McNeil Healthcare (Ireland) Ltd

Arret 2mg Hard Capsules

Each capsule contains loperamide hydrochloride 2 mg.

Excipients contain Lactose Monohydrate 127.0mg per capsule.

For a full list of excipients see Section 6.1.

Capsule, hard {Short term: Capsule}.

Brown and light green hard gelatin capsules containing a white powder.

As an adjunct in the management of diarrhoea together with fluid and electrolyte replacement.

Adults and children over 12 years only:

The usual dose is 2 capsules initially, followed by 1 capsule after each further episode of diarrhoea up to a maximum of 5 in 24 hours.

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, Arret should be used with caution in such patients because of reduced first pass metabolism (see 4.4 Special warning and precautions for use).

Method of Administration:

Oral.

• Arret is contraindicated in patients under 12 years of age

• Arret is contraindicated in patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients

• Arret should not be used as the primary therapy:

o In patients with acute dysentery, which is characterised by blood in the stools and high fever

o In patients with acute ulcerative colitis

o In patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella, and Campylobacter

o In patients with Pseudomembranous colitis associated with the use of broad spectrum antibiotics.

• In general, Arret should not be used when the inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. Arret must be discontinued promptly when constipation, abdominal distension or ileus develop.

1. Antimotility agents such as loperamide may precipitate ileus and toxic megacolon in patients with ulcerative colitis, or pseudomembranous colitis associated with broad-spectrum antibiotics and should be avoided in severe acute attacks. It may be used cautiously in mild or less severe attacks as an adjunct to other measures, but should be discontinued promptly should abdominal distension or other untoward symptoms occur.

2. Arret is not a substitute for rehydration therapy. In addition to taking Arret, the patient should be advised to drink plenty of fluids such as water, clear soup and squash.

3. Patients should be advised to consult their doctor if diarrhoea persists for more than 24 hours.

4. Loperamide should be used with caution when hepatic function, necessary for the drug's metabolism, is defective, as this may result in relative overdose leading to CNS toxicity.

5. Patients with AIDS treated with Arret 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.

6. The stated dose should not be exceeded.

7. 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.

Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritinovir, 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 safety of Arret in human pregnancy has not been established. Small amounts of loperamide may appear in human breast milk. Therefore, Arret 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.

Tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with Arret. Therefore, it is advisable to use caution when driving a car or operating machinery. See section 4.8 Undesirable effects.

In clinical trials constipation and dizziness have been reported with greater frequency in loperamide hydrochloride treated patients than placebo treated patients.

The following adverse events have also been reported with use of loperamide hydrochloride:

Skin and subcutaneous tissue disorders

Very rare: rash, urticaria and pruritus. Isolated occurrences of angioedema, and bullous eruptions including Stevens-Johnson Syndrome, erythema multiforme, and toxic epidermal necrolysis.

Immune system disorders

Very rare: isolated occurrences of allergic reactions and in some cases severe hypersensitivity reactions including anaphylactic shock and anaphylactoid reactions.

Gastrointestinal system disorders

Very rare: abdominal pain, ileus, abdominal distension, nausea, constipation, vomiting, megacolon including toxic megacolon, flatulence, and dyspepsia.

Renal and urinary disorders

Very rare: isolated reports of urinary retention.

Psychiatric system disorders

Very rare: drowsiness

Nervous system disorders

Very rare: Loss of consciousness, depressed level of consciousness, dizziness

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 (abdominal pain/discomfort, nausea, vomiting, dry mouth, tiredness, drowsiness, dizziness, constipation, and flatulence). These symptoms are often difficult to distinguish from undesirable drug effects.

In case of overdose the following effects may be observed: constipation, urinary retention, ileus and central nervous system depression (stupor, co-ordination abnormality, myosis, muscular hypertonia, somnolence and bradypnoea). If intoxication is suspected, naloxone may be given as an antidote. Since the duration of action of Arret is longer than that of naloxone (1 to 3 hours), the patient should be kept under constant observation for at least 48 hours in order to detect any possible depression of the central nervous system.

Pharmacotherapeutic Group: Antipropulsives; ATC code: A07DA03

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

In a double blind randomised clinical trial in 56 patients with acute diarrhoea receiving loperamide, onset of antidiarrhoeal 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.

The half-life of loperamide in man is 10.8 hours with a range of 9 to 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.

Lactose

Maize starch

Talc

Magnesium stearate

Capsule Shell:

Titanium dioxide (E171)

Black ferrous oxide (E172)

Red ferric oxide (E172)

Yellow ferric oxide (E172)

Gelatin

Indigotindisulphonate sodium (E132)

Not applicable

5 years.

Do not store above 25°C.

PVC/Alu blisters in packs containing 2, 6, 12 or 18 capsules.

Not all pack sizes may be marketed.

No special requirements.

McNeil Healthcare (Ireland) Ltd.

Airton Road

Tallaght

Dublin 24

Ireland

PA 823/53/1

3 May 1989 / 3 May 2009

May 2009