4.1. Therapeutic indications

For 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 6 years. For the symptomatic treatment of chronic diarrhoea in adults.

4.2. Posology and method of administration

Posology

Acute diarrhoea

Adults and children over 6 years of age:

Two tablets initially, followed by one tablet after each loose stool. The usual dose is 3-4 tablets a day. The total daily dose should not exceed 8 tablets.

Children between the ages of 2 and 5 years:

These tablets are not recommended for children between 2 and 5 years.An alternative formulation (Oral solution/liquid) of Loperamide suitable for children should be administered in this patient population.

Children under 2 years of age:

Loperamide is contraindicated in children under 2 years of age.

Chronic Diarrhoea

Adults

Studies have shown that patients may need widely differing amounts of loperamide. The starting dose should be between two and four tablets per day in divided doses, depending on severity. If required, this dose can be adjusted according to result up to a maximum of eight tablets daily.

Having established the patient's daily maintenance dose, the tablets may be administered on a twice daily regimen. Tolerance has not been observed and therefore subsequent dosage adjustment should be unnecessary.

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, Loperamide 2mg Tablets should be used with caution in such patients because of reduced first pass metabolism (see 4.4 Special warnings and precautions for use).

Method of administration

Oral use.

4.3. Contraindications

Loperamide 2mg Tablets are contraindicated in:

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

• children less than 6 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:

Loperamide hydrochloride must be discontinued promptly when ileus or constipation are present or when abdominal distension develops, particularly in severely dehydrated children,

• 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 2mg Tablets 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

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

Treatment of diarrhoea with Loperamide 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 Loperamide 2mg Tablets does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, Loperamide 2mg Tablets should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated.

Loperamide HCl should not be given to children aged 2 to 6 years of age without medical prescription and supervision. Loperamide 2mg Tablets must be used with caution when the hepatic function necessary for the drug's metabolism is defective (e.g. in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity.

Patients with AIDS treated with Loperamide 2mg Tablets 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.

This medicine contains lactose and sodium

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

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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 physician.

Hepatic impairment

Although no pharmacokinetic data are available in patients with hepatic impairment, Loperamide hydrochloride should be used with caution in such patients because of reduced first pass metabolism.

QT prolongation

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.

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 (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 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.

The results of one published pharmacokinetic study suggested that the concomitant administration of loperamide with oral desmopressin may result in a 3-fold increase of desmopressin plasma concentrations presumably due to slower gastrointestinal motility, although no clinical effects were reported.

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 studies in animals have not demonstrated any teratogenic effects or embryotoxic properties, the anticipated therapeutic benefits should be weighed against potential hazards before loperamide HCl is given during pregnancy, especially during the first trimester. As with other drugs, it is not advisable to administer Loperamide 2mg Tablets in pregnancy.

Breast-feeding

Small amounts of loperamide may appear in human breast milk. Therefore, Loperamide 2mg Tablets 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

Tiredness, dizziness, or drowsiness may occur in the setting of diarrheal syndromes when diarrhoea is treated with Loperamide 2mg Tablets. 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

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 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 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 the following effects may be observed (including relative overdose due to hepatic dysfunction), CNS depression (stupor, coordination abnormality, respiratory depression) constipation, urinary retention, ileus and neurological symptoms (miosis, muscular hypertonia, somnolence and bradypnoea). Children may be more sensitive to CNS effects than adults.

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

If intoxication is suspected, naloxone may 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, 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. Children, and patients with hepatic dysfunction, may be more sensitive to CNS effects. Gastric lavage, or induced emesis and or enema or laxatives may be recommended.