MIRATON Capsule Ref.[28277] Active ingredients: Loperamide

Treatment of diarrhoea with loperamide is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate. The priority in acute diarrhoea is the prevention or reversal of fluid and electrolyte depletion. This is particularly important in young children and in frail and elderly patients with acute diarrhoea. Use of this medicine does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, this medicine should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated.

In acute diarrhoea, if clinical improvement is not observed within 48 hours, the administration of loperamide should be discontinued and patients should be advised to consult their doctor.

Patients with AIDS treated with this medicine for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk for toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.

Although no pharmacokinetic data are available in patients with hepatic impairment, this medicine should be used with caution in such patients because of reduced first pass metabolism, as it may result in a relative overdose leading to CNS toxicity.

If patients are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome previously diagnosed by their doctor, and clinical improvement is not observed within 48 hours, the administration of loperamide HCl should be discontinued and they should consult with their doctor. Patients should also return to their doctor if the pattern of their symptoms changes or if the repeated episodes of diarrhoea continue for more than two weeks.

Special Warnings to be included on the leaflet

Only take loperamide to treat acute episodes of diarrhoea associated with Irritable Bowel Syndrome if your doctor has previously diagnosed IBS.

If any of the following now apply, do not use the product without first consulting your doctor, even if you know you have IBS:

• If you are aged 40 or over and it is some time since your last IBS attack.
• If you are aged 40 or over and your IBS symptoms are different this time.
• If you have recently passed blood from the bowel.
• If you suffer from severe constipation.
• If you are feeling sick or vomiting.
• If you have lost your appetite or lost weight.
• If you have difficulty or pain passing urine.
• If you have a fever.
• If you have recently travelled abroad.

Consult your doctor if you develop new symptoms, if your symptoms worsen, or your symptoms have not improved over two weeks.

Cardiac events including QT interval and QRS complex prolongation and 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.

Miraton contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Miraton contains sunset yellow (E110). May cause allergic reactions.

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 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.

The concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study 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 (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. Concomitant treatment with oral desmopressin resulted in a 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 from animal studies there are no indications that loperamide HCl possesses any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer this medicine in pregnancy, especially during the first trimester.

Breast-feeding

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

Women who are pregnant or 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 this medicine. Therefore, caution is advisable when driving a car or operating machinery (see section 4.8).

Adults and children aged ≥12 years

The safety of loperamide HCl was evaluated in 2755 adults and children aged ≥12 years who participated in 26 controlled and uncontrolled clinical trials of loperamide HCl used for the treatment of acute diarrhoea.

The most commonly reported (i.e. ≥1% incidence) adverse drug reactions (ADRs) in clinical trials with loperamide HCl in acute diarrhoea were: constipation (2.7%), flatulence (1.7%), headache (1.2%) and nausea (1.1%).

Table 1 displays ADRs that have been reported with the use of loperamide HCl from either clinical trial (acute diarrhoea) 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); not known (cannot be estimated from the available data).

Table 1. Adverse Drug Reactions:

^a Inclusion of this term is based on post-marketing reports for loperamide HCl. As the process for determining post marketing ADRs did not differentiate between chronic and acute indications or adults and children, the frequency is estimated from all clinical trials with loperamide HCl (acute and chronic), including trials in children ≤12 years (N=3683).
^b See section 4.4.

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 to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

Not applicable.