Document: spc-doc_PL 00289-1979 change

• spc-doc_PL 00289-1979
• spc-doc_PL 00289-1980

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Teva Diarrhoea Relief 2 mg Capsules Loperamide 2 mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 2 mg Loperamide Hydrochloride.

Excipient(s) with known effect:

This product contains lactose monohydrate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule, hard

Green and dark grey, size 4 capsules containing a fine white powder. Printed 'LOP2'.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Loperamide hydrochloride is indicated for the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over.

Loperamide hydrochloride is indicated for the symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome in adults following initial diagnosis by a doctor.

4.2 Posology and method of administration

For oral administration.

The capsules should be taken with liquid.

Acute diarrhoea

Adults and Children 12-17 years

The initial dose is 2 capsules (4 mg) for adults and 1 capsule (2 mg) for children; followed by 1 capsule (2 mg) after every subsequent loose stool.

The maximum dose is 8 capsules (16 mg) daily for adults; in children it must be related to the body weight (3 capsules/20 kg) but should not exceed a maximum of 8 capsules per day.

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

Symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome in adults

Two capsules to be taken initially. The usual dose is between 2 and 4 capsules per day in divided doses, depending on the severity. If required, this dose can be adjusted according to result, up to a maximum of 8 capsules daily.

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 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 a known hypersensitivity to

loperamide HCl or to any of the excipients listed in section 6.1.

•    Not to be used in children under 12 years of age.

•    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 HCl should not be used if inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon, toxic megacolon, constipation, abdominal distension particularly in severely dehydrated children, acute ulcerative colitis or pseudomembranous colitis associated with broad spectrum antibiotics. Loperamide HCl must be discontinued promptly when constipation, abdominal distension or ileus develop.

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.

In patients with diarrhoea, especially in children, fluid and electrolyte depletion may occur. The use of loperamide HCl does not preclude the need for appropriate fluid and electrolyte replacement therapy, which is essential in such patients. Loperamide HCl should not be given to children aged 2 to 6 years without medical prescription and supervision.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, loperamide hydrochloride 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 HCl 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 HCl 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.

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

If symptoms persist for more than 48 hours, consult your doctor.

Experience is lacking in patients with hepatic insufficiency. Loperamide HCl should be used with caution in such patients because of reduced first pass metabolism, which may result in overdose leading to CNS toxicity.

If you are taking loperamide hydrochloride 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.

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

It is not advisable to administer this medicine in pregnancy. Women who are pregnant or breast feeding should therefore be advised to consult their doctor for appropriate treatment.

4.7 Effects on ability to drive and use machines

Tiredness, dizziness, or drowsiness may occur in the setting of diarrhoeal syndromes treated with loperamide HCl. Therefore, it is advisable to use caution when driving a car or operating machinery.

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%).

List of adverse reactions

The data in Table 1 represent the results from 3076 adults and children aged >12 years of age 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 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: : Frequency of ADRs Reported with the Use of Loperamide HCl from Clinical

Trials in Adults and Children Aged > 12 Years of Age

System Organ Class	Indication
	Acute Diarrhoea (N=2755)	Chronic Diarrhoea (N=321)
Nervous system disorders
Headache	Common	Uncommon
Dizziness	Uncommon	Common
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
Skin and subcutaneous tissue disorders
Rash	Uncommon

Post-Marketing ADR Data

The process for determining post-marketing ADRs for loperamide HCl did not differentiate between chronic and acute diarrhoea indications or differentiate between adults or children; therefore, the ADRs listed below represents the combined indications and subject populations. The ADRs identified during post-marketing for loperamide HCl are listed below by System Organ Class and Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term (PT):

Immune system disorders:

Hypersensitivity reaction, anaphylactic reaction (including anaphylactic shock), and anaphylactoid reaction

Nervous system disorders:

Somnolence, loss of consciousness, stupor, depressed level of consciousness, hypertonia, and coordination abnormality

Eye disorders: Miosis

Gastrointestinal disorders:

Ileus (including paralytic ileus), megacolon (including toxic megacolon), and glossodynia

Skin and subcutaneous tissue disorders:

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

Renal and urinary disorder: Urinary retention

General disorders and administration site conditions: Fatigue

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.

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 overdosage (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 may be more sensitive to CNS effects than adults.

Treatment

Treatment is symptomatic and supportive. In patients who have not vomited, gastric lavage should precede the administration of activated charcoal. 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 possible CNS depression.

Children and patients with hepatic dysfunction may be more sensitive to the central nervous system effects. Neither forced diuresis nor haemodialysis is expected to be effective.

5.1 Pharmacodynamic properties

ATC Code: A07DA03 Antipropulsives.

Loperamide hydrochloride binds to the opiate receptor in the gut reducing propulsive peristalsis, increasing intestinal transit time. Loperamide hydrochloride increases the tone of the anal sphincter.

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 hydrochloride.

5.2 Pharmacokinetic properties

The half-life of loperamide hydrochloride 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 conjugated and excreted via the bile. Due to its high affinity for the gut wall and its high first pass metabolism, very little loperamide reaches the systemic circulation.

5.3 Preclinical safety data

Preclinical information has not been included because the safety profile of loperamide hydrochloride has been established after many years of clinical use. Please refer to section 4.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsules contain:

Maize starch Lactose monohydrate Povidone (E1201)

Sodium starch glycolate (Type A)

Magnesium Stearate (E572).

The capsule shell contains: Gelatin

Patent blue V (E131) Titanium dioxide (E171) Yellow iron oxide (E172).

The printing ink contains:

Shellac

Simeticone

Titanium dioxide (E171) Propylene glycol (E1520).

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 storage conditions.

6.5 Nature and contents of container

PVdC coated PVC film with hard temper aluminium foil strips in packs of 10 or 12 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

08/07/2016