Public Assessment Report. Decentralised Procedure

Public Assessment Report Decentralised Procedure Dulcosoft 10 g powder for oral solution in sachet Procedure No: UK/H/5470 & 5560/001/DC UK Licence No: PL 23022/0112-0113 PharOS-Pharmaceutical Oriented Services Ltd

Lay Summary Dulcosoft 10 g powder for oral solution in sachet (Macrogol 4000) This is a summary of the public assessment report (PAR) for Dulcosoft 10 g powder for oral solution in sachet (PL 23022/0112; ) and Macrogol 4000 10 g powder for oral solution in sachet (PL 23022/0113; ). Dulcosoft 10 g powder for oral solution in sachet and are identical products, except for the product names; these products will be referred to as Dulcosoft and Macrogol 4000 10 g powders for oral solution throughout this report, for ease of reading. It explains how Dulcosoft and Macrogol 4000 10 g powders for oral solution were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Dulcosoft and Macrogol 4000 10 g powders for oral solution. For practical information about using Dulcosoft and Macrogol 4000 10 g powders for oral solution, patients should read the package leaflet or contact their doctor or pharmacist. What are Dulcosoft and Macrogol 4000 10 g powders for oral solution and what are they used for? Dulcosoft and Macrogol 4000 10 g powders for oral solution are medicines with a well-established use. This means that the medicinal use of the active substance of Dulcosoft and Macrogol 4000 10 g powders for oral solution has been well-established in the European Union (EU) for at least ten years, with recognised efficacy and an acceptable level of safety. Dulcosoft and Macrogol 4000 10 g powders for oral solution are used for the treatment of constipation in adults and children aged 8 years and above. How do Dulcosoft and Macrogol 4000 10 g powders for oral solution work? Dulcosoft and Macrogol 4000 10 g powders for oral solution contain the active substance macrogol 4000 and belong to a group of medicines called osmotic laxatives. It works by carrying water to your stool, which loosens and increases stool volume, helping to overcome sluggish bowels, working gradually within 24 to 48 hours. Macrogol 4000 is not absorbed into the bloodstream or broken down in the body. How are Dulcosoft and Macrogol 4000 10 g powders for oral solution used? Dulcosoft and Macrogol 4000 10 g powders for oral solution should be dissolved in a glass of water (125 ml) and taken by mouth. The recommended dose is 1 to 2 sachets daily, preferably taken as a single dose in the morning. Please read Section 3 of the package leaflets for detailed information on dosing recommendations, the route of administration, and the duration of treatment. The daily dose should be adapted as required to produce regular soft stools and may range from one sachet every other day (especially in children) up to 2 sachets a day. If administered regularly, the frequency of bowel movements tends to be one movement per day. 2

Dulcosoft and Macrogol 4000 10 g powders for oral solution can be obtained without a prescription. What benefits of Dulcosoft and Macrogol 4000 10 g powders for oral solution have been shown in studies? As macrogol 4000 is a well-known substance, and the use of it in the treatment of constipation is well-established, the applicant presented data from the scientific literature. The literature provided confirmed the efficacy and safety of macrogol 4000 in the treatment of constipation. What are the possible side effects from Dulcosoft and Macrogol 4000 10 g powders for oral solution? The most common side effects with Dulcosoft and Macrogol 4000 10 g powders for oral solution in adults (which may affect up to 1 in 10 people) are abdominal pain, bloating, nausea and diarrhoea. The most common side effects with Dulcosoft and Macrogol 4000 10 g powders for oral solution in children (which may affect up to 1 in 10 people) are abdominal pain and diarrhoea. For the full list of all side effects reported with Dulcosoft and Macrogol 4000 10 g powders for oral solution, see Section 4 of the package leaflet. For the full list of restrictions, see the package leaflet or the Summary of Product Characteristics (SmPC) available on the Medicines and Healthcare products Regulatory Agency (MHRA) website. Why are Dulcosoft and Macrogol 4000 10 g powders for oral solution approved? It was decided that the benefits of Dulcosoft and Macrogol 4000 10 g powders for oral solution outweigh the risks and the grant of the marketing authorisations was recommended. What measures are being taken to ensure the safe and effective use of Dulcosoft and Macrogol 4000 10 g powders for oral solution? A risk management plan has been developed to ensure that Dulcosoft and Macrogol 4000 10 g powders for oral solution are used as safely as possible. Based on this plan, safety information has been included in the SmPCs and the package leaflets for these products, 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 Dulcosoft and Macrogol 4000 10 g powders for oral solution Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Greece, Finland, France, Ireland, Italy, Luxembourg, Malta, the Netherlands, Portugal, Romania, Spain, Sweden and the UK agreed to grant a marketing authorisation for Dulcosoft 10 g powder for oral solution on 12 December 2014. The marketing authorisation in the UK was granted on 30 January 2015. Austria, Belgium, Czech Republic, Greece, Finland, France, Italy, Portugal, Spain, Sweden and the UK agreed to grant a marketing authorisation for Macrogol 4000 10 g powders for oral solution on 12 December 2014. The marketing authorisation in the UK was granted on 30 January 2015. 3

The full PAR for Dulcosoft and Macrogol 4000 10 g powders for oral solution follows this summary. For more information about treatment with Dulcosoft and Macrogol 4000 10 g powders for oral solution, read the package leaflet or contact your doctor or pharmacist. This summary was last updated in March 2015. 4

TABLE OF CONTENTS I Introduction Page 6 II Quality aspects Page 8 III Non-clinical aspects Page 10 IV Clinical aspects Page 12 V User consultation Page 14 VI Overall conclusion, benefit/risk assessment and recommendation Page 14 Table of content of the PAR update for MRP and DCP Page 21 5

I Introduction Based on the review of the data on quality, safety and efficacy, the Member States have granted marketing authorisations (MAs) to PharOS-Pharmaceutical Oriented Services Ltd for the medicinal products Dulcosoft and Macrogol 4000 10 g powders for oral solution. These pharmacy (P) medicines are indicated for the symptomatic treatment of constipation in adults and children aged 8 years and above. An organic disorder should have been ruled out before initiation of treatment with Dulcosoft and Macrogol 4000 10 g powders for oral solution. These products should remain a temporary adjuvant treatment to appropriate lifestyle and dietary management of constipation, with a maximum 3 months treatment course in children. If symptoms persist despite associated dietary measures, an underlying cause should be suspected and treated. These applications were submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Greece, Finland, France, Ireland, Italy, Luxembourg, Malta, the Netherlands, Portugal, Romania, Spain and Sweden as Concerned Member States (CMSs) for Dulcosoft 10 g powder for oral solution (UK/5470/001/DC; PL 23022/0112) and Austria, Belgium, Czech Republic, Greece, Finland, France, Italy, Portugal, Spain, Sweden as CMSs for Macrogol 4000 10 g powder for oral solution (UK/5560/001/DC; PL 23022/0113). These applications were made under Article 10a of Directive 2001/83/EC, as amended, claiming to be applications for products containing an active substance of well-established use. Constipation is a functional disorder of the gastrointestinal (GI) tract characterised by dry faeces and difficult, infrequent evacuations in the absence of detectable abnormalities. This condition is very common in the general population, with a prevalence ranging from 2% to 27%; children, the elderly and females being the more affected. It is estimated that one-third of the population in western industrial countries suffer from constipation at least occasionally. These medicinal products contain the active substance macrogol 4000. High molecular weight macrogol (also known as PEG- polyethylene glycol) is a large, inert, water soluble polymer having the capacity to form hydrogen bonds with 100 molecules of water per molecule of macrogol. It opposes the dehydration of bowel contents and hydrates the bowel contents, leading to modification of stool consistency and increased stool volume, and decreases the duration of the colon passage. This, in turn, stretches muscle fibres in the bowel wall and triggers myogenic peristalsis. The increased retention of water in the colon lubricates and softens stools, and allows comfortable bowel action. Macrogol passes virtually unchanged through the whole gastrointestinal tract, including the colon. Macrogol, in varying forms (3350 or 4000), has been licensed in the EU for many years and has a well-established history of use as both a bowel preparation medicine and a laxative. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of these products. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. 6

No new clinical studies have been performed, which is acceptable for applications of this type. The RMS considers that the pharmacovigilance system, as described by the MA holder, fulfils the requirements and provides adequate evidence that the MA holder 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. The MA holder has provided a Risk Management Plan (RMP). A suitable justification has been provided for the non-submission of an Environmental Risk Assessment (ERA) and this is accepted. The RMS and CMSs considered that the applications could be approved at the end of procedure (Day 208) on 12 December 2014. After a subsequent national phase, licences were granted in the UK on 30 January 2015. 7

II Quality aspects II.1 Introduction These applications were made under Article 10a of Directive 2001/83/EC, as amended, claiming to be applications for products containing an active substance of well-established use. The products are formulated as white powders, free of large agglomerates, with an odour and taste of lemon, each packed in a sachet for the preparation of an oral solution. Each sachet contains 10 g of the active substance, macrogol 4000. The excipients are: anhydrous magnesium citrate, anhydrous citric acid, calcium citrate, acesulfame K, potassium chloride (with 0.9% colloidal anhydrous silica) and lemon-grapefruit flavour. The lemon-grapefruit flavour contains: natural lemon oil, liquid flavour grapefruit, powder flavour maracuja, powder flavour grenadine/raspberry, mannitol (E421), gluconolactone (E575), sorbitol (E420), colloidal anhydrous silica (E551). The powders for oral solution are presented in an aluminium/paper sachet, and unidose sachets are further packed into cartons, in packs of 10 or 20 sachets. II.2 Drug Substance Macrogol 4000 INN: Macrogol 4000 Chemical name: α-hydro-ω-hydroxypoly(oxyethylene) Other names: Carbowax 4000, polyethylene glycol 4000 Structure: Molecular formula: (C 2 H 4 0) n Average Molecular Mass: 4000 g.mol -1 Appearance: White or almost white solid with a waxy or paraffin-like appearance. Solubility: Very soluble in water and in methylene chloride; practically insoluble in alcohol, in fatty oils and in mineral oils Macrogol 4000 is the subject of a European Pharmacopoeia monograph. The manufacture and control of the active substance, macrogol 4000, is covered by European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificates of Suitability. Satisfactory information has been provided on the stability of the active substance and on the packaging materials. 8

II.3 Medicinal Product Pharmaceutical development The product development has been sufficiently described. The objective was to develop a powder form with a pleasant taste to be dissolved in water for easy administration. The formulation was developed to be kept as lean as possible without the presence of agglomerates. The active substance used in the proposed formulation, macrogol 4000, is a well-established substance, which is used in many pharmaceutical products marketed for the same purpose. The excipients and their proportions were selected from experience of similar existing products in powder form. All the excipients used in the manufacture of the proposed formulation, other than the lemon-grapefruit flavouring agent, comply with their respective European Pharmacopoeial monographs. The lemon-grapefruit flavouring agent complies with a satisfactory in-house specification. Satisfactory certificates of analysis have been provided for all excipients showing compliance with their proposed specifications. None of the excipients used contain material of animal or human origin. Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the finished product, together with an appropriate account of the manufacturing process. The in-process controls in place during the manufacture of the finished product have been described and are considered sufficient. Satisfactory process validation was performed on one pilot scale batch and two production scale batches of the finished product. Finished Product Specification The finished product specification is satisfactory. Test methods have been described that have been adequately validated, as appropriate. Batch data have been provided from the three validation batches that comply with the release specification. Certificates of analysis have been provided for all working standards used. Stability of the product Stability studies were performed in accordance with current guidelines on batches of the finished product, packed in the packaging proposed for marketing. The data from these studies support a shelf-life for the finished product of 3 years when stored below 30 ºC in its original container, to protect from light. Suitable post approval stability commitments have been provided. II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of marketing authorisations is recommended. 9

III Non-clinical aspects III.1 Introduction No new non-clinical data have been submitted and none are required for applications of this type. The applicant s non-clinical overview has been written by an appropriately qualified person and is satisfactory. III.2 Pharmacology Macrogol 4000 is a form of polyethylene glycol (PEG) that is used as an osmotic laxative. It softens the stool by increasing 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 defaecation. The efficacy of PEG has been demonstrated in a non-clinical model in cats, whereby soft stools were achieved in all animals. A number of clinical studies showed improved stool frequency and consistency in patients with chronic constipation. A number of secondary pharmacology effects of PEG have been reported in the literature, including potential anticancer and cardioprotective effects. They also include potential protective effects against colitis and effects against cold ischaemia and reperfusion injury protection. Parenteral injections of PEG (particularly intraperitoneal injection) can adversely affect gastric function and increase the damaging action of alcohol in the gastriointestinal (GI) tract. Standard safety pharmacology studies have not been conducted or reported for macrogol 4000. However, as it is not absorbed to a significant extent from the gastrointestinal tract, effects on the central nervous system, cardiovascular system and respiratory system are not to be expected. III.3 Pharmacokinetics The rate of absorption of 14 C-PEG 4000 was low in anaesthetised rats, particularly in the colon. Solid PEGs such as PEG 1000, 1540, 4000 and 6000 are designated as Carbowax compounds. No absorption of Carbowax compounds 4000 and 6000 was noted when administered orally to rats and with compounds 1000 and 1540 absorption was < 2%. Similarly in humans, compound 6000 was not absorbed, although about 8% of compound 1000 was absorbed. When administered via intravenous (i.v.) injection to human subjects, Carbowax compounds 6000 and 1000 were excreted readily and to a high degree. However, oral administration of lower molecular weight PEG 400 to both animals and humans resulted in a significant amount of PEG being absorbed. Distribution studies are limited. In dogs administered 4.23, 6.34 and 8.45 g/kg bodyweight (b.w.) PEG 400, the volume of distribution was 0.70 l/kg b.w. on Day 1 and 0.72 l/kg b.w. on Day 30. There are no reports of secretion of PEG into milk. 10

Higher molecular weight macrogols ( 3000) that enter the systemic circulation are generally excreted unchanged in the urine. PEG 4000 was cleared rapidly via the urine following an intravenous dose of 14 C-PEG 4000 to rats, with the majority excreted within 24 hours. Sixty-one percent of the dose was recovered in the urine and 20% in the faeces over a 7-day period. Following an oral dose, over 80% was recovered in the faeces, with only 4.1% in the urine over the 7-day collection period. The absorption of co-administered drugs may be affected by the presence of PEG and there is a general comment to this effect in Section 4.5 of the proposed SmPC. III.4 Toxicology The repeated-dose toxicity of PEG has been studied in rats, rabbits and dogs. Treatment-related effects were, in general, dose-dependent. Oral administration of 16% Carbowax 1500 and 4000 for 90 days to rats resulted in no deaths. Growth was equal to that of the control rats. At 4,050 mg/kg body weight/day of Carbowax 1500 ( 10-fold the maximum recommended human dose, MRHD) or 80 mg/kg body weight/day of Carbowax 4000 (0.2-fold the MRHD) a few kidneys had cloudy swelling. At 230 mg/kg body weight/day of Carbowax 4000 ( 0.6-fold the MRHD), testicular degeneration was occasionally found. Administration of Carbowax 4000 to rabbits (at a dose representing up 50-fold the MRHD) 5 days a week for 5 weeks did not resilt in any deaths. Blood urea remained normal and renal pathology was absent. In rats administered PEG 1540 for up to 2 years, only minor effects were found. Carbowax 1500 and 4000 administered to rats, orally, for 2 years, did not affect life span, fertility, micropathology or blood cytology. Information on the genotoxicity and carcinogenicity of PEG is incomplete, although PEG 4000 is not considered to be genotoxic. PEG 8000 at 5% concentration in multiple intestinal neoplasia (Min) mice increased the number of colon tumours and the number of animals with colonic tumours. While such effects cannot be excluded for macrogol 4000, years of clinical use do not suggest that these aspects are an issue. An in vitro embryotoxicity study of PEG 200 in 10 day cultured rat embryos showed a teratogenic potential with mouse S9 mix at 0.25 and 0.5% after PEG 200 exposure. Abnormalities involved mainly brain development (hypoplasia of proencephalon, fore and midbrain opened). With rat, hamster, rabbit or human S9 mix, PEG 200 was embryolethal at 0.5 and 0.75%. With any S9 mix sample, 1% PEG 200 was embryolethal. The available information on acute and repeated dose toxicity, mutagenicity and carcinogenicity has been reviewed adequately in the applicant s non-clinical overview. The reproductive toxicity data are limited and refer only to an in vitro study with PEG 200. This is reflected in Section 5.3 of the SmPC is in line with other macrogol 4000 UK approved products. 11

III.5 Ecotoxicity/environmental risk assessment (ERA) The MA holder provided a suitable justification for not submitting an Environmental Risk Assessment. The majority of macrogol-containing medicinal products in the EU are used as osmotic laxatives. No additional significant patient group is, therefore, expected to be added to this market by these applications. A decrease of market share of existing products containing macrogol is expected due to the switching of patients from existing products to Dulcosoft and Macrogol 4000 10 g powders for oral solution. Thus, the justification for non-submission of an Environmental Risk Assessment is accepted. III.6 Discussion on the non-clinical aspects The grant of marketing authorisations is recommended. IV Clinical aspects IV.1 Introduction No new clinical data have been submitted and none are required for applications of this type. The applicant s clinical overview has been written by an appropriately qualified person and is considered acceptable. IV.2 Pharmacokinetics High-molecular weight PEGs pass the GI tract unchanged (i.e. no degradation by intestinal bacteria occurs), with negligible absorption (<0.5%). In the absence of pharmacokinetic (PK) data for PEG 4000, and due to the similarity of the compounds, the results of a study of PEG 3350 can be extrapolated to PEG 4000. Peak PEG 3350 plasma concentrations occurred at 2 to 4 h and declined to non-quantifiable levels usually within 18 h after single and multiple doses, with a half-life of about 4 to 6 h. Steady state was reached within 5 days of dosing. The small amounts of PEGs absorbed are excreted, unchanged, into urine, and the majority of the dose was excreted into faeces (90% to 100%). Age, gender, or mild kidney impairment did not alter the pharmacokinetics of high molecular weight (MW) PEGs. Clinically significant drug interactions have not been reported. Considering that the absorption of other active principles may undergo a modification due to changes in the local osmotic pressure at the intestine, the following statement was introduced into Section 4.5 of the SmPC: Macrogol 4000 increases the osmotic pressure in the gut, and thus might modify the intestinal absorption of drugs concomitantly administered. IV.3 Pharmacodynamics Osmotic laxatives are poorly absorbed ions or molecules that create an osmotic gradient within the intestinal lumen, drawing water into the lumen and making stools soft and loose. Since PEG/macrogol is an inert molecule, which cannot be metabolised by the intestinal microflora, it is delivered from the small intestine to the colon, where it evokes its osmotic activity. This causes the volume of the faecal mass to increase (due to a higher water content), which in turn triggers propulsive motor processes, such as peristalsis, via distension of the colonic wall. The increased hydration also softens the faeces and eases defaecation. PEG has a linear dose-effect relationship; hence it has the potential to be dose titrated according to the stool output making it suitable for use in both, chronic and occasional constipation. 12

IV.4 Clinical efficacy The efficacy of high MW PEGs (3350/4000) for the treatment of constipation in adults, as well as children, has been successfully demonstrated across multiple randomised controlled trials, as well as in meta-analyses. There has been no evidence that the additional salts/electrolytes have any extra benefit in combating constipation. While PEG electrolyte solutions were initially proven to be efficacious, there has been sufficient recent research over the last decade to demonstrate that electrolyte-free PEG is equally effective in improving the stool frequency and consistency in the general adult population, as well as different subpopulations including paediatric, geriatric, and pregnant constipated patients. PEG is also found to be equivalent or superior to other active comparators such as lactulose and milk of magnesia (MOM) in treating constipation, with a better acceptance/compliance rate to the latter, which is especially important with children and the elderly. It is also recognised that studies have established that the PEG 3350 and 4000 formulations have similar efficacy and, therefore, the data submitted in the PEG 3350 formulations support these applications. IV.5 Clinical safety The safety of high MW PEGs (3350/4000) for the treatment of constipation in adults as well as children has been successfully demonstrated across multiple randomised controlled trials as well as in meta-analyses. The adverse events seen are mostly non-serious and self-limiting in nature. This is in line with the minimal systemic absorption seen with such preparations. Gastrointestinal disorders, in particular diarrhoea, are the most frequent adverse reactions associated with PEG use in constipation. Other adverse effects include abdominal pain, abdominal distension, nausea, flatulence, vomiting and faecal incontinence. All these events are, however, usually mild to moderate in nature, and mostly tolerable. There are no serious adverse events reported to be related with PEG use in controlled clinical trials. Other side effects of PEG may include allergic reactions, and more specific anaphylactic shock, anaphylactic reaction, angioedema or urticarial rash. IV.6 Risk Management Plan (RMP) The applicant 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 Dulcosoft and Macrogol 4000 10 g powders for oral solution. A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, are listed below: Summary of safety concerns Important identified Electrolyte disturbances risks Hypersensitivity (including anaphylactic Important potential risks Missing information reactions) Potential to alter absorption of other medicinal products Symptomatic treatment might mask/hide an underlying condition requiring medical attention and supervision Long-term use of the product > 6 months 13

Summary table of Risk Minimisation Measures Safety concern Important identified risks Electrolyte disturbances Hypersensitivity (including anaphylactic reactions) Important potential risks Potential to alter absorption of other medicinal products Symptomatic treatment might mask/hide an underlying condition requiring medical attention and supervision Missing information Long-term use of the product > 6 months Routine risk minimisation measures Specific warning included in sections Special Warnings and Precautions and Overdose of the SmPC Specific warning included in sections Contraindications and Special warnings and precautions of the SmPC. Specific information regarding this aspect has been included in the section Interactions of the SmPC. Specific warning included in section Special Warnings and Precautions Specific warning included in section Special Warnings and Precautions Additional risk minimisation measures None None None None None IV.7 Discussion on the clinical aspects The grant of marketing authorisations is recommended for these applications. V User consultation A 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. The language used for the purpose of user testing the package leaflet 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 products is acceptable, and no new non-clinical or clinical safety concerns have been identified. Macrogol 4000 is a well-established active substance. Extensive clinical experience with macrogol 4000 is considered to have demonstrated the therapeutic value of this compound. The benefit/risk assessment is, therefore, considered to be positive. 14

The Summaries of Product Characteristics (SmPC), package leaflets and labelling are satisfactory and in line with current guidelines. In accordance with Directive 2012/84/EU, the current approved UK versions of the SmPCs and package leaflets for these products are available on the MHRA website. The currently approved labelling text is listed below: Labelling text for Dulcosoft 10 g powder for oral solution in sachet PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Dulcosoft 10 g powder for oral solution in sachet Macrogol 4000 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each sachet contains 10 g macrogol 4000. 3. LIST OF EXCIPIENTS Each sachet contains 0.2 mg sorbitol. See package leaflet for more information 4. PHARMACEUTICAL FORM AND CONTENTS Powder for oral solution in sachet 10 sachets 20 sachets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 15

9. SPECIAL STORAGE CONDITIONS Do not store above 30 C. Store in its original container to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER PharOS - Pharmaceutical Oriented Services Ltd Lesvou str. (end), Thesi Loggos, Industrial Zone, Metamorfossi Attikis, 144 52 Greece 12. MARKETING AUTHORISATION NUMBER(S) PL 23022/0112 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY P 15. INSTRUCTIONS ON USE Used for the treatment of constipation in adults and children aged 8 years and above. Adults and children 8 years and above 1 to 2 sachets (10 to 20 g macrogol 4000) per day, preferably taken as a single dose in the morning. The daily dose should be adapted as required to produce regular soft stools and may range from one sachet every other day (especially in children) up to 2 sachets a day. Read the package leaflet before use. 16. INFORMATION IN BRAILLE Dulcosoft 10 g powder for oral solution in sachet 16

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Sachets 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Dulcosoft 10 g powder for oral solution in sachet Macrogol 4000 2. METHOD OF ADMINISTRATION Oral use. Each sachet should be dissolved in 125 ml of water just before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 10 g 6. OTHER MAH info Please read the leaflet. Keep out of sight and reach of children 17

Labelling text for PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Macrogol 4000 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each sachet contains 10 g macrogol 4000. 3. LIST OF EXCIPIENTS Each sachet contains 0.2 mg sorbitol. See package leaflet for more information 4. PHARMACEUTICAL FORM AND CONTENTS Powder for oral solution in sachet 10 sachets 20 sachets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Do not store above 30 C. Store in its original container to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 18

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER PharOS - Pharmaceutical Oriented Services Ltd Lesvou str. (end), Thesi Loggos, Industrial Zone, Metamorfossi Attikis, 144 52 Greece 12. MARKETING AUTHORISATION NUMBER(S) PL 23022/0113 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY P 15. INSTRUCTIONS ON USE Used for the treatment of constipation in adults and children aged 8 years and above. Adults and children 8 years and above 1 to 2 sachets (10 to 20 g macrogol 4000) per day, preferably taken as a single dose in the morning. The daily dose should be adapted as required to produce regular soft stools and may range from one sachet every other day (especially in children) up to 2 sachets a day. Read the package leaflet before use. 16. INFORMATION IN BRAILLE 19

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS Sachets 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Macrogol 4000 2. METHOD OF ADMINISTRATION Oral use. Each sachet should be dissolved in 125 ml of water just before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 10 g 6. OTHER MAH info Please read the leaflet. Keep out of sight and reach of children 20

Annex Table of content of the PAR update for MRP and DCP Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II variations, PSURs, commitments) Scope Procedure number Product information affected Date of start of the procedure Date of end of procedure Approval/ non approval Assessment report attached Y/N (version) 21