LOPERAMIDE HYDROCHLORIDE — loperamide hydrochloride capsule
Edenbridge Pharmaceuticals LLC.
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 Capsules (see WARNINGS and OVERDOSAGE).
- Loperamide Hydrochloride Capsules is contraindicated in pediatric patients less than 2 years of age (see CONTRAINDICATIONS).
- 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).
Loperamide Hydrochloride Capsules USP (loperamide hydrochloride), 4-(p-chlorophenyl)-4-hydroxy-N,N-dimethyl-a,a- diphenyl-1-piperidinebutyramide monohydrochloride, is a synthetic antidiarrheal for oral use.
Loperamide Hydrochloride Capsules USP is available in 2mg capsules.
The inactive ingredients are: Magnesium stearate, microcrystalline cellulose, sodium starch glycolate, lactose monohydrate, colloidal silicon dioxide. In addition, the hard gelatin capsule also contains gelatin, black iron oxide, red iron oxide, titanium dioxide and yellow iron oxide. The black printing ink contains black iron oxide, propylene glycol, shellac, and potassium hydroxide.
Mechanism of Action
In vitro and animal studies show that Loperamide Hydrochloride Capsules (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 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.
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 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 of the unchanged loperamide and its metabolites mainly occurs through the feces.
Loperamide Hydrochloride Capsules (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 is also indicated for reducing the volume of discharge from ileostomies.
Loperamide Hydrochloride Capsules 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.
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 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 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, 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.
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 Capsules does not preclude the need for appropriate fluid and electrolyte therapy.
In general, Loperamide Hydrochloride Capsules 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 Capsules must be discontinued promptly when constipation, abdominal distention or ileus develop.
Treatment of diarrhea with Loperamide Hydrochloride Capsules 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 Capsules, 2 mg 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 Capsules 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 Capsules. Loperamide Hydrochloride Capsules is contraindicated in pediatric patients less than 2 years of age due to the risks of respiratory depression and serious cardiac adverse reactions.
Extremely rare allergic reactions including anaphylaxis and anaphylactic shock have been reported.
The effects of hepatic impairment on the pharmacokinetics of loperamide have not been studied. Use Loperamide Hydrochloride Capsules 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.
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.
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 Loperamide Hydrochloride Capsules 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).
- to take Loperamide Hydrochloride Capsules 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 Loperamide Hydrochloride Capsules 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 Loperamide Hydrochloride Capsules 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 Loperamide Hydrochloride Capsules. (see ADVERSE REACTIONS) 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).
Effects of Other Drugs on Loperamide
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. 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.
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.
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.
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 Loperamide Hydrochloride Capsules USP, 2 mg 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
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 loperamide is of less clinical significance. Therefore, when Loperamide Hydrochloride Capsules is given with saquinavir, the therapeutic efficacy of saquinavir should be closely monitored.
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