reports received in relation to administration of the marketed product are provided in this section. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders
Allergic reactions and in some cases severe hypersensitivity reactions including anaphylactic shock and anaphylactoid reactions have been reported with the use of loperamide hydrochloride.
Nervous System Disorders
Dizziness, loss of consciousness and depressed level of consciousness.
Gastrointestinal Disorders
Abdominal pain, ileus, abdominal distension, nausea, constipation, vomiting, megacolon including toxic megacolon (See WARNINGS AND PRECAUTIONS), flatulence, and dyspepsia.
Renal and Urinary Disorders
Urinary retention
Psychiatric System Disorders
Drowsiness
Skin and Subcutaneous Tissue Disorders
Rash, urticaria and pruritus, angioedema, and bullous eruptions including Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis have been reported with use of loperamide hydrochloride. A number of the adverse events reported during the clinical investigations and post-marketing experience with loperamide are frequent symptoms of the underlying diarrheal syndrome (abdominal pain/discomfort, nausea, vomiting, dry mouth, tiredness, drowsiness, dizziness, constipation, and flatulence). These symptoms are often difficult to distinguish from undesirable drug effects.
Drug-Drug Interactions
Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both P- glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages (2 mg, up to 16 mg maximum daily dose), is unknown. No drug interactions have been reported. However, it is expected that drugs with similar pharmacological properties may potentiate the effect of IMODIUM(r)and that drugs that accelerate gastrointestinal transit may decrease its effect.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Recommended Dose and Dosage Adjustment
IMODIUM(r) Quick-Dissolve is a fast-dissolving tablet which can be taken without fluid. The tablet disintegrates within seconds on the surface of the tongue and is then swallowed with the saliva. Dose for the oral solution should be administered with the attached measuring cup only. ADULTS and CHILDREN 12 YEARS OF AGE and OLDER - IMODIUM(r) Caplets, IMODIUM(r) Quick-Dissolve Tablets and IMODIUM(r) Oral Solution Acute diarrhea: The initial dose of IMODIUM(r) (loperamide hydrochloride) is 2 caplets or 2 Quick-Dissolve tablets or 30 mL oral solution (4 mg) followed by 1 caplet or 1 Quick-Dissolve tablet or 15 mL oral solution (2 mg) after every subsequent loose stool. Clinical studies indicate that diarrheal control may be achieved after the initial dose in 50% of patients. Daily dosage should not exceed 8 caplets or Quick-Dissolve tablets or 120 mL oral solution (16 mg). Chronic diarrhea: The recommended initial dosage of IMODIUM(r) is 4 mg (2 caplets or 2 Quick- Dissolve tablets or 30 mL oral solution) followed by 2 mg (1 caplet or 1 Quick-Dissolve tablet or 15 mL oral solution) after each unformed stool until diarrhea is controlled; thereafter, the dosage of IMODIUM(r) should be reduced to meet individual requirements. When the optimal daily dosage has thus been established, this amount can be administered as a single dose daily or in divided doses. The average daily maintenance dosage used in clinical trial has been 4-8 mg. The maximum dose for chronic diarrhea is 8 caplets or 8 Quick-Dissolve tablets or 120 mL oral solution (16 mg) daily. If improvement is not observed after treatment with 16 mg per day for 10 days, symptoms are unlikely to be controlled by further administration. CHILDREN (6 to 12 years) - IMODIUM(r) Caplets and IMODIUM(r) Quick-Dissolve Tablets The use of IMODIUM(r) caplets and Quick-Dissolve tablets is not suitable for children under 6 years of age. IMODIUM(r) Oral Solution is intended for use in adults and children 12 years of age and older only. Acute or chronic diarrhea: Loperamide should be used in children only on the advice of a physician. For children up to but not including 12 years of age, the following schedule will usually fulfil initial dosage requirements: Recommended First-Day Dosage Schedule:
| Six to eight years: (20 to 30 kg) | 2 mg b.i.d. (4 mg daily dose) |
| Eight to twelve years: (greater than 30 kg) | 2 mg t.i.d. (6 mg daily dose) |
Following the first treatment day, it is recommended that subsequent IMODIUM(r) doses (1 mg/10 kg body weight) be administered only after a loose stool and not exceed the maximum daily dose.
IMODIUM(r) may be administered for prolonged periods of time. Blood, urine, liver and kidney function, ECG and ophthalmological examinations have revealed no significant abnormalities after several years of administration. No tolerance to the antidiarrheal effect has been observed. Naloxone pupil challenge studies in patients with chronic diarrhea who have received IMODIUM(r) orally for prolonged periods indicate a lack of CNS effects.
Symptoms
In case of overdose (including relative overdose due to hepatic dysfunction), central nervous system depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia, respiratory depression), urinary retention and ileus may occur. Children may be more sensitive to CNS effects than adults. In clinical trials, an adult who took three 20 mg doses within a 24-hour period was nauseated after the second dose and vomited after the third dose. In studies designed to examine the potential for side effects, intentional ingestion of up to 60 mg of loperamide hydrochloride in a single dose to healthy subjects resulted in no significant adverse effects.
Treatment
Treatment is symptomatic and supportive. Appropriate standard methods of gastrointestinal decontamination may be employed. Activated charcoal administered in appropriate dosages, promptly after ingestion of loperamide hydrochloride can reduce the amount of drug which is absorbed into the systemic circulation by as much as nine fold. In the event of overdosage, patients should be monitored for signs of CNS depression for at least 48 hours. If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of IMODIUM(r) is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. If responsive to naloxone, vital signs must be monitored carefully for recurrence of symptoms of drug overdose for at least 48 hours after the last dose of naloxone. Since relatively little drug is excreted in the urine, forced diuresis is not expected to be effective for IMODIUM(r) overdosage. Physicians without experience in managing loperamide overdose should seek consultation with a Regional Poison Control Centre.
Mechanism of Action
Diarrhea may be defined as a failure or imbalance of one or a combination of activities in the gut which include secretion, absorption and motility. IMODIUM(r) (loperamide hydrochloride) has been shown to act on all of these functions via cholinergic, non-cholinergic, opiate and non-opiate receptor-mediated mechanisms. In this way, IMODIUM(r) effectively reduces fecal output and frequency, improves stool consistency and relieves symptoms of abdominal cramping and fecal incontinence.
Pharmacodynamics
Loperamide binds to the opiate receptor in the gut wall. Consequently, it inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis, and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter, thereby reducing incontinence and urgency. Due to its high affinity for the gut wall and its high first-pass metabolism, loperamide hardly reaches the systemic circulation.
Pharmacokinetics
Loperamide is easily absorbed from the gut, but it is almost completely extracted by the liver, where it is metabolized, conjugated and excreted via the bile.
Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer.
Elimination mainly occurs by oxidative N-demethylation, which is the main metabolic pathway for loperamide.
Excretion of the unchanged loperamide and the metabolites mainly occurs through the feces. The half-life of loperamide in man is about 11 hours with a range of 9-14 hours.
IMODIUM(r) caplets and oral solution should be stored at room temperature (15-30degC). Protect from light. Store IMODIUM(r) Quick-Dissolve tablets at room temperature (15-30degC) and protect from moisture.
Keep out of reach of children.
IMODIUM(r) caplets are light green, capsule-shaped tablets, embossed with "Imodium A-D" on one side and "2mg" on the other side. Each caplet contains 2 mg of loperamide hydrochloride. Nonmedicinal ingredients in alphabetical order are: cellulose, colloidal silicon dioxide, D&C yellow No. 10, dibasic calcium phosphate, FD&C blue No. 1, magnesium stearate. Availability: Blister packs of 6, 12, 24 or 42 caplets
IMODIUM(r) Quick-Dissolve tablets (white, circular) each contain 2 mg of loperamide hydrochloride. Nonmedicinal ingredients in alphabetical order include aspartame, flavour, gelatin, mannitol and sodium bicarbonate. Availability:
Blister strips of 10 tablets. They are supplied in packages containing one (10 tablets) or two (20 tablet) blister strips.
To take the tablets out of the blister, pull up the edge of the foil, tear the foil completely off, press out and then remove the tablet.
IMODIUM(r) oral solution is an opaque green liquid with a mint odour, packaged in plastic bottles. IMODIUM(r) oral solution contains 2 mg/15 mL loperamide hydrochloride. Nonmedicinal ingredients in alphabetical order are: carboxymethylcellulose sodium, cellulose, citric acid, D&C yellow no.10, dimethyl siloxane, FD&C blue no.1, flavour, glycerin, methylcellulose, propylene glycol, purified water, simethicone, sodium benzoate, sorbic acid, sucralose, titanium dioxide, xanthan gum. Availability: 120 mL, 240 mL and 360 mL pack sizes.