Lactulose 3.3g-5ml Oral Solution PL 10321 0002 …

1 UKPAR Lactulose oral Solution PL 10321 /0002 1 Lactulose oral Solution PL 10321 /0002 UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 10 Steps taken after authorisation summary Page 11 Summary of Product Characteristics Page 12 Patient Information Leaflet Page 17 Labelling Page 21 UKPAR Lactulose oral Solution PL 10321 /0002 2 Lactulose oral Solution PL 10321 /0002 LAY SUMMARY The MHRA granted Resolution Chemicals Ltd a Marketing Authorisation (licence) for the medicinal product Lactulose oral Solution (PL 10321 /0002).

2 This medicine is available through pharmacies (P) for the treatment of chronic constipation and hepatic encephalopathy. Lactulose oral Solution contains the active ingredient Lactulose which is a laxative. The test product was considered to be equivalent to the original product Duphalac (Solvay Healthcare Ltd) based on the data submitted. No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of taking Lactulose oral Solution outweigh the risks, hence a Marketing Authorisation has been granted.

3 UKPAR Lactulose oral Solution PL 10321 /0002 3 Lactulose oral Solution PL 10321 /0002 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 5 Preclinical assessment Page 7 Clinical assessment (including statistical assessment) Page 8 Overall conclusion and risk benefit assessment Page 9 UKPAR Lactulose oral Solution PL 10321 /0002 4 INTRODUCTION Based on the review of the data on quality, safety and efficacy, the UK granted a Marketing Authorisation for the medicinal product Lactulose oral Solution to Resolution Chemicals Ltd on 26 June 2007.

4 This product is available through pharmacies. The application was submitted as an abridged application according to Article of Directive 2001/83/EC as amended, claiming to be a generic product of Duphalac (Solvay Healthcare Ltd). The reference product has been authorised in the UK since March 1988 and so the 10-year period of data exclusivity has expired. The product contains the active ingredient Lactulose and is indicated for the treatment of constipation and hepatic encephalopathy (hepatic coma). Lactulose is an osmotic laxative used to treat constipation by increasing faecal bulk and stimulating peristalsis after it is broken down by colonic bacteria.

5 Lactulose is used to treat hepatic encephalopathy by reducing the pH of the colon causing ammonia to form in the colon, thereby reducing blood-ammonia concentrations. No bioequivalence study has been performed. The product can be considered exempt from this requirement due to the nature of the formulation. UKPAR Lactulose oral Solution PL 10321 /0002 5 PHARMACEUTICAL ASSESSMENT COMPOSITION The product is formulated as an aqueous Solution containing 66% w/v of the active pharmaceutical ingredient Lactulose . There are no excipients present.

6 Lactulose oral Solution is presented in HDPE bottles with white HDPE tamper evident screw caps in packs of 200ml, 300ml, 500ml, 1000ml and 5000ml of Solution . DRUG SUBSTANCE Lactulose Synthesis of the drug substance from the designated starting material has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specifications are in place for all starting materials and reagents and these are supported by relevant certificates of analysis.

7 The applicant has provided a declaration stating that the lactose used in the manufacture of Lactulose is derived from milk sourced from healthy animals under the same conditions as those for human consumption. An appropriate specification based on the European Pharmacopoeia monograph is provided for Lactulose . Analytical methods have been validated and are satisfactory for ensuring compliance with the relevant specifications. Batch analysis data are provided for seven batches and comply with the proposed specification. Lactulose is stored in appropriate packaging.

8 Stability data have been generated supporting a retest period of 4 years when stored in the proposed packaging below 25 C. A warning is also included to not refrigerate or freeze the material. DRUG PRODUCT Other ingredients The water used for the aqueous Solution is potable water, but it is purified during the manufacturing process to a quality consistent with that of purified water that meets the European Pharmacopoeia standard. Impurity profiles A comparison of the impurity profiles of two batches of product with that of the reference product was provided.

9 This data was supplemented with comparative batch UKPAR Lactulose oral Solution PL 10321 /0002 6analysis data for an additional five batches. The results indicate that there were no significant differences between the test and reference products. Manufacture A full description and a detailed flow-chart of the manufacturing method including in-process control steps has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation has been carried out for all pack sizes.

10 The results are satisfactory. Additional validation data will be supplied on the first three commercial batches when available. Finished product specification The proposed finished product specification is acceptable and the analytical methods used have been suitably validated. Batch analysis data have demonstrated compliance with the proposed release specification. Suitable reference standards were used. Container Closure System Satisfactory specifications and certificates of analysis have been provided for the packaging components.