- Approval Id
- 30d08086cd416443
- Drug Approval Emc Name
- Loperamide Hydrochloride 2 mg Oral Lyophilisate
- Drug Name
- Loperamide Hydrochloride 2 mg Oral Lyophilisate
- Company Name
- Sigma Pharmaceuticals PLC (Special Concept Development / RxFarma)
- Company Address
- HD House, Imperial Way, North Watford, Hertfordshire, WD24 4LQ, UK
- Company Website
- http://www.sigmaplc.com/our-product-offerings/rxfa
- Company Telephone
- +44 (0)800 358 0163
- Company Medical Info Direct Line
- +44 (0)800 358 0163
- Company Medical Info Email
- medinfo@rxfarma.co.uk
- Company Customer Care Direct Line
- +44 (0)800 358 0163
- Atc Code
- A07DA03
- Legal Category
- Pharmacy
- Authorisation Holder
- Special Concept Development (UK) Limited T/A Rx Farma
Colonial Way, Watford, Hertfordshire,
WD24 4YR, United Kingdom
- Authorisation Number
- PL 36722/0200
- Authorisation Date
- 09/01/2025
- Instruction Authorisation Holder
- Special Concept Development (UK) Limited T/A Rx Farma
Colonial Way, Watford, Hertfordshire,
WD24 4YR, United Kingdom
- Instruction Authorisation Number
- PL 36722/0200
- Instruction Authorisation Date
- 09/01/2025
- Instruction Composition
- Loperamide Hydrochloride 2mg per Oral Lyophilisate
Excipients with known effect: 1.0 mg aspartame (E951) and sodium
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- oral lyophilisate.
White to off-white, round, lyophilised tablets, debossed with T on one side
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
For the symptomatic treatment of acute or chronic diarrhoea, when no effective causal therapy is possible in adults and children aged 12 years and over.
This treatment is a complement of dietary measures.4.2 Posology and method of administration
\*\*Posology\*\*
\*Adults and children 12 years and over:\*
\*\*\*Acute diarrhoea\*\*\*
Two tablets (4 mg) initially followed by 1 tablet (2 mg) after every loose stool. The usual dose is 3-4 tablets (6 mg-8 mg) daily; the maximum daily dose should not exceed 6 tablets (12 mg).
\*\*\*Symptomatic treatment of acute episodes of diarrhoea associated with irritable bowel syndrome in\*\* \*\*adults aged 18 years and over following diagnosis by a doctor.\*\*\*
Two tablets (4 mg) initially, followed by 1 tablet (2 mg) after every loose stool, or as previously advised by your doctor.
The maximum daily dose should not exceed 6 tablets (12 mg).
\*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, this medicine 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. Allow the tablet to disintegrate on the tongue and swallow the medication.
Loperamide hydrochloride Oral Lyophilisate should be placed on the tongue. The tablet will dissolve and is to be swallowed with saliva.
No liquid intake is needed for the oral lyophilizate.4.3 Contraindications
Loperamide is contraindicated:
• in patients with a known hypersensitivity to loperamide or to any of the excipients in children aged less than 12 years of age
• in patients with acute dysentery, which is characterised by blood in stools and elevated body temperature.
• 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 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 should be discontinued promptly when ileus or constipation are present or when abdominal distension develops.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.
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.
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.
In acute diarrhoea, if clinical improvement is not observed within 48 hours, the administration of loperamide should be discontinued and patients should be advised to consult their doctor.
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.
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, as it may result in a relative overdose leading to CNS toxicity.
If patients are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome (IBS) previously diagnosed by their doctor, and clinical improvement is not observed within 48 hours, the administration of loperamide 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 interval and QRS complex prolongation and torsades de pointes have been reported in association with overdose. Some cases had a fatal outcome (see section 4.9). Overdose can unmask existing Brugada syndrome. Patients should not exceed the recommended dose and/or the recommended duration of treatment.
Caution is needed in patients with a history of substance abuse. Abuse and misuse of loperamide, has been described (see section 4.9). Loperamide is an opioid with low bioavailability and limited potential to penetrate the blood brain barrier at therapeutic doses. However, addiction is observed with opioids as a class.
\*\*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.
Sulphites can cause allergy like reactions, most commonly asthma symptoms in those with underlying asthma. Allergic rhinitis like reactions, urticaria and anaphylaxis might be observed.
This medicine contains less than 1 mmol (23 mg) sodium per oral lyophilisate, that is to say essentially 'sodium-free'.
This medicine contains 1.0 mg aspartame in each 2 mg of Loperamide Hydrochloride Oral Lyophilisate. Aspartame is a source of phenylalanine. It may be harmful if you have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly4.5 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 from animal studies there are no indications that loperamide possesses any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer loperamide in pregnancy, especially during the first trimester.
\*\*Breast-Feeding\*\*
Small amounts of loperamide may appear in human breast milk. Therefore loperamide is not recommended during breast-feeding.
Women who are pregnant or breast-feeding should therefore be advised to consult their doctor for appropriate treatment.
\*\*Fertility\*\*
The effect on human fertility has not been evaluated.4.7 Effects on ability to drive and use machines
Loss of consciousness, depressed level of consciousness, tiredness, dizziness or drowsiness may occur in the setting of diarrheal syndromes treated with loperamide. 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 was evaluated in 2755 adults and children aged ≥ 12 years who participated in 26 controlled and uncontrolled clinical trials of loperamide used for the treatment of acute diarrhoea.
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%).
Table 1 displays ADRs that have been reported with the use of loperamide 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), not known (cannot be estimated from the available data)..
\*\*Table 1: Adverse Drug Reactions\*\*
| | | | | |
| --- | --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Indication\*\* | | | |
| \*\*Common\*\* | \*\*Uncommon\*\* | \*\*Rare\*\* | \*\*Not Known\*\* |
| \*\*Immune System Disorders\*\* | | | Hypersensitivity reactiona Anaphylactic reaction (including Anaphylactic shock)a Anaphylactoid reactiona | |
| \*\*Nervous System Disorders\*\* | Headache | Dizziness Somnolencea | Loss of consciousnessa Stupora Depressed level of consciousnessa Hypertoniaa Coordination abnormalitya | |
| \*\*Eye Disorders\*\* | | | Miosisa | |
| \*\*Gastrointestinal Disorders\*\* | Constipation Nausea Flatulence | Abdominal pain Abdominal discomfort Dry mouth Abdominal pain upper Vomiting Dyspepsiaa Dry Mouth | Ileusa (including paralytic ileus) Megacolona (including toxic megacolonb) Abdominal distension | Acute pancreatitis |
| \*\*Skin and Subcutaneous Tissue Disorders\*\* | | Rash | Bullous eruptiona (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme) Angioedemaa Urticariaa Pruritusa | |
| \*\*Renal and Urinary Disorders\*\* | | | Urinary retentiona | |
| \*\*General Disorders and Administration Site Conditions Site Conditions\*\* | | | Fatiguea | |
| 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), including trials in children ≤12years (N=3683). b: See section 4.4 Special Warnings and Special Precautions for use. | | | | |
\*\*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.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), 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 loperamide, cardiac events such as QT interval and QRS complex prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest and syncope have been observed (see section 4.4). Fatal cases have also been reported. Overdose can unmask existing Brugada syndrome. Upon cessation, cases of drug withdrawal syndrome have been observed in individuals abusing, misusing, or intentionally overdosing with excessively large doses of loperamide.
\*\*\*Treatment:\*\*\*
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 depression of the central nervous system.
- Instruction Pharmacology
- 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. 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 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 loperamide.5.2 Pharmacokinetic properties
\*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. Nonclinical data have shown that loperamide is a P-glycoprotein substrate.
\*Metabolism:\* loperamide 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 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.5.3 Preclinical safety data
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 – 20 times the maximum human use level (MHUL)), based on body surface area dose comparison (mg/m2), loperamide impaired fertility and foetal survival in association with maternal toxicity in rats. Lower doses (≥ 10mg/kg/day – 5 times MHUL) revealed no effects on maternal or foetal health and did not affect peri- and post-natal development.
Non-clinical in vitro and in vivo evaluation of loperamide indicates no significant cardiac electrophysiological effects within its therapeutically relevant concentration range and at significant multiples of this range (up to 47-fold). However, at extremely high concentrations associated with overdoses (see section 4.4), loperamide has cardiac electrophysiological actions consisting of inhibition of potassium (hERG) and sodium currents, and arrhythmias.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Pullulan (E1204)
Mannitol (E421)
Sodium hydrogen carbonate (E500)
Aspartame (E951)
Polysorbate 80 (E433)
Peppermint flavour (corn maltodextrin, flavouring ingredients and modified waxy maize starch, E1450)6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years6.4 Special precautions for storage
Store in the original package to protect from moisture. The medicinal product does not require any special temperature conditions.6.5 Nature and contents of container
Blister packaging in packs of 6 or 12 oral lyophilisates.
The blister comprising PVC/polyamide/aluminium/PVC blister with peel-off lidding of paper/PET/aluminium foil.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
Loperamide Hydrochloride 2mg per Oral Lyophilisate
Excipients with known effect: 1.0 mg aspartame (E951) and sodium
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
oral lyophilisate.
White to off-white, round, lyophilised tablets, debossed with T on one side
## Clinical Particulars
4.1 Therapeutic indications
For the symptomatic treatment of acute or chronic diarrhoea, when no effective causal therapy is possible in adults and children aged 12 years and over.
This treatment is a complement of dietary measures.4.2 Posology and method of administration
\*\*Posology\*\*
\*Adults and children 12 years and over:\*
\*\*\*Acute diarrhoea\*\*\*
Two tablets (4 mg) initially followed by 1 tablet (2 mg) after every loose stool. The usual dose is 3-4 tablets (6 mg-8 mg) daily; the maximum daily dose should not exceed 6 tablets (12 mg).
\*\*\*Symptomatic treatment of acute episodes of diarrhoea associated with irritable bowel syndrome in\*\* \*\*adults aged 18 years and over following diagnosis by a doctor.\*\*\*
Two tablets (4 mg) initially, followed by 1 tablet (2 mg) after every loose stool, or as previously advised by your doctor.
The maximum daily dose should not exceed 6 tablets (12 mg).
\*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, this medicine 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. Allow the tablet to disintegrate on the tongue and swallow the medication.
Loperamide hydrochloride Oral Lyophilisate should be placed on the tongue. The tablet will dissolve and is to be swallowed with saliva.
No liquid intake is needed for the oral lyophilizate.4.3 Contraindications
Loperamide is contraindicated:
• in patients with a known hypersensitivity to loperamide or to any of the excipients in children aged less than 12 years of age
• in patients with acute dysentery, which is characterised by blood in stools and elevated body temperature.
• 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 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 should be discontinued promptly when ileus or constipation are present or when abdominal distension develops.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.
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.
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.
In acute diarrhoea, if clinical improvement is not observed within 48 hours, the administration of loperamide should be discontinued and patients should be advised to consult their doctor.
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.
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, as it may result in a relative overdose leading to CNS toxicity.
If patients are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome (IBS) previously diagnosed by their doctor, and clinical improvement is not observed within 48 hours, the administration of loperamide 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 interval and QRS complex prolongation and torsades de pointes have been reported in association with overdose. Some cases had a fatal outcome (see section 4.9). Overdose can unmask existing Brugada syndrome. Patients should not exceed the recommended dose and/or the recommended duration of treatment.
Caution is needed in patients with a history of substance abuse. Abuse and misuse of loperamide, has been described (see section 4.9). Loperamide is an opioid with low bioavailability and limited potential to penetrate the blood brain barrier at therapeutic doses. However, addiction is observed with opioids as a class.
\*\*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.
Sulphites can cause allergy like reactions, most commonly asthma symptoms in those with underlying asthma. Allergic rhinitis like reactions, urticaria and anaphylaxis might be observed.
This medicine contains less than 1 mmol (23 mg) sodium per oral lyophilisate, that is to say essentially 'sodium-free'.
This medicine contains 1.0 mg aspartame in each 2 mg of Loperamide Hydrochloride Oral Lyophilisate. Aspartame is a source of phenylalanine. It may be harmful if you have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly4.5 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 from animal studies there are no indications that loperamide possesses any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer loperamide in pregnancy, especially during the first trimester.
\*\*Breast-Feeding\*\*
Small amounts of loperamide may appear in human breast milk. Therefore loperamide is not recommended during breast-feeding.
Women who are pregnant or breast-feeding should therefore be advised to consult their doctor for appropriate treatment.
\*\*Fertility\*\*
The effect on human fertility has not been evaluated.4.7 Effects on ability to drive and use machines
Loss of consciousness, depressed level of consciousness, tiredness, dizziness or drowsiness may occur in the setting of diarrheal syndromes treated with loperamide. 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 was evaluated in 2755 adults and children aged ≥ 12 years who participated in 26 controlled and uncontrolled clinical trials of loperamide used for the treatment of acute diarrhoea.
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%).
Table 1 displays ADRs that have been reported with the use of loperamide 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), not known (cannot be estimated from the available data)..
\*\*Table 1: Adverse Drug Reactions\*\*
| | | | | |
| --- | --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Indication\*\* | | | |
| \*\*Common\*\* | \*\*Uncommon\*\* | \*\*Rare\*\* | \*\*Not Known\*\* |
| \*\*Immune System Disorders\*\* | | | Hypersensitivity reactiona Anaphylactic reaction (including Anaphylactic shock)a Anaphylactoid reactiona | |
| \*\*Nervous System Disorders\*\* | Headache | Dizziness Somnolencea | Loss of consciousnessa Stupora Depressed level of consciousnessa Hypertoniaa Coordination abnormalitya | |
| \*\*Eye Disorders\*\* | | | Miosisa | |
| \*\*Gastrointestinal Disorders\*\* | Constipation Nausea Flatulence | Abdominal pain Abdominal discomfort Dry mouth Abdominal pain upper Vomiting Dyspepsiaa Dry Mouth | Ileusa (including paralytic ileus) Megacolona (including toxic megacolonb) Abdominal distension | Acute pancreatitis |
| \*\*Skin and Subcutaneous Tissue Disorders\*\* | | Rash | Bullous eruptiona (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme) Angioedemaa Urticariaa Pruritusa | |
| \*\*Renal and Urinary Disorders\*\* | | | Urinary retentiona | |
| \*\*General Disorders and Administration Site Conditions Site Conditions\*\* | | | Fatiguea | |
| 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), including trials in children ≤12years (N=3683). b: See section 4.4 Special Warnings and Special Precautions for use. | | | | |
\*\*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.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), 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 loperamide, cardiac events such as QT interval and QRS complex prolongation, torsades de pointes, other serious ventricular arrhythmias, cardiac arrest and syncope have been observed (see section 4.4). Fatal cases have also been reported. Overdose can unmask existing Brugada syndrome. Upon cessation, cases of drug withdrawal syndrome have been observed in individuals abusing, misusing, or intentionally overdosing with excessively large doses of loperamide.
\*\*\*Treatment:\*\*\*
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 depression of the central nervous system.
## 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. 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 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 loperamide.5.2 Pharmacokinetic properties
\*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. Nonclinical data have shown that loperamide is a P-glycoprotein substrate.
\*Metabolism:\* loperamide 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 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.5.3 Preclinical safety data
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 – 20 times the maximum human use level (MHUL)), based on body surface area dose comparison (mg/m2), loperamide impaired fertility and foetal survival in association with maternal toxicity in rats. Lower doses (≥ 10mg/kg/day – 5 times MHUL) revealed no effects on maternal or foetal health and did not affect peri- and post-natal development.
Non-clinical in vitro and in vivo evaluation of loperamide indicates no significant cardiac electrophysiological effects within its therapeutically relevant concentration range and at significant multiples of this range (up to 47-fold). However, at extremely high concentrations associated with overdoses (see section 4.4), loperamide has cardiac electrophysiological actions consisting of inhibition of potassium (hERG) and sodium currents, and arrhythmias.
## Pharmaceutical Particulars
6.1 List of excipients
Pullulan (E1204)
Mannitol (E421)
Sodium hydrogen carbonate (E500)
Aspartame (E951)
Polysorbate 80 (E433)
Peppermint flavour (corn maltodextrin, flavouring ingredients and modified waxy maize starch, E1450)6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years6.4 Special precautions for storage
Store in the original package to protect from moisture. The medicinal product does not require any special temperature conditions.6.5 Nature and contents of container
Blister packaging in packs of 6 or 12 oral lyophilisates.
The blister comprising PVC/polyamide/aluminium/PVC blister with peel-off lidding of paper/PET/aluminium foil.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
