Loperamide hydrochloride is 4-(4-chlorophenyl)-4-hydroxy-N, N-dimethyl-a,a-diphenyl-1- piperidinebutyramide monohydrochloride, a synthetic compound for oral use. It is a white to yellowish, amorphous or microcrystalline powder, insoluble in water. CAS: 34552-83-5 C29H33ClN202. HCl Mol wt. 513.49 Diamide Relief capsules contain Ioperamide hydrochloride 2mg in a size 4 gelatin capsule with a grey cap and green body. Diamide Relief capsules also contain the inactive ingredient lactose.
Pharmacological classification
- Antidiarrhoeal.
Antidiarrhoeal Activity
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. Studies suggest that loperamide may increase the tone of the anal sphincter, reducing incontinence and urgency. Due to its high affinity for the gut wall and its high first-pass metabolism, loperamide hardly reaches the systemic circulation. In man, as a constipating agent, loperamide on a mg to mg basis is about 3 times more potent than diphenoxylate hydrochloride and 25 times more potent than codeine phosphate. The onset of action, as determined in clinical studies with volunteers, indicated that clinical improvement occurs within 1-3 hours following drug administration (4 mg dose). The duration of action was determined from the interval between the time treatment was stopped due to constipation and the time bowel motion and stool consistency were again normal. In normal test subjects, a single 4 mg dose of Ioperamide significantly increased the median time of defaecation from 23 hours to 41 hours. In those patients where biochemical and haematological parameters were monitored during clinical trials, no trends toward abnormality during Ioperamide therapy were noted. Similarly, urinalysis, ECG, and clinical ophthalmological examinations did not show trends towards abnormality.
CNS Activity
Animal studies indicate that Ioperamide is devoid of analgesic properties (2-16 mg/kg). Studies in morphine- dependent monkeys demonstrated that loperamide hydrochloride in high S.C. doses prevented signs of morphine withdrawal. However, in humans the naloxone challenge pupil test which when positive indicated opiate-like effects, was negative when performed after a single high dose or after more than two years of therapeutic use (mean dose 4 mg/day) of Ioperamide hydrochloride.
Cardiovascular Effects
In human volunteers, analysis of electrocardiograms obtained pre-therapy, and then two and six hours after administration of Ioperamide hydrochloride (16 mg), revealed no evidence of cardiovascular toxicity.
Metabolism and Excretion
The absorption, excretion and tissue distribution of a single oral dose of 3H-labelled Ioperamide was studied in rats (1.25 mg/kg) and man (2 mg). In man, peak plasma levels of about 2 ng/ml of intact drug occurred at 4 hours. In the rat, approximately 15% of the administered dose was recovered after 96 hours. The highest residual concentration was found in the liver; the lowest in fatty tissue. About 60% of the administered dose was recovered from the faeces mainly as unchanged drug. Urinary excretion accounted for approximately 5% of which only 20% was unmetabolised Ioperamide. The existence of an enterohepatic shunt has been shown in rats and is assumed in man. The half-life of loperamide in man is about 11 hours with a range of 9-14 hours. Elimination mainly occurs by oxidative N-demethylation, which is the main metabolic pathway of loperamide. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces. The combined cumulative urinary excretion of Ioperamide and its conjugates accounts for only about 2% of the administered dose.
Diamide Relief is indicated for:
The control and symptomatic treatment of acute nonspecific diarrhoea, and of chronic diarrhoea. Reducing the volume of discharge in patients with ileostomies, colostomies, and other intestinal resections.
Diamide Relief is contraindicated in patients with known hypersensitivity to Ioperamide or to any of the excipients (see Description). Diamide Relief should not be used as the primary therapy: in patients with acute dysentery, which is characterised 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-spectum antibiotics. In general, Diamide Relief 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. Diamide Relief must be discontinued promptly when constipation, abdominal distension or ileus develop. Treatment of diarrhoea with Diamide Relief is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.
Diamide Relief is contraindicated in children under the age of 12 years.
Fluid and electrolyte depletion may occur in patients who have diarrhoea. The use of loperamide hydrochloride does not preclude the administration of appropriate fluid and electrolyte therapy. In acute diarrhoea, 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.
Category B3 Safe use of loperamide hydrochloride during pregnancy has not been established. Reproduction studies performed in rats and rabbits with high doses did not demonstrate evidence of impaired fertility or harm to the offspring due to Ioperamide hydrochloride. Higher doses impaired maternal and neonate survival, but even higher doses did not demonstrate teratogenicity. Such experience cannot exclude the possibility of damage to the foetus. Loperamide should be used in pregnant women only if the potential benefit justifies the risk to the foetus.
There is little information on the excretion of loperamide hydrochloride in human milk, but as small amounts of the drug are detectable in the milk of nursing mothers, the use of loperamide hydrochloride is not recommended in breast feeding subjects. In a peri- and postnatal study, Ioperamide administered to female rats at dosage of 40mg/kg indicated a possible adverse effect of lactation as evidenced in a decreased pup- survival rate.
(See Contraindications).
Physical dependence to loperamide hydrochloride in humans has not been observed. However, studies in monkeys demonstrated that Ioperamide hydrochloride at high dose produced symptoms of physical dependence of the morphine type.
Loperamide hydrochloride should be used with caution in patients with hepatic insufficiency because of reduced first pass metabolism. Patients with hepatic dysfunction should be monitored closely for signs of central nervous system (CNS) toxicity.
Since the majority of the drug is metabolised, and the metabolites or the unchanged drug is excreted in the faeces, dose adjustments in patients with a kidney disorder are not required.
Use with caution in patients with AIDS. Patients with AIDS treated with loperamide hydrochloride for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.
Tiredness, dizziness or drowsiness may occur in the setting of diarrhoeal syndromes treated with loperamide. Therefore it is advisable to use caution when driving a car or operating machinery.
In vitro
studies have demonstrated anti-cholinergic properties. Hence, caution should be used in patients with glaucoma, urinary bladder neck obstruction, pyloric obstruction, significant gastric retention, or intestinal stasis.
Although the pharmacological effect of Ioperamide hydrochloride is not associated with a central action, patients with concomitant administration of tranquillisers or alcohol should be carefully observed.
Consideration should always be given with new drugs as to possible interaction with monoamine oxidase inhibitors. Theoretically, the combination of loperamide hydrochloride with monoamine oxidase inhibitors (which are also inhibitors of liver microsomal enzymes) may potentiate the action of Ioperamide by blocking its metabolic pathway. Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both P-glycoprotein inhibitors, resulted in a 2-3 fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages (2 mg, up to 16 mg maximum daily dose), is unknown.
Clinical trial data
The adverse effects reported during clinical investigations of loperamide hydrochloride are difficult to distinguish from symptoms associated with the diarrhoeal 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 treatment of chronic diarrhoea. Adverse events reported from 76 controlled and uncontrolled studies in patients with acute or chronic diarrhoea, irrespective of the causality assessment of the investigators, are summarised in the Table 1.
Table 1:
Adverse events with an incidence of 1.0% or greater in patients from all studies
| Acute Diarrhoea | Chronic Diarrhoea | All Studies # | |
| No. of treated patients Gastrointestinal AE% | 1913 | 1371 | 3740 |
| Nausea | 0.7% | 3.2% | 1.8% |
| Constipation | 1.6% | 1.9% | 1.7% |
| Abdominal cramps | 0.5% | 3.0% | 1.4% |
# All patients in all studies, including those in which it was not specified if the adverse events occurred in patients with acute or chronic diarrhoea.
Post-marketing experience
The following spontaneous adverse experiences have been reported, and within each system organ class, are ranked by frequency, using the following convention: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, < 1/100); rare (>1/10,000, <1/1,000); very rare (>1/10,000), including isolated reports. The frequency provided is a reflection of reporting rates for spontaneous adverse experiences and does not represent true incidence or frequency as seen with clinical trials or epidemiological studies.
Skin and subcutaneous tissue disorders:
Very rare - rash, urticaria and pruritus. Isolated occurrences of angioedema, and bullous eruptions including Stevens-Johnson syndrome, erythema multiforme, 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 use of loperamide hydrochloride.
Gastrointestinal disorders:
Very rare - abdominal pain, ileus, abdominal distension, nausea, constipation, vomiting, megacolon including toxic megacolon, flatulence and dyspepsia (see Contraindications and Precautions).
Renal and urinary disorders:
Isolated reports of urinary retention.
Psychiatric system disorders:
Very rare - drowsiness.
Nervous system disorders:
Very rare:Loss of consciousness, depressed level of consciousness, dizziness. A number of the adverse events reported during the clinical investigations and post-marketing experience with loperamide are frequent symptoms of the underlying diarrhoeal 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.
Diamide Relief capsules should be administered orally with the aid of liquid. Diamide Relief capsules are contraindicated in children under the age of 12 years.
The recommended initial dose of Diamide Relief in adults is two capsules (4 mg) followed by one capsule (2 mg) after each unformed stool. Daily dose should not exceed eight capsules (16 mg). Clinical improvement is usually observed within 48 hours.
The recommended initial dose of Diamide Relief is two capsules (4 mg) followed by one capsule (2 mg) after each unformed stool until diarrhoea is controlled, after which dosage of Diamide Relief should be reduced to meet individual requirements. When the optimal maintenance daily dosage has thus been established, this amount can then be administered as a single dose or in two or three divided doses. The average daily maintenance dosage in clinical trials was two to four capsules (4-8 mg). A dosage of five capsules (10 mg) was rarely exceeded. A temporary exacerbation of diarrhoea was controlled by increasing the Ioperamide dosage to achieve further control followed by titration back to the established maintenance dose.
In case of overdose (including relative overdose due to hepatic dysfunction), central nervous system depression (stupor, co-ordination abnormality, somnolence, miosis, muscular hypertonia, respiratory depression), urinary retention and paralytic ileus may occur. Children may be more sensitive to CNS effects than adults. In clinical trials using loperamide hydrochloride, an adult took three 20mg doses within a 24-hour period, was nauseated after the second, and vomited after the third dose.
If vomiting has occurred spontaneously, a slurry of 100 g of activated charcoal should be administered orally as soon as fluids can be maintained. If vomiting has not occurred, gastric lavage should be performed, followed by administration of 100 g of activated charcoal slurry through gastric tube. In the case of overdosage, patient should be monitored for signs of CNS depression and/or respiratory 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 overdosage for at least 24 hours after the last dose of naloxone. In view of the prolonged action of Ioperamide and the short duration (one to three hours) of naloxone, the patient must be monitored closely and treated repeatedly with naloxone as indicated. Based on the fact that relatively little Ioperamide is excreted in urine, forced diuresis is not expected to be effective for Loperamide overdosage. Contact the Poisons Information Centre in New Zealand on 0800 POISON or 0800 764 766 for the latest advice on the treatment of oral poisoning.
Diamide Relief capsules - Prescription Medicine.
Diamide Relief capsules are available in blister packs containing 400 capsules. Store below 25degC.
Mylan New Zealand Ltd PO Box 11-183 Ellerslie AUCKLAND Telephone: 09-579-2792
29 October 2010