Loperamide Hydrochloride

LOPERAMIDE HYDROCHLORIDE- loperamide hydrochloride capsule
Contract Pharmacy Services-PA

WARNING: TORSADES DE POINTES AND SUDDEN DEATH

  1. ● Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosage of loperamide hydrochloride capsules (see WARNINGS and OVERDOSAGE).
  2. ● Loperamide hydrochloride capsules are contraindicated in pediatric patients less than 2 years of age (see CONTRAINDICATIONS).
  3. ● Avoid loperamide hydrochloride capsules 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

Loperamide hydrochloride, 4-(p-chlorophenyl)-4-hydroxy-N, N-dimethyl-α,α-diphenyl-1-piperidinebutyramide monohydrochloride, is a synthetic antidiarrheal for oral use.

Loperamide Hydrochloride Structural Formula

Loperamide hydrochloride is available in 2 mg capsules.

Loperamide hydrochloride capsules, USP contain the following inactive ingredients: black iron oxide, colloidal silicon dioxide, gelatin, lactose monohydrate, magnesium stearate, microcrystalline cellulose, red iron oxide, sodium lauryl sulfate, sodium starch glycolate, titanium dioxide, and yellow iron oxide. In addition, the black imprinting ink also contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol, and shellac glaze.

CLINICAL PHARMACOLOGY

Mechanism of Action

In vitro and animal studies show that loperamide hydrochloride capsules act 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.

Pharmacokinetics

Absorption

Plasma concentrations of unchanged drug remain below 2 ng/mL after the intake of a 2 mg capsule of loperamide hydrochloride capsules. 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 loperamide hydrochloride capsules 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

Loperamide hydrochloride capsules are 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.

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 (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.

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 capsules. 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 capsules are 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 capsules 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 and OVERDOSAGE).

Avoid loperamide hydrochloride capsules 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.

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