SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Normaloe 2mg Tablets

Loperamide Hydrochloride 2mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMSITION

Each tablet contains 2mg of Loperamide hydrochloride

Excipients with known effect: Each tablet contains approximately 110mg of lactose monohydrate

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablets.

White, round, biconvex tablet with an approximate diameter of 6.35 mm, marked ‘T3’ on one side, scored on reverse

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

Symptomatic treatment of acute diarrhoea of any aetiology.

4.2 Posology and method of administration

Tablets to be taken orally with liquid. Adults and Children over 12 years

Acute diarrhoea

The initial dose is two tablets (4mg) for adults and one tablet (2mg) for children followed by one tablet (2mg) after every subsequent loose stool for up to five days.

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

Children

Under 12 years not recommended

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

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 HCl should be used in caution with such patients because of the 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 should not be used in children under 2 years of age.

•    Loperamide 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.

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. 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 rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because it contains lactose.

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 Hcl.

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.

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

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.

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, 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. 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 Pregnancy and lactation

Pregnancy

Safety in human pregnancy has not been established. Although studies in animals have not demonstrated that loperamide Hcl possesses any any teratogenic or embyogenic 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 during pregnancy, especially during the first trimester.

Breast-feeding

Although the level of loperamide secreted in human breast milk is low, 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 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 acute 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 System Organ Class

			Acute + Chronic
	Acute	Chronic	Diarrhoea
	Diarrhoea	Diarrhoea	and post-
	(N=2755)	(N=321)	marketing experience
Immune System Disorders
Hypersensitivity reaction3, Anaphylactic reaction (including Anaphylactic shock)a, Anaphylactoid reactiona			Rare
Nervous System Disorders Headache	Common	Uncommon	Common
Dizziness	Uncommon	Common	Common
Somnolence*1 Loss of consciousnessa,			Uncommon
Stupora, Depressed level of consciousness*1,			Rare
Hypertoniaa, Coordination abnormality*1
Eye Disorders Miosisa			Rare
Gastrointestinal Disorders Constipation, Nausea, Flatulence	Common	Common	Common
Abdominal pain, Abdominal discomfort,	Uncommon	Uncommon	Uncommon
Dry mouth Abdominal pain upper, Vomiting	Uncommon		Uncommon
Dyspepsia*1 Ileusa (including paralytic ileus),		Uncommon	Uncommon
Megacolona (including toxic megacolonb),			Rare
Glossodyniaa Abdominal distension	Rare		Rare
Skin and Subcutaneous Tissue Disorders Rash	Uncommon		Uncommon
Skin and Subcutaneous Tissue Disorders

System Organ Class	Indication
	Acute Diarrhoea (N=2755)	Chronic Diarrhoea (N=321)	Acute + Chronic Diarrhoea and postmarketing experience
Urticaria3, Pruritus3 Bullous eruption*1 (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme), Angioedemaa,			Rare
Renal and Urinary Disorders Urinary retention*1			Rare
General Disorders and Administration Site Conditions Fatiguea			Rare

a: Inclusion of this term is based on post-marketing reports for loperamide. 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 (acute and chronic) 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.

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 internet at www.mhra.gov.uk/yellowcard.

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 and respiratory depression).

Treatment

If symptoms of overdose occur, 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. Therefore, 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 PHARMACOLOGICAL PROPERTIES

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 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 conjugated and 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. 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.

6    PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Magnesium stearate, Lactose monohydrate, Povidone

6.2. Incompatibilities

None

6.3    Shelf Life

4 years.

6.4    Special Precautions for Storage

Store below 25°C in the original package in order to protect from light and moisture.

6.5    Nature and contents of container

PVC/aluminium foil blister pack containing 10,20, or 30 tablets (10 tablets per blister strip) in an outer cardboard carton.

PVC/aluminium foil and blister packs containing 6, 12, or 18 tablets (6 tablets per blister strip) in an outer cardboard carton.

A patient information leaflet will be enclosed.

Not all pack sizes may be marketed

6.6    Special precautions for disposal and other handling

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Limited 3 Howard Road Eaton Socon

St. Neots Cambs. PE198ET

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0025

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 March 1995 Date of latest renewal: 22 July 2004

10    DATE OF REVISION OF THE TEXT

11/06/2015