Public Assessment Report. Mebeverine hydrochloride 50mg/5ml Oral Suspension. (Mebeverine hydrochloride) UK Licence No: PL 44710/0024

Transcription

1 Public Assessment Report Mebeverine hydrochloride 50mg/5ml Oral Suspension (Mebeverine hydrochloride) UK Licence No: PL 44710/0024 Kinedexe UK Limited 1

2 LAY SUMMARY Mebeverine hydrochloride 50mg/5ml Oral Suspension (Mebeverine hydrochloride) This is a summary of the Public Assessment Report (PAR) for Mebeverine hydrochloride 50mg/5ml Oral Suspension (PL 44710/0024). For ease of reading, this medicinal product will be referred to as Mebeverine hydrochloride Oral Suspension in this Lay Summary. This summary explains how Mebeverine hydrochloride Oral Suspension was assessed and its authorisation recommended, as well as the conditions of use. It is not intended to provide practical advice on how to use Mebeverine hydrochloride Oral Suspension. For practical information about using Mebeverine hydrochloride Oral Suspension, patients should read the Patient Information Leaflet (PIL) or contact their doctor or pharmacist. What is Mebeverine hydrochloride Oral Suspension and what is it used for? Mebeverine hydrochloride Oral Suspension is a generic medicine. This means that this product is similar to a reference medicine, already authorised in the UK called Mebeverine 50mg/5ml sugar free Oral suspension (Chemidex Pharma Limited; PL 17736/0084). Mebeverine hydrochloride Oral Suspension is used to treat the symptoms of a variety of bowel problems, and works by relaxing the muscles in the gut, thereby relieving the symptoms of irritable bowel, such as: colicky abdominal pain and cramps persistent diarrhoea with no obvious cause (this may not occur between bouts of constipation) wind Mebeverine hydrochloride Oral Suspension can also be used to relieve spasms in the gut resulting from certain other diseases. How does Mebeverine hydrochloride Oral Suspension work? Mebeverine hydrochloride Oral Suspension contain the active ingredient mebeverine hydrochloride, which belongs to a group of medicines called antispasmodics. This medicine works by relieving the spasm, pain and other symptoms of irritable bowel symptom (IBS). How is Mebeverine hydrochloride Oral Suspension used? Mebeverine hydrochloride Oral Suspension is taken orally. The bottle containing the suspension should be well shaken before use. The suspension must be taken preferably 20 minutes before meals to reduce symptoms after eating. The usual dose in adults and children over 10 years of age is 15 ml, three times a day. The dose may be gradually reduced after a few weeks when the condition improves. This medicine is NOT suitable for children under 10 years of age. Mebeverine hydrochloride Oral Suspension can only be obtained with a prescription from a doctor. Please read Section 3 of the PIL for detailed information on dosing recommendations, the route of administration, and the duration of treatment. 2

3 How has Mebeverine hydrochloride Oral Suspension been studied? Because Mebeverine hydrochloride Oral Suspension is a generic medicine, studies in patients have been limited to tests to determine that it is bioequivalent to the reference medicine, Mebeverine 50mg/5ml sugar free oral suspension (Chemidex Pharma Ltd). Two medicines are bioequivalent when they produce the same levels of the active substance in the body. What are the benefits and risks of Mebeverine hydrochloride Oral Suspension? Because Mebeverine hydrochloride Oral Suspension is a generic medicine, and is bioequivalent to the reference medicine, Mebeverine 50mg/5ml sugar free oral suspension (Chemidex Pharma Ltd), its benefits and risks are taken as being the same as the reference medicine. Why is Mebeverine hydrochloride Oral Suspension approved? It was concluded that, in accordance with EU requirements, Mebeverine hydrochloride Oral Suspension has been shown to have comparable quality and to be bioequivalent to Mebeverine 50mg/5ml sugar free oral suspension (Chemidex Pharma Ltd). Therefore, the view was that, as for Mebeverine 50mg/5ml sugar free oral suspension, the benefits outweigh the identified risks. What measures are being taken to ensure the safe and effective use of Mebeverine hydrochloride Oral Suspension? A risk management plan has been developed to ensure that Mebeverine hydrochloride Oral Suspension is used as safely as possible. Based on this plan, safety information has been included in the Summary of Product Characteristics (SmPC) and the PIL for Mebeverine hydrochloride Oral Suspension, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore, new safety signals reported by patients and healthcare professionals will be monitored and reviewed continuously as well. Other information about Mebeverine hydrochloride Oral Suspension A Marketing Authorisation for Mebeverine hydrochloride Oral Suspension was granted on 26 March The full PAR for Mebeverine hydrochloride Oral Suspension follows this summary. This summary was last updated in May

4 TABLE OF CONTENTS I Introduction Page 5 II Quality aspects Page 6 III Non-clinical aspects Page 7 IV Clinical aspects Page 8 V User consultation Page 11 VI Overall conclusion, benefit/risk assessment and recommendation Page 11 Table of content of the PAR update Page 14 4

5 I Introduction Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products Regulatory Agency (MHRA) granted Kinedexe UK Limited a Marketing Authorisation for the medicinal product Mebeverine hydrochloride 50mg/5ml Oral Suspension (PL 44710/0024) on 26 March This medicinal product is a prescription only medicine (legal status POM ), indicated: For the symptomatic treatment of irritable bowel syndrome and other conditions usually included in this grouping, such as chronic irritable colon, spastic constipation, mucous colitis, spastic colitis. Mebeverine is effectively used to treat the symptoms of these conditions, such as colicky abdominal pain and cramps, persistent, non-specific diarrhoea (with or without alternating constipation) and flatulence. For the symptomatic treatment of gastro-intestinal spasm secondary to organic diseases. This application was submitted under Article 10(1) of Directive 2001/83/EC, as amended. The applicant has cross-referred to Mebeverine 50mg/5ml sugar free Oral suspension, which was granted a Marketing Authorisation to Abbott Healthcare Products Limited on 11 May Following a change of ownership procedure on 22 August 2005, this Marketing Authorisation was transferred to Chemidex Pharma Ltd (PL 17736/0084). Mebeverine is a musculotropic antispasmodic with a direct action on the smooth muscle of the gastrointestinal tract, relieving spasm without affecting normal gut motility. No new non-clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of an originator product that has been licensed for over 10 years. One bioequivalence study (conducted under fasting conditions) was submitted to support this application. The bioequivalence study is stated to have been conducted in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence study, no new non-clinical or clinical data were submitted, which is acceptable given that this application was based on being a generic medicinal product of the originator product that has been in clinical use for over 10 years. A summary of the pharmacovigilance system and a detailed Risk Management Plan (RMP) have been provided with this application, and these are satisfactory. No new or unexpected safety concerns arose during the review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Mebeverine hydrochloride 50mg/5ml Oral Suspension outweigh the risks and a Marketing Authorisation was granted. 5

6 II Quality Aspects II.1 Introduction The finished product is an oral suspension. Each 5ml dose contains 50mg of mebeverine hydrochloride (as pamoate complex in the drug product), as active ingredient. The excipients present are disodium pamoate, microcrystalline cellulose, carmellose sodium, citric acid monohydrate, polysorbate 20, sodium benzoate, trisodium citrate dihydrate, macrogol glycerol hydroxystearate, saccharin sodium, simethicone emulsion and banana flavour. All excipients comply with their respective European Pharmacopoeia monographs with the exception of disodium pamoate and banana flavour which comply with in-house specifications, and simethicone emulsion which is controlled in line with the United States Pharmacopeia (USP). Satisfactory Certificates of Analysis have been provided for all excipients showing compliance with their proposed specifications. This product does not contain or consist of genetically modified organisms (GMO). The finished product is packaged in 300 ml amber coloured glass bottle with white click-lock tamper evident cap. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. II.2. Drug Substance Mebeverine hydrochloride INN: Mebeverine hydrochloride Chemical Name: 4-[(1RS)-Ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino]butyl 3,4-dimethoxybenzoate hydrochloride Structure: Molecular formula: Molecular weight: Appearance: Solubility: C25H35NO5.HCl g/mol White or almost white crystalline powder. Mebeverine hydrochloride is very soluble in water and in methylene chloride; freely soluble in ethanol (96%). Mebeverine hydrochloride is the subject of an active substance master file (ASMF). Synthesis of the active substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents, and these are supported by relevant Certificates of Analysis. No materials of animal or human origin are used in the production of the active substance. 6

7 Appropriate proof-of-structure data have been supplied for the active substance. All potential impurities have been identified and monitored appropriately. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Batch analysis data are provided that comply with the proposed specification. Satisfactory Certificates of Analysis have been provided for all working standards. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with food. Appropriate stability data have been provided supporting a suitable retest period when stored in the proposed packaging. II.3. Medicinal Product Pharmaceutical Development The objective of the development programme was to formulate a safe, efficacious oral suspension containing 50mg/5ml of mebeverine hydrochloride, that is a generic version of the reference product Mebeverine 50mg/5ml Sugar Free Oral Suspension (Chemidex Pharma Ltd). A satisfactory account of the pharmaceutical development has been provided. Comparative in vitro dissolution profiles have been provided between the test and reference products. Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. A validation report for commercial scale batches has been provided. The process validation data provided are satisfactory. Finished Product Specification The proposed finished product specification is acceptable. The test methods have been described that have been adequately validated. Batch data have been provided that comply with the release specification. Certificates of Analysis have been provided for all working standards used. Stability of the Product Finished product stability studies were performed in accordance with current guidelines on batches of finished product in the packaging proposed for marketing. The data from these studies support a shelf life of 36 months with special storage conditions Do not store above 25 C and Store in the original package. Once the bottle is opened the product must be used within 14 days. Suitable post approval stability commitments have been provided that stability testing will be continued on batches of finished product. II.4 Discussion on chemical, pharmaceutical and biological aspects There are no objections to the approval of this application from a pharmaceutical viewpoint. III Non-Clinical Aspects III.1 Introduction As the pharmacodynamic, pharmacokinetic and toxicological properties of mebeverine hydrochloride are well-known, no new non-clinical studies are required, and none have been provided. An overview based on the literature review is, thus, appropriate. 7

8 The Applicant s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. III.2 Pharmacology Not applicable for this product type. Refer to section III.1; Introduction detailed above. III.3 Pharmacokinetics Not applicable for this product type. Refer to section III.1; Introduction detailed above. III.4 Toxicology Not applicable for this product type. Refer to section III.1; Introduction detailed above. III.5 Ecotoxicity/environmental risk assessment (ERA) Since this product is intended for generic substitution, this will not lead to an increase of the environmental exposure. An environmental risk assessment is therefore not deemed necessary. III.6 Discussion on the non-clinical aspects No new non-clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of the originator product that has been licensed for over 10 years. There are no objections to the approval of this application from a non-clinical viewpoint. IV Clinical Aspects IV.1 Introduction The clinical pharmacology of mebeverine hydrochloride is well-known. With the exception of data from the bioequivalence study detailed below, no new pharmacodynamics or pharmacokinetic data are provided or are required for this application. No new efficacy or safety studies have been performed and none are required for this type of application. A comprehensive review of the published literature has been provided by the applicant, citing the well-established clinical pharmacology, efficacy and safety of mebeverine hydrochloride. Based on the data provided, Mebeverine hydrochloride 50mg/5ml Oral Suspension can be considered bioequivalent to Mebeverine 50mg/5ml sugar free Oral suspension (Chemidex Pharma Ltd). IV.2 Pharmacokinetics In support of this application, the applicant submitted the following bioequivalence study: An open-label, balanced, randomised, single-dose, two-treatment, two-sequence, two-period, crossover, oral bioequivalence study of the applicant s test product, Mebeverine 50mg/5ml oral suspension versus the reference product, Mebeverine 50mg/5ml sugar free oral suspension (Chemidex Pharma Ltd) in healthy, adult, subjects under fasting conditions. Primary objective: To characterize the rate and extent of absorption of veratric acid, mebeverine acid, desmethylmebeverine acid (DMAC) and desmethyl mebeverine alcohol after oral administration and to assess the bioequivalence of the test and reference products under fasting conditions. 8

9 The 90% confidence interval of the test/reference (T/R) ratio (difference in least square means) from the ANOVA of the log transformed data for the pharmacokinetic parameters AUC0 1 and Cmax for veratric acid for fasting study should fall within 80.00% to (both inclusive). Data from mebeverine acid, desmethylmebeverine acid (DMAC) and desmethyl mebeverine alcohol are proposed as supportive data. Secondary objective: To investigate the safety and tolerability of both the formulations on the basis of clinical and laboratory examination, documentation of the Adverse Events (AEs) and/or Adverse Drug Reactions (ADRs). In each period, following an overnight fast of at least 8 hours, subjects received a single oral dose (15 ml) of test or reference product while in sitting posture with about 200 ml of water at ambient temperature. Blood samples were collected for determination of plasma levels before dosing and up to and including 12 hours after each administration. The washout period between the treatment phases was 14 days. The pharmacokinetic results are presented below: Results Veratric acid (N=32) The main pharmacokinetic findings of the study are presented in Tables 1. Table 1 Summary of statistical analysis for veratric acid For veratric acid, the pharmacokinetic and statistical results of this study indicated that the Test/Reference ratios of geometric LSmeans of Cmax and AUC0-T are within 80.00% and %. In addition, the 90% confidence intervals of Cmax and AUC0-T are contained within the predefined acceptance range of 80.00% to %. Bioequivalence has been demonstrated for the pivotal analyte. Mebeverine acid The main pharmacokinetic findings of the study are presented in Table 2. Table 2 Summary of statistical analysis for mebeverine acid 9

10 Desmethyl mebeverine acid (DMAC) (N=32) The main pharmacokinetic findings of the study are presented in Table 3. Table 3 Summary of statistical analysis for Desmethyl mebeverine acid (DMAC) Desmethyl mebeverine alcohol (DMAC) (N=32) The main pharmacokinetic findings of the study are presented in Table 4. Table 4 Summary of statistical analysis for Desmethyl mebeverine alcohol No significant carry over effect was observed in any subjects, which were all included in the statistical evaluation of the pharmacokinetic (PK) parameters. Bioequivalence has been demonstrated in line with the requirements set out in CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** for the selected pivotal analyte, veratric acid. Mebeverine acid, desmethyl mebeverine acid and desmethyl mebeverine alcohol have also been quantified and analysed to generate supporting data; the pharmacokinetic parameters measured are all in compliance with the bioequivalence criteria, with the exception of Cmax for mebeverine acid. This is accepted since mebeverine acid is considered as supportive data. The justification provided by the applicant is acceptable. IV.3 Pharmacodynamics No new pharmacodynamic data were submitted and none are required for an application of this type. IV.4 Clinical efficacy No new data on efficacy have been submitted and none are required for an application of this type. IV.5 Clinical safety No new data on clinical safety have been submitted and none are required for an application of this type. IV.6 Risk Management Plan (RMP) and Pharmacovigilance system The Marketing Authorisation Holder (MAH) has submitted an RMP, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Mebeverine hydrochloride 50mg/5ml Oral Suspension. 10

11 A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, is listed below: Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns. IV.7 Discussion on the clinical aspects The grant of a Marketing Authorisation is recommended for this application, from a clinical point of view. V User consultation The package leaflet has been evaluated via a user consultation study, in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC, as amended. The language used for the purpose of user testing the PIL was English. The results show that the package leaflet meets the criteria for readability, as set out in the guideline on the readability of the label and package leaflet of medicinal products for human use. VI Overall conclusion, benefit/risk assessment and recommendation The quality of the product is acceptable, and no new non-clinical or clinical concerns have been identified. Bioequivalence has been demonstrated between the applicant s product and the reference product. The benefit-risk assessment is, therefore, considered to be positive. 11

12 Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website. The approved labelling for Mebeverine hydrochloride 50mg/5ml Oral Suspension is presented below: 12

13 13

14 Table of content of the PAR update Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II variations, PSURs, commitments) Date submitted Application type Scope Outcome 14