DESCRIPTION
`IMODIUM® (loperamide hydrochloride), 4-(p-chlorophenyl)-4-hydroxy-N, N-dimethyl-
`a, a-diphenyl-1-piperidinebutyramide monohydrochloride, is a synthetic antidiarrheal for
`oral use.
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`IMODIUM® is available in 2mg capsules.
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`The inactive ingredients are: Lactose, cornstarch, talc, and magnesium stearate.
`IMODIUM® capsules contain FD&C Yellow No. 6.
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`CLINICAL PHARMACOLOGY
`
`In vitro and animal studies show that IMODIUM® (loperamide hydrochloride) acts by
`slowing intestinal motility and by affecting water and electrolyte movement through the
`bowel. Loperamide binds to the opiate receptor in the gut wall. Consequently, it inhibits
`the release of acetylcholine and prostaglandins, thereby reducing peristalsis, and
`increasing intestinal transit time. Loperamide increases the tone of the anal sphincter,
`thereby reducing incontinence and urgency.
`
`In man, IMODIUM® prolongs the transit time of the intestinal contents. It reduces the
`daily fecal volume, increases the viscosity and bulk density, and diminishes the loss of
`fluid and electrolytes. Tolerance to the antidiarrheal effect has not been observed.
`Clinical studies have indicated that the apparent elimination half-life of loperamide in
`man is 10.8 hours with a range of 9.1 - 14.4 hours. Plasma levels of unchanged drug
`remain below 2 nanograms per mL after the intake of a 2mg capsule of IMODIUM®.
`Plasma levels are highest approximately five hours after administration of the capsule and
`2.5 hours after the liquid. The peak plasma levels of loperamide were similar for both
`formulations. Elimination of loperamide mainly occurs by oxidative N-demethylation.
`Cytochrome P450 (CYP450) isozymes, CYP2C8 and CYP3A4, are thought to play an
`important role in loperamide N-demethylation process since quercetin (CYP2C8
`inhibitor) and ketoconazole (CYP3A4 inhibitor) significantly inhibited the N-
`demethylation process in vitro by 40% and 90%, respectively. In addition, CYP2B6 and
`CYP2D6 appear to play a minor role in loperamide N-demethylation. Excretion of the
`unchanged loperamide and its metabolites mainly occurs through the feces. In those
`patients in whom biochemical and hematological parameters were monitored during
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`clinical trials, no trends toward abnormality during IMODIUM® therapy were noted.
`Similarly, urinalyses, EKG and clinical ophthalmological examinations did not show
`trends toward abnormality.
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`INDICATIONS AND USAGE
`IMODIUM® (loperamide hydrochloride) is indicated for the control and symptomatic
`relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory
`bowel disease. IMODIUM® is also indicated for reducing the volume of discharge from
`ileostomies.
`
`CONTRAINDICATIONS
`IMODIUM is contraindicated in patients with a known hypersensitivity to loperamide
`hydrochloride or to any of the excipients.
`IMODIUM is contraindicated in patients with abdominal pain in the absence of diarrhea.
`IMODIUM is not recommended in infants below 24 months of age.
`IMODIUM should not be used as the primary therapy:
`-
`in patients with acute dysentery, which is characterized
` by blood in stools and high fever,
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`in patients with acute ulcerative colitis,
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`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.
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`-
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`WARNINGS
`Fluid and electrolyte depletion often occur in patients who have diarrhea. In such cases,
`administration of appropriate fluid and electrolytes is very important. The use of
`IMODIUM® does not preclude the need for appropriate fluid and electrolyte therapy.
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`In general, IMODIUM should not be used when inhibition of peristalsis is to be avoided
`due to the possible risk of significant sequelae including ileus, megacolon and toxic
`megacolon. IMODIUM must be discontinued promptly when constipation, abdominal
`distention or ileus develop.
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`Treatment of diarrhea with IMODIUM is only symptomatic. Whenever an underlying
`etiology can be determined, specific treatment should be given when appropriate (or
`when indicated).
`
`Patients with AIDS treated with IMODIUM for diarrhea should have therapy stopped at
`the earliest signs of abdominal distention. There have been isolated reports of toxic
`megacolon in AIDS patients with infectious colitis from both viral and bacterial
`pathogens treated with loperamide hydrochloride. {ref EDMS-PSDB-2564186, pg 12}
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`IMODIUM® should be used with special caution in young children because of the
`greater variability of response in this age group. Dehydration, particularly in younger
`children, may further influence the variability of response to IMODIUM®.
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`PRECAUTIONS
`General
`Extremely rare allergic reactions including anaphylaxis and anaphylactic shock have been
`reported. In acute diarrhea, if clinical improvement is not observed in 48 hours, the
`administration of IMODIUM® (loperamide hydrochloride) should be discontinued and
`patients should be advised to consult their physician. Although no pharmacokinetic data
`are available in patients with hepatic impairment, IMODIUM should be used with
`caution in such patients because of reduced first pass metabolism. Patients with hepatic
`dysfunction should be monitored closely for signs of CNS toxicity. No pharmacokinetic
`data are available in patients with renal impairment. Since it has been reported that the
`majority of the drug is metabolized and metabolites or the unchanged drug is excreted
`mainly in the feces, dosage adjustments in patients with renal impairment are not
`required. No formal studies have been conducted to evaluate the pharmacokinetics of
`loperamide in elderly subjects. However, in two studies that enrolled elderly patients,
`there were no major differences in the drug disposition in elderly patients with diarrhea
`relative to young patients.
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`Information for Patients
`Patients should be advised to check with their physician if their diarrhea does not
`improve in 48 hours or if they note blood in their stools, develop a fever or develop
`abdominal distention.
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`Tiredness, dizziness, or drowsiness may occur in the setting of diarrheal syndromes
`treated with IMODIUM. Therefore, it is advisable to use caution when driving a car or
`operating machinery. (see Adverse Reactions).
`
`Drug Interactions
`Nonclinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant
`administration of loperamide (16 mg single dose) with a 600 mg single dose of either
`quinidine, or ritonavir, both of which are P-glycoprotein inhibitors, resulted in a 2- to 3-
`fold increase in loperamide plasma levels. Due to the potential for enhanced central
`effects when loperamide is coadministered with quinidine and with ritonavir, caution
`should be exercised when loperamide is administered at the recommended dosages (2
`mg, up to 16 mg maximum daily dose) with P-glycoprotein inhibitors.
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`When a single 16-mg dose of loperamide is coadministered with a 600 mg single dose of
`saquinavir, loperamide decreased saquinavir exposure by 54%, which may be of clinical
`relevance due to reduction of therapeutic efficacy of saquinavir. The effect of saquinavir
`on loperamide is of less clinical significance. Therefore, when loperamide is given with
`saquinavir, the therapeutic efficacy of saquinavir should be closely monitored.
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`Carcinogenesis, mutagenesis, impairment of fertility
`In an 18-month rat study with oral doses up to 40 mg/kg/day (21 times the maximum
`human dose of 16 mg/day, based on a body surface area comparison), there was no
`evidence of carcinogenesis.
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`Loperamide was not genotoxic in the Ames test, the SOS chromotest in E. coli, the
`dominant lethal test in female mice, or the mouse embryo cell transformation assay.
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`Fertility and reproductive performance was evaluated in rats using oral doses of 2.5, 10,
`and 40 mg/kg/day in one study, and 1, 5, 10, 20, and 40 mg/kg/day (females only) in a
`second study. Oral administration of 20 mg/kg/day (approximately 11 times the human
`dose based on a body surface area comparison) and higher produced strong impairment
`of female fertility. Treatment of female rats with up to 10 mg/kg/day p.o. (approximately
`5 times the human dose based on a body surface area comparison) had no effect on
`fertility. Treatment of male rats with 40 mg/kg/day p.o. (approximately 21 times the
`human dose based on a body surface area comparison) produced impairment of male
`fertility, whereas administration of up to 10 mg/kg/day (approximately 5 times the human
`dose based on a body surface area comparison) had no effect.
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`Pregnancy
`Teratogenic Effects
`Pregnancy Category C
`Teratology studies have been performed in rats using oral doses of 2.5, 10, and 40
`mg/kg/day, and in rabbits using oral doses of 5, 20, and 40 mg/kg/day. These studies
`have revealed no evidence of impaired fertility or harm to the fetus at doses up to 10
`mg/kg/day in rats (5 times the human dose based on body surface area comparison) and
`40 mg/kg/day in rabbits (43 times the human dose based on body surface area
`comparison). Treatment of rats with 40 mg/kg/day p.o. (21 times the human dose based
`on a body surface area comparison) produced marked impairment of fertility. The studies
`produced no evidence of teratogenic activity. There are no adequate and well-controlled
`studies in pregnant women. Loperamide should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus.
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`Non-teratogenic Effects
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`In a peri- and post-natal reproduction study in rats, oral administration of 40 mg/kg/day
`produced impairment of growth and survival of offspring.
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`Nursing Mothers
`Small amounts of loperamide may appear in human breast milk. Therefore, IMODIUM
`is not recommended during breast-feeding.
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`Pediatric Use
`See the "Warnings" Section for information on the greater variability of response in this
`age group.
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`In case of accidental overdosage of IMODIUM® by children, see "Overdosage" Section
`for suggested treatment.
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`ADVERSE REACTIONS
`Clinical Trial Data
`The adverse effects reported during clinical investigations of IMODIUM® (loperamide
`hydrochloride) are difficult to distinguish from symptoms associated with the diarrheal
`syndrome. Adverse experiences recorded during clinical studies with IMODIUM® were
`generally of a minor and self-limiting nature. They were more commonly observed
`during the treatment of chronic diarrhea.
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`The adverse events reported are summarized irrespective of the causality assessment of
`the investigators.
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`1) Adverse events from 4 placebo-controlled studies in patients with acute diarrhea
`The adverse events with an incidence of 1.0% or greater, which were reported at least as
`often in patients on loperamide hydrochloride as on placebo, are presented in the table
`below.
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`Placebo
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`Acute Diarrhea
`Loperamide
`Hydrochloride
`231
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`2.6%
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`236
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`0.8%
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`No. of treated patients
`Gastrointestinal AE%
`Constipation
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`The adverse events with an incidence of 1.0% or greater, which were more frequently
`reported in patients on placebo than on loperamide hydrochloride, were: dry mouth,
`flatulence, abdominal cramp and colic.
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`2) Adverse events from 20 placebo-controlled studies in patients with chronic diarrhea
`The adverse events with an incidence of 1.0% or greater, which were reported at least as
`often in patients on loperamide hydrochloride as on placebo, are presented below in the
`table below.
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`No. of treated patients
`Gastrointestinal AE%
`Constipation
`Central and peripheral
`nervous system AE%
`Dizziness
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`Chronic Diarrhea
`Loperamide
`Placebo
`Hydrochloride
`285
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`5.3%
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`1.4%
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`277
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`0.0%
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`0.7%
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`The adverse events with an incidence of 1.0% or greater, 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) Adverse events from seventy-six controlled and uncontrolled studies in patients with
`acute or chronic diarrhea
`The adverse events with an incidence of 1.0% or greater in patients from all studies are
`given in the table below.
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`
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`Acute
`Diarrhea
`1913
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`Chronic
`Diarrhea
`1371
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`All
`Studiesa
`3740
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`No. of treated
`patients
`Gastrointestinal
`AE%
`Nausea
`Constipation
`Abdominal cramps
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`0.7%
`3.2%
`1.8%
`1.6%
`1.9%
`1.7%
`0.5%
`3.0%
`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.
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`Post –marketing experience
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`The following adverse events have been reported:
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`Skin and subcutaneous tissue disorders
`Rash, pruritus, urticaria, angioedema, and extremely rare cases of bullous eruption
`including erythema multiforme, Stevens-Johnson syndrome and Toxic Epidermal
`Necrolysis have been reported with use of IMODIUM.
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`Immune system disorders
`Isolated occurrences of allergic reactions and in some cases severe hypersensitivity
`reactions including anaphylactic shock and anaphylactoid reactions have been reported
`with the use of IMODIUM.
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`Gastrointestinal disorders
`Dry mouth, abdominal pain, distention or discomfort, nausea, vomiting, flatulence,
`dyspepsia, constipation, paralytic ileus, megacolon, including toxic megacolon (see
`Contraindications and Warnings).
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`Renal and urinary disorders
`Urinary retention
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`Nervous system disorders
`Drowsiness, dizziness
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`General disorders and administrative site conditions
`Tiredness
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` A
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` 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.
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`DRUG ABUSE AND DEPENDENCE
`Abuse
`A specific clinical study designed to assess the abuse potential of loperamide at high
`doses resulted in a finding of extremely low abuse potential.
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`Dependence
`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 indicates
`opiate-like effects, performed after a single high dose, or after more than two years of
`therapeutic use of IMODIUM® (loperamide hydrochloride), was negative. Orally
`administered IMODIUM® (loperamide formulated with magnesium stearate) is both
`highly insoluble and penetrates the CNS poorly.
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`OVERDOSAGE
`In cases of overdosage, (including relative overdose due to hepatic dysfunction), urinary
`retention, paralytic ileus and CNS depression may occur. Children may be more
`sensitive to CNS effects than adults. Clinical trials have demonstrated that a slurry of
`activated charcoal administered promptly after ingestion of loperamide hydrochloride can
`reduce the amount of drug which is absorbed into the systemic circulation by as much as
`ninefold. If vomiting occurs spontaneously upon ingestion, a slurry of 100 gms of
`activated charcoal should be administered orally as soon as fluids can be retained.
`
`If vomiting has not occurred, gastric lavage should be performed followed by
`administration of 100 gms of the activated charcoal slurry through the gastric tube. In the
`event of overdosage, patients should be monitored for signs of CNS depression for at
`least 24 hours.
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`If symptoms of overdose occur, naloxone can be given as an antidote. If responsive to
`naloxone, vital signs must be monitored carefully for recurrence of symptoms of drug
`overdose for at least 24 hours after the last dose of naloxone.
`
`In view of the prolonged action of loperamide and the short duration (one to three hours)
`of naloxone, the patient must be monitored closely and treated repeatedly with naloxone
`as indicated. Since relatively little drug is excreted in the urine, forced diuresis is not
`expected to be effective for IMODIUM® (loperamide hydrochloride) overdosage.
`
`In clinical trials an adult who took three 20mg 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.
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`DOSAGE AND ADMINISTRATION
`(1 capsule = 2 mg)
`Patients should receive appropriate fluid and electrolyte replacement as needed.
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`Acute Diarrhea
`Adults: The recommended initial dose is 4mg (two capsules) followed by 2 mg (one
`capsule) after each unformed stool. Daily dose should not exceed 16mg (eight capsules).
`Clinical improvement is usually observed within 48 hours.
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`Children: In children 2 to 5 years of age (20 kg or less), the non-prescription liquid
`formulation (IMODIUM® A-D 1 mg/5 mL) should be used; for ages 6 to 12, either
`IMODIUM® Capsules or IMODIUM® A-D Liquid may be used. For children 2 to 12
`years of age, the following schedule for capsules or liquid will usually fulfill initial
`dosage requirements:
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`Recommended First Day Dosage Schedule
`Two to five years: 1 mg t.i.d. (3mg daily dose) (13 to 20 kg)
`Six to eight years: 2 mg b.i.d. (4mg daily dose) (20 to 30 kg)
`Eight to twelve years: 2mg t.i.d. (6mg daily dose) (greater than 30 kg)
`
`Recommended Subsequent Daily Dosage
`Following the first treatment day, it is recommended that subsequent IMODIUM® doses
`(1 mg/10 kg body weight) be administered only after a loose stool. Total daily dosage
`should not exceed recommended dosages for the first day.
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`Chronic Diarrhea
` Children: Although IMODIUM® has been studied in a limited number of children
`with chronic diarrhea; the therapeutic dose for the treatment of chronic diarrhea in a
`pediatric population has not been established.
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`
` Adults: The recommended initial dose is 4 mg (two capsules) followed by 2 mg (one
`capsule) after each unformed stool until diarrhea is controlled, after which the dosage
`of IMODIUM® should be reduced to meet individual requirements. When the
`optimal daily dosage has been established, this amount may then be administered as a
`single dose or in divided doses.
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`The average daily maintenance dosage in clinical trials was 4 to 8 mg (two to four
`capsules). A dosage of 16 mg (eight capsules) was rarely exceeded. If clinical
`improvement is not observed after treatment with 16 mg per day for at least 10 days,
`symptoms are unlikely to be controlled by further administration. IMODIUM®
`administration may be continued if diarrhea cannot be adequately controlled with diet
`or specific treatment.
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`Children under 2 Years
`The use of IMODIUM in children under 2 years is not recommended. There have been
`rare reports of paralytic ileus associated with abdominal distention. Most of these
`reports occurred in the setting of acute dysentery, overdose, and with very young
`children less than two years of age.
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`Elderly
` No formal pharmacokinetic studies were conducted in elderly subjects. However, there
`were no major differences reported in the drug disposition in elderly patients with
`diarrhea relative to young patients. No dosage adjustment is required for the elderly.
`
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`Renal Impairment
`No pharmacokinetic data are available in patients with renal impairment. Since the
`metabolites and the unchanged drug are mainly excreted in the feces, no dosage
`adjustment is required for patients with renal impairment (see PRECAUTIONS
`section).
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`
`Hepatic Impairment
`Although no pharmacokinetic data are available in patients with hepatic impairment,
`IMODIUM should be used with caution in such patients because of reduced first pass
`metabolism. (see Precautions).
`
`
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`HOW SUPPLIED
`Capsules - each capsule contains 2 mg of loperamide hydrochloride. The capsules have a
`light green body and a dark green cap with "JANSSEN" imprinted on one segment and
`"IMODIUM" on the other segment. IMODIUM® capsules are supplied in bottles of 100.
`
`NDC 50458-400-10
`(100 CAPSULES)
`
`Store at 15°-25°C (59°-77°F).
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`Revised September 1996, July 1998, [Insert Date]
`©Janssen Pharmaceutica Inc. 1998
`
`
`Rx Only
`
`
`Printed in USA
`U.S. Patent 3, 714,159 [XXXXXXX]
`
`