4.1. Therapeutic indications

The symptomatic treatment of acute diarrhoea of any aetiology, including acute exacerbations of chronic diarrhoea, for periods of up to 5 days in adults and children over 9 years.

The symptomatic treatment of chronic diarrhoea in adults.

4.2. Posology and method of administration

Posology:

Acute Diarrhoea

Adults and Children (9 – 17) years:

The initial dose is two capsules (4mg) for adults and one capsule (2mg) for children, followed by one capsule (2mg) after every subsequent loose stool for up to five days.

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

Chronic Diarrhoea

Adults only

The initial dosage is two capsules (4mg) daily. This initial dose should be adjusted until one to two solid stools per day are obtained, which is usually achieved with a maintenance dose of one to six capsules (2 mg-12 mg) daily.

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

Paediatric population

Loperamide is contraindicated in children less than 9 years of age.

Elderly

No dose adjustment is required for the elderly.

Patients with renal impairment

No dose adjustment is required for patients with renal impairment.

Patients with hepatic impairment

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

Method of administration

For oral administration.

The capsules should be taken with liquid.

4.3. Contraindications

The medicine is contraindicated:

• Patients with a known hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• In children under 9 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:

o when ileus, constipation or abdominal distension develop,

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.

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

4.4. Special warnings and precautions for use

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

Treatment of diarrhoea with loperamide is only symptomatic.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, loperamide should not be used for prolonged periods of time and the underlying cause of the diarrhoea should be investigated if clinical improvement is not observed within 48 hours of initiating treatment. 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, loperamide must be used with caution in these patients because of reduced first-pass metabolism (e.g. in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity.

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

Patients with AIDS treated with loperamide 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.

Cardiac events including QT interval and QRS complex prolongation, 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.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Caution is needed in patients with a history of drug abuse. Loperamide is an opioid and addiction is observed with opioids as a class.

4.5. Interaction with other medicinal products and other forms of interaction

Non-clinical, and 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 P-glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of these pharmacokinetic interactions 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 CYP 3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study a CYP 2C8 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 resulted in 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. Pregnancy and lactation

Pregnancy

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

Breast-feeding

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

Women who are breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.

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 loperamide. Therefore, it is advisable to use caution when driving a car or operating machinery. See section 4.8 Undersirable effects.

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) adverse reactions were: flatulence (2.8%), constipation (2.2%), nausea (1.2%) and dizziness (1.2%).

Table 1 displays adverse reactions 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 Reactions

System Organ Class

Adverse Reaction

Common

Uncommon

Rare

Not known

Immune System Disorders

Hypersensitivity reaction, Anaphylactic reaction (including Anaphylactic shock), Anaphylactoid reaction

Nervous System Disorders

Headache, Dizziness

Somnolence

Loss of consciousness, Stupor, Depressed level of consciousness, Hypertonia, Coordination abnormality

Eye Disorders

Miosis

Gastrointestinal Disorders

Constipation, Nausea, Flatulence

Abdominal pain, Abdominal discomfort, Dry mouth, Abdominal pain upper, Vomiting, Dyspepsia

Ileus (including paralytic ileus), Megacolon (including toxic megacolon – see section 4.4), Abdominal distension

Acute Pancreatitis

Skin and Subcutaneous Tissue Disorders

Rash

Bullous eruption (including Stevens Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme), Urticaria, Pruritus, Angioedema

Renal and Urinary Disorders

Urinary retention

General Disorders and Administration Site Conditions

Fatigue

A number of the adverse reactions reported during the clinical investigations and post-marketing experience with loperamide hydrochloride 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

The safety of loperamide hydrochloride was evaluated in 607 patients aged 10 days to 13 years who participated in 13 controlled and uncontrolled clinical trials of loperamide hydrochloride used for the treatment of acute diarrhoea. In general, the adverse reactions profile in this patient population was similar to that seen in clinical trials of loperamide hydrochloride in adults and children aged 12 years and over.

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 via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9. Overdose

Symptoms

In cases 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 the patient develops respiratory depression, airway obstruction, vomiting with impaired consciousness or other CNS symptoms of overdose, give naloxone urgently. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated, the patient should be kept under constant observation for at least 48 hours in order to detect any possible CNS depression. Other measures should be as indicated by the patient's clinical condition.