This information is intended for use by health professionals

1. Name of the medicinal product

Loperamide 2 mg tablets

2. Qualitative and quantitative composition

Each tablet contains 2 mg loperamide hydrochloride.

Excipients with known effects:

Each tablet contains 100 mg lactose monohydrate.

Each tablet contains 0.42 mg sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

Light green coloured capsule shaped, biconvex uncoated tablets with '2' debossed on one side and score line on other side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical particulars
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 9 years. For the symptomatic treatment of chronic diarrhoea in adults.

4.2 Posology and method of administration

Posology

Acute diarrhoea

Adults and children over 12 years

Two tablets (4 mg) initially, followed by one tablet (2 mg) after every loose stool. The usual dosage is 3-4 tablets (6 mg-8 mg) per day. The maximum daily dose should not exceed 8 tablets (16 mg).

Children 9 to 12 years

One tablet (2 mg) four times daily until diarrhoea is controlled (up to 5 days). This dose should not be exceeded.

Further investigation into the cause of the diarrhoea should be considered if there is no improvement within two days of starting treatment with loperamide.

Chronic diarrhoea

Adults

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, loperamide may be administered on a twice daily regimen. Tolerance has not been observed and therefore subsequent dosage adjustment should be unnecessary.

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

Method of administration

Oral use. The tablets should be taken with liquid.

4.3 Contraindications

Loperamide is contraindicated in:

• patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients listed in section 6.1.

• children less than 9 years of age.

• Loperamide should not be used as the primary therapy:

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

o patients with acute ulcerative colitis.

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

o patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics.

Loperamide should 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 constipation, abdominal distension or ileus develop.

4.4 Special warnings and precautions for use

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 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 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 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 from both viral and bacterial pathogens treated with loperamide.

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. Patients with hepatic dysfunction should be monitored closely for sign of central nervous system (CNS) toxicity.

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'.

To be used with caution in children or in patients with a low sodium diet.

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

Cardiac events including QT prolongation and torsades de pointes have been reported in association with overdose. Some cases had a fatal outcome (see section 4.9). 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, 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 possesses 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 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.

Fertility

There is no relevant data to demonstrate the effect of loperamide on human fertility. Only high doses of loperamide hydrochloride affected female fertility in non-clinical studies (see section 5.3).

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).

4.8 Undesirable effects

Adults and children aged ≥ 12 years

The safety of loperamide was evaluated in 3076 adults and children aged ≥ 12 years who participated in 31 controlled and uncontrolled clinical trials of loperamide 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 reactions 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 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 Drug Reactions

System Organ Class

Indication

Acute Diarrhoea (N=2755)

Chronic Diarrhoea (N=321)

Post-marketing Experience

Immune System Disorders

Hypersensitivity reaction

Anaphylactic reaction (including Anaphylactic shock)

Anaphylactoid reaction

Rare

Nervous System Disorders

Headache

Common

Uncommon

Dizziness

Uncommon

Common

Somnolence

Uncommon

Loss of consciousness,

Stupor,

Depressed level of consciousness,

Hypertonia,

Coordination abnormality.

Rare

Eye Disorders

Miosis

Rare

Gastrointestinal Disorders

Constipation,

Nausea,

Flatulence

Common

Common

Abdominal pain,

Abdominal discomfort,

Dry mouth,

Uncommon

Uncommon

Abdominal pain upper,

Vomiting.

Uncommon

Dyspepsia.

Uncommon

Abdominal distension,

Rare

Ileus (including paralytic ileus),

Megacolon (including toxic megacolon- see section 4.4),

Glossodynia

Rare

Skin and Subcutaneous Tissue Disorders

Rash

Uncommon

Bullous eruption (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme)

Angioedema

Urticaria

Pruritus

Rare

Renal and Urinary Disorders

Urinary retention

Rare

General Disorders and Administration Site Conditions

Fatigue

Rare

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 was evaluated in 607 patients aged 10 days to 13 years who participated in 13 controlled and uncontrolled clinical trials of loperamide used for the treatment of acute diarrhoea. In general, the adverse reaction profile (ADR) profile in this patient population was similar to that seen in clinical trials of loperamide 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 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 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.

Management

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, 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 any possible CNS depression. Other measures should be as indicated by the patient's clinical condition.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antipropulsives

ATC code: A07DA03

Mechanism of action

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.

Clinical efficacy and safety

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 results of significant first pass metabolism, systemic bioavailability is only approximately 0.3%.

Distribution

Studies on distribution in rats show high affinity for the gut wall with a preference for binding to the receptors in 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.

Biotransformation

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 effects, plasma concentrations of unchanged drug remain extremely low.

Elimination

The half-life of loperamide in man is about 11 hours with a range of 9-14 hours. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.

Paediatric population:

No pharmacokinetic studies were performed in the paediatric population. It is expected that pharmacokinetic behaviour of loperamide and drug-drug interactions with loperamide will be similar to those in adults.

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 – 240 times the maximum human use level) loperamide impaired fertility and foetal survival in association with maternal toxicity in rats. Lower doses had no effects on maternal or foetal 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

Maize starch,

Lactose monohydrate,

Povidone (K-30),

Brilliant Blue FCF (E133),

Quinoline Yellow (E104),

Magnesium stearate,

Talc,

Colloidal anhydrous silica,

Sodium starch glycolate (Type A),

Purified water.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

Clear PVC/PVdC film/Aluminium blister strips. The blister strips are packed in cartons to contain 12 or 30 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal

7. Marketing authorisation holder

Cipla (EU) Limited

Dixcart House

Addlestone Road

Bourne Business Park,

Addlestone, Surrey,

KT15 2LE

United Kingdom

8. Marketing authorisation number(s)

PL 36390/0111

9. Date of first authorisation/renewal of the authorisation

04/05/2011

10. Date of revision of the text

03/12/2018