LOPERAMIDE HYDROCHLORIDE- loperamide hydrochloride capsule
Teva Pharmaceuticals USA, Inc.
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 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-?,?-diphenyl-1-piperidinebutyramide monohydrochloride, is a synthetic antidiarrheal for oral use. Its structural formula is:
Structural formula for loperaminde hydrochloride
C29 H33 ClN2 O2 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.
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.