Loperamide 2 mg Capsules, hard

Sigma Pharmaceuticals PLC (Special Concept Development / RxFarma)🇬🇧 Electronic Medicines Compendium

Approval Date: N/A
Approval ID: f4a0446d1edd6249
Company: Sigma Pharmaceuticals PLC (Special Concept Development / RxFarma)
Type: Standard

Approval Details

Approval Id: f4a0446d1edd6249
Drug Approval Emc Name: Loperamide 2 mg Capsules, hard
Drug Name: Loperamide 2 mg Capsules, hard
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: Prescription only medicine
Authorisation Holder: Special Concept Development (UK) Ltd T/A RxFarma Colonial Way, Watford, Hertfordshire, WD24 4YR, UK
Authorisation Number: PL 36722/0126
Authorisation Date: 18/04/2018
Instruction Authorisation Holder: Special Concept Development (UK) Ltd T/A RxFarma Colonial Way, Watford, Hertfordshire, WD24 4YR, UK
Instruction Authorisation Number: PL 36722/0126
Instruction Authorisation Date: 18/04/2018
Instruction Composition: Each capsule contains Loperamide hydrochloride 2 mg. \*\*Excipients with known effect\*\* Each capsule contains lactose 127 mg, sunset yellow (E110) 0.0235 mg and carmoisine (E122) 0.0115mg. For a full list of excipients, see section 6.1
Instruction Dosage Form: Capsule, hard (Capsule). Green/Mauve hard gelatin size '4' capsule filled with white to off-white powder.
Instruction Clinical Particulars: 4.1 Therapeutic indications 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.4.2 Posology and method of administration \*\*Posology\*\* The capsules should be taken with liquid. \*\*\*\*Acute diarrhoea\*\*\*\* Adults and children aged 12 years and over: Two capsules (4 mg) initially, followed by one capsule (2 mg) after each loose stool. The usual dose is 3 to 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 one 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). \*\*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, Loperamide capsules should be used with caution in such patients because of reduced first pass metabolism. (see section 4.4 ) \*\*Method of administration\*\* Oral use.4.3 Contraindications This medicine is contraindicated: • in patients with a known hypersensitivity to loperamide hydrochloride 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 characteri\*\*s\*\*ed 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 capsules 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 capsules must be discontinued promptly when ileus, constipation or abdominal distension develop.4.4 Special warnings and precautions for use Treatment of diarrhoea with Loperamide capsules 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. Caution is needed in patients with a history of drug abuse. Loperamide is an opioid and addiction is observed with opioids as a class. 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 Loperamide capsules 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 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. This medicine contains sunset yellow (E110) and carmoisine (E122) which may cause allergic reactions. 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, 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. \*\*Special Warnings to be included on the leaflet:\*\* Only take Loperamide capsules 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. 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 HCl possesses any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer this medicine in pregnancy, especially during the first trimester. \*\*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\*\* 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 when diarrhoea is treated with this medicine. Therefore, it is advisable to use caution when driving a car or operating machinery. See Section 4.8, Undesirable Effects.4.8 Undesirable effects \*\*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). | | | | | | --- | --- | --- | --- | | System Organ Class | Indication | | | | Common | Uncommon | Rare | | 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) Abdominal distension | | 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 HCl. As the process for determining post marketing ADRs did not differentiate between chronic and acute indications or adults and children, the frequency is estimated from all clinical trials with loperamide HCl (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 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 HCl, 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 been reported. Overdose can unmask existing Brugada syndrome. \*\*Treatment\*\*\*\*:\*\* In cases of overdose, ECG monitoring for QT interval prolongation should be initiated. If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.
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 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. 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 fetal survival in association with maternal toxicity in rats. Lower doses (≥ 10mg/kg/day – 5 times MHUL) revealed had no effects on maternal or fetal 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 Lactose monohydrate Maize starch Talc Magnesium stearate \*\*Capsule cap:\*\* Patent Blue E131 Quinoline Yellow E104 Sunset Yellow E110 Titanium dioxide E171 Gelatin Sodium laurilsulfate Purified water \*\*Capsule body:\*\* Carmoisine E122 Patent Blue E131 Sunset Yellow E110 Titanium dioxide E171 Gelatin Sodium laurilsulfate Purified water6.2 Incompatibilities Not applicable.6.3 Shelf life 36 months.6.4 Special precautions for storage Do not store above 30°C. Store in the original package.6.5 Nature and contents of container Blister packs consisting of aluminium foil/ PVC/PVDC film. The blister strips are packed in cardboard cartons to contain 18 or 30 capsules.6.6 Special precautions for disposal and other handling Not applicable.
Instruction Content: ## Composition Each capsule contains Loperamide hydrochloride 2 mg. \*\*Excipients with known effect\*\* Each capsule contains lactose 127 mg, sunset yellow (E110) 0.0235 mg and carmoisine (E122) 0.0115mg. For a full list of excipients, see section 6.1 ## Pharmaceutical Form Capsule, hard (Capsule). Green/Mauve hard gelatin size '4' capsule filled with white to off-white powder. ## Clinical Particulars 4.1 Therapeutic indications 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.4.2 Posology and method of administration \*\*Posology\*\* The capsules should be taken with liquid. \*\*\*\*Acute diarrhoea\*\*\*\* Adults and children aged 12 years and over: Two capsules (4 mg) initially, followed by one capsule (2 mg) after each loose stool. The usual dose is 3 to 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 one 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). \*\*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, Loperamide capsules should be used with caution in such patients because of reduced first pass metabolism. (see section 4.4 ) \*\*Method of administration\*\* Oral use.4.3 Contraindications This medicine is contraindicated: • in patients with a known hypersensitivity to loperamide hydrochloride 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 characteri\*\*s\*\*ed 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 capsules 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 capsules must be discontinued promptly when ileus, constipation or abdominal distension develop.4.4 Special warnings and precautions for use Treatment of diarrhoea with Loperamide capsules 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. Caution is needed in patients with a history of drug abuse. Loperamide is an opioid and addiction is observed with opioids as a class. 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 Loperamide capsules 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 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. This medicine contains sunset yellow (E110) and carmoisine (E122) which may cause allergic reactions. 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, 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. \*\*Special Warnings to be included on the leaflet:\*\* Only take Loperamide capsules 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. 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 HCl possesses any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer this medicine in pregnancy, especially during the first trimester. \*\*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\*\* 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 when diarrhoea is treated with this medicine. Therefore, it is advisable to use caution when driving a car or operating machinery. See Section 4.8, Undesirable Effects.4.8 Undesirable effects \*\*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). | | | | | | --- | --- | --- | --- | | System Organ Class | Indication | | | | Common | Uncommon | Rare | | 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) Abdominal distension | | 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 HCl. As the process for determining post marketing ADRs did not differentiate between chronic and acute indications or adults and children, the frequency is estimated from all clinical trials with loperamide HCl (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 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 HCl, 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 been reported. Overdose can unmask existing Brugada syndrome. \*\*Treatment\*\*\*\*:\*\* In cases of overdose, ECG monitoring for QT interval prolongation should be initiated. If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression. ## 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 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. 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 fetal survival in association with maternal toxicity in rats. Lower doses (≥ 10mg/kg/day – 5 times MHUL) revealed had no effects on maternal or fetal 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 Lactose monohydrate Maize starch Talc Magnesium stearate \*\*Capsule cap:\*\* Patent Blue E131 Quinoline Yellow E104 Sunset Yellow E110 Titanium dioxide E171 Gelatin Sodium laurilsulfate Purified water \*\*Capsule body:\*\* Carmoisine E122 Patent Blue E131 Sunset Yellow E110 Titanium dioxide E171 Gelatin Sodium laurilsulfate Purified water6.2 Incompatibilities Not applicable.6.3 Shelf life 36 months.6.4 Special precautions for storage Do not store above 30°C. Store in the original package.6.5 Nature and contents of container Blister packs consisting of aluminium foil/ PVC/PVDC film. The blister strips are packed in cardboard cartons to contain 18 or 30 capsules.6.6 Special precautions for disposal and other handling Not applicable.

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