(British Approved Name Modified, US Adopted Name, rINN)
Pharmacopoeias. In China, Europe, International, and US.
European Pharmacopoeia, 6th ed. (Loperamide Hydrochloride). A white or almost white powder. It exhibits polymorphism. Slightly soluble in water freely soluble in alcohol and in methyl alcohol. Protect from light.
The United States Pharmacopeia 31, 2008 (Loperamide Hydrochloride). A white to slightly yellow powder. Slightly soluble in water and in dilute acids freely soluble in chloroform and in methyl alcohol very slightly soluble in isopropyl alcohol.
(British Approved Name, rINN)
Pharmacopoeias. Europe includes the monohydrate.
European Pharmacopoeia, 6th ed. (Loperamide Oxide Monohydrate Loperamidi Oxidum Monohydricum). A white or almost white, slightly hygroscopic, powder. Practically insoluble in water freely soluble in alcohol and in dichloromethane. Store in airtight containers. Protect from light.
Adverse Effects and Treatment
Abdominal pain or bloating, nausea, constipation, dry mouth, dizziness, fatigue, and hyper sensitivity reactions including skin rashes have been reported. Loperamide has been associated with paralytic ileus, particularly in infants and young children, and deaths have been reported. Depression of the CNS, to which children or those with hepatic impairment may be more sensitive, maybe seen in overdosage constipation and urinary retention also occur. Naloxone hydrochloride has been recommended for treatment of severe overdosage.
Toxicity. Toxic megacolon has been reported’ after use of loperamide. Severe effects reported in young children have included loss of consciousness’ and delirium. Several cases of paralytic ileus have also occurred in children, some of which were fatal.
Loperamide should notbe used when inhibition of peristalsis is to be avoided, in particular where ileus or constipation occur, and should be avoided in patients with abdominal distension, acute inflammatory bowel disease, or antibiotic-associated colitis. Loperamide should not be used alone in patients with dysentery. Loperamide should be used with caution in patients with hepatic impairment because of its considerable first-pass metabolism in the liver. It should also be used with caution in young children because of a greater variability of response in this age group it is not recommended for use in infants (see Uses and Administration).
Breast feeding. Loperamide is distributed into breast milk in small amounts. The American Academy of Pediatrics states that there have been no reports of any clinical effect on the infant associated with the use of loperamide by breast-feeding mothers, and that therefore it may be considered to be usually compatible with breast feeding.
Loperamide may increase the gastrointestinal absorption of desmopressin.
Antifungals. A pharmacokinetic study in 12 healthy subjects found that itraconazole significantly increased peak plasma concentrations and area under the concentration-time curve of loperamide, and also prolonged the half-life of loperamide. Itraconazole also inhibited metabolism of loperamide to N-desmethylloperamide, suggesting that metabolism of loperamide in humans concurs with in-vitro data (see Metabolism). Use of itraconazole with gemfibrozil (see Cardiovascular Drugs) synergistically increased exposure to loperamide.
Antivirals. In a single-dose study, oral ritonavir significantly increased the bioavailability of loperamide, possibly through inhibition of the cytochrome P450 isoenzyme CYP3A4, and not necessarily as originally supposed through P-glycoprotein inhibition. No serious adverse effects occurred. Licensed information for one UK preparation of loperamide (Imodium; Janssen-Cilag, UK) states that the clinical relevance of the pharmacokinetic interaction with P-glycoprotein inhibitors such as ritonavir is unknown.
For the effect of loperamide on saquinavir, and the corresponding effect of the antiviral on loperamide concentrations, see Gastrointestinal Drugs, under Interactions of Indinavir0.
Cardiovascular drugs. A pharmacokinetic study in 12 healthy subjects found that gemfibrozil significantly increased peak plasma concentrations and area under the concentration-time curve of loperamide, and also prolonged the half-life of loperamide. Gemfibrozil also inhibited metabolism of loperamide to N-des-methylloperamide, suggesting that metabolism of loperamide in humans concurs with in-vitro data (see Metabolism). Use of gemfibrozil with itraconazole (see Antifungals) synergistically increased exposure to loperamide.
Co-trimoxazole. Use with co-trimoxazole increases the bioavailability of loperamide, apparently by inhibiting its first-pass metabolism.
Quinidine. A small study found that giving quinidine with loperamide caused respiratory depression in 8 healthy subjects when given with placebo, loperamide produced no respiratory depression. The authors supposed that inhibition of P-glycoprotein by quinidine had increased entry of loperamide into the CNS.
About 40% of a dose of loperamide is reported to be absorbed from the gastrointestinal tract to undergo first-pass metabolism in the liver and excretion in the faeces via the bile as inactive conjugate there is slight urinary excretion. Little intact drug reaches the systemic circulation. The elimination half-life is reported to be about 10 hours.
Metabolism. Toperamide is metabolised to desmethyllopera-mide through N-demethylation. An in-vitro study established that this occurs mainly via cytochrome P450 isoenzymes CYP2C8 and CYP3A4 CYP2B6 and CYP2D6 also play a role. Toperamide is also a substrate of P-glycoprotein.
Uses and Administration
Loperamide is a synthetic derivative of pethidine that inhibits gutmotility and may also reduce gastrointestinal secretions. It is given orally as an antidiarrhoeal drug as an adjunct in the management of acute and chronic diarrhoeas and may also be used in the management of colostomies or ileostomies to reduce the volume of discharge.
In acute diarrhoea the usual initial dose for adults is loperamide hydrochloride 4 mg followed by 2 mg after each loose stool to a maximum of 16 mg daily the usual daily dose is 6 to 8 mg. In the UK, it is not licensed for children under 4 years of age. Suggested doses for older children are: 4 to 8 years, 1 mg three or four times daily for up to 3 days 9 to 12 years, 2 mg four times daily for up to 5 days. In the USA, loperamide is not recommended for children under the age of 2 years and an initial dose of 1 mg three times daily is suggested for children aged 2 to 5 years. (For restrictions on the use of loperamide in children and the view that antidiarrhoeal drugs should not be used at all in children, see Diarrhoea.)
In chronic diarrhoea the usual initial dose for adults is 4 to 8 mg daily in divided doses subsequently adjusted as necessary doses of 16 mg daily should not be exceeded. If no improvement has been seen after treatment with 16 mg daily for at least 10 days, further use is unlikely to be of benefit. Although not licensed for use in children for chronic diarrhoea, in the UK the BNFC allows for the following oral doses of loperamide hydrochloride:
• 1 month to 1 year: 100 to 200 micrograms/kg twice daily, given 30 minutes before feeds up to a maximum of 2 mg/kg daily in divided doses may be required
• 1 to 12 years: 100 to 200 micrograms/kg (maximum dose 2mg) three to four times daily up to 1.25 mg/kg daily in divided doses may be required, to a maximum of 16 mg daily
• 12 to 18 years: 2 to 4 mg two to four times daily, to a maximum of 16 mg daily
Loperamide is also given as the prodrug, loperamide oxide, which is converted to loperamide in the gastrointestinal tract. It has been given for acute diarrhoea in doses of 2 to 4 mg initially followed by 1 mg after each loose stool, to a maximum of 8 mg daily.
Diarrhoea. The mainstay of treatment for acute diarrhoea is rehydration therapy. Antidiarrhoeals may have a role for symptomatic relief in adults with acute diarrhoea, and loperamide is often chosen in such circumstances, but WHO does not recommend the use of any antidiarrhoeal drug in children with diarrhoea. Similarly, in the UK the BNFC considers that antimo-tility drugs are not to be recommended for acute diarrhoea in children under 12 years of age. There have been problems regarding the use of antidiarrhoeals such as loperamide in young children in developing countries. Manufacturers have considered that a lower age limit is acceptable in those countries than is recommended in the UK or USA even that lower limit is not always observed in practice and there have been reports of serious toxicity in very young children. In response to such reports the manufacturers withdrew concentrated drops of loperamide worldwide and the syrup from countries where the WHO had a programme for control of diarrhoeal diseases, but tablets and capsules remain available. In some countries the use of antidiarrhoeals is now restricted by law.
In the UK, NICE states that loperamide is the antidiarrhoeal of first choice in adults with faecal incontinence it can be used long-term in doses from 500 micrograms to 16 mg daily as needed. Loperamide should be started at a very low dose which can be increased as needed, and then adjusted in response to stool consistency. It should not be given to those with hard or infrequent stools, those with acute diarrhoea of unknown cause, or with acute ulcerative colitis. Patients who are unable to tolerate loperamide may be offered codeine phosphate or co-phe-notrope (see Diphenoxylate Hydrochloride).
For mention of the use of loperamide in the management of diarrhoea caused by chemotherapy.
British Pharmacopoeia 2008: Loperamide Capsules
The United States Pharmacopeia 31, 2008: Loperamide Hydrochloride Capsules Loperamide Hydrochloride Oral Solution Loperamide Hydrochloride Tablets.
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
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