4.1. Therapeutic indications

Loperamide is indicated for the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over.:

Loperamide is also indicated for the symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome (IBS) in adults aged 18 years and over following initial diagnosis by a doctor.

4.2. Posology and method of administration

Loperamide hydrochloride 2mg capsules are for oral administration. The capsules should be taken with liquid.

Adults and children aged 12 years and over

Acute diarrhoea:

Two capsules initially (4mg), followed by 1 capsule (2mg) 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).

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, this medicine should be used with caution in such patients because of reduced first pass metabolism (see section 4.4).

Method of administration

Oral use.

4.3. Contraindications

Loperamide hydrochloride 2mg capsule is contraindicated:

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

• in children aged less than 12 years

• 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 broad spectrum antibiotics

Loperamide 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.

Loperamide must be discontinued promptly when ileus or constipation are present or when abdominal distension develops.

4.4. Special warnings and precautions for use

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

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.

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 loperamide hydrochloride should be discontinued and patients should be advised to consult their doctor.

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 obstipation with an increased risk for toxic megacolon in AIDS patients with infectious colitis (viral or bacterial pathogens) treated with loperamide hydrochloride.

Although no pharmacokinetic data are available in patients with hepatic impairment, loperamide should be used with caution in such patients because of reduced first pass metabolism as it may result in a relative over dosage leading to CNS toxicity.

Excipients

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

If patients are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome (IBS) 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.

Special Warnings to be included on the leaflet:

Only take this medicine to treat acute episodes of diarrhoea associated with Irritable Bowel Syndrome (IBS) 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

• you are aged 40 or over and your IBS symptoms are different this time

• you have recently passed blood from the bowel

• you suffer from severe constipation

• you are feeling sick or vomiting

• you have lost your appetite or lost weight

• you have difficulty or pain passing urine

• you have a fever

• 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.

Caution is needed in patients with a history of drug abuse. . Abuse and misuse of loperamide has been described (see section 4.9). Loperamide is an opioid with low bioavailability and limited potential to penetrate the blood brain barrier at therapeutic doses. However, addiction is observed with opioids as a class.

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

Effect of other medications on loperamide

In vitro studies have shown that loperamide is metabolised by cytochrome P450 3A4 and 2C8 enzymes and is a substrate for P-glycoprotein.

Opioid–like central nervous system effects have been reported in volunteer studies with concomitant administration of loperamide (16mg or 24mg single dose) with quinidine (600mg or 800mg). Quinidine may increase penetration of loperamide into the brain due to inhibition of central P-glycoprotein. The clinical significance of the pharmacokinetic interaction with P-glycoprotein inhibitors when loperamide is given at recommended dosages (2mg, up to 16mg maximum daily dose) is unknown.

Concomitant administration of loperamide 16 mg and ritonavir, an inhibitor of both P-glycoprotein and CYP3A4, resulted in a two to three-fold increase in the AUC of loperamide but without evidence of enhanced central nervous system effect.

The concomitant administration of loperamide (4mg 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 (16mg 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.

Effect of loperamide on other medications

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 the effect of loperamide and the drugs that accelerate gastrointestinal transit may decrease its effect.

4.6. Fertility, pregnancy and lactation

Fertility

The effect on human fertility has not been evaluated.

Pregnancy

Although there are no indications that loperamide possesses teratogenic or embryotoxic properties, the anticipated therapeutic benefits should be weighed against potential hazards before loperamide is given during pregnancy, especially during the first trimester.

Breast-Feeding

Small amounts of loperamide may appear in human breast milk. Therefore, loperamide 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

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).

4.8. Undesirable effects

Adults and children aged ≥ 12 years

The safety of loperamide hydrochloride 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); not known (cannot be estimated from the available data).

Table 1: Adverse Drug Reactions

System Organ Class

Indication

Common

Uncommon

Rare

Not known

Immune System Disorders

Hypersensitivity reactiona

Anaphylactic reaction (including Anaphylactic shock)a

Anaphylactoid reactiona

Nervous System Disorders

Headache

Dizziness

Somnolencea

Loss of consciousnessa

Stupora

Depressed level of consciousnessa

Hypertoniaa

Coordination

Abnormalitya

Eye Disorders

Miosisa

Gastrointestinal Disorders

Constipation

Nausea

Flatulence

Abdominal pain

Abdominal discomfort

Dry mouth

Abdominal pain upper

Vomiting

Dyspepsiaa

Ileusa (including paralytic ileus)

Megacolona (including toxic megacolonb)

Abdominal distension

acute pancreatitis

Skin and Subcutaneous Tissue Disorders

Rash

Bullous eruptiona (including Stevens- Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme)

Angioedemaa

Urticariaa

Pruritusa

Renal and Urinary Disorders

Urinary retentiona

General Disorders and Administration Site Conditions

Fatiguea

a: Inclusion of this term is based on post-marketing reports for loperamide hydrochloride. 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 hydrochloride (acute and chronic), including trials in children ≤ 12 years (N=3683).

b: See section 4.4.

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 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 than adults.

In individuals who have ingested overdoses of loperamide HCl, 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.

Upon cessation, cases of drug withdrawal syndrome have been observed in individuals abusing, misusing, or intentionally overdosing with excessively large doses of loperamide.

Treatment:

If symptoms of overdose occur, 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.