IMODIUM™ SYRUP

Loperamide hydrochloride 0.2 mg/ml

For a full list of excipients, see section 6.1

Syrup for oral administration.

A clear, red, slightly viscous fruit-flavoured oral solution.

Acute diarrhoea

Not recommended for children under 4 years of age.

Further investigation into the cause of the diarrhoea should be considered if there is no improvement within two days of starting treatment with Imodium.

Chronic Diarrhoea

Use in Elderly:

No dose adjustment is required for the elderly.

Renal impairment

No dose adjustment is required for patients with renal impairment.

Hepatic impairment

Although no pharmacokinetic data are available in patients with hepatic impairment, Imodium should be used with caution in such patients because of reduced first pass metabolism (see 4.4 Special warnings and special precautions for use).

Method of Administration: Oral use.

Imodium is contraindicated in:

• patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.

• children less than 4 years of age.

• when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon, in particular:

-when ileus, constipation or abdominal distension develop,

- 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-spectrum antibiotics.

Imodium should not be used alone in acute dysentery, which is characterised by blood in stools and elevated body temperatures.

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

Treatment of diarrhoea with Imodium is only symptomatic.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, Imodium should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated. 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, Imodium must be used with caution in these patients because of reduced first pass metabolism (eg in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity.

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

Patients with AIDS treated with Imodium 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.

Also for P use only.

If symptoms persist for more than 24 hours, consult your doctor.

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 (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 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.

The concomitant administration of loperamide with oral desmopressin may result 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 which accelerate gastrointestinal transit may decrease its effect.

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

Small amounts of loperamide may appear in human breast milk. Therefore, Imodium 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 Imodium. 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 drug reactions (ADRs) 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) ADRs were: flatulence (2.8%), constipation (2.2%), nausea (1.2%) and dizziness (1.2%).

Table 1 displays ADRs 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 Drug Reactions

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 (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

Symptoms

In case of overdose (including relative overdose due to hepatic dysfunction), CNS depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia, and respiratory depression), constipation, urinary retention and ileus may occur. Children and patients with hepatic dysfunction may be more sensitive to CNS effects than adults.

Treatment

If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.

Pharmacotherapeutic Group: Antipropulsives; ATC code: A07DA03

Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter.

The half-life of loperamide in man is 10.8 hours with a range of 9-14 hours. Studies on distribution in rats show high affinity for the gut wall with preference for binding to the receptors in the longitudinal muscle layer. Loperamide is well absorbed from the gut, but is almost completely extracted and metabolised by the liver where it is conjugated and excreted via the bile. Due to its high affinity for the gut wall and its high first pass metabolism, very little loperamide reaches the systemic circulation.

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

Glycerol

Sodium saccharin

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Cochineal Red A

Raspberry Flavour

Red Currant Flavour

Ethanol (96%)

Citric acid monohydrate

Purified water

Not applicable.

60 months.

None.

Amber glass bottle with either a pilfer-proof aluminium screw cap coated on the inside with PVC or a child resistant polypropylene screw cap lined inside with an LDPE insert and a 5 ml or 10 ml polypropylene measuring cup.

Imodium syrup may be presented in bottle sizes of 30, 40, 50, 90 and 100 mls.

(Not all pack sizes may be marketed.)

Not applicable.

Janssen-Cilag Ltd.

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

PL 0242/0040

Date of first authorisation: 03 December 1975

Date of renewal of authorisation: 20 December 1996

14 January 2012

POM/P.