Safe

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. For the symptomatic treatment of chronic diarrhoea in adults.

For the symptomatic treatment of acute diarrhoea, in adults and children 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.

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.

Acute diarrhoea

Not recommended for children under 4 years of age.

There is limited data available regarding use in children below 12 years of age.

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

Chronic diarrhoea

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, Safe 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.

Posology:

Acute diarrhoea

Adults and children over 12:

2 capsules (4 mg) initially, followed by 1 capsule (2mg) after every loose stool.

The usual dose is 3-4 capsules (6 mg - 8 mg) a day. The total daily dose should not exceed 6 capsules (12 mg).

Symptomatic treatment of acute episodes of diarrhoea associated with irritable bowel syndrome in adults aged 18 and over

Two capsules (4 mg) to be taken initially, followed by 1 capsule (2mg) after every loose stool, or as previously advised by your doctor. The maximum daily dose should not exceed 6 capsules (12mg).

Paediatric population

Safe hydrochloride is contraindicated in children less than 12 years of age.

Elderly

No dose adjustment is required for the elderly.

Renal Impairment

No dose adjustment is required for patients with renal impairment.

Hepatic Impairment

Method of administration

Oral use. The capsules should be taken with liquid.

Posology:

Acute Diarrhoea

Adults and children aged 12 years and over:

The initial dose is 2 capsules (4 mg), followed by 1 capsule after every subsequent loose stool. The usual dose is 3-4 capsules (6-8 mg) a day. The total daily dose should not exceed 6 capsules (12 mg).

Paediatric population

Not to be given to children under 12 years of age.

Symptomatic treatment of acute episodes of diarrhoea associated with irritable bowel syndrome in adults aged 18 years and over

Two capsules (4 mg) to be taken initially, followed by 1 capsule (2 mg) after every loose stool, or as previously advised by your doctor. The maximum daily dose should not exceed 6 capsules (12 mg).

Elderly

No dose adjustment is required for the elderly.

Renal Impairment

No dose adjustment is required for patients with renal impairment.

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Method of administration

For oral use. The capsules should be swallowed with liquid.

Safe is contraindicated in:

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

- children less than 4 years of age.

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

-when ileus, constipation or abdominal distension develop,

- 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.

Safe should not be used alone in acute dysentery, which is characterised by blood in stools and elevated body temperatures.

This medicine is contraindicated:

-

- in children less than 12 years of age.

- 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.

Safe hydrochloride must 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. Safe hydrochloride must be discontinued promptly when ileus, constipation or abdominal distension develop.

This medicine is contraindicated:

-

- in children under the age of 12 years old.

- 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 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.

In patients with diarrhoea, especially young children, fluid and electrolyte depletion may occur. Use of Safe does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Treatment of diarrhoea with Safe is only symptomatic.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, Safe should not be used for prolonged periods of time and the underlying cause of the diarrhoea should be investigated if clinical improvement is not observed within 48 hours of initiating treatment. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.

Although no pharmacokinetic data are available in patients with hepatic impairment, Safe must be used with caution in these patients because of reduced first pass metabolism (eg in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity.

Safe must be discontinued promptly when constipation, abdominal distension or ileus develop.

Patients with AIDS treated with Safe for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.

Cardiac events including QT prolongation and torsades de pointes have been reported in association with overdose. Some cases had a fatal outcome. Patients should not exceed the recommended dose and/or the recommended duration of treatment.

Safe oral solution contains:

- glycerol: may cause headache, stomach upset and diarrhoea

- sodium saccharin (4.85 mg of sodium per 5 ml dose): To be taken into consideration by patients on a controlled sodium diet

- methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216): these may cause an allergic reaction (possibly delayed)

- cochineal red A (E124): may cause allergic reactions

- small amounts of ethanol (alcohol), less than 100 mg per dose

Treatment of diarrhoea with Safe 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 this medicine does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, this medicine 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 Safe hydrochloride should be discontinued and patients should be advised to consult their doctor.

Patients with AIDS treated with this medicine 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 Safe hydrochloride.

Although no pharmacokinetic data are available in patients with hepatic impairment, this medicine should be used with caution in such patients because of reduced first pass metabolism, as it may result in a relative overdose 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.

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 Safe 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.

Cardiac events including QT prolongation and torsades de pointes have been reported in association with overdose. Some cases had a fatal outcome. Patients should not exceed the recommended dose and/or the recommended duration of treatment.

Special Warnings to be included on the leaflet:

Only take this medicine to 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 if your symptoms have not improved over two weeks.

Treatment of diarrhoea with loperamide HCl 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 this medicine does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

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 Safe.

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.

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

Cardiac events including QT prolongation and torsades de pointes have been reported in association with overdose. Some cases had a fatal outcome. Patients should not exceed the recommended dose and/or the recommended duration of treatment.

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 to 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.

Loss of consciousness, depressed level of consciousness, tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with Safe. Therefore, it is advisable to use caution when driving a car or operating machinery.

Loss of consciousness, depressed level of consciousness, tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with this medicine.

Loss of consciousness, depressed level of consciousness, tiredness, dizziness or drowsiness may occur 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.

The safety of loperamide hydrochloride was evaluated in 3076 adults and children aged >12 years who participated in 31 controlled and uncontrolled clinical trials of loperamide hydrochloride 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 reactions in clinical trials with loperamide hydrochloride 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) adverse reactions were: flatulence (2.8%), constipation (2.2%), nausea (1.2%) and dizziness (1.2%).

Table 1 displays adverse reactions that have been reported with the use of loperamide hydrochloride from either clinical trials (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 Reactions

A number of the adverse reactions reported during the clinical investigations and post-marketing experience with loperamide hydrochloride 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 difficult to distinguish from undesirable drug effects.

Paediatric population

The safety of loperamide hydrochloride was evaluated in 607 patients aged 10 days to 13 years, who participated in 13 controlled and uncontrolled clinical trials of loperamide hydrochloride used for the treatment of acute diarrhoea. In general, the adverse reactions profile in this patient population was similar to that seen in clinical trials of loperamide hydrochloride 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.yellowcard.mhra.gov.uk.

Adults and children aged >12 years

The safety of Safe hydrochloride was evaluated in 2755 adults and children aged > 12 years who participated in 26 controlled and uncontrolled clinical trials of Safe HCl used for the treatment of acute diarrhoea.

The most commonly reported (i.e., >1% incidence) adverse drug reactions (ADRs) in clinical trials with Safe hydrochloride 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 Safe 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

a: Inclusion of this term is based on post-marketing reports for Safe 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 Safe HCl (acute and chronic), including trials in children ≤ 12 years (N=3683).

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.

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

a: Inclusion of this term is based on post-marketing reports for loperamide HCl. As the process for determining postmarketing ADRs did not differentiated 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).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 than adults.

In individuals who have ingested overdoses of loperamide HCl, cardiac events such as QT interval prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest and syncope have been observed. Fatal cases have also been reported.

Treatment

In cases of overdose, ECG monitoring for QT interval prolongation should be initiated.

If the patient develops respiratory depression, airway obstruction, vomiting with impaired consciousness or other CNS symptoms of overdose, give naloxone urgently. 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. Other measures should be as indicated by the patient's clinical condition.

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.

In individuals who have ingested overdoses of Safe HCl, cardiac events such as QT interval prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest and syncope have been observed. Fatal cases have also been reported.

Management:

If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of Safe 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.

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 and patients with hepatic dysfunction may be more sensitive to CNS effects.

In individuals who have ingested overdoses of loperamide HCl, cardiac events such as QT interval prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest and syncope have been observed. Fatal cases have also been reported.

Management:

In cases of overdose, ECG monitoring for QT interval prolongation should be initiated.

If CNS 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 CNS depression.

Pharmacotherapeutic Group: Antipropulsives; ATC code: A07DA03

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

Pharmacotherapeutic Group: Antipropulsives; ATC code: A07DA03

Safe binds to the opiate receptor in the gut wall, reducing propulsive peristalsis, increasing intestinal transit time and enhancing resorption of water and electrolytes. Safe increases the tone of the anal sphincter, which helps reduce faecal incontinence and urgency.

In a double blind randomised clinical trial in 56 patients with acute diarrhoea receiving Safe, onset of antidiarrhoeal 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 Safe.

Pharmacotherapeutic group: Antipropulsives: ATC code A07DA03

By binding to opiate receptors in the gut wall, Safe reduces propulsive peristalsis, increases intestinal transit time and enhances resorption of water and electrolytes. Loperamide increases the tone of the anal sphincter, which helps reduce faecal incontinence and urgency.

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.

Absorption: Most ingested loperamide is absorbed from the gut, but as a result of significant first pass metabolism, systemic bioavailability is only approximately 0.3%.

Distribution: Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of loperamide is 95%, mainly to albumin. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.

Metabolism: Loperamide is almost completely extracted by the liver, where it is predominantly metabolised, conjugated and excreted via the bile.

Oxidative N-demethylation is the main metabolic pathway for loperamide, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.

Elimination: The half-life of loperamide in man is about 11 hours with a range of 9-14 hours. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.

Paediatric Population: No pharmacokinetic studies were performed in the paediatric population. It is expected that pharmacokinetic behaviour of loperamide and drug-drug interactions with loperamide will be similar to those in adults.

Absorption: Most ingested Safe is absorbed from the gut, but as a result of significant first pass metabolism, systemic bioavailability is only approximately 0.3%.

Distribution: Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of Safe is 95%, mainly to albumin. Non-clinical data have shown that Safe is a P-glycoprotein substrate.

Metabolism: Safe is almost completely extracted by the liver, where it is predominantly metabolized, conjugated and excreted via the bile. Oxidative N-demethylation is the main metabolic pathway for Safe, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.

Elimination: The half-life of Safe in man is about 11 hours with a range of 9-14 hours. Excretion of the unchanged Safe and the metabolites mainly occurs through the faeces.

Absorption

Most ingested loperamide is absorbed from the gut, but as a result of significant first pass metabolism, systemic bioavailability is only approximately 0.3%.

Distribution

Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of loperamide is 95%, mainly to albumin. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.

Metabolism

Loperamide is almost completely extracted by the liver, where it is predominantly metabolised, conjugated and excreted via the bile. Oxidative N-demethylation is the main metabolic pathway for loperamide, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.

Elimination

The half-life of loperamide in man is about 11 hours with a range of 9-14 hours. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.

Paediatric population

No pharmacokinetic studies were performed in the paediatric population. It is expected that pharmacokinetic behaviour of loperamide and drug-drug interactions with loperamide will be similar to those in adults.

Not applicable.

None known.

None known.

No special requirements.

No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

No special requirements

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