NORIMODE Tablet Ref.[50237] Active ingredients: Loperamide

In patients with diarrhoea, especially young children, fluid and electrolyte depletion may occur. Use of loperamide does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Treatment of diarrhoea with loperamide is only symptomatic.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, loperamide should not be used for prolonged periods of time and the underlying cause of the diarrhoea should be investigated if clinical improvement is not observed within 48 hours of initiating treatment. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.

Although no pharmacokinetic data are available in patients with hepatic impairment, loperamide must be used with caution in these patients because of reduced first-pass metabolism (e.g. in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity.

Loperamide must be discontinued promptly when constipation, abdominal distension or ileus develop.

Patients with AIDS treated with loperamide 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.

Cardiac events including QT interval and QRS complex prolongation, torsades de pointes have been reported in association with overdose. Some cases had a fatal outcome (see section 4.9). Overdose can unmask existing Brugada syndrome. Patients should not exceed the recommended dose and/or the recommended duration of treatment.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Caution is needed in patients with a history of drug abuse. Loperamide is an opioid and addiction is observed with opioids as a class.

Non-clinical and 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 P-glycoprotein inhibitors, resulted in a 2 to 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.

The concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP 3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study a CYP 2C8 inhibitor, gemfibrozil increased loperamide by approximately 2-fold. The combination of itraconazole and gemfibrozil resulted in a 4-fold increase in peak plasma levels of loperamide and a 13-fold increase in total plasma exposure. These increases were not associated with central nervous system (CNS) effects as measured by psychomotor tests (i.e., subjective drowsiness and the Digit Symbol Substitution Test).

The concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations. This increase was not associated with increased pharmacodynamic effects as measured by pupillometry.

The concomitant administration of loperamide with oral desmopressin resulted in 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.

It is expected that drugs with similar pharmacological properties may potentiate loperamide’s effect and that drugs that accelerate gastrointestinal transit may decrease its effect.

Pregnancy

Safety in human pregnancy has not been established, although studies in animals have not demonstrated any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer loperamide in pregnancy, especially during the first trimester.

Breast-feeding

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

Women who are breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.

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. See section 4.8, Undesirable effects.

The safety of loperamide hydrochloride was evaluated in 3076 adults and children aged ≥12 years who participated in 31 controlled and uncontrolled clinical trials of loperamide hydrochloride used for the treatment of diarrhoea. Of these, 26 trials were in acute diarrhoea (N=2755) and 5 trials were in chronic diarrhoea (N=321).

The most commonly reported (i.e., ≥1% incidence) adverse reactions in clinical trials with loperamide hydrochloride in acute diarrhoea were: constipation (2.7%), flatulence (1.7%), headache (1.2%) and nausea (1.1%). In clinical trials in chronic diarrhoea, the most commonly reported (i.e. ≥1% incidence) adverse reactions were: flatulence (2.8%), constipation (2.2%), nausea (1.2%) and dizziness (1.2%).

Table 1 displays adverse reactions that have been reported with the use of loperamide hydrochloride from either clinical trials (in acute or chronic diarrhoea or both) or post-marketing experience.

The frequency categories use the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); and very rare (<1/10,000).

Table 1. Adverse Reactions:

A number of the adverse reactions reported during the clinical investigations and post-marketing experience with loperamide hydrochloride are frequent symptoms of the underlying diarrhoeal syndrome (for example abdominal pain/discomfort, nausea, vomiting, dry mouth, tiredness, drowsiness, dizziness, constipation, and flatulence). These symptoms are often difficult to distinguish from undesirable drug effects.

Paediatric population

The safety of loperamide hydrochloride was evaluated in 607 patients aged 10 days to 13 years, who participated in 13 controlled and uncontrolled clinical trials of loperamide hydrochloride used for the treatment of acute diarrhoea. In general, the adverse reactions profile in this patient population was similar to that seen in clinical trials of loperamide hydrochloride in adults and children aged 12 years and over.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

None Known.