LOPERAMIDE HYDROCHLORIDE

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. Each capsule, for oral administration, contains 2 mg loperamide hydrochloride. Loperamide hydrochloride capsules USP also contain 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. Structural formula for loperaminde hydrochloride

Loperamide hydrochloride capsules are indicated for the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. Loperamide hydrochloride capsules are also indicated for reducing the volume of discharge from ileostomies.

(1 capsule = 2 mg) Patients should receive appropriate fluid and electrolyte replacement as needed. Acute Diarrhea Adults The recommended initial dose is 4 mg (two capsules) followed by 2 mg (one capsule) after each unformed stool. Daily dosage should not exceed 16 mg (eight capsules). Clinical improvement is usually observed within 48 hours. Children In children 2 to 5 years of age (20 kg or less), the non-prescription liquid formulation (loperamide hydrochloride for oral solution, 1 mg/5 mL) should be used; for ages 6 to 12, either loperamide hydrochloride capsules or loperamide hydrochloride for oral solution may be used. For children 2 to 12 years of age, the following schedule for capsules or liquid will usually fulfill initial dosage requirements: Recommended First Day Dosage Schedule Two to five years: 1 mg t.i.d. (3 mg daily dose) (13 to 20 kg) Six to eight years: 2 mg b.i.d. (4 mg daily dose) (20 to 30 kg) Eight to twelve years: 2 mg t.i.d. (6 mg daily dose) (greater than 30 kg) Recommended Subsequent Daily Dosage Following the first treatment day, it is recommended that subsequent loperamide hydrochloride doses (1 mg/10 kg body weight) be administered only after a loose stool. Total daily dosage should not exceed recommended dosages for the first day. Chronic Diarrhea Children Although loperamide hydrochloride has been studied in a limited number of children with chronic diarrhea; the therapeutic dose for the treatment of chronic diarrhea in a pediatric population has not been established. Adults The recommended initial dose is 4 mg (two capsules) followed by 2 mg (one capsule) after each unformed stool until diarrhea is controlled, after which the dosage of loperamide hydrochloride capsules should be reduced to meet individual requirements. When the optimal daily dosage has been established, this amount may then be administered as a single dose or in divided doses. The average daily maintenance dosage in clinical trials was 4 to 8 mg (two to four capsules). A dosage of 16 mg (eight capsules) was rarely exceeded. If clinical improvement is not observed after treatment with 16 mg per day for at least 10 days, symptoms are unlikely to be controlled by further administration. Loperamide hydrochloride capsules administration may be continued if diarrhea cannot be adequately controlled with diet or specific treatment. Children Under 2 Years The use of loperamide hydrochloride in children under 2 years is not recommended. There have been rare reports of paralytic ileus associated with abdominal distention. Most of these reports occurred in the setting of acute dysentery, overdose, and with very young children less than two years of age. Elderly No formal pharmacokinetic studies were conducted in elderly subjects. However, there were no major differences reported in the drug disposition in elderly patients with diarrhea relative to young patients. No dosage adjustment is required for the elderly. Renal Impairment No pharmacokinetic data are available in patients with renal impairment. Since the metabolites and the unchanged drug are mainly excreted in the feces, no dosage adjustment is required for patients with renal impairment (see PRECAUTIONS ). Hepatic Impairment Although no pharmacokinetic data are available in patients with hepatic impairment, loperamide hydrochloride should be used with caution in such patients because of reduced first pass metabolism (see PRECAUTIONS ).

Loperamide hydrochloride capsules are contraindicated in patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients. Loperamide hydrochloride is contraindicated in patients with abdominal pain in the absence of diarrhea. Loperamide hydrochloride is not recommended in infants below 24 months of age. Loperamide hydrochloride should not be used as the primary therapy: in patients with acute dysentery, which is characterized by blood in stools and high fever, in patients with acute ulcerative colitis, in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter, in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics.

Clinical Trial Data 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. Acute Diarrhea Loperamide Hydrochloride Placebo No. of treated patients 231 236 Gastrointestinal AE% Constipation 2.6% 0.8% 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. 2) 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. Chronic Diarrhea Loperamide Hydrochloride Placebo No. of treated patients 285 277 Gastrointestinal AE% Constipation 5.3% 0% Central and peripheral nervous system AE% Dizziness 1.4% 0.7% 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. 3) 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. Acute Diarrhea Chronic Diarrhea All Studies All patients in all studies, including those in which it was not specified if the adverse events occurred in patients with acute or chronic diarrhea. No. of treated patients 1913 1371 3740 Gastrointestinal AE% Nausea 0.7% 3.2% 1.8% Constipation 1.6% 1.9% 1.7% Abdominal cramps 0.5% 3.0% 1.4% Postmarketing Experience The following adverse events have been reported: Skin and Subcutaneous Tissue Disorders Rash, pruritus, urticaria, 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 (see CONTRAINDICATIONS and WARNINGS ). 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.

Nonclinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with a 600 mg single dose of either quinidine or ritonavir, both of which are P-glycoprotein inhibitors, resulted in a 2 to 3 fold increase in loperamide plasma levels. Due to the potential for enhanced central effects when loperamide is coadministered with quinidine and with ritonavir, caution should be exercised when loperamide is administered at the recommended dosages (2 mg, up to 16 mg maximum daily dose) with P-glycoprotein inhibitors. When a single 16 mg dose of loperamide 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 is given with saquinavir, the therapeutic efficacy of saquinavir should be closely monitored.