AMITIZA 24 MICROGRAM SOFT CAPSULES PL …

1 UKPAR AMITIZA 24 micrograms soft CAPSULES PL 21341/0003 - 1 - AMITIZA 24 MICROGRAM soft CAPSULES PL 21341/0003 UKPAR TABLE OF CONTENTS Lay Summary Page 2 scientific discussion Page 3 Steps taken for assessment Page 38 Steps taken after authorisation summary Page 39 Summary of Product Characteristics Page 40 Patient Information Leaflet Page 41 Labelling Page 42 UKPAR AMITIZA 24 micrograms soft CAPSULES PL 21341/0003 - 2 - AMITIZA 24 MICROGRAM soft CAPSULES PL 21341/0003 UKPAR LAY SUMMARY The Medicines Healthcare products Regulatory Agency granted Sucampo Pharma Europe Limited a Marketing Authorisation (licence) for the medicinal product AMITIZA 24 micrograms soft CAPSULES (PL 21341/0003) on 10 September 2012.

2 This is a prescription-only medicine (POM). AMITIZA 24 micrograms soft CAPSULES contains the active ingredient, lubiprostone and works by increasing the amount of fluids into the bowels. This helps the passage of stool and reduces the feeling of uncomfortable and difficult bowel movements that occurs with constipation. AMITIZA 24 micrograms soft CAPSULES is used to treat chronic idiopathic constipation. Based on the data submitted by Sucampo Pharma Europe Limited it was judged that the benefits of AMITIZA 24 micrograms soft CAPSULES outweigh the risks; hence Marketing Authorisations have been granted. UKPAR AMITIZA 24 micrograms soft CAPSULES PL 21341/0003 - 3 - AMITIZA 24 MICROGRAM soft CAPSULES PL 21341/0003 UKPAR scientific DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 5 Non-clinical assessment Page 8 Clinical assessment Page 13 Overall conclusions and risk benefit assessment Page 37 UKPAR AMITIZA 24 micrograms soft CAPSULES PL 21341/0003 - 4 - INTRODUCTION The UK granted a Marketing Authorisation for the medicinal product AMITIZA 24 micrograms soft CAPSULES (PL 21341/0003) to Sucampo Pharma Europe Limited on 10th September 2012.

3 This product is a prescription-only medicine. This application was submitted as full application according to Article 8(3) of Directive 2001/83/EC as amended. The product is indicated for the treatment of chronic idiopathic constipation and associated symptoms in adults, when response to diet and other non-pharmacological measures ( , educational measures, physical activity) are inappropriate. The product contains a new bicyclic fatty acid compound, lubiprostone. Lubiprostone is a prostone, a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion, without altering electrolyte concentrations in the serum. Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A independent fashion. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation.

4 An extensive battery of GLP non-clinical studies designed to assess the toxicity of lubiprostone and its metabolites have been conducted. Clinical studies include seven Phase I studies, two Phase II studies, and seven Phase III studies (three pivotal studies and four long-term safety studies); two of the Phase I studies, one Phase II study, one pivotal study and one of the long-term studies were conducted in Japan. Three separate clinical studies of lubiprostone were conducted in subjects with renal or hepatic impairment, as well as paediatric patients diagnosed with chronic constipation. The applicant has submitted a satisfactory pharmacovigilance system and fulfils the requirements and provides adequate evidence that the MAH 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.

5 The applicant submitted a suitable Risk Management Plan. The applicant has submitted a suitable Environmental Risk Assessment. The application was referred to Commission on Human Medicines on 10th July 2012; recommendations were made and have been carried out by the applicant. A Marketing Authorisation was granted on 12th September 2012. UKPAR AMITIZA 24 micrograms soft CAPSULES PL 21341/0003 - 5 - PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE Lubiprostone INN/ BAN: Lubiprostone Chemical name: (-)-7-[(2R,4aR,5R,7aR)-2-(1,1-difluorope ntyl)-2-hydroxy-6-oxooctahydrocyclopenta [b]pyran-5-yl]heptanoic acid Structure Molecular formula: C20H32F2O5 Molecular weight: General Properties Description: White odourless crystals or crystalline powder Solubility: Soluble in ether, ethanol, 2-propanol, acetonitrile, DMSO and practically insoluble in water and n-hexane The active substance, lubiprostone, is currently not the subject of a European Pharmacopeia ( ) or British Pharmacopeia (BP) monograph.

6 Manufacture Synthesis of the drug substance from the designated starting materials 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. Confirmation has been provided that the raw materials, intermediates and auxiliary agents used in synthesis of the active substance are not of animal, biological or genetically modified origin. Appropriate data have been supplied to characterise the active substance. All potential known impurities have been identified and characterised. 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. Satisfactory Certificates of Analysis have been provided for all working standards.

7 Batch analysis data are provided and comply with the proposed specification. UKPAR AMITIZA 24 micrograms soft CAPSULES PL 21341/0003 - 6 - Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with foodstuffs. Appropriate stability data have been generated for the active substance stored in the proposed commercial packaging. These data demonstrate the stability of the active substance and an appropriate retest period has been supplied. MEDICINAL PRODUCT Description and Composition The finished product is presented as an oval, clear, soft gelatine capsule imprinted with the letters SPI . Each soft capsule contains 24 micrograms of the active ingredient, lubiprostone dissolved in medium-chain triglycerides. Other ingredients consist of pharmaceutical excipients: the capsule contains medium-chain triglycerides (MCT); the gelatine capsule shell consists of gelatine, sorbitol liquid partially dehydrated (E420), purified water and the ink composition is made up of propylene glycol, black iron oxide, polyvinyl acetate phthalate and polyethylene glycol.

8 Appropriate justification for the inclusion of each excipient has been provided. All excipients used to make up the capsule shell and its content complies with their respective European Pharmacopoeia monographs. The excipients used in the printing ink all comply with in-house specifications which are satisfactory. Satisfactory Certificates of Analysis have been provided for all excipients. With the exception of gelatin none of the excipients used contain material derived from animal or human origin. The applicant has provided from each supplier, Certificates of Suitability issued by the European Directorate for the Quality of Medicines (EDQM), confirming that the gelatin has been manufactured in-line with current European guidelines concerning the minimising of risk of transmission of Bovine Spongiform Encephalopathy/Transmissible Spongiform Encephalopathies (BSE/TSE). None of the excipients are sourced from genetically modified organisms.

9 There are no novel excipients used. Pharmaceutical Development Pharmaceutical development was conducted to support the clinical studies carried out for the finished product. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies have been conducted on commercial scale batches and results were acceptable. Finished Product Specification Finished product specifications are provided for both release and shelf-life, and are satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. The data demonstrate that the batches are compliant with the UKPAR AMITIZA 24 micrograms soft CAPSULES PL 21341/0003 - 7 - proposed release specifications.

10 Certificates of Analysis have been provided for any reference standards used. Container Closure System The finished product is licensed for marketing in high density polyethylene (HDPE) bottles containing rayon filler with a screw cap. Each bottle contains 56 CAPSULES and is packed with the Patient Information Leaflet (PIL) into cardboard outer carton. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Stability Finished product stability studies have been conducted in accordance with current guidelines and results were within the proposed specification limits. Based on the results, a shelf-life of 4 years before first opening the bottle and a shelf-life of 4 weeks after first opening have been set.