NAME OF THE MEDICINAL PRODUCT

Loperamide Hydrochloride Capsules 2 mg Loperamide Diarrhoea Relief Capsules

Diaquitte Capsules (only when marketed by Peach Ethical Ltd)

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

The dosage form contains Loperamide Hydrochloride 2 mg.

Excipient with known effect: Lactose Monohydrate Each capsule contains 100 mg Lactose Monohydrate

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Capsule.

Hard gelatin capsules size 4 with a mauve opaque body and a dark green opaque cap. Marked “LOPERA-MIDE 2” on the cap.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Indications

Loperamide is indicated 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 8 years and 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 the diarrhoea has been investigated.

Indications

Loperamide HCl is indicated for the treatment of acute diarrhoea in persons aged 12 years and over.

Indications

Loperamide HCl is indicated for the symptomatic treatment of acute diarrhoea in persons aged 12 years and over.

4.2. Posology and method of administration

Oral

The capsules should be taken with liquid.

POM

P

GSL

Acute Diarrhoea

Adults and children aged 12 years and over:

The initial dose is 2 capsules (4 mg) for adults; followed by 1 capsule after every subsequent loose stool, for up to five days. The maximum recommended daily dose for acute diarrhoea is 8 capsules (16 mg) for adults in any 24 hours.

For GSL: The maximum daily dose should not exceed 6 capsules.

Children For POM only:

9-12 years: The maximum dose is 1 capsule four times daily until diarrhoea is controlled, for up to five days.

4-8 years: Loperamide hydrochloride capsules 2 mg cannot be divided and are therefore not recommended for use in children aged 4-8 years. A suitable alternative presentation of Loperamide should be used in these patients.

For GSL and P: Not to be given to children under 12 years

If there is no improvement within 24 hours of starting treatment further investigation of the cause of diarrhoea should be considered.

POM

P

GSL

Chronic diarrhoea

Adults: The initial dose is between2 capsules (4 mg) and 4 capsules (8 mg) daily in divided doses, depending on severity If required, this dose can be adjusted according to response.

The maximum recommended daily dose for chronic diarrhoea is 8 capsules (16 mg) for adults.

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

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

Use in elderly: Acute and chronic diarrhoea, as for adults - no dose adjustment is required..

Renal Impairment: No dose adjustment is required for patients with renal impairment.

Hepatic Impairment: Although no pharmacokinetics data is 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)

4.3. Contraindications

Loperamide HCl is contraindicated in patients with known hypersensitivity to the active substance,or to any of the excipients (listed in section 6.1).

Loperamide capsules are contraindicated in children under the age of 8 years old.

Loperamide HCl should not be used as the primary therapy:

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

•    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 must not be used when inhibition of peristalsis is to be avoided e.g. constipation, diverticular disease and ulcerative colitis due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. Loperamide HCl must be discontinued promptly when constipation, abdominal distension or ileus develop.

For GSL and P: Loperamide is not to be given to children under 12 years of age to treat acute diarrhoea.

4.4 Special warnings and precautions for use

Treatment of diarrhoea with loperamide HCl is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.

Loperamide 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.

Dehydration and electrolyte depletion can occur in patients with diarrhoea, particularly in children. In such cases administration of appropriate fluid and electrolyte replacement therapy is the most important measure. Loperamide HCl should not be given to children aged 2 to 6 years of age without medical prescription and supervision.

Persistent diarrhoea can be an indicator of potentially more serious conditions and as such 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 HCl should be discontinued and patients should be advised to consult their physician.

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.

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 signs of central nervous system (CNS) toxicity.

For P and GSL products:

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. This medicine must be used with caution in patients with hepatic impairment as it may result in a relative overdose leading to CNS toxicity.

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

For GSL: If symptoms persist for more than 24 hours, consult your doctor. Patients suffering from irritable bowel syndrome should not use this product. The first line of treatment in acute diarrhoea is prevention or treatment of fluid and electrolyte depletion. This is of particular importance in frail and elderly patients with diarrhoea.

This medicine is for the relief of the symptoms of diarrhoea and is not a substitute for oral rehydration therapy.

Loperamide capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 there are no indications that loperamide possesses teratogenic or embryotoxic properties, the anticipated therapeutic benefits should be weighed against potential hazards before loperamide is given during pregnancy, especially during the first trimester.

Breastfeeding

Small amounts of loperamide may appear in human breast milk. Therefore, loperamide HCl is not recommended during breastfeeding.

For P and GSL products:

It is not advisable to administer this medicine in pregnancy.

Women who are pregnant or breastfeeding should therefore be advised to consult their doctor for appropriate treatment.

4.7 Effects on ability to drive and use machines

Drowsiness, dizziness and tiredness have been observed when diarrhoea is treated with loperamide HCl. Therefore it is advisable to exercise caution when operating machinery or driving a car following administration of loperamide HCl (see section 4.8).

4.8 Undesirable effects

Adults and children aged > 12 years

The safety of loperamide HCl was evaluated in 3076 adults and children aged > 12 years who participated in 31 controlled and uncontrolled clinical trials of loperamide HCl 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 HCl 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 HCl 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
System Organ Class	Acute Diarrhoea (N=2755)	Chronic Diarrhoea (N=321)	Acute + Chronic Diarrhoea and post-marketing experience
Immune System Disorders
Hypersensitivity reaction3, Anaphylactic reaction (including Anaphylactic shock)*1, Anaphylactoid reaction*1			Rare
Nervous System Disorders
Headache	Common	Uncommon	Common
Dizziness	Uncommon	Common	Common
Somnolence*1			Uncommon
Loss of consciousness*1, Stupor*1, Depressed level of consciousness*1, Hypertonia*1, Coordination abnormality*1			Rare
Eye Disorders
Miosis*1			Rare
Gastrointestinal Disorders

	Indication
System Organ Class	Acute Diarrhoea (N=2755)	Chronic Diarrhoea (N=321)	Acute + Chronic Diarrhoea and post-marketing experience
Constipation, Nausea, Flatulence	Common	Common	Common
Abdominal pain, Abdominal discomfort, Dry mouth	Uncommon	Uncommon	Uncommon
Abdominal pain upper, Vomiting	Uncommon		Uncommon
Dyspepsia		Uncommon	Uncommon
Ileusa (including paralytic ileus), Megacolona (including toxic megacolonb), Glossodyniaa			Rare
Abdominal distension	Rare		Rare
Skin and Subcutaneous Tissue Disorders
Rash	Uncommon		Uncommon
Bullous eruptiona (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme), Angioedemaa, Urticariaa, Pruritusa			Rare
Renal and Urinary Disorders
Urinary retentiona			Rare
General Disorders and Administration Site Conditions
Fatiguea			Rare

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

b: See section 4.4

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 HCl was evaluated in 607 patients aged 10 days to 13 years who participated in 13 controlled and uncontrolled clinical trials of loperamide HCl 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 HCl in adults and children aged 12 years and over.

A number of other adverse events reported during the clinical investigations and postmarketing experience with loperamide 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 hard to distinguish from undesirable drug events.

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), urinary retention, constipation and ileus may occur. Children may be more sensitive to CNS effects than adults.

Treatment

Treatment would be symptomatic. 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 kept under constant observation 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

By binding to opiate receptors in the gut wall, loperamide hydrochloride reduces propulsive peristalsis, increases intestinal transit time and enhances resorption of water and electrolytes.

Loperamide inhibits peristalsis and is used in the treatment of some diarrhoeas. Studies remain to be done to show the value of Loperamide in acute infective diarrhoea. It should not be used to treat young children.

Loperamide is also used in ileostomy management to control the volume in discharge.

5.2 Pharmacokinetic properties

Following partial absorption in the gastrointestinal tract, loperamide undergoes first-pass metabolism in the liver and is excreted predominantly in the faeces. The elimination half-life is reported as about 10 hours.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to those already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Each capsule contains:

Lactose Monohydrate Maize Starch Magnesium Stearate

The capsule cap contains:

Quinoline Yellow Oxide (E104)

Indigo Carmine (E132)

Titanium Dioxide (E171)

Gelatin

The capsule body contains:

Erythrosin (E127)

Indigo Carmine (E132)

Black Iron Oxide (E172) Titanium Dioxide (E171) Gelatin

Printing ink contains:

Ammonium hydroxide (E527)

Povidone

Shellac

Simeticone

Sodium Hydroxide

Titanium dioxide (E171)

6.2 Incompatibilities

None known.

6.3.    Shelf life

5 years: Blister packaging 4 years: Polypropylene pots

6.4    Special precautions for storage

Store below 25°C.

Nature and contents of container

Blister packaging in packs of 4, 6, 8, 10, 12, 16, 18, 20, 24, 28, 30, 60, 250 or 500 capsules.

Polypropylene pots with white polyethylene caps with optional polyethylene ullage fillers in packs of 4, 6, 8, 10, 12, 18, 20, 28, 50, 100, 250 or 500 capsules.

Restriction on sale and supply:

Maximum pack size when marketed as a GSL medicine - 6 capsules.

6.6 Special precautions for disposal

There are no special instructions for use/handling.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited T/A Mylan Station Close Potters Bar Hertfordshire EN6 1TL

8.    MARKETING AUTHORISATION NUMBER

PL 04569/0201

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

17^th November 1987 / 29^th March 2000

10 DATE OF REVISION OF THE TEXT

08/09/2014