- Approval Id
- a5f67d41544780ed
- Drug Approval Emc Name
- Loperamide 2mg Capsules
- Drug Name
- Loperamide 2mg Capsules
- Company Name
- Aurobindo Pharma - Milpharm Ltd.
- Company Address
- Odyssey Business Park, Ares Block, West End Road, South Ruislip, Middlesex, HA4 6QD
- Company Website
- http://www.aurobindo.com
- Company Telephone
- + 44 (0)208 845 8811
- Company Medical Info Email
- medinfo@aurobindo.com
- Company Customer Care Direct Line
- +44 (0)208 845 8811
- Company Medical Info Fax
- +44 (0)208 845 8795
- Atc Code
- A07DA03
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Milpharm Limited
Ares Block, Odyssey Business Park
West End Road
South Ruislip HA4 6QD
United Kingdom
- Authorisation Number
- PL 16363/0534
- Authorisation Date
- 23/05/2018/ 12/03/2025
- Instruction Authorisation Holder
- Milpharm Limited
Ares Block, Odyssey Business Park
West End Road
South Ruislip HA4 6QD
United Kingdom
- Instruction Authorisation Number
- PL 16363/0534
- Instruction Authorisation Date
- 23/05/2018/ 12/03/2025
- Instruction Composition
- Each hard capsule contains 2 mg of loperamide hydrochloride.
Excipient with known effect:
Each hard capsule contains 144.6 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Hard capsule,
White opaque cap/White opaque body, size '4' hard gelatin capsule shells, imprinted with '2'on cap and 'L' on body with black ink filled with white to off-white powder.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
For 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.4.2 Posology and method of administration
Posology:
\*\*ACUTE DIARRHOEA\*\*
Adults and children over 12 years of age:
Two capsules (4 mg) initially, followed by one capsule (2 mg) after each 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 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).
\*Paediatric population\*
Loperamide 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\*
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 (see section 4.4 Special warnings and precautions for use).
\*Method of administration\*
Oral use. The capsules should be taken with liquid.4.3 Contraindications
This medicine is contraindicated:
• hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• 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.
Loperamide 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. Loperamide hydrochloride must be discontinued promptly when ileus, constipation or abdominal distension develop.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 hydrochloride 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 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 hydrochloride should be discontinued and patients should be advised to consult their doctor.
Patients with AIDS treated with loperamide hydrochloride for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk of 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, 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 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.
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 drug 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.4.5 Interaction with other medicinal products and other forms of interaction
Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Furthermore, loperamide is mainly metabolised by CYP3A4 and CYP2C8.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 results of one published pharmacokinetic study suggested that the concomitant administration of loperamide with oral desmopressin may result in a 3-fold increase of desmopressin plasma concentrations although no clinical effects were reported.
Possible interactions may occur with drugs that delay intestinal peristalsis (for instance anti-cholinergic drugs) because the effects of loperamide could be enhanced.
Administration of itraconazole with loperamide (4 mg single dose) increased loperamide plasma levels 3- to 4-fold. In addition, gemfibrozil, a CYP2C8 inhibitor, increased the AUC of loperamide 2-fold. Concomitant use of itraconazole and gemfibrozil with loperamide raised the mean Cmax and AUC of loperamide about 2- and 13-fold, respectively. This increase did not lead to measurable CNS effects.
The concomitant administration of loperamide (16mg 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.
The clinical relevance of these pharmacokinetic interactions, when loperamide is given at recommended dosages (2 mg, up to 12 mg maximum daily dose), is unknown.4.6 Fertility, pregnancy and lactation
Pregnancy
A limited amount of data from the use of loperamide in pregnant women is available. In one of two epidemiological studies the use of loperamide during early pregnancy suggested a possible moderate increased risk for hypospadia, however, an increased risk for major malformations could not be identified. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Safety in human pregnancy has not been established, although from animal studies there are no indications that loperamide HCl possesses any teratogenic or embryotoxic properties.
If possible the use of loperamide should be avoided during the first trimester of pregnancy, however, it may be used during the second and third trimester of pregnancy
Breast-feeding
Small amounts of loperamide may appear in human breast milk. Therefore, this medicine is not recommended during breast-feeding. Women who are pregnant or breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.
Fertility
Only high doses of loperamide hydrochloride affected female fertility in non-clinical studies (see section 5.3).4.7 Effects on ability to drive and use machines
Loperamide hydrochloride has moderate influence on the ability to drive and use machines. Loss of consciousness, depressed level of consciousness, tiredness, dizziness or drowsiness may occur when diarrhoea is treated with loperamide hydrochloride.
Therefore, it is advisable to use caution when driving or operating machinery. (See section 4.8 Undesirable effects).4.8 Undesirable effects
\*Adults and children aged ≥ 12 years\*
The safety of loperamide hydrochloride was evaluated in 2755 adults and children aged ≥ 12 years who participated in 26 controlled and uncontrolled clinical trials of loperamide hydrochloride used for the treatment of acute diarrhoea.
The most commonly reported (i.e. ≥1% incidence) adverse drug reactions (ADRs) in clinical trials with loperamide 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 loperamide hydrochloride 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) and 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 | Ileusa (including paralytic ileus) Megacolona (including toxic megacolonb) Glossodyniaa 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\* | | | Fatiguea | |
a: Inclusion of this term is based on post‑marketing reports for loperamide hydrochloride. 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 hydrochloride (acute and chronic), including trials in children ≤ 12 years (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 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), urinary retention and ileus may occur. Children 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 (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 possible CNS depression.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Antipropulsives;
ATC code: A07DA03
Loperamide hydrochloride is a synthetic opioid which inhibits gut motility by binding to opiate receptors in the gut wall and may also reduce gastrointestinal secretions, resulting in improvement in diarrhoea symptoms.
Loperamide also increases the tone of the anal sphincter. Onset of antidiarrhoeal effect occurred as soon as one hour after intake of a 4 mg dose of loperamide.
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.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. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.
Biotransformation: 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.5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Acute and chronic studies on loperamide showed no specific toxicity.
Loperamide had no effect on fertility in male rats when administered orally prior to mating at doses up to approximately 40 mg/kg. No pregnancy occurred in females dosed with approximately 40 mg/kg. Lower doses (approximately 10 and 2.5mg/kg) did not affect female fertility. In rabbits no differences in pregnancy rate were observed when females were administered orally up to 40mg/kg.
No malformations of offspring were noted in rats and rabbits dosed up to 40 mg/kg. Loperamide did no show genotoxic potential.
In an 18-month carcinogenicity study in rats, with doses up to 100 times the maximum human dose no evidence of carcinogenesis was found.
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
\*Capsules content:\*
Lactose monohydrate
Maize Starch
Talc
Magnesium Stearate
\*Capsules shell:\*
Titanium Dioxide (E171)
Gelatin
\*Printing Ink:\*
Shellac
Black Iron Oxide (E172)6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
Store below 30°C.6.5 Nature and contents of container
Loperamide 2 mg hard capsules are available in clear PVC/Aluminium blisters pack.
\*\*Pack sizes:\*\*
Blister packs: 6, 8, 10, 12, 15, 18, 20, 30 & 50 hard capsules.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
No special requirements.
- Instruction Content
- ## Composition
Each hard capsule contains 2 mg of loperamide hydrochloride.
Excipient with known effect:
Each hard capsule contains 144.6 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Hard capsule,
White opaque cap/White opaque body, size '4' hard gelatin capsule shells, imprinted with '2'on cap and 'L' on body with black ink filled with white to off-white powder.
## Clinical Particulars
4.1 Therapeutic indications
For 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.4.2 Posology and method of administration
Posology:
\*\*ACUTE DIARRHOEA\*\*
Adults and children over 12 years of age:
Two capsules (4 mg) initially, followed by one capsule (2 mg) after each 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 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).
\*Paediatric population\*
Loperamide 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\*
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 (see section 4.4 Special warnings and precautions for use).
\*Method of administration\*
Oral use. The capsules should be taken with liquid.4.3 Contraindications
This medicine is contraindicated:
• hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• 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.
Loperamide 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. Loperamide hydrochloride must be discontinued promptly when ileus, constipation or abdominal distension develop.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 hydrochloride 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 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 hydrochloride should be discontinued and patients should be advised to consult their doctor.
Patients with AIDS treated with loperamide hydrochloride for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk of 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, 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 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.
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 drug 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.4.5 Interaction with other medicinal products and other forms of interaction
Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Furthermore, loperamide is mainly metabolised by CYP3A4 and CYP2C8.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 results of one published pharmacokinetic study suggested that the concomitant administration of loperamide with oral desmopressin may result in a 3-fold increase of desmopressin plasma concentrations although no clinical effects were reported.
Possible interactions may occur with drugs that delay intestinal peristalsis (for instance anti-cholinergic drugs) because the effects of loperamide could be enhanced.
Administration of itraconazole with loperamide (4 mg single dose) increased loperamide plasma levels 3- to 4-fold. In addition, gemfibrozil, a CYP2C8 inhibitor, increased the AUC of loperamide 2-fold. Concomitant use of itraconazole and gemfibrozil with loperamide raised the mean Cmax and AUC of loperamide about 2- and 13-fold, respectively. This increase did not lead to measurable CNS effects.
The concomitant administration of loperamide (16mg 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.
The clinical relevance of these pharmacokinetic interactions, when loperamide is given at recommended dosages (2 mg, up to 12 mg maximum daily dose), is unknown.4.6 Fertility, pregnancy and lactation
Pregnancy
A limited amount of data from the use of loperamide in pregnant women is available. In one of two epidemiological studies the use of loperamide during early pregnancy suggested a possible moderate increased risk for hypospadia, however, an increased risk for major malformations could not be identified. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Safety in human pregnancy has not been established, although from animal studies there are no indications that loperamide HCl possesses any teratogenic or embryotoxic properties.
If possible the use of loperamide should be avoided during the first trimester of pregnancy, however, it may be used during the second and third trimester of pregnancy
Breast-feeding
Small amounts of loperamide may appear in human breast milk. Therefore, this medicine is not recommended during breast-feeding. Women who are pregnant or breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.
Fertility
Only high doses of loperamide hydrochloride affected female fertility in non-clinical studies (see section 5.3).4.7 Effects on ability to drive and use machines
Loperamide hydrochloride has moderate influence on the ability to drive and use machines. Loss of consciousness, depressed level of consciousness, tiredness, dizziness or drowsiness may occur when diarrhoea is treated with loperamide hydrochloride.
Therefore, it is advisable to use caution when driving or operating machinery. (See section 4.8 Undesirable effects).4.8 Undesirable effects
\*Adults and children aged ≥ 12 years\*
The safety of loperamide hydrochloride was evaluated in 2755 adults and children aged ≥ 12 years who participated in 26 controlled and uncontrolled clinical trials of loperamide hydrochloride used for the treatment of acute diarrhoea.
The most commonly reported (i.e. ≥1% incidence) adverse drug reactions (ADRs) in clinical trials with loperamide 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 loperamide hydrochloride 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) and 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 | Ileusa (including paralytic ileus) Megacolona (including toxic megacolonb) Glossodyniaa 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\* | | | Fatiguea | |
a: Inclusion of this term is based on post‑marketing reports for loperamide hydrochloride. 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 hydrochloride (acute and chronic), including trials in children ≤ 12 years (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 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), urinary retention and ileus may occur. Children 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 (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 possible CNS depression.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Antipropulsives;
ATC code: A07DA03
Loperamide hydrochloride is a synthetic opioid which inhibits gut motility by binding to opiate receptors in the gut wall and may also reduce gastrointestinal secretions, resulting in improvement in diarrhoea symptoms.
Loperamide also increases the tone of the anal sphincter. Onset of antidiarrhoeal effect occurred as soon as one hour after intake of a 4 mg dose of loperamide.
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.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. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.
Biotransformation: 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.5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Acute and chronic studies on loperamide showed no specific toxicity.
Loperamide had no effect on fertility in male rats when administered orally prior to mating at doses up to approximately 40 mg/kg. No pregnancy occurred in females dosed with approximately 40 mg/kg. Lower doses (approximately 10 and 2.5mg/kg) did not affect female fertility. In rabbits no differences in pregnancy rate were observed when females were administered orally up to 40mg/kg.
No malformations of offspring were noted in rats and rabbits dosed up to 40 mg/kg. Loperamide did no show genotoxic potential.
In an 18-month carcinogenicity study in rats, with doses up to 100 times the maximum human dose no evidence of carcinogenesis was found.
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
\*Capsules content:\*
Lactose monohydrate
Maize Starch
Talc
Magnesium Stearate
\*Capsules shell:\*
Titanium Dioxide (E171)
Gelatin
\*Printing Ink:\*
Shellac
Black Iron Oxide (E172)6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
Store below 30°C.6.5 Nature and contents of container
Loperamide 2 mg hard capsules are available in clear PVC/Aluminium blisters pack.
\*\*Pack sizes:\*\*
Blister packs: 6, 8, 10, 12, 15, 18, 20, 30 & 50 hard capsules.
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
No special requirements.
