SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Loperamide Hydrochloride Capsules 2mg Asda Diarrhoea Relief 2mg Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Loperamide Hydrochloride USP: 2mg.

3    PHARMACEUTICAL FORM

Hard Gelatin Capsule.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Loperamide is indicated as an adjunct to rehydration therapy 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 4 years. Also indicated for chronic diarrhoea in adults.

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 diarrhoea has been investigated.

As a Pharmacy Medicine

Loperamide is indicated only for the treatment of acute diarrhoea, for up to 5 days, in adults and children over 12 years.

As a GSL medicine

Loperamide is indicated only for the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over. The duration of treatment should not exceed 24 hours, without seeking the advice of a doctor.

4.2 Posology and method of administration

Oral

The capsules should be taken with liquid. Acute Diarrhoea - GSL

Adults and children over 12 years: Initial dose is two capsules (4mg), followed by one capsule after each loose stool. The usual dosage is 3 to 4 capsules a day. If symptoms persist for longer than 24 hours, the advice of a doctor should be sought.

The maximum daily dose should not exceed six capsules (12mg) daily for adults and children over 12 years.

Acute Diarrhoea - P

Adults and children over 12 years: Initial dose is two capsules (4mg) for adults and one capsule (2 mg) for children, followed by one capsule (2mg) after every subsequent loose stool for up to five days.

The usual dosage is three to four capsules (6 - 8mg) a day. The maximum dose for acute diarrhoea is eight capsules (16 mg) daily for adults; in children it must be related to the body weight (3 capsules/20 kg) but should not exceed eight capsules (16mg).

Acute Diarrhoea - POM

Adults and Children over 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 usual dosage is three to four capsules (6 - 8mg) a day; the maximum dose for acute diarrhoea is eight capsules (16mg) daily for adults: in children it must be related to the body weight (3 capsules/20kg) but should not exceed eight capsules (16mg).

Children 4-8 years: The capsule preparation is not suitable for children under 9 years. A suitable alternative presentation of loperamide should be used in these patients.

Children under 2 years: Loperamide HCl should not be used in children under 2 years of age.

Chronic Diarrhoea - POM

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

The maximum dose for chronic diarrhoea is eight capsules (16 mg) daily.

Children: Loperamide is not recommended for treatment of chronic diarrhoea in children.

POM, P and GSL

Use in elderly: acute and chronic diarrhoea - as for adults 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 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).

4.3 Contraindications

•    Loperamide is contraindicated in patients with a known hypersensitivity to loperamide HCl or to any of the excipients.

•    Loperamide HCl should not be used in children under 2 years of age.

•    Loperamide HCl should not be used as the primary therapy:

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

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 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 particularly in severely dehydrated children

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. Loperamide should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated, as persistent diarrhoea can be an indicator of potentially more serious condition.

In patients with diarrhoea, especially children, fluid and electrolyte depletion may occur. Use of loperamide does not preclude the administration of appropriate fluid and electrolyte replacement therapy. Loperamide should not be given to children aged 2 to 6 years of age without medical prescription and supervision.

In acute diarrhoea, if clinical improvement is not observed within 48 hours, the administration of loperamide HCl should be discontinued and patients should be advised to consult their physician.

Although no pharmacokinetic data are available in patients with hepatic impairment, loperamide should be used with caution in patients with hepatic dysfunction, .Its considerable first-pass metabolism in the liver could result in relative overdosage, leading to CNS toxicity.

Patients with inflammatory bowel disease receiving loperamide should be carefully observed for signs of toxic megacolon.

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 hydrochloride.

The simultaneous use of antipsychotics with anticholinergic properties causing constipation, and antimotility drugs such as loperamide in patients, with gastroenteritis, should be carefully evaluated. Patients on such a combination should be closely monitored.

Concurrent intake of quinidine, and loperamide, may induce signs of respiratory depression.

Also for P use only

If symptoms persist for more than 24 hours, consult your doctor.

If you are taking loperamide to control episodes of diarrhoea associated with Irritable Bowel Syndrome diagnosed by your doctor, you should return to him/her if the pattern of your symptoms changes. You should also return to your doctor if your episodes of acute symptoms continue for more than two weeks or there is a need for continuous treatment of more than two weeks.

The first line of treatment in acute diarrhoea is the prevention or treatment of fluid and electrolyte depletion. This is of particular importance in frail and elderly patients with acute diarrhoea.

If symptoms persist for more than 24 hours, consult your doctor.

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. Furthermore, it is metabolised by CYP34A and CYP2C8. Concomitant administration of loperamide (16 mg single dose) with quinidine, digoxin, ritonavir or tipranavir, which are P-glycoprotein inhibitors, , resulted in a 2 to 3-fold increase in loperamide plasma levels,. The clinical relevance of these pharmacokinetic interactions, when loperamide is given concomitantly with P-glycoprotein inhibitors, at recommended dosages (2 mg, up to 16 mg maximum daily dose), is unknown. However, these interactions could contribute to the development of serious toxic effects, and abuse potential”.

Concomitant administration of loperamide (4 mg single dose) with itraconazole (CYP 3A4 and and P-glycoprotein inhibitor) resulted in a 3 to 4-fold increase in loperamide plasma concentrations , In the same study gemfibrozil (CYP 2C8 inhibitor) increased loperamide by approximately 2-fold.resulted in an increase in loperamide plasma levels. 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.

Loperamide increases plasma concentrations (3-fold increase) of oral desmopressin 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

Use in pregnancy: Safety in human pregnancy has not been established. Although studies in animals have not demonstrated teratogenic or embryotoxic effects. The anticipated therapeutic benefits should be weighed against

potential hazards before loperamide is given during pregnancy, especially during the first trimester . As with other drugs, it is not advisable to administer Loperamide in pregnancy.

Use during lactation: Although the quantity of Loperamide secreted in human milk is extremely low, loperamide is not recommended during breast-feeding.

4.7 Effects on ability to drive and use machines

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 drug reactions (ADRs) in clinical trials with loperamide 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) ADRs were: flatulence (2.8%), constipation (2.2%), nausea (1.2%) and dizziness (1.2%).

Table 1 displays ADRs that have been reported with the use of loperamide from either clinical trial (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

	Indication
			Acute +
System Organ	Acute	Chronic	Chronic Diarrhoea
Class	Diarrhoea	Diarrhoea	and post-
	(N=2755)	(N=321)	marketing experience
Immune System Disorders
Hypersensitivity reactiona,
Anaphylactic reaction (including Anaphylactic shock)a, Anaphylactoid reactiona			Rare
Nervous System Disorders Headache	Common	Uncommon	Common
Dizziness	Uncommon	Common	Common
Somnolencea Loss of consciousnessa, Stupora, Depressed			Uncommon
level of consciousnessa, Hypertoniaa, Coordination abnormalitya			Rare
Eye Disorders Miosisa			Rare
Gastrointestinal Disorders
Constipation, Nausea, Flatulence	Common	Common	Common
Abdominal pain, Abdominal discomfort, Dry mouth	Uncommon	Uncommon	Uncommon
Abdominal pain upper, Vomiting	Uncommon		Uncommon
Dyspepsia		Uncommon	Uncommon

System Organ Class	Indication
	Acute Diarrhoea (N=2755)	Chronic Diarrhoea (N=321)	Acute + Chronic Diarrhoea and postmarketing experience
Ileusa (including paralytic ileus), Megacolona (including toxic megacolonb), Glossodyniaa Abdominal distension	Rare		Rare Rare
Skin and Subcutaneous Tissue Disorders Rash	Uncommon		Uncommon
Skin and Subcutaneous Tissue Disorders Urticariaa, Pruritusa Isolated occurrences of Bullous eruptiona (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme), Angioedemaa,			Rare
Renal and Urinary Disorders isolated reports of Urinary retentiona			Rare
General Disorders and Administration Site Conditions Fatiguea			Rare

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 combined, including trials in children <12 years (N=3683).

b: See section 4.4 Special Warnings and Special Precautions for use.

For clinical trial ADRs where no frequency is presented, the term was not observed or considered an ADR for this indication.

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 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.

4.9 Overdose

Symptoms

In cases of overdosage (including relative overdose due to hepatic dysfunction) the following effects may be observed - constipation, urinary retention, ileus and neurological symptoms (CNS depression - stupor, coordination abnormality, miosis, muscular hypertonia, somnolence, respiratory depression and bradypnoea).

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. Give oral activated charcoal, provided the airway can be protected, if a substantial amount has been ingested within 2 hours.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antipropulsives ATC - code: A07DA03

Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis, increasing intestinal transit time and enhancing resorption of water and electrolytes. It does not change the physiological flora. Loperamide increases the tone of the anal sphincter. It does not act centrally because, due to its high affinity for the gut wall and its high first pass metabolism, very little reaches the systemic circulation.

5.2 Pharmacokinetic properties

The half-life of Loperamide in man is 10.8 hours, with a range of 9-14 hours. 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 well absorbed from the gut, but is almost completely extracted and metabolised by the liver where it is excreted via the bile. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low. Excretion occurs mainly through the faeces.

5.3 Preclinical safety data

There is no evidence of teratogenicity with Loperamide.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose BP Maize starch BP Talc BP

Magnesium stearate BP

Capsule shell Cap:

Gelatin

Yellow orange S (E110) Patent blue (E131) Titanium dioxide (E171)

Body:

Gelatin

Erythrosine (127) Indigotine (E132) Yellow orange S (E110) Titanium dioxide (E171)

6.2 Incompatibilities

None known.

6.3    Shelf life

36 months.

6.4    Special precautions for storage

Do not store above 25°C , protect from light.

6.5 Nature and contents of container

Blister Strips PVC: 250 micron Aluminium Foil:20 micron.

Prescription only medicine-30, 60 Pack size.

Pharmacy Medicine- 8, 10, 12, 18 or 30 Pack size.

GSL- 6 Pack size.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Limited 3 Howard Road Eaton Socon St. Neots

Cambs. PE198ET

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0151

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/07/2006

10 DATE OF REVISION OF THE TEXT

19/05/2015