ACTION AND CLINICAL PHARMACOLOGY

:

Pharmacology:

Loperamide hydrochloride is a piperidine derivative. It slows intestinal motility through a direct effect on the nerve endings and/or intramural ganglia of the intestinal wall. The drug is believed to act by interfering with the cholinergic and noncholinergic mechanisms involved in the peristaltic reflex, decreasing the activity of circular and longitudinal muscles in the intestinal wall, presumably as a result of its interactions with opioid receptors in the intestine. Some part of its antidiarrheal effect may be due to a reduction of gastrointestinal secretion. Loperamide prolongs the transit time of intestinal contents and therefore reduces fecal volume, increases fecal viscosity and bulk density, and diminishes loss of fluid and electrolytes. As an antidiarrheal agent, loperamide is reported to be more specific, longer acting, and 2-3 times more potent on a weight basis than others (e.g. diphenoxylate). Tolerance to the antidiarrheal effect of loperamide has not been reported. Physical dependence on loperamide has not been reported in humans.

PHARMACOKINETICS:

Absorption: Peak plasma concentrations of loperamide occur about 4-5 hours following administration of the oral capsules. After a 2 mg oral dose of loperamide hydrochloride capsules, peak plasma concentrations of 2 ng/ml have been reported. Peak plasma concentrations of loperamide metabolites are reached 8 hours following oral administration of capsules of the drug.

Distribution

: It is not known if loperamide crosses the placenta or is distributed into milk.

Elimination

: After oral administration of 4 mg of loperamide hydrochloride, less than 2 % of the dose is excreted in urine and 30 % of the dose is excreted in feces as intact drug.

The apparent elimination half-life of loperamide in healthy adults is 10.8 hours (range 9.1-14.4 hours).

INDICATIONS AND CLINICAL USE:

Diarrhea: Loperacap (Loperamide) is used as an adjunct in the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. Loperacap has also been effective in controlling chronic functional (idiopathic) diarrhea and chronic diarrhea caused by bowel resection or organic lesions. Fluid and electrolyte depletion may occur in patients who have diarrhea, and the use of Loperacap does not preclude the administration of appropriate fluid and electrolyte therapy. Ileostomy Discharge: Loperacap is used to reduce the volume of discharge from ileostomies, colostomies and other intestinal resections.

CONTRAINDICATIONS:

Antiperistaltic agents such as Loperacap should not be used in acute diarrhea associated with organisms that penetrate the intestinal mucosa as are toxigenic Escherichia coli, Salmonella and Shigella, or in patients with pseudomembranous colitis associated with broadspectrum anti-infectives. Loperacap is contraindicated in patients with a known hypersensitivity to the drug and in patients in whom constipation must be avoided. Loperacap is contraindicated in the treatment of acute diarrhea in children under 2 years of age.

WARNINGS AND PRECAUTIONS:

Fluid and electrolyte depletion may occur in patients with diarrhea. The use of Loperacap does not preclude administration of appropriate fluid and electrolyte therapy. In some patients with acute ulcerative colitis, agents which inhibit intestinal motility or delay intestinal transit time have been reported to induce toxic megacolon. Loperacap should be discontinued promptly if abdominal distention or other untoward symptoms develop in patients with acute ulcerative colitis. Loperacap should not be used in the case of acute dysentery, which is characterized by blood in the stools and elevated temperature. Patients with hepatic dysfunction should be monitored closely for signs and symptoms of CNS toxicity during Loperacap therapy, since first-pass metabolism of the drug may be decreased in these patients. Loperacap should be used with special caution in patients with compromised blood brain barrier (e.g., meningitis) because of the greater variability of response in this group. Patients receiving Loperacap should be advised to consult their physician if the diarrhea does not stop after a few days or if fever develops. The use of Loperacap should be discontinued if improvement in symptoms of acute diarrhea is not observed within 48 hours. The safe use of Loperacap during pregnancy and lactation has not been established.

Pediatric Precautions

The use of Loperacap is not recommended for children under 12 years of age except on the advice of a physician. Loperacap should be used with particular caution in young children because of the greater variability of response in this age group. The presence of dehydration, especially in younger children, may further influence the variability of response to the drug.

ADVERSE EFFECTS:

Loperacap is generally well tolerated; however, abdominal pain, distention or discomfort, constipation, drowsiness, dizziness, fatigue, dry mouth, nausea and vomiting, and epigastric pain may occur. Children may be more sensitive to adverse CNS effects of the drug than adults and in children under 3 years of age, opiate-like effects (CNS) have been reported. Hypersensitivity reactions including rash have been reported. Adverse effects of loperacap are difficult to distinguish from symptoms associated with the diarrheal syndrome.

OVERDOSAGE:

Symptoms and Treatment:

Activated charcoal administered shortly after ingestion of Loperacap can reduce the absorption of the drug into the systemic circulation by as much as 9-fold. If vomiting occurs spontaneously upon ingestion, a slurry of 100 g of activated charcoal should be administered orally as soon as fluids can be retained. If vomiting has not occurred, gastric lavage should be performed followed by administration of 100 g of the activated charcoal slurry through the gastric tube. In the event of overdosage, patients should be monitored for signs of CNS depression for at least 24 hours. If CNS depression is observed, naloxone may be administered. If responsive to naloxone, vital signs must be monitored carefully for recurrence of symptoms of drug overdose for at least 24 hours after the last dose of naloxone. In view of the prolonged action of loperacap and the short duration (1 to 3 hours) of naloxone, the patient must be monitored closely and treated repeatedly with naloxone as indicated. Since relatively little drug is excreted in the urine, forced diuresis is not expected to be effective for loperacap overdosage. In clinical trials, an adult who took three 20 mg doses within a 24 hour period was nauseated after the second dose and vomited after the third dose. In studies designed to examine the potential for side effects, intentional ingestion of up to 60 mg of loperamide in a single dose to healthy subjects resulted in no significant adverse effects.

DOSAGE AND ADMINISTRATION

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Administration: Loperacap (Loperamide hydrochloride) is administered orally. Dosage: Acute Diarrhea: For the management of acute diarrhea in adults, the initial dosage of Loperacap is 4 mg, followed by 2 mg after each unformed stool. The maximum daily (i.e. in 24 hours) dosage should not exceed 16 mg (8 caplets). For the management of acute diarrhea in children 6-12 years of age, dosage of Loperacap is based on age and body weight. The following pediatric dosages are recommended for the first day of therapy: Age (weight) Dosage (initial 24 hours)

6-8 years (20-30 kg) 2 mg twice daily
8-12 years (>30 kg) 2 mg 3 times daily

On the second and subsequent days of therapy, children should receive 0.1 mg/kg doses only after each unformed stool. Dosage on the second and subsequent days should not exceed that appropriate for age recommended for the first day. Chronic Diarrhea: For the management of chronic diarrhea in adults, the initial dosage of Loperacap is 4 mg, followed by 2 mg after each unformed stool until symptoms are controlled; dosage should then be reduced for maintenance as required. In clinical trials, the average adult maintenance dosage was 4-8 mg daily, administered as a single dose or in divided doses. If improvement does not occur in patients with chronic diarrhea after treatment with 16 mg daily for 10 days, symptoms are unlikely to be controlled by further administration of the drug. If diarrhea is not controlled after 10 days of treatment, medication should be stopped and a physician should be consulted. Although loperamide has been used in a limited number of children for the management of chronic diarrhea, the usual dosage for this age group has not been established and the drug should be given on the advice of a physician only.

PHARMACEUTICAL INFORMATION:

Proper name: Loperamide hydrochloride

Chemical name: (1) 1-Piperidinebutanamide,4-(4-chlorophenyl)-4-
hydroxy-N,N-dimethyl- a , a -diphenyl,mono-
hydrochloride;
(2) 4-(p-Chlorophenyl)-4-hydroxy-N,N-dimethyl- a , a -
diphenyl-1-piperidine butyramide monohydrochloride

Chemical Structure: C H ClN O ,HCl Structural Formula:

29 33 2 2

N-CH2CH2CCON(CH3)2 * HCl CI Molecular weight: 513.5

Description of the drug substance:

Loperamide hydrochloride is a white to slightly yellow powder. It is slightly soluble in water and dilute acids; freely soluble in chloroform, isopropyl alcohol, and methyl alcohol.

COMPOSITION:

Each light green, capsule-shaped LOPERACAP (loperamide hydrochloride) tablet contains:

STABILITY AND STORAGE CONDITIONS:

Loperacap (Loperamide hydrochloride) caplets (capsule-shaped tablets) should be stored in well-closed containers at controlled room temperature (15-30 C).

AVAILABILITY

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LOPERACAP (Loperamide hydrochloride) caplets (capsule-shaped tablets) are available in bottles of 100's and 500's and blister packs of 6, 12 and 18 caplets.

INFORMATION TO THE CONSUMER

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Description

Loperacap is a medicine used along with other measures to treat diarrhea. Loperacap helps stop diarrhea by slowing down the movements of the intestines. LOPERACAP is available in tablet form.

Before Using LOPERACAP

If you are taking LOPERACAP without a prescription, carefully read and follow any precautions on the label. For LOPERACAP, the following should be considered:

longer. narcotic pain medicine (there is a greater chance that severe constipation may occur if loperamide is used together with narcotic pain medicine. Other medical problems: the presence of other medical problems may affect the use of LOPERACAP. Inform your doctor if you have any other medical problem, especially

Proper Use of LOPERACAP follow your doctor's instructions or the package insert in addition to using LOPERACAP for diarrhea, it is very important that you replace the fluid lost by the body and follow a proper diet. (drink plenty of caffeine-free cola, ginger ale, decaffeinated tea, and broth. You may eat bland foods, such as cooked cereals, bread, crackers, and applesauce. DO NOT eat fruits, vegetables, fried or spicy foods, bran, candy, caffeine, and alcoholic beverages, they may worsen your condition). too much fluid loss may cause a serious condition. Consult with your doctor if any of the following signs of too much fluid loss occur: decreased urination, dizziness, lightheadedness, dryness of mouth, increased thirst, wrinkled skin. Storage: to store LOPERACAP o keep away from children

Precautions while using LOPERACAP

Side Effects of LOPERACAP

When LOPERACAP is used for short periods of time at low doses, side e effects usually are rare. However, if any of the following side effects occur consult with your physician:

PHARMACOLOGY:

In animals, loperamide has no analgesic activity even in extremely high doses. Although loperamide binds to opiate receptors in the brain and myenteric plexus, the drug has not produced opiate-like CNS effects in rats, even in large doses. Studies in monkeys, however, have demonstrated that high doses of loperamide can produce morphine-like symptoms of physical dependence and prevent signs of morphine withdrawal in morphine-dependent animals. In humans, the naloxone challenge pupil test, which when positive indicates opiate-like effects, was negative when performed after a single 16 mg dose of loperamide, and after more than 2 years of therapeutic use of the drug.

TOXICOLOGY:

Carcinogenicity

In a study in rats using loperamide hydrochloride dosages up to 133 times the maximum human dosage (on a mg/kg basis) for 18 months, there was no evidence of carcinogenicity.

Pregnancy, Fertility and Lactation

Reproduction studies in rats and rabbits using loperamide hydrochloride dosages up to 30 times the usual human dosage did not reveal evidence of impaired fertility or harm to the fetus; higher dosages impaired maternal and neonatal survival. Reproduction studies in rats indicated that high dosages (150-200 times the human dosage) could cause marked female infertility and reduced male fertility. There are no adequate and well-controlled studies using loperamide in pregnant women, and the drug should be used during pregnancy only when clearly needed. Since it is not known whether loperamide is distributed into milk, the drug should be used with caution in nursing women.

BIBLIOGRAPHY:

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