Loperam

COMPOSITION AND EXCIPIENTS

Active ingredient:

• Each film coated tablet of Loperam contains loperamide hydrochloride 2 mg.

Excipients:

• Pregelatinized starch, Lactose anhydrous, Magnesium stearate, Microcrystalline cellulose, Hypromellose, Polyethylene glycol, Carnauba wax, Green colorant.

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 hydrochloride prolongs the transit time of the intestinal contents. It reduces the daily fecal volume, increases the viscosity and bulk density, and diminishes the loss of fluid and electrolytes.

PHARMACOKINETICS

Plasma levels of unchanged drug remain below 2 nanograms per mL after the intake of a 2 mg loperamide hydrochloride tablet. Plasma loperamide concentrations are highest approximately 5 hours after administration of the tablet and 2.5 hours after the liquid. The peak plasma concentrations of loperamide were similar for both formulations. The apparent elimination half-life of loperamide hydrochloride in man is about 11 hours with a range of 9-14 hours. The plasma protein binding of loperamide is about 95%. 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 addition, CYP2B6 and CYP2D6 appear to play a minor role in loperamide demethylation.

Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces.

INDICATIONS

Loperam is indicated for the control and symptomatic relief of acute nonspecific diarrhea in patients 4 years of age and older and of chronic diarrhea in adults associated with inflammatory bowel disease. Loperam is also indicated for reducing the volume of discharge from ileostomies.

CONTRAINDICATIONS

Loperamide hydrochloride is contraindicated in:

• pediatric patients less than 4 years of age.
• 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 difficile) associated with the use of broad-spectrum antibiotics.

WARNINGS AND PRECAUTIONS

The use of loperamide hydrochloride does not preclude the need for appropriate fluid and electrolyte therapy in patients who have diarrhea, especially young children.

• Loperamide hydrochloride must be discontinued promptly when constipation, abdominal distention or ileus develop.
• Treatment of diarrhea with loperamide hydrochloride is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate (or when indicated).
• Loperamide hydrochloride should be used with special caution in young children because of the greater variability of response in this age group. Dehydration, particularly in younger children, may further influence the variability of response to loperamide hydrochloride.
• Extremely rare allergic reactions including anaphylaxis and anaphylactic shock have been reported.
• In acute diarrhea, if clinical improvement is not observed in 48 hours, the administration of loperamide hydrochloride should be discontinued and patients should be advised to consult their physician.
• Patients with AIDS treated with loperamide hydrochloride tablets 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.
• Cardiac events including QT prolongation and torsades de pointes have been reported in association with overdose.
• Loperamide hydrochloride 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 must be discontinued promptly when constipation, abdominal distention or ileus develop.

Hepatic Impairment: Loperamide hydrochloride should be used with caution in patients with hepatic impairment, because of reduced first pass metabolism. No dose adjustment is required for patients with renal impairment.

Renal Impairment: Dosage adjustments in patients with renal impairment are not required.

Pregnancy (Category C): Loperamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not advisable to administer loperamide in pregnancy, especially during the first trimester.

Nursing Mothers: Small amounts of loperamide may appear in human breast milk. Therefore, loperamide hydrochloride is not recommended during breast-feeding.

Effects on ability to drive and use machines: Loss of consciousness, depressed level of consciousness, tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with loperamide. Therefore, it is advisable to use caution when driving a car or operating machinery.

DRUG INTERACTIONS

Concomitant use of loperamide hydrochloride tablets 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. Monitor patients for cardiac adverse reactions.

When loperamide hydrochloride tablets are given with saquinavir, the therapeutic efficacy of saquinavir should be closely monitored.

Combination with other 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) should be avoided.

SIDE EFFECTS

The most common side effects: Headache, Dizziness, Constipation, Nausea, Flatulence.

Uncommon: Somnolence, Abdominal pain, Abdominal discomfort, Dry mouth, Abdominal pain upper, Vomiting, Dyspepsia, Rash.

DOSAGE AND ADMINISTRATION

Patients should receive appropriate fluid and electrolyte replacement as needed.

1. Acute Diarrhea:

Adults: The recommended initial dose is 4 mg (two tablets) followed by 2 mg (one tablet) after each unformed stool. Daily dosage should not exceed 16 mg (eight tablets). Clinical improvement is usually observed within 48 hours.

Children: Recommended First Day Dosage Schedule:

• 4 to 5 years (15 to 20 kg): 1 mg t.i.d. (3 mg daily dose).
• 6 to 8 years (20 to 30 kg): 2 mg b.i.d. (4 mg daily dose).
• 8 to 12 years (greater than 30 kg): 2 mg t.i.d. (6 mg daily dose).

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.

2. Chronic Diarrhea:

Adults: The recommended initial dose is 4 mg (two tablets) followed by 2 mg (one tablet) after each unformed stool until diarrhea is controlled, after which the dosage of loperamide hydrochloride tablets 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.

OVERDOSE

Symptoms: In cases of overdosage (including relative overdose due to hepatic dysfunction), urinary retention, paralytic ileus and CNS depression may occur. Children may be more sensitive to CNS effects than adults.

In individuals who have ingested overdoses of loperamide HCl, cardiac events such as QT interval prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest and syncope have been observed. Fatal cases have also been reported.

Treatment: If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.

STORAGE CONDITIONS

Store at temperature between 20 – 25 °C.

PACKAGING

Loperam is supplied as blister strips (Aluminum – Clear P.V.C), each strip contains 10 F.C. Tablets and each pack contains 2 or 25 strips with enclosed leaflet (20 or 250 F.C. Tablets per pack).