Loperamide

A CYP2C8 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 (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and Pglycoprotein, resulted in a 3- to 4-fold increase in loperamide plasma concentrations. The concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and Pglycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations. This increase was not associated with increased pharmacodynamic effects as measured by pupillometry.

Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both 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, is unknown.

Concomitant treatment with oral desmopressin resulted in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.

Safety in human pregnancy has not been established. Although from animal studies there are no indications that loperamide possess any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer this medicine in pregnancy, especially during the first trimester.

Small amounts of loperamide may appear in human breast milk. Therefore, this medicine is not recommended during breastfeeding.

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

Fertility

The effect on human fertility has not been evaluated.

Loss of consciousness, depressed level of consciousness, tiredness, dizziness or drowsiness may occur when diarrhoea is treated with loperamide. Therefore, it is advisable to exercise caution when operating machinery or driving a car following administration of loperamide.

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%).

The following table 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).

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.