Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 UKPAR TABLE OF CONTENTS Lay summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 13 Summary of product characteristics Page 14 Patient information leaflet Page 20 Labelling Page 22 Annex I Page 25 Annex II Page 31 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 IMODIUM LIQUID, 2 MG/15 ML ORAL SOLUTION PL 15513/0182 LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted a Marketing Authorisation (licence) for the medicinal product Imodium Liquid, 2 mg/15 ml oral solution (Product Licence number: 15513/0182). Imodium Liquid, 2 mg/15 ml oral solution is used to treat sudden, short-lived (acute) attacks of diarrhoea in adults and children aged 12 years and over. It can also be used to treat diarrhoea associated with Irritable Bowel Syndrome (IBS) in adults. Imodium Liquid, 2 mg/15 ml oral solution raised no clinically significant safety concerns and it was, therefore, judged that the benefits of using this product outweigh the risks; hence a Marketing Authorisation has been granted. 2 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 IMODIUM LIQUID, 2 MG/15 ML ORAL SOLUTION PL 15513/0182 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 5 Non-clinical assessment Page 7 Clinical assessment Page 8 Overall conclusions and risk benefit assessment Page 12 3 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted McNeil Products Ltd a Marketing Authorisation for the medicinal product Imodium Liquid, 2 mg/15 ml oral solution (PL 15513/0182) on 5 May 2010. This medicine is available without prescription from pharmacies. This application for Imodium Liquid, 2 mg/15 ml oral solution is submitted under Article 8.3 of EC Directive 2001/83 as a line extension application. This application cross-refers to Imodium Capsules (PL 00242/0028), licensed to Jansen-Cilag Limited since 17 March 1975. Imodium Liquid, 2 mg/ 15 ml oral solution is indicated for the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over and 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 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 PHARMACEUTICAL ASSESSMENT DRUG SUBSTANCE: LOPERAMIDE HYDROCHLORIDE Chemical Name: 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1piperidinebutanamide monohydrochloride Structure: Molecular Weight: 513.50 CAS Number: 034552-83-5 Molecular Formula: C29H33ClN2O2.HCl General Properties Loperamide hydrochloride is a white or almost white powder that is slightly soluble in water, freely soluble in alcohol and in methanol. The method of manufacture of loperamide hydrochloride is appropriate. The proposed drug substance specification and its justification, analytical procedures and their validation, batch analyses and reference standards used by the drug substance manufacturer are satisfactory. Satisfactory certificates of analysis have been provided for working standards used by the active substance manufacturer and finished product manufacturer during validation studies. Loperamide hydrochloride is stored in appropriate packaging. The specifications and typical analytical test reports are provided and are satisfactory. Appropriate stability data have been generated supporting the retest period. 5 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 DRUG PRODUCT Description The drug product is a drinkable solution, intended as a soothing formulation for people having difficulties swallowing capsules. The drug product contains propylene glycol, aspartame E951, opatint green dispersion, microcrystalline cellulose and carboxymethyl cellulose, xanthan gum, glycerol, anhydrous citric acid, sodium benzoate E211 and peppermint flavour. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation has been carried out and the results are satisfactory. Finished product specification The finished product specification is satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for any working standards used. Container Closure System The solution is stored in 90 ml polypropylene bottles with child resistant cap and polyethylene measuring cup. Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf-life of 2 years has been set, which is satisfactory. There are no special storage precautions. Product literature All product literature (SmPC, PIL and labelling) are satisfactory. The package leaflet was submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. Conclusion From a quality point of view, it is recommended that a Marketing Authorisation is granted for this application. 6 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 NON-CLINICAL ASSESSMENT No new non-clinical data have been supplied with this application and none are required for an application of this type. 7 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 CLINICAL ASSESSMENT INTRODUCTION This formulation has been developed as an alternative Imodium formulation for patients who prefer a liquid formulation. Clinical Background Loperamide is a synthetic piperidine which binds with high affinity to the µ-opiate receptor in the myenteric plexus within the muscular layers of the intestinal wall. It acts by slowing peristaltic activity, reducing intestinal motility and increasing mucosal contact time, allowing more complete absorption of electrolytes and water. Loperamide also increases the tone of the anal sphincter and inhibits fluid and electrolyte secretion in the small intestine. The net result is firmer stool passed less frequently. Proposed Indications The following indications are proposed: “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.” These indications are satisfactory. Proposed Dose and Dose Regimen The following posology is proposed: “Acute diarrhoea: Adults, the elderly, and children 12 years and over: 30 ml initially followed by 15 ml after every loose stool. The maximum daily dose should not exceed 90 ml. Symptomatic treatment of acute episodes of diarrhoea associated with irritable bowel syndrome Adults aged 18 years and over: 30 ml initially, followed by 15 ml after every loose stool, or as previously advised by your doctor. The maximum daily dose should not exceed 90 ml. 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, Imodium Liquid 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.” 8 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 This posology is satisfactory. CLINICAL PHARMACOLOGY Pharmacokinetics Overview The pharmacokinetics of loperamide have been well characterised. In summary, the half-life is 10.8 hours with a range of 9-14 hours. It is well absorbed from the gut, but is almost completely extracted and metabolised by the liver where it is conjugated and excreted via the bile. Due to its high affinity for the gut wall and its high first pass metabolism, very little loperamide reaches the systemic circulation. Most of the dose remains localised to the gut or is metabolised during first-pass. About 1 % is systemically available after oral administration. Excretion occurs mainly through the faeces. Less than 1 % of the dose is excreted unchanged in the urine. Bioequivalence A single centre, randomised, single dose, open-label, two-period crossover bioequivalence study was carried out. The proposed product (8 mg in 60 ml) and the reference product (4 x 2 mg capsules) were administered to healthy volunteers under fasting conditions. Thirty-two subjects were enrolled and 30 subjects (15 male, 15 female) completed the trial. The randomisation scheme is balanced for sequence and appears random. The study objective was to evaluate the pharmacokinetic characteristics and bioequivalence of the test formulation and the marketed reference formulation. The company has used a unit dose which is double the recommended dose approved for Imodium to ensure sufficient plasma levels for reliable quantification, given the low level of systemic exposure at therapeutic dose. Subjects were fasted for at least 10 hours prior to drug administration and for at least 4.5 hours after drug administration. The washout period between the two phases was 7 days. The pharmacokinetic parameters to be derived were AUC0-t, AUC0-∞, Cmax, tmax, Kel, MRT and t1/2. The protocol defines acceptance criteria for bioequivalence of 80 % - 125 % for both AUC and Cmax. In each study period, 16 blood samples were taken over 72 hours following dose administration. Concentrations of loperamide in plasma were measured using a validated chromatographic assay. Pharmacokinetic parameters were calculated from plasma concentration data. Population Studied Thirty-two subjects were enrolled and randomised. Two subjects were withdrawn from the study. One subject fainted following cannulation and the second patient was wheezing. Thirty subjects completed the whole study. Method of data analysis Data were presented with 90 % confidence intervals and intra-individual coefficients of variation. Comparisons of tmax, Kel, MRT and t1/2 were performed through descriptive statistics. The area under the plasma concentration versus time curve was calculated using a mixed log linear rule. Pharmacokinetic parameter calculations were conducted. ANOVA were performed on ln values of Cmax, AUC0-t and AUC0-∞ of loperamide. ANOVA were also 9 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 used to evaluate period, treatment and sequence effects. The arithmetic mean, geometric mean, standard deviation, coefficient of variation, absolute minimum, maximum and median were reported for each parameter. Results The primary objective of the study was to show bioequivalence of Imodium liquid and Imodium capsules. Log-transformed test/reference ratios with 90 % Confidence Intervals: Arithmetic Mean (± SD) Confidence intervals (%) Imodium liquid (treatment A) Imodium capsule (treatment B) Point estimate Cmax(ng/ml) 2.16 (0.79) 2.20 (0.85) 99.10 AUC0-t 35.55 (13.28) 36.04 (14.14) 99.88 37.84 (14.39) 38.60 (15.16) 98.94 (ng/ml.h) AUC0-∞ (ng/ml.h) 90 % confidence intervals 90.75108.21 93.36106.85 92.92105.35 There were no statistically significant treatment, sequence or period effects. No deaths, serious or significant adverse events were reported during the study. The study was carried out and the data analysed according to the protocol. There were no subjects with positive plasma concentrations at the start of period two, so the washout period was of adequate duration. Dropouts were handled according to study protocol. Conclusion The use of loperamide as an anti-diarrhoeal agent is well established. The Clinical Overview details the pharmacokinetics of loperamide, providing relevant bibliographic references on the clinical pharmacology, efficacy and safety of loperamide hydrochloride. The applicant has given an adequate description of the pharmacokinetics of loperamide to determine that, although it acts locally, some drug is absorbed systemically for a reliable assessment of bioavailability using a bioequivalence study. The bioequivalence study showed the 90 % confidence interval for AUC and Cmax ratio for the reference and test products to be within the acceptance range of 80 – 125 %. The result of this bioequivalence study is, therefore, adequate to conclude that this oral solution of loperamide is bioequivalent to the 2 mg capsule. 10 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 OVERALL CLINICAL CONCLUSION Pharmacokinetics The pharmacokinetic parameters obtained in this bioequivalence study are comparable for both formulations. Efficacy and safety No new efficacy or safety data are presented. The applicant has referred to the well established efficacy and safety of loperamide hydrochloride. The Overview provides a comprehensive review of the published literature. Risk Benefit The safety and efficacy of loperamide hydrochloride in the management of diarrhoea is well established. The applicant has provided a clinical study report of a bioequivalence study which demonstrates bioequivalence between their proposed product and a licensed capsule formulation of loperamide hydrochloride. The Clinical Overview gives details on the clinical pharmacology, efficacy and safety of loperamide hydrochloride with the appropriate references provided. From a clinical point of view, it is recommended that a Marketing Authorisation is granted for this application. 11 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Imodium Liquid, 2 mg/15 ml oral solution are well defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. EFFICACY The efficacy of loperamide hydrochloride is well established. The SmPC, PIL and labelling are satisfactory and consistent with those for the cross-reference product. RISK BENEFIT ASSESSMENT The quality of the product is acceptable, no significant non-clinical or clinical safety concerns were identified, and benefit has been shown to be associated with loperamide hydrochloride. The risk benefit is therefore considered to be positive. 12 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 IMODIUM LIQUID, 2 MG/15 ML ORAL SOLUTION PL 15513/0182 STEPS TAKEN FOR ASSESSMENT 1 2 3 4 5 6 7 The MHRA received the Marketing Authorisation application on 15 July 2008 Following standard checks and communication with the applicant the MHRA considered the application valid on 17 July 2008. Following assessment of the application the application was discussed by the Commission on Human Medicines (CHM) on 12 March 2009 The applicant responded to the CHM’s requests, providing further information on the dossier 8 October 2009 The applicant’s response was considered by the CHM and a request for further information was sent on 18 February 2010 The applicant responded to the CHM’s requests, providing further information on the dossier on 19 March 2010 The application was determined on 5 May 2010 13 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 STEPS TAKEN AFTER AUTHORISATION – SUMMARY The following table lists non-safety updates to the Marketing Authorisation for this product that have been approved by the MHRA since the product was first licensed. The update has been added as an annex to this PAR. This is not a complete list of the post-authorisation changes that have been made to this Marketing Authorisation. Date submitted 28/08/2011 Application type Type II Scope Outcome To harmonise the maximum treatment period for the currently approved indications by changing it for acute diarrhoea from 24 hours to 48 hours and for IBS-related diarrhoea from 3 days to 48 hours. Consequently, section 4.4 (Special warnings) of the SmPC and PIL are updated. There are also some minor changes to the PIL and labelling. Approved 27/11/2011 19/05/2012 Type IB To update section 5.2 (Pharmacokinetic Properties) of the SmPC in- line with reference product 'Imodium Plus caplets' (PL 15513/0342). Approved 23/07/2012 14 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT Imodium Liquid, 2 mg/ 15 ml oral solution 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Loperamide hydrochloride 2 mg per 15 ml. Excipients include: Aspartame (E951) For a full list of excipients, see section 6.1. 3 PHARMACEUTICAL FORM Oral solution Imodium Liquid is a green liquid. 4 4.1 CLINICAL PARTICULARS 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 Acute diarrhoea: Adults, the elderly, and children 12 years and over: 30 ml initially followed by 15 ml after every loose stool. The maximum daily dose should not exceed 90 ml. Symptomatic treatment of acute episodes of diarrhoea associated with irritable bowel syndrome Adults aged 18 years and over: 30 ml initially, followed by 15 ml after every loose stool, or as previously advised by your doctor. The maximum daily dose should not exceed 90 ml. 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, Imodium Liquid 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. 4.3 Contraindications Imodium Liquid is contraindicated in patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients. Imodium Liquid should not be used in children less than 12 years of age. Imodium Liquid 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, in particular: • • • • When ileus or constipation are present or when abdominal distension develops, particularly in severely dehydrated children 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 15 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 Imodium Liquid should not be used alone in acute dysentery, which is characterised by blood in stools and elevated body temperatures. 4.4 Special warnings and precautions for use 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 Imodium does not preclude the administration of appropriate fluid and electrolyte replacement therapy. Since persistent diarrhoea can be an indicator of potentially more serious conditions, Imodium Liquid should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated. Imodium Liquid must be used with caution when the hepatic function necessary for the drug’s metabolism is defective (e.g. in cases of severe hepatic disturbance), as this might result in a relative overdose leading to CNS toxicity. Patients with AIDS treated with Imodium Liquid for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride. If symptoms persist for more than 24 hours, patients should be advised to consult their physician. Patients taking Imodium to control episodes of diarrhoea associated with Irritable Bowel Syndrome previously diagnosed by a physician should be advised to return to their physician for medical advice if their pattern of symptoms changes. Patients should also return to their physician if episodes of diarrhoea continue for more than two weeks or there is a need for continued treatment of more than two weeks. Contains Aspartame (E951) a source of phenylalanine. May be harmful for people with phenylketonuria. Special Warnings to be included on the leaflet: Only take Imodium 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 40 years or over and it is some time since your last attack of IBS or the 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, or 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 Pglycoprotein 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 (2 mg, up to 16 mg maximum daily dose), is unknown. 4.6 Pregnancy and lactation Safety in human pregnancy has not been established although studies in animals have not demonstrated any teratogenic effects. As with other drugs, it is not advisable to administer loperamide in pregnancy. 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. 16 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 4.7 Effects on ability to drive and use machines Tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with loperamide. Therefore, it is advisable to use caution when driving a car or operating machinery. See Section 4.8 Undesirable effects. 4.8 Undesirable effects In clinical trials constipation and dizziness have been reported with greater frequency in loperamide hydrochloride treated patients than placebo treated patients. The following adverse experiences have also been reported, and within each system organ class, are ranked by frequency, using the following convention: Very common (>1/10), Common (>1/100, < 1/10), Uncommon (> 1/ 1,000, < 1/100), Rare (>1/10,000, < 1/1,000), Very rare (<1/10,000), including isolated reports. Skin and subcutaneous tissue disorders Very rare: rash, urticaria and pruritus. Isolated occurrences of angioedema, and bullous eruptions including Stevens-Johnson Syndrome, erythema multiforme, and toxic epidermal necrolysis. Immune system disorders Very rare: isolated occurrences of allergic reactions and in some cases severe hypersensitivity reactions including anaphylactic shock and anaphylactoid reactions. Gastrointestinal Disorders Very rare: abdominal pain, ileus, abdominal distension, nausea, constipation, vomiting, megacolon including toxic megacolon, flatulence, and dyspepsia. Renal and urinary disorders Very rare: isolated reports of urinary retention. Psychiatric system disorders Very rare: drowsiness Nervous system disorders Very rare: Loss of consciousness, depressed level of consciousness, dizziness A number of the adverse events reported during the clinical investigations and post-marketing experience with loperamide are frequent symptoms of the underlying diarrhoeal syndrome (abdominal pain/discomfort, nausea, vomiting, dry mouth, tiredness, drowsiness, dizziness, constipation, and flatulence). These symptoms are often difficult to distinguish from undesirable drug effects. 4.9 Overdose In case of overdose the following effects may be observed: constipation, urinary retention, ileus and neurological symptoms (miosis, muscular hypertonia, somnolence and bradypnoea). If intoxication is suspected, naloxone may be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone, the patient should be kept under constant observation for at least 48 hours in order to detect any possible depression of the central nervous system. Children, and patients with hepatic dysfunction, may be more sensitive to CNS effects. Gastric lavage, or induced emesis and or enema or laxatives may be recommended. 5 5.1 PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeutic group: Antipropulsives; ATC Code: A07DA03 Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter. 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 anti-diarrhoeal drugs confirmed this exceptionally rapid onset of action of loperamide. 17 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 5.2 Pharmacokinetic properties The half-life of loperamide in man is 10.8 hours with a range of 9 - 14 hours. Studies on distribution in rats show high affinity for the gut wall with preference for binding to the receptors in the longitudinal muscle layer. Loperamide is well absorbed from the gut, but is almost completely extracted and metabolised by the liver where it is conjugated and excreted via the bile. Due to its high affinity for the gut wall and its high first pass metabolism, very little loperamide reaches the systemic circulation. 5.3 Preclinical safety data 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 (40mg/kg/day - 240 times the maximum human use level) loperamide impaired fertility and foetal survival in association with maternal toxicity in rats. Lower doses had no effects on maternal or foetal health and did not affect peri- and post-natal development. 6 6.1 PHARMACEUTICAL PARTICULARS List of excipients Propylene glycol Aspartame E951 Opatint green dispersion Microcrystalline cellulose and carboxymethyl cellulose Xanthan gum Glycerol Anhydrous citric acid Sodium benzoate E211 Peppermint flavour. 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years unopened. 12 months opened. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Polypropylene bottle with child resistant cap and polyethylene measuring cup. Pack size: 90 ml. 6.6 Special precautions for disposal No special requirements 7 MARKETING AUTHORISATION HOLDER McNeil Products Ltd. Foundation Park Roxborough Way Maidenhead Berkshire SL6 3UG UK 8 MARKETING AUTHORISATION NUMBER(S) PL 15513/0182 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 05/05/2010 10 DATE OF REVISION OF THE TEXT 05/05/2010 18 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 PATIENT INFORMATION LEAFLET 19 UKPAR Imodium Liquid, 2 mg/15 ml Oral Solution PL 15513/0182 20 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 LABELLING Label: 21 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 Carton: 22 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 Annex I Reference: PL 15513/0182-variation 0004 Product: Imodium Liquid 2 mg/15 ml oral solution (GSL) Marketing Authorisation Holder: McNeil Products Limited Active Ingredient(s): Loperamide hydrochloride Reason To harmonise the maximum treatment period for both indications, before patients must consult a doctor i.e. change acute diarrhoea from 24 hours to 48 hours, and IBS-related diarrhoea from 3 days to 48 hours. Evaluation The first amendment to Section 4.4 proposes to increase the period of self-medication in acute diarrhoea from 24 to 48 hours before medical advice is sought. This is not likely to represent a significant safety concern provided ‘red flag’ symptoms are not present. Such symptoms are covered by the contraindications and special warnings. The SmPC and PIL highlight the importance of rehydration, particularly in children and frail or elderly patients, and the products are not licensed for use in children under the age of 12 years. This amendment also aligns the duration of use in the UK with that in the rest of the world. The second amendment to Section 4.4 proposes to decrease the period of self-medication in IBS-associated diarrhoea from 3 to 2 days, and clarifies the need to visit the physician if episodes of diarrhoea continue for more than 2 weeks. This amendment harmonises the period of self-medication with that for acute diarrhoea, and is endorsed. Satisfactory, updated SmPC fragment was submitted in support of the variation application. The variation was approved on 27 November 2011 and the following updated SmPC fragment, PIL and labelling have been incorporated into the Marketing Authorisation. Conclusion The proposed amendments to the SmPC, PIL and labelling are acceptable, and clarify the use of the products for patients, without altering the benefit-risk balance. 23 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 Summary of Product Characteristics - updated The SmPC fragment updated in-line with the variation is reproduced below: 4.4 Special warnings and precautions for use Treatment of diarrhoea with Imodium Liquid is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate. The priority in acute diarrhoea is the prevention or reversal of fluid and electrolyte depletion. This is particularly important in young children and in frail and elderly patients with acute diarrhoea. Use of this medicine does not preclude the administration of appropriate fluid and electrolyte replacement therapy. Since persistent diarrhoea can be an indicator of potentially more serious conditions, Imodium Liquid 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 Imodium Liquid 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. Contains Aspartame (E951) a source of phenylalanine. May be harmful for people with phenylketonuria. If patients are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome previously diagnosed by their doctor, and clinical improvement is not observed within 48 hours, the administration of loperamide HCl should be discontinued and they should consult with their doctor. Patients should also return to their doctor if the pattern of their symptoms changes or if the repeated episodes of diarrhoea continue for more than two weeks. Special Warnings to be included on the leaflet: Only take Imodium Liquid 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, or if your symptoms worsen, or your symptoms have not improved over two weeks. 24 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 Patient Information Leaflet – updated The following text is the approved Patient Information Leaflet (PIL) text. No PIL mock-ups have been provided. In accordance with medicines legislation, the product shall not be marketed in the UK until approval of the PIL mock-ups has been obtained. Imodium® Liquid loperamide This medicine is used for two different types of diarrhoea. They have different age limits. . See Section 1 Do not take this medicine: There are some people who should not use this medicine. To find out if you are one of them, see Section 2 If you have ever had a bad reaction to any of the ingredients. For the list of ingredients, see Section 6 Speak to your doctor: If you suffer from any of the conditions mentioned in Section 2 If you are taking any other medicines. See Section 2 If you have Irritable Bowel Syndrome (IBS) see also Section 2 Extra warnings for IBS patients Follow the dosage instructions carefully. See Section 3 Now read this whole leaflet carefully before you use this medicine. Keep the leaflet: you might need it again. 1 What the medicine is for Imodium Liquid is used to treat two types of diarrhoea. The two types have different age limits. Short-term diarrhoea For adults and children aged 12 and over. To treat attacks that last up to 48 hours. If your attack lasts longer than 48 hours, talk to your doctor. IBS diarrhoea For adults and young people aged 18 and over who have been diagnosed with IBS (Irritable Bowel Syndrome). To treat attacks that last up to 48 hours. You can use this medicine for up to 2 weeks for repeated attacks, but if any one attack lasts continuously for longer than 48 hours, talk to your doctor. The liquid contains loperamide hydrochloride, a substance that helps reduce diarrhoea by slowing down an overactive bowel. This allows water and salts that are usually lost in diarrhoea to be absorbed by the body. 25 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 2 Before taking this medicine Warnings for everyone This medicine is suitable for most people, but a few people should not use it: Do not take this medicine… If you have ever had a bad reaction to any of the ingredients. If it is for a child aged under 12 (or under 18 for an IBS patient). If you have severe diarrhoea after taking antibiotics. If you are having a flare-up of an inflammatory bowel condition like ulcerative colitis. If you are constipated, or your stomach appears swollen (especially in children with severe dehydration). If you have acute dysentery, the symptoms of which may include blood in your stools and a high temperature. If any of these applies to you, talk to a doctor or pharmacist and do not take Imodium. Talk to your doctor first… If you have AIDS and your stomach becomes swollen, stop taking the tablets immediately and contact your doctor. If you suffer from liver disease. If you have diarrhoea that lasts for more than 48 hours. If you have severe diarrhoea as your body loses more fluid, sugars and salts than normal. If you are taking any other medicines, including: ritonavir (used to treat HIV) quinidine (used to treat abnormal heart rhythms or malaria) oral desmopressin (used to treat excessive urination). itraconazole or ketoconazole (used to treat fungal infections) gemfibrozil (used to treat high cholesterol) If you are unsure about any of the medicines you are taking, show the bottle or pack to your pharmacist. If any of these applies to you (now or in the past), talk to a doctor or pharmacist. Pregnancy or breast-feeding If you are pregnant, think you are pregnant or planning a pregnancy: ask your doctor or pharmacist for advice before taking this medicine. If you are breast-feeding do not take this medicine. Small amounts may get into your milk. Talk to your doctor about a suitable treatment. Special warnings about this medicine This medicine may make you feel dizzy, tired or sleepy. You may feel less alert, feel faint or pass out. If you’re affected do not drive or use machines. Your body can lose large amounts of fluids and salts when you have diarrhoea. You need to replace the fluid by drinking more liquid than usual. Ask your pharmacist about rehydration therapy to replace lost salts. This is especially important for children, and frail or older people. Some of the ingredients can cause problems Aspartame (E951) contains a source of phenylalanine. This may be harmful for people with phenylketonuria. 26 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 Extra warnings for IBS patients Use only if your doctor has previously diagnosed IBS. Check the following: Do not take this medicine… If you are aged under 18. Talk to your doctor first… 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. If any of these applies to you, talk to your doctor before taking Imodium. 3 How to take this medicine Check the tables below to see how much medicine to take. For oral use only. Do not use more than the dose shown in the tables. The liquid is not for long-term treatment. Short-term diarrhoea Age Dose Adults and children aged 12 and over Take 30 ml (2 measuring cup doses) to start treatment Take 15 ml (1 measuring cup dose) after each loose bowel movement Do not take for attacks lasting longer than 48 hours. Do not take more than 90 ml (6 measuring cup doses) in a 24-hour period. Replace lost fluid by drinking more liquid than usual. Not for children aged under 12. How long to take Imodium for short-term diarrhoea You can use this medicine for up to 48 hours. If your attack lasts longer than 48 hours, stop taking Imodium and talk to your doctor. 27 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 IBS diarrhoea Age Dose Adults aged 18 and over Take 30 ml (2 measuring cup doses) to start treatment Take 15 ml (1 measuring cup dose) after each loose bowel movement (or as advised by your doctor) You can use this medicine for up to 2 weeks for repeated attacks, but do not take for any one attack lasting longer than 48 hours. Do not take more than 90 ml (6 measuring cup doses) in a 24-hour period. Replace lost fluid by drinking more liquid than usual. Not for children and young people aged under 18. Talk to your doctor and stop taking this medicine: If you have been using this medicine continuously for 48 hours. If you develop new IBS symptoms. If your IBS symptoms get worse. If your IBS symptoms have not improved after 2 weeks. How long to take Imodium for IBS diarrhoea You can use this medicine for up to 2 weeks for repeated attacks of IBS diarrhoea. But if any one attack lasts for longer than 48 hours, stop taking Imodium and talk to your doctor. If anyone takes too much of this medicine If anyone takes too much Imodium liquid, contact your doctor or nearest Accident and Emergency department taking this bottle with you. If you forget to take the medicine You should only take this medicine as you need it, following the dosage instructions above carefully. If you forget to take a dose, take a dose after the next loose stool (bowel movement). Do not take a double dose. 4 Possible side-effects Imodium can have side-effects, like all medicines, although these don’t affect everyone and most are usually mild. Get medical help at once Rare: (affects less than 1 in 1,000 but 1 or more in 10,000 people) Allergic reactions including unexplained wheezing, shortness of breath, passing out or swelling of face and throat. Skin rashes, which may be severe and include blistering or peeling skin. Loss of consciousness or reduced level of consciousness (passing out, feeling faint or less alert), uncoordinated movements. If you get any of these, stop using the medicine and get medical help at once. 28 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 Talk to a doctor as soon as possible Uncommon: (affects less than 1 in 100 but 1 or more in 1,000 people) Itchiness or hives. Stomach pain or swollen stomach. Rare: (affects less than 1 in 1,000 but 1 or more in 10,000 people) Difficulties passing water. Severe constipation. Miosis (narrowing of the pupils of the eye). If you notice any of the above, stop using the medicine and talk to a doctor. Other effects that may occur Common: (affects less than 1 in 10 but 1 or more in 100 people) Feeling sick, constipation or wind Headache Uncommon: (affects less than 1 in 100 but 1 or more in 1,000 people) Dizziness or drowsiness Vomiting, indigestion Dry mouth Rare: (affects less than 1 in 1,000 but 1 or more in 10,000 people) Tiredness. If you experience any side-effects not included in this leaflet or are not sure about anything, talk to your doctor or pharmacist. 5 Storing this medicine Keep the product out of the reach and sight of children. There are no special storage conditions. Use within 6 months of opening. Do not use your medicine after the date shown as the expiry date on the packaging. 6 Further information What’s in this medicine The active ingredient in Imodium Liquid is: Loperamide hydrochloride 2 mg per 15 ml. Other ingredients are: Propylene glycol, aspartame (E951), Opatint green dispersion, microcrystalline cellulose and carboxymethylcellulose, xanthan gum, glycerol, citric acid, sodium benzoate (E211), peppermint flavour and purified water. What the medicine looks like Imodium Liquid is a green oral liquid available in 90 ml bottles. Product Licence holder: McNeil Products Ltd, Maidenhead, Berkshire, SL6 3UG, UK. Manufacturer: Janssen Pharmaceutica NV, Turnhoutseweg 30, B2340, Beerse, Belgium. This leaflet was revised October 2011. Imodium is a registered trade mark 29 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 Labelling – updated The following text is the approved label text. No label mock-ups have been provided. In accordance with medicines legislation, the product shall not be marketed in the UK until approval of the label mock-ups has been obtained. Imodium® Liquid Loperamide hydrochloride Fresh mint flavour Soothing relief from diarrhoea 90 ml e Each 15ml contains 2mg loperamide hydrochloride. Also contains E951 Dosage: Short-term diarrhoea: Adults and children over 12 years: Take 30 ml to start treatment. Take 15 ml after each loose bowel movement, up to a maximum of 90 ml per day. If your diarrhoea lasts for more than 48 hours, consult your doctor. Not recommended for children under 12 years. IBS diarrhoea, previously diagnosed by a doctor: Adults aged 18 years and over: Take 30 ml to start treatment. Take 15 ml after each loose bowel movement, or as previously advised by a doctor, up to a maximum of 90 ml per day. You can use this medicine for up to 2 weeks for repeated attacks, but do not take for any one attack lasting longer than 48 hours. If your symptoms change, worsen or are not improved after 2 weeks, consult your doctor. Read the leaflet before use. Keep out of the reach and sight of children. McNeil Products Limited, Maidenhead, Berkshire, SL6 3UG, UK OPEN HERE PL 15513/0182 Stamping area for Batch No/Expiry date Barcode Decision-Approved 27/11/2011. 30 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 Annex II Product Licence Number: PL 15513/0182 - 0006 Product: Imodium Liquid 2 mg/15 ml Oral Solution Marketing Authorisation Holder: McNeil Products Limited Active Ingredient(s): Loperamide hydrochloride Reason: To update Section 5.2 (Pharmacokinetic Properties) of the SmPC in line with reference product 'Imodium Plus Caplets' (PL 15513/0342). Supporting Evidence In this National Type IB variation application, the applicant has proposed to change Section 5.2 (Pharmacokinetic Properties) to bring it into line with 'Imodium Plus Caplets' (PL 15513/0342). The applicant has submitted: - Current and proposed SmPC Evaluation The proposed SmPC with amendments to Section 5.2 provided by the MAH is considered satisfactory. THE FINAL APPROVED SMPC FRAGMENT, 5.2 (PHARMACOKINETIC PROPERTIES) FOR BOTH IMODIUM CLASSIC 2MG CAPSULES AND IMODIUM ORIGINAL 2MG CAPSULES IS PRESENTED BELOW: 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 Ndemethylation 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. 31 UKPAR Imodium Liquid 2 mg/15 ml oral solution PL 15513/0182 Conclusion The proposed SmPC is acceptable. Decision PL 15513/0182 - 0006: Approved 23/07/2012 32
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