SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Asda Anti-Diarrhoea Instants 2 mg Orodispersible Tablets

Boots Diarrhoea Relief Instant-Melts 2 mg Orodispersible Tablets Entrocalm Instants Diarrhoea Relief 2 mg Orodispersible Tablets Galpharm Diarrhoea Relief Instants 2 mg Orodispersible Tablets

Superdrug Diarrhoea Relief Instant-Melts 2 mg Orodispersible Tablets Tesco Anti-Diarrhoea Instants 2 mg Orodispersible Tablets Numark Diarrhoea Relief Instants 2 mg Orodispersible Tablets Sainsbury’s Healthcare Anti-Diarrhoea Instants 2 mg Orodispersible Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Loperamide hydrochloride 2 mg per orodispersible tablet.

For excipients see Section 6.1.

3 PHARMACEUTICAL FORM

Orodispersible Tablet

Flat round white, uncoated, orodispersible tablets.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over.

For the symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome in adults aged 18 years and over following initial diagnosis by a doctor.

4.2 Posology and method of administration

The orodispersible tablets should be placed on the tongue. The tablet will dissolve and is to be swallowed with saliva. No liquid intake is needed for the orodispersible tablet.

Acute Diarrhoea:

Adults and children 12 years and over:

2 tablets initially followed by 1 tablet after every loose stool. The maximum daily dose should not exceed 6 tablets

Symptomatic treatment of acute episodes of diarrhoea associated with irritable bowel syndrome:

Adults aged 18 years and over:

Two tablets initially, followed by 1 tablet after every loose stool, or as previously advised by your doctor. The maximum daily dose should not exceed 6 tablets.

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 4.4 special Warnings and Special precautions for use).

Method of administration:

Oral use. Allow the tablet to disintegrate on the tongue and swallow the medication.

4.3 Contraindications

Patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.

Children under 12 years of age

When inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon, toxic megacolon and certain poisonings, in particular:

•    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 hydrochloride 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

Treatment of diarrhoea with loperamide hydrochloride 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 hydrochloridedoes not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, loperamide hydrochlorideshould 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 hydrochlorideshould be discontinued and patients should be advised to consult their doctor.

Loperamide hydrochloride must be used with caution when the hepatic function necessary for the drug's metabolism is defective (eg in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity.

Patients with AIDS treated with loperamide hydrochloridefor 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.

If patients are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome 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 loperamide hydrochlorideto treat acute episodes of diarrhoea associated with Irritable Bowel Syndrome 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

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

•    If you have recently passed blood from the bowel

•    If you suffer from severe constipation

•    If you are feeling sick or vomiting

•    If you have lost your appetite or lost weight

•    If you have difficulty or pain passing urine

•    If you have a fever

•    If you have recently travelled abroad

Consult your doctor if you develop new symptoms, if your symptoms worsen, or your symptoms have not improved over two weeks.

4.5 Interaction with other medicinal products and other forms of interaction

Non-clinical data have shown that loperamide hydrochloride is a P-glycoprotein substrate. Furthermore, loperamide is mainly metabolisedby CYP3A4 and CYP2C8.

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 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 although no clinical effects were reported.

Possible interactions may occur with drugs that delay intestinal peristalsis (for instance anti-cholinergic drugs) because the effects of loperamide could be enhanced.

Administration of itraconazole with loperamide (4 mg single dose) increased loperamide plasma levels 3- to 4-fold. In addition, gemfibrozil, a CYP2C8 inhibitor, increased the AUC of loperamide 2-fold. Concomitant use of itraconazole and gemfibrozil with loperamide raised the mean Cmax and AUC of loperamide about 2-and 13-fold, respectively. This increase did not lead to measurable CNS effects.

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.

The clinical relevance of these pharmacokinetic interactions, when loperamide is given at recommended dosages (2 mg, up to 12 mg maximum daily dose), is unknown.

4.6    Pregnancy and lactation

Pregnancy

A limited amount of data from the use of loperamide in pregnant women is available. In one of two epidemiological studies the use of loperamide during early pregnancy suggested a possible moderate increased risk for hypospadia, however, an increased risk for major malformations could not be identified. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

If possible the use of loperamide should be avoided during the first trimester of pregnancy, however, it may be used during the second and third trimester of pregnancy

Lactation

Only very small amounts of loperamide hydrochloride may appear in human breast milk. Therefore, Loperamide Galpharm 2mg Capsules may be used during breast feeding when dietary measures are insufficient and a drug-induced inhibition of intestinal motility is indicated.

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 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
Immune System Disorders			Hypersensitivity reaction*1 Anaphylactic reaction (including Anaphylactic shock)*1 Anaphylactoid reaction*1
Nervous System Disorders	Headache Dizziness	Somnolence3	Loss of consciousness*1 Stupor*1 Depressed level of consciousness*1 Hypertonia*1 Coordination abnormality*1
Eye Disorders			Miosis*1
Gastrointestinal Disorders	Constipation Nausea Flatulence	Abdominal pain Abdominal discomfort Dry mouth Abdominal pain upper Vomiting Dyspepsia*1	Ileus*1 (including paralytic ileus) Megacolona (including toxic megacolonb) Glossodyniaa Abdominal distension

System Organ Class	Indication
	Common	Uncommon	Rare
Skin and Subcutaneous Tissue Disorders		Rash	Bullous eruption3 (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme) Angioedemaa Urticaria*1 Pruritus*1
Renal and Urinary Disorders			Urinary retention*1
General Disorders and Administration Site Conditions			Fatigue*1

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.

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.

Treatment:

If 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 any possible depression of the central nervous system.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Antipropulsives;

ATC Code: A07DA03

Loperamide hydrochloride is a synthetic opioid which inhibits gut motility by binding to opiate receptors in the gut wall and may also reduce gastrointestinal secretions, resulting in improvement in diarrhoea symptoms.

Loperamide also increases the tone of the anal sphincter. Onset of antidiarrhoeal effect occurred as soon as one hour after intake of a 4 mg dose of loperamide.

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

Loperamide hydrochloride is well absorbed from the gut. 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 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 hydrochloride reaches the systemic circulation.

The half-life of loperamide hydrochloride in man is about 11 hours with a range of 9 -14 hours. Excretion takes place mainly via faeces.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

Acute and chronic studies on loperamide showed no specific toxicity.

Loperamide had no effect on fertility in male rats when administered orally prior to mating at doses up to approximately 40 mg/kg. No pregnancy occurred in females dosed with approximately 40 mg/kg. Lower doses (approximately 10 and 2.5mg/kg) did not affect female fertility. In rabbits no differences in pregnancy rate were observed when females were administered orally up to 40mg/kg.

No malformations of offspring were noted in rats and rabbits dosed up to 40 mg/kg. Loperamide did not show genotoxic potential.

In an 18-month carcinogenicity study in rats, with doses up to 100 times the maximum human dose no evidence of carcinogenesis was found.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Citric Acid, Anhydrous Croscarmellose Sodium Crospovidone Magnesium Stearate Mannitol

Peppermint Flavour Silica, Colloidal Anhydrous Silica, Colloidal Hydrated Starch, Pregelatinised Sucralose

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years

6.4    Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

Aluminium/Aluminium foil blisters. Each blister contains 6 orodispersible tablets. The blisters are packed into cardboard cartons.

Pack size: 6 or 12 orodispersible tablets.

6.6 Special precautions for disposal

Not applicable

7. MARKETING AUTHORISATION HOLDER

Galpharm Healthcare Limited

Wrafton

Braunton

Devon

EX33 2DL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16028/0155

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/08/2012

10 DATE OF REVISION OF THE TEXT

11/09/2014