McNeil Healthcare (Ireland) Ltd

Imodium Plus 2mg/125mg Chewable Tablets

Each chewable tablet contains loperamide hydrochloride 2 mg and simeticone equivalent to 125 mg dimeticone.

Excipients: include 300 mg sorbitol (E420) and approximately 50 mg sucrose.

For a full list of excipients, see section 6.1.

Chewable tablet.

White, round, flat-faced tablets with a vanilla-mint odour debossed with “IMO” on one side.

Imodium Plus is indicated for the symptomatic treatment of acute diarrhoea in adults and adolescents over 12 years when acute diarrhoea is associated with gas-related abdominal discomfort including bloating, cramping or flatulence.

Adults over 18 years

Chew two tablets initially, followed by one tablet after every loose stool. Not more than 4 tablets should be taken in a day, limited to no more than 2 days.

Adolescents between 12 and 18 years

Chew one tablet initially, followed by one tablet after every loose stool. Not more than 4 tablets should be taken in a day, limited to no more than 2 days.

Use in children

Imodium Plus must not be used in children under 12 years.

Use in the elderly

No dosage adjustments are required for the elderly.

Renal impairment

No dosage adjustment is necessary in renal impairment.

Hepatic impairment

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

Imodium Plus must not be used in:

• Children less than 12 years of age

• Patients with a known hypersensitivity (allergy) to loperamide hydrochloride, simeticone or of the excipients.

• Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency, because the product contains sorbitol and sucrose

• Patients with acute dysentery, which is characterised by blood in stool and high fever

• Patients with acute ulcerative colitis

• Patients with pseudomembranous colitis associated with broad spectrum antibiotics

• Patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella and Campylobacter

Imodium Plus 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. It must be discontinued promptly if constipation, ileus or abdominal distension develop.

Treatment of diarrhoea with loperamide-simeticone is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.

In patients with (severe) diarrhoea, fluid and electrolyte depletion may occur. It is important that attention is paid to appropriate fluid and electrolyte replacement. If clinical improvement is not observed within 48 hours, the administration of Imodium Plus must be discontinued. Patients should be advised to consult their physician.

Patients with AIDS treated with Imodium Plus for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk of 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, Imodium Plus should be used with caution in such patients because of reduced first pass metabolism. This medicine must be used with caution in patients with hepatic impairment as it may result in a relative overdose leading to central nervous system (CNS) toxicity. Imodium Plus should be used under medical supervision in patients with severe hepatic dysfunction.

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 concentrations. 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 levels. 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. As these increases were not associated with measured central nervous system central nervous system (CNS) effects, as measured by psychomotor tests (ie.subjective drowsiness and the Digit Symbol Substitutions 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.

Use in pregnancy

Safety in human pregnancy has not been established, although from animal studies there are no indications that loperamide or simeticone possesses teratogenic or embryotoxic properties. Imodium Plus should not be given during pregnancy, especially during the first trimester, unless clinically justified.

Use in lactation

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

Tiredness, dizziness and drowsiness have been reported in patients taking loperamide. If affected, patients should not drive or operate machinery. See Section 4.8 Undesirable effects.

The use of loperamide plus simeticone, in the treatment of the symptoms of diarrhoea, and gas-related abdominal discomfort associated with acute diarrhoeal illness, was studied in five placebo-controlled, and active-controlled, clinical trials involving 462 adults treated with loperamide plus simeticone. The most frequently reported Adverse Drug Reactions (ADRs) associated with the use of the drug in these clinical trials were nausea and dysgeusia, reported in 1.7% and 1.9% of patients, respectively, and were considered Common.

Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of loperamide plus simeticone, or loperamide alone, from either clinical trial or post marketing experiences. The displayed 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); Very rare (< 1/10,000), Not known (cannot be estimated from the available data)

Symptoms

In case of overdosage (including relative overdosage due to hepatic dysfunction), central nervous system depression (stupor, co-ordination abnormality, somnolence, miosis, muscular hypertonia, respiratory depression), dry mouth, abdominal discomfort, nausea and vomiting, constipation, urinary retention and paralytic ileus may occur. Children may be more sensitive to CNS effects than adults.

Treatment

If symptoms of overdosage 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 may be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.

Pharmacotherapeutic group: Antipropulsive antidiarrheals, ATC code: A07D A53

Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis, increasing intestinal transit time and enhancing resorption of water and electrolytes. Loperamide does not change the physiological flora. Loperamide increases the tone of the anal sphincter.

Simeticone is an inert surface-active agent with anti-foaming properties thereby potentially relieving gas-related symptoms associated with diarrhoea.

Absorption: Most ingested loperamide is absorbed from the gut, but as a result of significant first pass metabolism, systemic bioavailability is only approximately 0.3%. The simeticone component of loperamide-simeticone is not absorbed.

Distribution: Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of loperamide is 95%, mainly to albumin. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.

Metabolism: Loperamide is almost completely extracted by the liver, where it is predominantly metabolized, conjugated and excreted via the bile. Oxidative N-demethylation is the main metabolic pathway for loperamide, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.

Elimination: The half-life of loperamide in man is about 11 hours with a range of 9-14 hours. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.

Acute and chronic studies on loperamide showed no specific toxicity. Results of in vivo and in vitro studies carried out indicated that loperamide is not genotoxic. In reproductive toxicity studies in rats, very high doses of loperamide, associated with maternal toxicity, impaired fertility and foetal survival. Lower doses had no effects on maternal or foetal health and did not affect peri- and post-natal development.

Simeticone is a member of the class of linear polydimethylsilicones, which have been in wide general and medicinal use for many years and are regarded as biologically inert and not exhibiting toxic properties and has not been the subject of specific animal toxicity studies.

Sucrose and corn starch

Microcrystalline cellulose

Basic butylated methacrylate copolymer

Cellulose acetate

Sorbitol (E420)

Dextrates

Natural and artificial vanilla mint flavour (including sucrose, maltodextrin, modified corn starch, corn syrup solids, polyglycerol ester of fatty acids, calcium phosphate, enzyme modified milk powder)

Saccharin sodium

Stearic acid

Calcium phosphate.

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Chewable tablets are packaged in non child resistant push through blisters. The blister consists of: ACLAR/PVC film, aluminium foil and heat seal coating. The heat seal coating contains vinyl and acrylic.

Blister strips of 2, 4, 5, or 6 tablets in pack sizes of 2, 4, 5, 6, 8, 10, 12, 15, 16, 18 and 20 tablets packed in printed cardboard cartons.

Not all pack sizes may be marketed.

No special requirements.

McNeil Healthcare (Ireland) Limited

Airton Road

Tallaght

Dublin 24

Ireland

PA 823/60/1

Date of first authorisation: 14^th August 1998

Date of latest renewal: 1^st September 2007

March 2012