Reference ID: 4007556
`
`IMODIUM CAPSULES Rx
`
`WARNING: TORSADES DE POINTES AND SUDDEN DEATH
`
`● Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the
`use of a higher than recommended dosages of IMODIUM® (see WARNINGS and
`OVERDOSAGE).
`
`● IMODIUM® is contraindicated in pediatric patients less than 2 years of age (see
`CONTRANIDICATIONS).
`
`● Avoid IMODIUM® dosages higher than recommended in adults and pediatric patients
`2 years of age and older due to the risk of serious cardiac adverse reactions (see
`DOSAGE AND ADMINISTRATION).
`
`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.
`
`IMODIUM® is available in 2mg capsules.
`
`The inactive ingredients are: Lactose, cornstarch, talc, and magnesium stearate. IMODIUM®
`capsules contain FD&C Yellow No. 6.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`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 propulsive peristalsis, and increasing
`intestinal transit time. Loperamide increases the tone of the anal sphincter, thereby reducing
`incontinence and urgency.
`
`Pharmacodynamics
`Loperamide prolongs the transit time of the intestinal contents. It reduces 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.
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`Pharmacokinetics
`Absorption
`Plasma concentrations of unchanged drug remain below 2 ng/mL after the intake of a 2 mg
`capsule of IMODIUM®. Plasma loperamide concentrations are highest approximately 5 hours
`after administration of the capsule and 2.5 hours after the liquid. The peak plasma
`concentrations of loperamide were similar for both formulations.
`
`Distribution
`Based on literature information, the plasma protein binding of loperamide is about 95%.
`Loperamide is a P-glycoprotein substrate.
`
`Elimination
`The apparent elimination half-life of loperamide is 10.8 hours with a range of 9.1 to 14.4 hours.
`Elimination of loperamide mainly occurs by oxidative N-demethylation.
`
`Metabolism
`In vitro loperamide is metabolized mainly by cytochrome P450 (CYP450) isozymes, CYP2C8
`and CYP3A4, to form- N-demethyl loperamide. In an in vitro study quercetin (CYP2C8 inhibitor)
`and ketoconazole (CYP3A4 inhibitor) significantly inhibited the N-demethylation process by 40%
`and 90%, respectively. In addition, CYP2B6 and CYP2D6 appear to play a minor role in
`loperamide N-demethylation.
`
`Concomitant use of IMODIUM® with inhibitors of CYP3A4 (e.g., itraconazole) or CYP2C8 (e.g.,
`gemfibrozil) or inhibitors of P-glycoprotein (e.g., quinidine, ritonavir) can increase exposure to
`loperamide (see PRECAUTIONS, Drug Interactions).
`
`Excretion
`Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces.
`
`INDICATIONS AND USAGE
`IMODIUM® (loperamide hydrochloride) is indicated for the control and symptomatic relief of
`acute nonspecific diarrhea in patients 2 years of age and older and of chronic diarrhea in adults
`associated with inflammatory bowel disease. IMODIUM® is also indicated for reducing the
`volume of discharge from ileostomies.
`
`
`
`CONTRAINDICATIONS
`IMODIUM® is contraindicated in:
`pediatric patients less than 2 years of age due to the risks of respiratory depression and
`
`serious cardiac adverse reactions (see WARNINGS).
`patients with a known hypersensitivity to loperamide hydrochloride or to any of the
`excipients.
`patients with abdominal pain in the absence of diarrhea.
`patients with acute dysentery, which is characterized by blood in stools and high fever.
`patients with acute ulcerative colitis.
`patients with bacterial enterocolitis caused by invasive organisms including Salmonella,
`Shigella, and Campylobacter.
`patients with pseudomembranous colitis (e.g., Clostridium difficle) associated with the
`use of broad-spectrum antibiotics.
`
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`
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`WARNINGS
`
`Cardiac Adverse Reactions, Including Torsades de Pointes and Sudden Death
`Cases of prolongation of the QT/QTc interval, Torsades de Pointes, other ventricular
`arrhythmias, cardiac arrest, some resulting in death, have been reported in adults with use of
`higher than recommended doses per day of IMODIUM®. Cases include patients who were
`abusing or misusing loperamide hydrochloride (see OVERDOSAGE and DRUG ABUSE AND
`DEPENDENCE). Cases of syncope and ventricular tachycardia have been reported in adult
`patients receiving the recommended dosage of IMODIUM®. Some of these patients were taking
`other drugs or had other risk factors that may have increased their risk of cardiac adverse
`reactions. Additionally, postmarketing cases of cardiac arrest, syncope, and respiratory
`depression have been reported in pediatric patients less than 2 years of age.
`
`IMODIUM® is contraindicated in pediatric patients less than 2 years of age due to the risks of
`respiratory depression and serious cardiac adverse reactions. Avoid IMODIUM® dosages
`higher than recommended in adults and pediatric patients 2 years of age and older due to the
`risk of serious cardiac adverse reactions (see DOSAGE AND ADMINISTRATION,
`OVERDOSAGE)
`
`Avoid IMODIUM® in:
`combination with others drugs or herbal products that are known to prolong the QT
`
`interval, including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone,
`sotalol) antiarrhythmics, antipsychotics (e.g., chlorpromazine, haloperidol, thioridazine,
`ziprasidone), antibiotics (e.g., moxifloxacin), or any other drug known to prolong the QT
`interval (e.g., pentamidine, levomethadyl acetate, methadone)
`patients with risk factors for QT prolongation, including patients with congenital long QT
`syndrome, with a history of cardiac arrhythmias or other cardiac conditions, elderly
`patients and those with electrolyte abnormalities.
`
`
`
`Dehydration
`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.
`
`Gastrointestinal Disorders
`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.
`
`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.
`
`Variability in Pediatric Response
`IMODIUM® should be used with special caution in pediatric patients because of the greater
`variability of response in this age group. Dehydration, particularly in pediatric patients less than
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`6 years of age, may further influence the variability of response to IMODIUM®. IMODIUM® is
`contraindicated in pediatric patients less than 2 years of age due to the risks of respiratory
`depression and serious cardiac adverse reactions.
`
`PRECAUTIONS
`General
`Allergic Reactions
`Extremely rare allergic reactions including anaphylaxis and anaphylactic shock have been
`reported.
`
`Hepatic Impairment
`The effects of hepatic impairment on the pharmacokinetics of loperamide have not been
`studied. Use IMODIUM® with caution in such patients because the systemic exposure to
`loperamide may be increased due to reduced metabolism. Monitor patients with hepatic
`impairment closely for signs of central nervous system (CNS) toxicity.
`
`Renal Impairment
`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 are
`excreted mainly in the feces, dosage adjustments in patients with renal impairment are not
`required.
`
`Geriatric Use
`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.
`
`In general, elderly patients may be more susceptible to drug-associated effects on the QT
`interval. Avoid IMODIUM® in elderly patients taking drugs that can result in prolongation of the
`QT interval (for example, Class IA or III antiarrhythmics) or in patients with risk factors for
`Torsades de Pointes (see WARNINGS).
`
`Information for Patients
`
`Advise patients:
`
`
`
`to take IMODIUM® at the prescribed dosage. Use of a higher than prescribed dosage is
`not recommended (see WARNINGS). Report to a healthcare facility if you or someone
`you are caring for taking IMODIUM® experiences fainting episode, a rapid or irregular
`heartbeat or become unresponsive.
`
` with acute diarrhea, that if clinical improvement is not observed in 48 hours, discontinue
`IMODIUM® and contact their healthcare provider.
`
`
`
`
`
`to contact their healthcare provider if they see blood in their stools, or if they develop a
`fever or abdominal distention.
`
`to use caution when driving a car or operating machinery, as tiredness, dizziness, or
`drowsiness may occur in the setting of diarrheal syndromes treated with IMODIUM®.
`(see ADVERSE REACTIONS).
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`
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`to tell their healthcare provider about all the medications they are taking, including
`prescription and over-the-counter medications, vitamins and herbal supplements,
`especially if they take Class 1A (e.g., quinidine, procainamide) or Class III (e.g.,
`amiodarone, sotalol) antiarrhythmics, antipsychotics (e.g., chlorpromazine, haloperidol,
`thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), or any other drug known to
`prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone).
`
`Drug Interactions
`Effects of Other Drugs on Loperamide
`Concomitant use of IMODIUM® with inhibitors of CYP3A4 (e.g., itraconazole) or CYP2C8 (e.g.,
`gemfibrozil) or inhibitors of P-glycoprotein (e.g., quinidine, ritonavir) can increase exposure to
`loperamide. The increased systemic exposure to loperamide may increase a risk for cardiac
`adverse reactions especially in patients who are taking multiple CYP enzyme inhibitors, or in
`patients with underlying cardiac conditions (see WARNINGS). Monitor patients for cardiac
`adverse reactions.
`
`CYP3A4 Inhibitors
`Itraconazole
`Concomitant administration of multiple doses of 100 mg itraconazole twice daily, an inhibitor of
`both CYP3A4 and P-glycoprotein, with a single 4-mg dose of loperamide hydrochloride
`increased the peak plasma concentration and the systemic exposure to loperamide by 2.9-fold
`and 3.8-fold, respectively.
`
`CYP2C8 Inhibitors
`Gemfibrozil
`When a single 4-mg dose of loperamide hydrochloride was co-administered with 600 mg
`gemfibrozil, a strong inhibitor of CYP2C8, on day 3 of a 5-day treatment with gemfibrozil twice
`daily, the mean peak plasma concentration and the systemic exposure to loperamide was
`increased by 1.6-fold and 2.2-fold, respectively.
`
`CYP3A4 and CYP2C8 Inhibitors
`When multiple doses of both 100 mg itraconazole and 600 mg gemfibrozil twice daily were
`administered with a single 4-mg dose of loperamide hydrochloride, the mean peak plasma
`concentration and the systemic exposure to loperamide was increased by 4.2-fold and 12.6-fold,
`respectively.
`
`P-glycoprotein Inhibitors
`Concomitant administration of a 16 mg single dose of loperamide hydrochloride with a 600 mg
`single dose of quinidine or ritonavir, both of which are P-glycoprotein inhibitors, resulted in a 2-
`to 3-fold increase in loperamide plasma concentrations. Due to the potential for enhanced CNS
`adverse reactions when loperamide is co-administered with quinidine and with ritonavir, caution
`should be exercised when IMODIUM® is administered at the recommended dosages (2 mg, up
`to 16 mg maximum daily dose) with P-glycoprotein inhibitors.
`
`Effects of Loperamide on Other Drugs
`Saquinavir
`When a single 16-mg dose of loperamide hydrochloride 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
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`loperamide is of less clinical significance. Therefore, when IMODIUM® is given with saquinavir,
`the therapeutic efficacy of saquinavir should be closely monitored.
`
`Carcinogenesis, mutagenesis, impairment of fertility
`In an 18-month rat study with oral loperamide hydrochloride 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.
`
`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.
`
`Fertility and reproductive performance was evaluated in rats using oral doses of 2.5, 10, 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 a
`strong impairment of female fertility. Treatment of female rats with up to 10 mg/kg/day
`(approximately 5 times the human dose based on a body surface area comparison) had no
`effect on fertility. Treatment of male rats with oral doses of 40 mg/kg/day (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.
`
`Pregnancy
`Teratogenic Effects
`Pregnancy Category C
`Teratology studies have been performed in rats using oral loperamide hydrochloride 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 oral doses of 40 mg/kg/day (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. IMODIUM® should be used during pregnancy only if the potential benefit justifies the
`potential risk to the fetus.
`
`Nonteratogenic Effects
`In a peri- and post-natal development study in rats, oral administration of 40 mg/kg/day
`produced impairment of growth and survival of offspring.
`
`Nursing Mothers
`Small amounts of loperamide may appear in human breast milk. Therefore, IMODIUM® is not
`recommended during breast-feeding.
`
`Pediatric Use
`IMODIUM® is contraindicated in pediatric patients less than 2 years of age due to the risks of
`respiratory depression and serious cardiac adverse reactions (see CONTRAINDICATIONS).
`Postmarketing cases of cardiac arrest, syncope, and respiratory depression have been reported
`in pediatric patients less than 2 years of age (see WARNINGS). Pediatric patients may be more
`sensitive to CNS effects, such as altered mental status, somnolence, and respiratory
`depression, than adults. There have been rare reports of paralytic ileus associated with
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`abdominal distention. Most of these reports occurred in the setting of acute dysentery,
`overdose, and with pediatric patients less than two years of age.
`
`IMODIUM® should be used with special caution in pediatric patients because of their greater
`variability of response (see WARNINGS). Dehydration, particularly in pediatric patients less
`than 6 years of age, may further influence the variability of response to IMODIUM®.
`
`The safety and effectiveness of IMODIUM® in pediatric patients with chronic diarrhea have not
`been established. Although IMODIUM® has been studied in a limited number of pediatric
`patients with chronic diarrhea; the therapeutic dose for the treatment of chronic diarrhea in a
`pediatric population has not been established.
`
`In case of accidental overdosage of IMODIUM® by pediatric patients, see OVERDOSAGE for
`suggested treatment.
`
`ADVERSE REACTIONS
`Clinical Trial Experience
`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.
`
`The adverse events reported are summarized irrespective of the causality assessment of the
`investigators.
`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.
`
`Acute Diarrhea
`Loperamide
`Hydrochloride
`231
`
`2.6%
`
`Placebo
`
`236
`
`0.8%
`
`No. of treated
`patients
`Gastrointestinal
`AE%
`Constipation
`
`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.
`
`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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`Chronic Diarrhea
`Loperamide
`Placebo
`Hydrochloride
`285
`
`277
`
`5.3%
`
`0.0%
`
`1.4%
`
`0.7%
`
`No. of treated
`patients
`Gastrointestinal
`AE%
`Constipation
`Central and
`peripheral
`nervous system
`AE%
`Dizziness
`
`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.
`
`All Studies a
`
`3740
`
`Acute
`Diarrhea
`1913
`
`Chronic
`Diarrhea
`1371
`
`No. of treated
`patients
`Gastrointestinal
`AE%
`Nausea
`0.7%
`3.2%
`1.8%
`Constipation
`1.6%
`1.9%
`1.7%
`Abdominal cramps
`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.
`
`Postmarketing Experience
`The following adverse events have been reported:
`
`Cardiac disorders
`QT/QTc interval prolongation, Torsades de Pointes, other ventricular arrhythmias, cardiac
`arrest, syncope, and death (see WARNINGS, OVERDOSAGE).
`
`Skin and subcutaneous tissue disorders
`Rash, pruritus, urticaria, and angioedema and extremely rare cases 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®.
`
`Gastrointestinal disorders
`Dry mouth, abdominal pain, distention or discomfort, nausea, vomiting, flatulence, dyspepsia,
`constipation, paralytic ileus, megacolon; including toxic megacolon (see
`CONTRAINDICATIONS, WARNINGS).
`
`Renal and urinary disorders
`Urinary retention
`
`Nervous system disorders
`Drowsiness, dizziness
`
`General disorders and administrative site conditions
`Tiredness
`
`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 ABUSE AND DEPENDENCE
`Controlled Substance
`Loperamide is not a controlled substance.
`
`Abuse
`Loperamide is a mu-opioid agonist. A human abuse potential study of loperamide hydrochloride
`at single doses up to 60 mg (3.75 times the recommended maximum adult dosage of 16 mg per
`day) was compared, in a double-blind cross-over design using nine subjects who had been
`active opiate users, to a threshold dose of codeine sulfate at 120 mg (96 mg base) or placebo.
`This resulted in one subject (11%) feeling a drug on placebo and identifying it as "dope" (heroin)
`and liking it slightly. Codeine was felt by 56% of subjects and identified as "dope" by 44%.
`Loperamide was felt by 44% of subjects and identified as "dope" by 11% and possibly dope
`mixed with some other kind of drug by another 22%. Loperamide abuse and misuse have been
`reported, especially at doses of 60 mg or greater. Loperamide can have greater CNS opioid
`effects at higher doses or with co-administration of drugs that increase systemic exposure
`and/or increase CNS penetration of loperamide (through inhibition of the CYP450 enzyme
`system or inhibition of P-glycoprotein). Loperamide is primarily being misused for relief from
`opioid withdrawal, and abused by a few users who obtain some (reportedly mild-moderate) level
`of euphoria.
`
`Dependence
`In animals, parenteral administration of loperamide hydrochloride can cause physical
`dependence, cross-tolerance to opioids, and all the other pharmacologic effects typical of mu-
`opioid agonists.
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`Studies in morphine-dependent monkeys demonstrated that loperamide hydrochloride at doses
`above those recommended for humans prevented signs of morphine withdrawal.
`
`OVERDOSAGE
`The use of higher than recommended IMODIUM® doses may result in life-threatening cardiac,
`CNS and respiratory adverse reactions.
`
`If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current
`information on the management of poisoning or overdosage.
`
`Cardiac Effects
`Symptoms
`Cases of overdosage with loperamide hydrochloride (chronic ingestion of doses ranging from 70
`mg to 1600 mg daily; 4 to 100 times the recommended dose) have resulted in life-threatening
`cardiac adverse reactions, including QT/QTc and QRS interval prolongation, Torsades de
`Pointes, Brugada syndrome and other ventricular arrhythmias, syncope, cardiac arrest, and
`death. Cases include patients who were abusing (using supratherapeutic doses in place of
`opioids to induce euphoria) or misusing (taking higher than recommended doses to control
`diarrhea or to prevent opioid withdrawal) loperamide. The following are representative cases
`that included cardiac adverse reactions:
`25 year old abused loperamide and presented to the hospital on multiple occasions with
`
`symptoms of syncope, nausea, vomiting, bradycardia, hypotensive shock. The patient
`also experienced ventricular tachycardia, a prolonged QTc of 527 ms and QRS interval
`of 170 ms, frequent premature ventricular contractions, and subsequent cardiac arrest
`and death (elevated loperamide blood concentration of 32 ng/ml).
`
`
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`
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`54 year old misused loperamide hydrochloride (up to 144 mg per day) as a self-
`treatment for chronic diarrhea for over 2 years. Signs of cardiac toxicity included
`syncope, prolonged QT of 500 ms sinus arrest with junctional escape rhythm, and
`polymorphic ventricular tachycardia, which required cardioversion and implantable
`cardioverter-defibrillator (ICD) management.
`
`26 year old, with prior opioid abuse, presented to the hospital with recurrent syncope
`and developed Torsades de Pointes requiring electrical cardioversion. An ECG revealed
`a sinus rhythm with a heart rate of 85 bpm and a markedly prolonged QTc interval of
`greater than 700 ms. The patient reported ingesting 100 to 250 mg of loperamide
`hydrochloride with 400 mg of cimetidine daily for several months to simulate the
`euphoric sensation associated with opioids.
`
`Management
`Consider loperamide as a possible cause of cardiac arrhythmias in patients who may have a
`history of opioid abuse or recent ingestion of unknown drugs and in the differential diagnosis of
`unstable arrhythmias, prolonged QTc or QRS intervals, and Torsades de Pointes.
`
`If loperamide-induced cardiac toxicity is suspected, promptly discontinue the drug and initiate
`therapy to manage and prevent cardiac arrhythmias and serious outcomes.
`
`In many cases of loperamide overdosage, anti-arrhythmic medications (e.g., magnesium
`sulfate) were ineffective in resolving the arrhythmias and preventing further episodes of
`Torsades de Pointes. Electrical cardioversion and overdrive pacing, and isoproterenol
`continuous infusion were reported to manage QTc prolongation in the setting of overdose.
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`Laboratory Testing
`Loperamide serum concentrations are not widely available or clinically useful to guide patient
`management.
`
`CNS and Respiratory Depression
`Symptoms
`Cases of loperamide overdose (including relative overdose due to hepatic dysfunction), may
`cause opioid toxic effects including CNS depression (e.g. altered mental status, stupor,
`coordination disorders, somnolence, miosis, muscular hypertonia, respiratory depression),
`hypotension, urinary retention, and paralytic ileus. Pediatric patients may be more sensitive to
`CNS effects, including respiratory depression, than adults.
`
`Management
`Loperamide non-cardiac arrhythmia overdosages should be treated as opioid overdosages.
`Naloxone may reverse the opioid-related toxicity, including CNS and respiratory depression,
`and hypotension, associated with loperamide overdosage.
`
`In adults and pediatric patients, naloxone may be administered intravenously. Appropriate
`doses of naloxone, via intranasal, intramuscular, intraosseus, or subcutaneous administration
`may be necessary if the intravenous route is not available. If the desired degree of opioid-
`related toxicity counteraction and improvement are not obtained, naloxone may be repeated at
`two- to three-minute intervals. If no response in opioid-related effects is observed after naloxone
`has been administered, then diagnosis of opioid-induced toxicity should be questioned.
`
`Refer to the naloxone prescribing information for complete information on initial and subsequent
`dosages.
`
`For patients whose adverse reactions are responsive to naloxone, monitor vital signs,
`neurologic and cardiopulmonary status for recurrence of opioid overdose symptoms for at least
`24 hours after the last dose of naloxone, due to the prolonged intestinal retention of loperamide
`and the short duration (one to three hours) of naloxone. Patients with severe CNS or respiratory
`depression, and those who require multiple doses of naloxone to reverse symptoms, should be
`admitted to the hospital and may require intensive care.
`
`Laboratory Testing
`Standard drug screens for opioids do not include an assay for loperamide; such testing for
`opioids will yield negative results even in the presence of loperamide.
`
`DOSAGE AND ADMINISTRATION
`IMODIUM® is contraindicated in pediatric patients less than 2 years of age due to the risks of
`respiratory depression and serious cardiac adverse reactions (see CONTRAINDICATIONS).
`
`Avoid IMODIUM® dosages higher than recommended in adult or pediatric patients 2 years of
`age and older due to the risk of serious cardiac adverse reactions (See WARNINGS,
`OVERDOSAGE).
`
`(1 capsule = 2 mg)
`Patients should receive appropriate fluid and electrolyte replacement as needed.
`
`11
`
`

`

`Reference ID: 4007556
`
`IMODIUM CAPSULES Rx
`
`Acute Diarrhea
`Adults and Pediatric Patients 13 Years and Older: The recommended initial dose is 4mg (two
`capsules) followed by 2 mg (one capsule) after each unformed stool. The maximum daily dose
`is 16mg (eight capsules). Clinical improvement is usually observed within 48 hours.
`
`Pediatric Patients 2 to 12 Years of Age: In pediatric patients 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 pediatric
`patients 2 to 12 years of age, the following schedule for capsules or liquid will usually fulfill initial
`dosage requirements:
`
`Recommended First Day Dosage Schedule
`Two to five years (13 to 20 kg): 1 mg three times daily (3 mg total daily dosage)
`Six to eight years (20 to 30 kg): 2 mg twice daily. (4 mg total daily dosage)
`Eight to twelve years (greater than 30kg): 2 mg three times daily (6 mg total daily dosage)
`
`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. The total daily dosage should
`not exceed recommended dosages for the first day.
`
`Chronic Diarrhea
`
`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. The average daily
`maintenance dosage in clinical trials was 4 to 8 mg (two to four capsules per day). The
`maximum daily dosage is 16 mg (eight capsules per day). 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.
`
`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 dose adjustment is required for the elderly.
`
`In general, elderly patients may be more susceptible to drug-associated effects of the QT
`interval. Avoid IMODIUM® in elderly patients taking drugs that can result in prolongation of the
`QT interval (for example, Class IA or III antiarrhythmics) or in patients with risk factors for
`Torsades de Pointes (see WARNINGS).
`
`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).
`
`Hepatic Impairment
`The pharmacokinetics of loperamide have not been studied in patients with hepatic impairment.
`
`12
`
`

`

`Reference ID: 4007556
`
`IMODIUM CAPSULES Rx
`
`Use IMODIUM® with caution in such patients because the systemic exposure may be increased
`due to reduced metabolism (see PRECAUTIONS).
`
`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).
`
`Revised September 1996, July 1998, April 2004
`Janssen Pharmaceutica Inc. 1998
`
`Revised October 2016
`Johnson & Johnson Consumer Inc.
`McNeil Consumer Healthcare Division
`
`Rx Only
`
`Printed in USA
`U.S. Patent 3, 714,159