Public Assessment Report Decentralised Procedure …

1 1 Public Assessment Report Decentralised Procedure Plenvu powder for oral solution (Macrogol 3350, sodium ascorbate, sodium sulfate anhydrous, ascorbic acid, sodium chloride, potassium chloride) Procedure No: UK/H/6370/001/DC UK Licence No: PL 20142/0020 Norgine PAR Plenvu powder for oral solution UK/H/6370/001/DC 2 LAY SUMMARY Plenvu powder for oral solution This is a summary of the Public Assessment Report (PAR) for Plenvu powder for oral solution (PL 20142/0020; UK/H/6370/001/DC). It explains how Plenvu powder for oral solution was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Plenvu powder for oral solution. The product will be referred to Plenvu throughout the remainder of this Public Assessment Report (PAR).

2 For practical information about using Plenvu, patients should read the package leaflet or contact their doctor or pharmacist. What is Plenvu and what is it used for? Plenvu contains the combination of active substances macrogol 3350, sodium ascorbate, sodium sulfate anhydrous, ascorbic acid, sodium chloride and potassium chloride. Plenvu is a laxative. Plenvu is intended for adults 18 years of age and older prior to any clinical Procedure requiring a clean bowel. How does Plenvu work? Plenvu cleans the patient s bowel by causing them to have diarrhoea. How is Plenvu used? The pharmaceutical form of Plenvu is a powder for oral solution and the route of administration is oral. The patient s treatment with Plenvu must be completed before their clinical Procedure . This course of treatment should be taken as divided doses as described below: Two-day split dosing schedule Dose 1 taken in the evening before the clinical Procedure (approximately ) and Dose 2 in the early morning of the day of the clinical Procedure (approximately ), or Morning only dosing schedule Dose 1 and Dose 2 taken in the morning of the day of the clinical Procedure (Dose 1 at approximately ); the two doses separated by a minimum 1 hour interval, or Day before dosing schedule Dose 1 and Dose 2 taken in the evening of the day before the clinical Procedure (Dose 1 at approximately ); the two doses separated by a minimum 1 hour interval.

3 The patient s doctor will inform them which dosing schedule to follow. DO NOT add any other ingredients to the doses. The patient can only consume food and drink in accordance with the details provided for the chosen schedule but must not eat while taking Plenvu and until after their clinical Procedure . Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment. PAR Plenvu powder for oral solution UK/H/6370/001/DC 3 The medicine can be obtained without a prescription. What benefits of Plenvu have been shown in studies? Plenvu is a fixed combination product of known active substances. The company provided its own data on efficacy and safety studies. These studies have shown that Plenvu is effective for bowel cleansing prior to any Procedure requiring a clean bowel.

4 What are the possible side effects of Plenvu? Like all medicines, this medicine can cause side effects, although not everybody gets them. The most common side effects with Plenvu (which may affect up to 1 in 10 people) are: Dehydration Nausea (feeling sick) Vomiting. For the full list of restrictions, see the package leaflet. For the full list of all side effects reported with Plenvu, see section 4 of the package leaflet available on the MHRA website. Why is Plenvu approved? The MHRA decided that Plenvu s benefits are greater than its risks and recommended that it be approved for use. What measures are being taken to ensure the safe and effective use of Plenvu? A risk management plan (RMP) has been developed to ensure that Plenvu is used as safely as possible. Based on this plan, safety information has been included in the Summary of Product Characteristics and the package leaflet for Plenvu including the appropriate precautions to be followed by healthcare professionals and patients.

5 Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously. Other information about Plenvu. Austria, Belgium, Bulgaria, the Czech Republic, Germany, Denmark, Spain, Finland, France, Croatia, Hungary, Iceland, Ireland, Italy, Luxembourg, the Netherlands, Norway, Poland, Portugal, Romania, Sweden, Slovenia, the Slovak Republic and the UK agreed to grant a Marketing Authorisation for Plenvu on 27 September 2017. A Marketing Authorisation was granted in the UK on 23 October 2017. Austria, Netherlands and Spain agreed to grant a Marketing Authorisation with the name Pleinvue. The full PAR for Plenvu follows this summary. For more information about treatment with Plenvu read the package leaflet, or contact your doctor or pharmacist.

6 This summary was last updated in December 2017. PAR Plenvu powder for oral solution UK/H/6370/001/DC 4 TABLE OF CONTENTS I Introduction Page 5 II Quality aspects Page 7 III Non-clinical aspects Page 12 IV Clinical aspects Page 14 V User consultation Page 30 VI Overall conclusion, benefit/risk Assessment and recommendation Page 30 Annex 1 - Table of content of the PAR update for MRP and DCP Page 36 PAR Plenvu powder for oral solution UK/H/6370/001/DC 5 I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the application for Plenvu (PL 20142/0020; UK/H/6370/001/DC) could be approved. The product is available from a pharmacy without a prescription (legal classification P) and is indicated in adults for bowel cleansing prior to any Procedure requiring a clean bowel.

7 The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Austria, Belgium, Bulgaria, the Czech Republic, Germany, Denmark, Spain, Finland, France, Croatia, Hungary, Iceland, Ireland, Italy, Luxembourg, the Netherlands, Norway, Poland, Portugal, Romania, Sweden, Slovenia and the Slovak Republic as Concerned Member States (CMS). The application was submitted under Article 10(b) of Directive 2001/83/EC, as amended, applicable for a fixed combination product of known active substances. Plenvu contains the active ingredients macrogol 3350, sodium ascorbate, sodium sulfate anhydrous, ascorbic acid, sodium chloride and potassium chloride. Plenvu is a novel combination product developed for bowel clearance. It is formulated as a split-dosing formulation containing two osmotically-active powders for reconstitution; one containing polyethylene glycol (PEG or macrogol) 3350 and sodium sulfate , and the second containing ascorbate components ( sodium ascorbate with ascorbic acid (vitamin C)) combined with a lower amount of macrogol 3350.

8 Both doses contain electrolytes, sweetener and flavouring. The composition of the powders is presented as three sachets contained in a clear secondary overwrap within a cardboard carton, and comprise a single treatment of Plenvu. Dose 1 contains g of powder, Dose 2 Sachet A contains g of powder and Dose 2 Sachet B contains g of powder. The doses are each reconstituted with 500 mL water to produce palatable oral solutions and administered in a split-dosing regimen either where one solution is given in the evening and the other in the morning prior to the clinical Procedure , or where the two solutions are both given on the same day but about 1 to 2 hours apart. Such dosing results in a total oral administration of PEG 3350, sodium ascorbate, sodium sulfate , ascorbic acid, sodium chloride, and potassium chloride at approximately 2000, 687, 129, 108, 74, and 31 mg/kg body weight (BW), respectively, for a 70 kg adult.

9 Plenvu is not recommended for use in children below 18 years of age. The composition of Plenvu is based on the applicant s experience with PEG-based laxatives, including Movicol (PL 00322/0070) marketed by the applicant, Norgine Limited, in the UK since December 1995, and the bowel preparation Moviprep (PL 20142/0005), also marketed by the applicant since January 2006. The applications cross-refer to non-clinical and clinical data provided for the existing marketing authorisations (MA) for Movicol and Moviprep, although no new non-clinical studies have been conducted to support this application for Plenvu. Moviprep also contains the following ingredients as in Plenvu, however at different quantities: PEG 3350, sodium sulfate , sodium ascorbate, ascorbic acid and electrolytes. The oral administration of macrogol-based electrolyte solutions causes moderate diarrhoea and results in rapid emptying of the colon.

10 Macrogol 3350, sodium sulfate and high doses of ascorbic acid exert an osmotic action in the gut, which induces a laxative effect. Macrogol 3350 increases the stool volume, which triggers colon motility via neuromuscular pathways. PAR Plenvu powder for oral solution UK/H/6370/001/DC 6 The physiological consequence is a propulsive colonic transportation of the softened stools. The electrolytes present in the formulation and the supplementary clear liquid intake are included to prevent clinically significant variations of sodium , potassium or water, and thus reduce dehydration risk. The clinical development programme for this application consisted of one Phase I study, one Phase II study and three Phase III studies. These studies are discussed in more detail in the IV, Clinical Aspects section of this Report .