IMODIUM ORIGINAL 2 MG CAPSULES - summary of medicine characteristics

Imodium Original 2mg Capsules.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 2 mg Loperamide hydrochloride.

Excipient with known effect: lactose

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Capsule, hard

Opaque green cap and grey body, hard gelatin capsule imprinted with ‘Imodium’ on cap and ‘Janssen’ on body containing white powder.

4.1 Therapeutic indications

For the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over.

For the symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome in adults aged 18 years and over following initial diagnosis by a doctor.

4.2 Posology and method of administration

Posology:

ACUTE DIARRHOEA

Adults and children over 12:

2 capsules (4 mg) initially followed by 1 capsule (2 mg) after every loose stool.

The maximum daily dose should not exceed 6 capsules (12 mg).

SYMPTOMATIC TREATMENT OF ACUTE EPISODES OF DIARRHOEA ASSOCIATED WITH IRRITABLE BOWEL SYNDROME IN ADULTS AGED 18 YEARS AND OVER

Two capsules (4 mg) to be taken initially, followed by 1 capsule (2 mg) after every loose stool, or as previously advised by your doctor. The maximum daily dose should not exceed 6 capsules (12 mg).

Paediatric population

Imodium is contraindicated in children less than 12 years of age.

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. The capsules should be taken with liquid.

4.3 Contraindications

This medicine is contraindicated:

hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

in children less than 12 years of age.

in patients with acute dysentery, which is characterised by blood in stools and high fever.

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 broadspectrum antibiotics.

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

4.4 Special warnings and precautions for use

Treatment of diarrhoea with Imodium 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 Imodium 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.

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

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.

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.

Special Warnings to be included on the leaflet:

Only take this medicine 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, or if your symptoms worsen, or your symptoms have not improved over two weeks.

4.5 Interaction with other medicinal products and other forms of interaction

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.

4.6 Fertility, pregnancy and lactation

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.

Fertility

The effect on human fertility has not been evaluated.

4.7 Effects on ability to drive and use machines

Loss of consciousness, depressed level of consciousness, tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with this medicine. Therefore, it is advisable to use caution when driving a car or operating machinery. See Section 4.8, Undesirable Effects.

4.8 Undesirable effects

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).

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 Special Warnings and Special Precautions for use.

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.

4.9 Overdose

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.

In individuals who have ingested overdoses of loperamide, cardiac events such as QT interval and QRS complex prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest and syncope have been observed (see section 4.4). Fatal cases have also been reported. Overdose can unmask existing Brugada syndrome.

Treatment:

In cases of overdose, ECG monitoring for QT interval prolongation should be initiated.

If CNS 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Antipropulsives: ATC code: A07DA03

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 increases the tone of the anal sphincter, which helps reduce faecal incontinence and urgency.

In a double blind randomised clinical trial in 56 patients with acute diarrhoea receiving loperamide, onset of anti-diarrhoeal action was observed within one hour following a single 4 mg dose. Clinical comparisons with other antidiarrhoeal drugs confirmed this exceptionally rapid onset of action of loperamide.

5.2 Pharmacokinetic properties

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%.

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 914 hours. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.

5.3 Preclinical safety data

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 reproduction studies, very high doses (40 mg/kg/day – 20 times the maximum human use level (MHUL)), based on body surface area dose comparisons (mg/m2), loperamide impaired fertility and fetal survival in association with maternal toxicity in rats. Lower doses (> 10mg/kg/day – 5 times MHUL) revealed no effects on maternal or fetal health and did not affect peri- and post-natal development.

Non-clinical in vitro and in vivo evaluation of loperamide indicates no significant cardiac electrophysio­logical effects within its therapeutically relevant concentration range and at significant multiples of this range (up to 47-fold. However, at extremely high concentrations associated with overdoses (see section 4.4), loperamide has cardiac electrophysio­logical actions consisting of inhibition of potassium (hERG) and sodium currents, and arrhythmias.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose

Maize starch

Talc

Magnesium stearate (E572)

Capsule cap:

Titanium dioxide (E171)

Yellow ferric oxide (E172)

Indigo carmine (E132)

Gelatin

Capsule body:

Titanium dioxide (E171)

Black ferrous oxide (E172)

Indigo carmine (E132)

Erythrosine (E127)

Gelatin

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage condition.

6.5 Nature and contents of container

Blister packs consisting of aluminium foil and polyvinyl chloride glass clear.

The blister strips are packed in cardboard cartons to contain 2, 4, 6 or 12 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

McNeil Products Limited

50–100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 15513/0310

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

15/12/2009