LOPERAMIDE HYDROCHLORIDE- loperamide hydrochloride capsule
Denton Pharma, Inc. dba Northwind Pharmaceuticals
- 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 and OVERDOSAGE).
- 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).
Loperamide hydrochloride is a white to slightly yellow powder and is freely soluble in methanol, isopropyl alcohol, chloroform and slightly soluble in water.
Loperamide hydrochloride, 4-(p-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutyramide monohydrochloride, is a synthetic antidiarrheal for oral use. Its structural formula is:
C 29 H 33 ClN 2 O 2 •HCl M.W. 513.51
Loperamide hydrochloride is available in 2 mg capsules.
The inactive ingredients: dimethylpolysiloxane, gelatin, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate, pregelatinized corn starch, magnesium stearate, shellac, and titanium dioxide.
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 propulsive peristalsis, and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter, thereby reducing incontinence and urgency.
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.
Plasma concentrations of unchanged drug remain below 2 ng/mL after the intake of a 2 mg loperamide hydrochloride capsule. 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.
Based on literature information, the plasma protein binding of loperamide is about 95%. Loperamide is a P-glycoprotein substrate.
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.
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 (see PRECAUTIONS, Drug Interactions).
Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces.
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.
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 (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 difficile) associated with the use of broad-spectrum antibiotics.
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 (see OVERDOSAGE and DRUG 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.
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.
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.
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