CLINICAL PHARMACOLOGY SECTION

CLINICAL PHARMACOLOGY

Mechanism of Action
In vitro and animal studies show that 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.

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.

Pharmacokinetics
Absorption
Plasma concentrations of unchanged drug remain below 2 ng/mL after the intake of a 2 mg loperamide hydrochloride capsule. Plasma 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 loperamide 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 (seePRECAUTIONS, Drug Interactions).

Excretion
Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces.

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INDICATIONS & USAGE SECTION

INDICATIONS AND USAGE

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. Loperamide hydrochloride capsules are also indicated for reducing the volume of discharge from ileostomies.

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CONTRAINDICATIONS SECTION

CONTRAINDICATIONS

Loperamide hydrochloride capsules are contraindicated in:

• pediatric patients less than 2 years of age due to the risks of respiratory depression and serious cardiac adverse reactions (seeWARNINGS).
• 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 difficile) associated with the use of broad-spectrum antibiotics.

WARNINGS SECTION

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 loperamide hydrochloride. Cases include patients who were abusing or misusing loperamide hydrochloride (seeOVERDOSAGE andDRUG ABUSE AND DEPENDENCE). Cases of syncope and ventricular tachycardia have been reported in adult patients receiving the recommended dosage of loperamide hydrochloride capsules. 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.

Loperamide hydrochloride is contraindicated in pediatric patients less than 2 years of age due to the risks of respiratory depression and serious cardiac adverse reactions. Avoid loperamide hydrochloride 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 loperamide hydrochloride 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 loperamide hydrochloride does not preclude the need for appropriate fluid and electrolyte therapy.

Gastrointestinal Disorders
In general, loperamide hydrochloride 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. Loperamide hydrochloride must be discontinued promptly when constipation, abdominal distention or ileus develop.

Treatment of diarrhea with loperamide hydrochloride 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 loperamide hydrochloride 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
Loperamide hydrochloride 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 6 years of age, may further influence the variability of response to loperamide hydrochloride. Loperamide hydrochloride is contraindicated in pediatric patients less than 2 years of age due to the risks of respiratory depression and serious cardiac adverse reactions.

BOXED WARNING SECTION

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 loperamide hydrochloride (see**WARNINGS*** andOVERDOSAGE).** Loperamide hydrochloride is contraindicated in pediatric patients less than 2 years of age (see**CONTRAINDICATIONS***).** Avoid loperamide hydrochloride 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***).**

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ADVERSE REACTIONS SECTION

ADVERSE REACTIONS

Clinical Trial Experience

The adverse effects reported during clinical investigations of loperamide hydrochloride are difficult to distinguish from symptoms associated with the diarrheal syndrome. Adverse experiences recorded during clinical studies with loperamide hydrochloride 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.

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.

1. 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.

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.

1. 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.

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 of bullous eruption including erythema multiforme, Stevens-Johnson syndrome and Toxic Epidermal Necrolysis have been reported with use of loperamide hydrochloride.

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 loperamide hydrochloride.

Gastrointestinal disorders

Dry mouth, abdominal pain, distention or discomfort, nausea, vomiting, flatulence, dyspepsia, constipation, paralytic ileus, megacolon, including toxic megacolon (seeCONTRAINDICATIONS andWARNINGS).

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 postmarketing 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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OVERDOSAGE SECTION

OVERDOSAGE

The use of higher than recommended loperamide hydrochloride 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).
• 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.

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.

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HOW SUPPLIED SECTION

HOW SUPPLIED

Loperamide hydrochloride capsules USP, 2 mg are available as:
A light brown opaque body and dark brown opaque capsule, imprinted "TEVA" on the cap and "0311" on the body and packaged in unit dose packages of 100 (10 x 10) NDC 60687-229-01.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

PACKAGING INFORMATION
American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Teva Pharmaceuticals USA, Inc. as follows:
(2 mg / 100 UD) NDC 60687-229-01 packaged from NDC 0093-0311

Distributed by:
American Health Packaging
Columbus, OH 43217

8422901/0717

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