Public Assessment Report Decentralised Procedure · Public Assessment Report Decentralised Procedure MOVICOL UNO 6.9 G, POWDER FOR ORAL SOLUTION (Macrogol 3350, sodium hydrogen carbonate,

Public Assessment Report

Decentralised Procedure MOVICOL UNO 6.9 G, POWDER FOR ORAL SOLUTION

(Macrogol 3350, sodium hydrogen carbonate, sodium

chloride, potassium chloride)

Procedure No: UK/H/3914/001/DC

UK Licence No: PL 20011/0018

NORGINE PHARMACEUTICALS LIMITED

PAR Movicol Uno 6.9 g, powder for oral solution UK/H/3914/001/DC

2

LAY SUMMARY

On 08 June 2011, Bulgaria, Czech Republic, Estonia, Lithuania, Latvia, Poland, Romania, Slovenia, Slovakia and the UK agreed to grant a Marketing Authorisation to Norgine Pharmaceuticals Limited for the medicinal product Movicol Uno 6.9 g, powder for oral solution (PL 20011/0018; UK/H/3914/001/DC). The licence was granted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS). After a subsequent national phase, a Marketing Authorisation was granted in the UK on 01 July 2011. This product is a Prescription-Only Medicine (POM) and contains the active ingredients Macrogol 3350, sodium chloride, potassium chloride and sodium hydrogen carbonate. Movicol Uno 6.9 g, powder for oral solution is a laxative for the treatment of chronic constipation in adults, the elderly, adolescents (aged 12 years and above) and children (aged 2-11 years). It can also be used as a laxative for the treatment of very bad constipation (called faecal impaction) in adults, the elderly, children (aged 5 to 11 years) and adolescents (aged 12 years and above). Movicol Uno 6.9 g, powder for oral solution helps you (or your child) to have a comfortable bowel movement, even if you have been constipated for a long time. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Movicol Uno 6.9 g, powder for oral solution outweigh the risks, hence a Marketing Authorisation has been granted.


3

TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 6 Module 4: Labelling Page 7 Module 5: Scientific Discussion Page 11 I Introduction II About the product III Scientific Overview and discussion III.1 Quality aspects III.2 Non-clinical aspects III.3 Clinical aspects IV Overall Conclusions and benefit-risk assessment Module 6 Steps taken after initial procedure Page 23 Annex 1 – Clinical Variation Assessment Report Page 24


4

Module 1

Product Name

Movicol Uno 6.9 g, powder for oral solution

Type of Application

Full dossier, Article 8.3

Active Substances

Macrogol 3350, sodium hydrogen carbonate, sodium chloride and potassium chloride

Form

Powder for oral solution

Strength

6.9 g

MA Holder

Norgine Pharmaceuticals Limited, Norgine House Widewater Place, Moorhall Road, Harefield, Uxbridge, Middlesex, UB9 6NS, UK

Reference Member State (RMS)

UK

Concerned Member States (CMS)

Bulgaria, Czech Republic, Estonia, Lithuania, Latvia, Poland, Romania, Slovenia, Slovakia

Procedure Number

UK/H/3914/001/DC

Timetable

Day 210 – 08 June 2011


5

Module 2 Summary of Product Characteristics

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) for products that are granted Marketing Authorisations at a national level are available on the MHRA website.


6

Module 3 In accordance with Directive 2010/84/EU the Patient Information Leaflets (PIL) for products that are granted Marketing Authorisations at a national level are available on the MHRA website.


7

Module 4

Labelling

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.


8


9


10


11

Module 5 Scientific discussion during initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the application for Movicol Uno 6.9 g, powder for oral solution (PL 20011/0018; UK/H/3914/001/DC) could be approved. The product is a prescription-only medicine (POM) indicated for the treatment of: chronic constipation in children 2 to 11 years of age, adolescents (above 12 years) and

adults. faecal impaction in children from the age of five years, adolescents (above 12 years) and

adults, defined as refractory constipation with faecal loading of the rectum and/or colon.

This is a full-dossier application for a known active substance submitted via the decentralised procedure in accordance with Article 8.3 of 2001/83/EC, as amended. The UK acted as Reference Member State (RMS) and Bulgaria, Czech Republic, Estonia, Lithuania, Latvia, Poland, Romania, Slovenia and Slovakia were Concerned Member States (CMS). Movicol Uno 6.9 g, powder for oral solution belongs to a group of medicines called “osmotically acting laxatives” (ATC code A06A D65) and contains the active ingredients Macrogol 3350, sodium hydrogen carbonate, sodium chloride and potassium chloride. Macrogol 3350 acts by virtue of its osmotic action in the gut, which induces a laxative effect. Macrogol 3350 increases the stool volume, which triggers colon motility via neuromuscular pathways. The physiological consequence is an improved propulsive colonic transportation of the softened stools and a facilitation of the defecation. Electrolytes combined with Macrogol 3350 are exchanged across the intestinal barrier (mucosa) with serum electrolytes and excreted in faecal water without net gain or loss of sodium, potassium and water. No new non-clinical or clinical studies were submitted with this application, which is acceptable given that the product contains well-known active substances, namely Macrogol 3350, sodium hydrogen carbonate, sodium chloride and potassium chloride. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture, assembly and batch release of this product. The RMS and CMSs considered that the application could be approved with the end of procedure (Day 210) on 08 June 2011. After a subsequent national phase, the licence was granted in the UK on 01 July 2011.


12

II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Movicol Uno 6.9 g, powder for oral solution

Name(s) of the active substance(s) (INN) Macrogol 3350, sodium hydrogen carbonate, sodium chloride and potassium chloride

Pharmacotherapeutic classification (ATC code)

Osmotically acting laxatives (A06A D65)

Pharmaceutical form and strength(s) Powder for oral solution, 6.9 g.

Reference numbers for the Mutual Recognition Procedure

UK/H/3914/001/DC

Reference Member State United Kingdom

Member States concerned Bulgaria, Czech Republic, Estonia, Lithuania, Latvia, Poland, Romania, Slovenia and Slovakia

Marketing Authorisation Number(s) PL 20011/0018

Name and address of the authorisation holder Norgine Pharmaceuticals Limited, Norgine HouseWidewater Place, Moorhall Road, Harefield, Uxbridge, Middlesex, UB9 6NS, UK


13

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substances The product contains four active substances, Macrogol 3350, sodium chloride, sodium hydrogen carbonate and potassium chloride. (1) Macrogol 3350 INN: Macrogol 3350 Molecular formular: H-(OCH2-CH2)n –OH Molecular weight: 84.0 Appearance: White or almost white solid with a waxy or paraffin-like

appearance. Macrogol 3350 is very soluble in water and in methylene chloride, very slightly soluble in alcohol and practically insoluble in fatty oils and mineral oils.

(2) Sodium chloride INN: Sodium chloride Molecular formular: NaCl Molecular weight: 58.4 Appearance: Sodium chloride is a white, crystalline powder or colourless

crystals or white pearls, freely soluble in water, practically insoluble in ethanol

(3) Sodium hydrogen carbonate INN: Sodium hydrogen carbonate Molecular formular: NaHCO3 Molecular weight: 84.0 Appearance: Sodium hydrogen carbonate is a white or almost white, slightly

granular powder, soluble in water, practically insoluble in alcohol.

(4) Potassium chloride INN: Potassium chloride Molecular formular: KCl Molecular weight: 74.6 Appearance: Potassium chloride is a white or almost white crystalline powder

or colourless crystals, freely soluble in water, practically insoluble in anhydrous ethanol.

All four drug substances comply with their respective European Pharmacopoeia monograph. All aspects of the manufacture and control of Macrogol 3350 by all suppliers is covered by European Directorate for the Quality of Medicines (EDQM) Certificates of Suitability. Synthesis of the other three active substances (sodium chloride, sodium hydrogen carbonate and potassium chloride) 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.


14

Appropriate specifications are provided for the other three active substances. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Appropriate proof-of-structure data have been supplied for the other three active substances. All potential known impurities have been identified and characterised. Satisfactory certificates of analysis have been provided for all working standards. Batch analysis data are provided and comply with the proposed specifications. Suitable specifications have been provided for all packaging used for the other three active substances. The primary packaging has been shown to comply with current guidelines concerning contact with food. For these active substances, appropriate stability data have been generated supporting a suitable retest period when stored in the proposed packaging. P. Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipients, acesulfame potassium (E950), and lemon and lime flavour (consisting of acacia solids, maltodextrin, lime oil, lemon oil, citral, citric acid and water). Acesulfame potassium (E950) complies with its European Pharmacopoeia monograph. Lemon and lime flavour is controlled to a suitable in-house specification. Suitable batch analysis data have been provided for each excipient. The natural flavouring substances used in the lemon and lime flavouring conform with Directive 88/388/EEC, concerning food additives and flavouring. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Pharmaceutical Development The objective of the development program was to produce a product that was half the strength of the original Movicol 13.8g sachet, powder for oral solution (PL 00322/0070) in order to facilitate the benefits of Movicol to a wider patient population. Satisfactory product development data were submitted. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the product along with an appropriate account of the manufacturing process. Suitable in-process controls are applied during the manufacturing process to ensure the quality of the product. The manufacturing process has been validated on commercial-scale batches of the product and has shown satisfactory results. Finished Product Specification The finished product specification proposed is acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of analysis have been provided for all working standards used.


15

Container-Closure System The finished product is packaged in low-density polyethylene/aluminium/paper laminate sachets and packed into cartons in pack sizes of 6, 8, 10, 20, 30, 40, 50, 60 or 100 sachets. It has been stated that not all pack sizes may be marketed, however, the Marketing Authorisation Holder has committed to submitting the mock-ups for any pack size to the relevant regulatory authorities for approval before marketing. Satisfactory specifications and certificates of analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food. Stability of the product Stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 3 years for the powder and 24 hours for the reconstituted solution. The storage conditions are “Do not store above 25 °C” for the powder and “Store at 2°C to 8°C. The solution may be refrigerated. Keep the solution covered” for the reconstituted solution. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labels are acceptable. A package leaflet has been 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, as amended. 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. MAA form The MAA form is satisfactory. Expert report The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion There are no objections to the approval of this product from a pharmaceutical viewpoint. III.2 NON-CLINICAL ASPECTS The pharmacological, pharmacokinetic and toxicological properties of Macrogol 3350, sodium chloride, sodium hydrogen carbonate and potassium chloride are well-known. As these four active substances are well-known, no further studies are required and the applicant has provided none. An overview based on a literature review is, thus, appropriate. The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the product’s pharmacology and toxicology. The applicant has provided an assessment of the environmental risk for Macrogol 3350. The use of this product is not expected to increase the overall use of Macrogol 3350. PECsurfacewater was 525 µg/L for macrogol 3350, this is above the action limit of 0.01 µg/L. A calculation


16

for logKow has not been provided, although the applicant has screened for biodegradability, persistence, bioaccumulation and toxicity. The applicant has argued that Macrogol 3350 is not likely to reach surface waters as it will be removed by sewage treatment and continuous exposure to the aquatic environment is not expected. This is acceptable. There are no objections to the approval of this product from a non-clinical viewpoint.


17

III.3 CLINICAL ASPECTS Pharmacokinetics Macrogol 3350 is a biologically inert polymer. It is taken together with a fixed amount of water and passes through the gut unchanged. It is not absorbed to any significant extent nor does it undergo any metabolism. Any small amounts of Macrogol 3350 which might be absorbed are excreted unchanged by the kidneys. Pharmacodynamics The active constituents are Macrogol 3350, sodium hydrogen carbonate, sodium chloride and potassium chloride. Macrogol 3350 acts by virtue of its osmotic action in the gut, which induces a laxative effect. Macrogol 3350 increases the stool volume, which triggers colon motility via neuromuscular pathways. The physiological consequence is an improved propulsive colonic transportation of the softened stools and a facilitation of the defecation. Electrolytes combined with Macrogol 3350 are exchanged across the intestinal barrier (mucosa) with serum electrolytes and excreted in faecal water, without net gain or loss of sodium, potassium and water. Clinical efficacy The clinical studies presented in support of this application have been previously assessed by the relevant authorities within the European Union where the product is approved. No new clinical data have been submitted. The products of the Movicol range have been used extensively in practice in around twenty two Member States for over 10 years with accepted efficacy for the indications of chronic constipation and faecal impaction. A range of both controlled and uncontrolled studies have evaluated the efficacy of Movicol in the therapeutic indication of chronic constipation in adults and children. The principle studies are outlined as follows: Chronic constipation Controlled clinical studies evaluating the efficacy of Movicol in the treatment of constipation were in accordance with the general symptoms of constipation; less than three stools per week and defaecation problems of straining, hard or lumpy stools, sensation of incomplete evacuation and sensation of blockage. The symptoms were also required to have been present for at least the preceding 3 months (i.e. chronic constipation). The studies focused on primary causes of chronic constipation and excluded secondary chronic constipation. Diagnostic and exclusion criteria included mechanical obstructions, such as intestinal perforation or obstruction; endocrine disorders, such as diabetes; pregnancy; liver, renal or cardiac impairment; malignancies; inflammatory bowel diseases, such as Crohn’s disease, ulcerative colitis, toxic megacolon. The exclusion criteria of inflammatory bowel diseases are in accordance with contraindications in the SmPC. Chaussade 1995 Multi-centre randomised, placebo-controlled study in four centres in France (32 adult patients) designed to evaluate the efficacy of Movicol for two 15-day crossover periods, followed by a longer term 3-month open study. This study demonstrated superiority to placebo for the following primary endpoints: increase in frequency of stools per week, improvement in ease of defaecation and overall patient satisfaction. Thomson 2004 A 4-week paediatric study in 47 children, aged 24 months to 11 years, experiencing constipation. This study demonstrated superiority to placebo for the primary endpoint (mean


18

number of complete defecations per week in each treatment period), and pain and strain on defaecation were considerably less in the treatment group than in the placebo group.

Candy 2003 Part two of a two-part study to assess the safety and efficacy of Movicol in 58 children age 2 to 11 years, with the objective to compare the safety and efficacy of Movicol and Duphalac Dry as maintenance therapy in chronic constipation. Patients were orally administered one sachet of Movicol per day dissolved in 125ml water or a 10g sachet of Duphalac Dry (lactulose) in solution. Seven children re-impacted whilst taking Duphalac Dry, compared to no children reimpacting whilst taking Movicol. For amount of stool, pain or strain on defaecation, or abdominal pain, there was no statistically significant difference between the Movicol and Duphalac Dry groups.

Göbel 2007 A single-centre, randomised, double-blind, parallel group Phase III trial to compare the efficacy and tolerability of Movicol versus lactulose in relieving opiate-induced constipation in 106 patients aged 18 to 75 years. There was no difference in the change in mean weekly number of stools from the last week prior to treatment start to the last treatment week between the two treatment groups, demonstrating non-inferiority of Movicol to lactulose. Gruss and Schütte 2004 Multi-centre, randomised double-blind, parallel-group study of Movicol versus lactulose in the treatment of chronic constipation in patients with Parkinson’s Disease (19 patients, only eight of whom completed the study). The primary endpoint of this study was to show the superiority of Movicol in the reduction of colon transit time and to show non-inferiority in reducing associated defaecation and gastrointestinal symptoms. The study failed to show superiority of Movicol in the primary endpoint.

Habermann & Gruss 2000 A multi-centre, randomised, double-blind trial to investigate the efficacy, tolerance and safety of Movicol versus lactulose in elderly patients suffering from chronic constipation. After a 1-week run-in phase, during which the patients received a bulk laxative containing sterculia, a double-blind treatment phase of 28 days began, during which patients received either Movicol or lactulose; finally there was an optional open-label follow-up phase of another 28 days, in which all patients were administered Movicol. The results showed no clinically relevant differences between lactulose and Movicol.

Lemann 1995 This was a 4-week multi-centre, randomised, parallel groups, active-controlled (lactulose) study, to compare the efficacy of Movicol and lactulose in 105 patients with idiopathic, chronic constipation. A significant difference was observed in favour of the Movicol group and in both age sub-groups for the three efficacy criteria – number of stools, dyschezia index and global satisfaction.

Oster 2003 This was a randomised, double-blind, parallel-group comparison with a standard therapy (lactulose) in 25 geriatric patients with opiate-induced constipation. Stool frequency recorded with Movicol was significantly greater compared to lactulose, although the number of subjects was too low to draw firm conclusions.


19

Tack 2000 The aim of this randomised, double-blind study was to compare the efficacy of Movicol versus Lactitol over 28 days in patients suffering from chronic constipation. The number of stools increased significantly and visual analog score (VAS) constipation scores decreased significantly for both groups, but no differences were detected between both treatments for the 7-day and 28-day treatment periods.

Wang 2004 A randomised, controlled comparison of Movicol with ispaghula husk in the treatment of adults with chronic functional constipation. Primary outcome measures were weekly defaecation rates, stool consistency according to the Bristol Stool Form Scale, time to first defaecation and overall efficacy. Treatment was highly effective in 50 of the 63 patients randomised to the Movicol group, compared with 26 out of 63 in the ispaghula husk group; and overall efficacy rates were 92% and 73%, respectively (p= 0.005). Increase in the weekly defaecation rate was from 1.18 at baseline to 7.95 (week 1) and 8.4 (week 2) with Movicol. A lower increase was observed with ispaghula husk, from a baseline of 1.33 to 5.33 (week 1) and 5.71 (week 2). These differences were all significantly different (p<0.001). Stool consistency was also normalised after 2 weeks of treatment. Larger, uncontrolled post marketing studies, involving only Movicol as the treatment confirmed findings from these controlled clinical trials that it is efficacious not only in the subset populations of children and the elderly but also when chronic constipation is secondary to disease states such as Parkinson’s Disease (Ulm, 2001) or to opiate or antidepressant medication use (Habermann, 1997), or in severely mentally handicapped subjects (Schlosser, 1997; Migeon Duballet, 1999). The Habermann 1996 postmarketing surveillance study in 2029 patients, whose mean age was 65 years ± 17 years (age range 17 to 99 years), also confirms the benefits shown in controlled clinical trials of the use of Movicol in adults for the treatment of chronic constipation. Faecal Impaction Four studies, only one of which was controlled, have investigated the effectiveness of Movicol for the treatment of faecal impaction in the adult population, the elderly population and children aged 2 to 11 years. Schulze 2004 A Phase IV, double-blind, placebo-controlled, multi-centre study in 27 geriatric patients (aged 64 to 93 years) with acute faecal impaction. Patients were given eight sachets per day of Movicol or placebo. Eleven patients of the Movicol and nine patients of the placebo group had a complete defecation at the second visit. Using a log-rank test, the results were statistically significant (p=0.04). However, using a two-sided Fisher’s exact test, no statistical significance was seen (p=0.5956).

Alix 1999 A multi-centre, uncontrolled, open-label trial to evaluate the efficacy and safety of Movicol in the treatment of faecal impaction in eleven elderly hospitalised patients (age 65 to 88 years), when given eight sachets per day for 3 days. After 3 days of treatment, faecal impaction in all patients had been resolved.

Candy 2002 Part one of a two-part study to assess the safety and efficacy of Movicol in 46 children, aged 2 to 11 years, who had constipation requiring hospitalisation for disimpaction. Disimpaction was achieved in 42 out of 44 children (two children withdrew before completion of Phase I),


20

with a mean disimpaction time of 3 to 7 days. A maximum dose of four sachets per day (2-4 year old group) and six sachets per day (5-11 year old group) was required for disimpaction.

Ferguson 1996 A single-centre, uncontrolled, open-label Phase III study to evaluate the efficacy and safety of Movicol given at a dosage of 1 litre per day for up to 3 days in the treatment of faecal impaction (27 patients). Faecal impaction in 12 out of 27 patients was completely resolved after 1 day’s treatment, and a further 11 patients had their faecal impaction cleared after 2 days’ treatment. A retrospective study by Vincent 2001 reports on 30 patients with faecal impaction aged between 2 and 15 years. An escalating dosage regime was employed and Movicol 13.8g was administered until the children were passing watery stools, and then adjusted until a soft and regular stool resulted. Disimpaction was achieved in all 30 patients (100%) without the intervention of further laxatives. In addition, the applicant has provided extensive supportive data with accompanying review and discussion regarding the use of polyethylene glycol and electrolytes bowel lavage solutions for bowel preparation in children. Overall, the studies discussed demonstrate the effectiveness of these preparations as lavage solutions and for treating children with faecal impaction. Clinical safety Since its first authorisation in December 1995 in the UK, Movicol has been marketed in 47 countries worldwide, and the product range has increased its exposure to the paediatric age group with Movicol Paediatric and Movicol Paediatric Plain. For all marketing authorisations granted during this period, no regulatory actions, such as withdrawals, revocations or rejections have occurred because of safety reasons, nor have there been any changes to the core safety information. Clinical trials involving the Movicol product range and post-marketing safety data both demonstrate a favourable risk-benefit profile. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labels are acceptable. The PIL is consistent with the SmPC and in-line current guidelines. The labelling is in-line with current guidelines. Clinical Expert Report The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Pharmacovigilance system The pharmacovigilance system, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.


21

Risk Management Plan No Risk Management Plan other than documentation of pharmacovigilance system has been provided. The justification for this is satisfactory, namely that Movicol Uno 6.9 g, powder for oral solution contains known actives of well-established use

in the therapeutic indication and target population, the qualitative and quantitative composition of Movicol Uno 6.9 g, powder for oral solution

is identical or similar to other products in the Movicol range, the intended target populations are the same as those currently approved for other products

in the Movicol range, there have been no product safety concerns since grant of the first marketing authorisation

that have required actions by the regulatory authorities or risk minimisation activities by the Marketing Authorisation Holder,

the regular PSURs produced for the current Movicol range do not suggest that there are any particular safety issues which are not already being monitored through the current pharmacovigilance systems, for which a Risk Management Plan is required,

the company will continue to monitor the safety of all products in the Movicol range. Periodic Safety Update Report (PSUR) The applicant has applied for a PSUR submission scheme harmonised with that of Movicol 13.8g sachet, powder for oral solution (PL 00322/0070) and its range of line-extension products as the active substances are well-known and have been marketed for many years throughout the EU. The suggestion is acceptable because the Movicol family of products are well-known and no current special risk situation is present. Conclusion There are no objections to the approval of this product from a clinical viewpoint.


22

IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Movicol Uno 6.9 g, powder for 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 an application of this type. EFFICACY No new clinical data were submitted and none are required for an application of this type. There were no safety concerns arising from the studies submitted and cumulative data on the safety of Macrogol 3350, sodium hydrogen carbonate, sodium chloride and potassium chloride confirm the good safety profile with this product. Movicol products have been marketed for many years throughout the EU. Their efficacy is well-established and they have an acceptable safety profile. The SmPC, PIL and labelling are satisfactory. BENEFIT RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with the four active substances is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.


23

Module 6

Movicol Uno 6.9 g powder for oral solution

PL 20011/0018

STEPS TAKEN AFTER INITIAL PROCEDURE

Date submitted

Application type

Description Outcome

12/12/2012 VAR Medical Type II

To update the indications of the product by modifying the indication ‘chronic constipation’ and deleting the indication ‘faecal impaction’ in line with the P status of the product; sections 4.1, 4.2, 4.4, 4.5, 4.8 and 5.1 of the SmPC and consequentially the leaflet is amended.

Variation granted 12/06/2013


24

ANNEX 1 – CLINICAL VARIATION ASSESSMENT REPORT I. Recommendation Based on the review of the data on safety and efficacy, the RMS considers that the group of variations application UK/H/3914/001/II/006/G for Movicol Uno 6.9g, powder for oral solution (Macrogol 3350, Sodium hydrogen carbonate, Sodium chloride, Potassium chloride), for the treatment of chronic constipation in children 2 to 11 years of age, adolescents (above 12 years) and adults, for the following proposed changes: ‘modification of the chronic constipation indication and deletion of the faecal impaction indication’ is approvable. II. Executive Summary II.1 Scope of the variation This variation application and the proposed change to the Summary of Product Characteristics (SmPC) and Patient Information Leaflet (PIL), is in preparation for the submission of national applications to switch the legal status of Movicol Uno 6.9g from a prescription only medication (POM) to over the counter (OTC) status in the concerned member states. Following this variation, the applicant then proposes to apply for a legal status change in the member states. As a result, this is not an assessment of the legal status change but focuses only on the proposed modifications to the indication. The suitability of the indication for an OTC medication should be considered as part of the assessment for the legal status change. III. Scientific Discussion With an estimated prevalence between 1.9% and 31.7% in Western populations [Higgins 2004, Brandt 2005, Peppas 2008], constipation is a common condition affecting around twice as many women as men and associated with increasing age. As well as a considerable impact on patient quality of life (QoL), constipation and its sequelae represent a significant economic consideration for healthcare providers [Dennison 2005, Belsey 2010]. Various treatment options are available for constipation relief, including dietary and lifestyle modifications, and pharmacological agents [Tack 2011, Quigley 2012]. Laxative treatments using polyethylene glycol 3350 (PEG 3350) have been recognised as effective, well-tolerated treatments in randomised trials and extensively in clinical practice. Products of the Movicol

range have been used extensively in practice in approximately

twenty two Member States for over 15 years with accepted efficacy for the indications of chronic constipation and faecal impaction. A range of both controlled and uncontrolled studies have evaluated the efficacy of

MOVICOL®

in the therapeutic indication of chronic constipation in adults and children. Movicol (PEG 3350 and electrolytes) acts by increasing stool volume through increased hydration, triggering colon motility to improve transit of softened stools and defecation mechanics. III.1 Quality Aspects N/A


25

III.2 Non-Clinical Aspects N/A III.3 Clinical Aspects To support the changes proposed to the product labelling, no new studies have been conducted by the applicant and none are required. A summary is provided of clinical studies which have been conducted in adults and children to support the efficacy and safety of Movicol, for the treatment of chronic constipation, in the intended population since the product was approved. The changes proposed by the applicant in this application are summarised below with the applicant’s rationale for the changes: Type 1b change: The faecal impaction indication has been deleted. This indication is not suitable for an OTC product since the condition can only be diagnosed by a physician. In addition, the dose required for faecal impaction would be too high to warrant OTC status. Type II change: The wording of the chronic constipation indication has also been modified and the age limit increased in order to align it with the age limit and wording commonly used for OTC laxatives, particularly in the Concerned Member States. III.3.1 Clinical pharmacology N/A III.3.2 Clinical efficacy No new studies have been conducted and none are required to support the changes proposed by the applicant.


26

Since launch of Movicol, studies have been conducted investigating the safety and efficacy in adults, as summarised in the table below:


27


28

It is estimated that the prevalence of constipation in children is between 5% and 30%, depending upon the criteria used to define the diagnosis of the condition [Chaussade, 2003]. Over the last 10 years there have been significant changes in the management and treatment of constipation in children. Although there will be a degree of prescribing variability, the current management is now very much based on using macrogol-based laxatives as first-line treatment for constipation. Clinical studies have been conducted investigating the use of Movicol in children (age 2 – 11 years) for the treatment of constipation, as summarised in the table below:


29

III.3.3 Clinical safety The applicant has provided a summary of post-marketing safety information for Movicol. This covers the use of Movicol for both its currently approved indications of faecal impaction and chronic constipation. It is estimated that since the first registration of macrogol + electrolytes in 1995, over 126 million adults and over 4 million children have been exposed to macrogol therapy. The safety profile for macrogol is well established. It is well tolerated, and undesirable effects are usually those associated with the therapeutic class and mode of action of this compound, such as abdominal pain, diarrhoea, vomiting, nausea, dyspepsia, abdominal distension, borborygmi, flatulence and anal discomfort. There have also been isolated reports of allergic reactions associated with macrogol. Since launch, there have been a total of 17 case reports of overdose associated with the use of PEG 3350. Of these, seven case reports relate to the inappropriate use of the adult formulation of macrogol in children and two cases refer to reports of dosing errors. Overdose may result in fluid loss by diarrhoea or vomiting and these symptoms may necessitate a correction of electrolyte disturbances. Over 90% of reported off-label use of PEG 3350 has been associated with the incorrect administration of the adult formulation to children. As a consequence of the mode of action of macrogol, there is a theoretical possibility of lack of efficacy of any concomitant medications resulting from a decrease in gastrointestinal transit time. However, this is most likely to happen with the larger doses of macrogol solution used for the treatment of faecal impaction, rather than the relatively low doses used for treating constipation.


30

Serious Adverse events (SAEs) There have been 16 SAEs in completed Norgine-sponsored studies investigating the use of

MOVICOL®

in adults. Of these, there have been 11 reports of death. The Investigator and Norgine assessed all of these as unrelated, very unlikely or unlikely to be related to

MOVICOL®

. There have been nine SAEs in completed Norgine-sponsored studies investigating the use of

MOVICOL®

in children. These are described in detail below: Hardikar: Six SAEs were reported by four patients. The events reported were: faecal impaction (two events) and one event each of diarrhoea, vomiting, pyrexia and viral infection. All SAEs were assessed by the investigator as unlikely to be related to study medication. Thomson: Two SAEs were reported: one report of faecal impaction considered related to treatment but confounded by the previous administration of placebo, and one report of constipation considered to be not assessable. Candy: No SAEs were reported in the first open-label part of the study. In the second part of the study, one SAE was reported, a case of chest infection in a 6 year old girl, but this was considered to be unrelated to study medication. Suplementary Information 1. PIL: Section 1: As the product is still a POM medicine until the reclassification procedure, for the purpose of this Type 2 Variation, the original text for POM medicines should be maintained. 2. PIL: Section 4: It is suggested that the proposed sentences are removed and the section is split for children and adults as below:

Other side effects include: In children Very common side effects (i.e. occurring in more than 1 in 10 patients who received the treatment) are: stomach ache, stomach rumbles Common side effects (i.e. occurring in less than 1 in 10 but more than 1 in 100 patients who received the treatment) are: mild diarrhoea, nausea (feeling sick), vomiting. Uncommon side effects (i.e. occurring in less than 1 in 100 but more than 1 in 1,000 patients who received the treatment) are: feeling bloated, suffering from wind (flatulence). In adults The frequency of these side effects cannot be estimated from the available data: stomach ache, stomach rumbles, mild diarrhoea, nausea (feeling sick), vomiting, feeling bloated, suffering from wind (flatulence). In adults and children, these side effects generally get better if you reduce the amount of MOVICOL Uno you take. Other side effects where the frequency cannot be estimated from the available data are: allergic reactions which may cause an itchy skin rash, reddening of the skin or a


31

nettle rash. Tiredness, swelling of hands, feet or ankles, headaches, high and low levels of potassium in the blood, indigestion, soreness of the anus (bottom). If any of the above become serious or last more than a few days or if you notice any side effects not mentioned in this leaflet, please tell your doctor

IV. OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT Based on the evidence provided, the applicant has submitted information from their post-marketing data to support the efficacy and safety of Movicol Uno in the treatment of chronic constipation in adults, adolescents and children (age 8 – 11). The proposed changes of sections 4.1, 4.2, 4.4, 4.5, 4.8 and 5.1 of the SmPC are acceptable. The PIL is in line with the proposed SmPC.

Documents

Public Assessment Report Decentralised Procedure · Public Assessment Report Decentralised Procedure MOVICOL UNO 6.9 G, POWDER FOR ORAL SOLUTION (Macrogol 3350, sodium hydrogen carbonate,