Depodur Suspension for injection morphine …

1 Depodur Suspension for injection PL 13621/0040-2 - 1 - Depodur 10MG/1ML Suspension FOR injection ( morphine SULPHATE PENTAHYDRATE) PL 13621/0040 Depodur 15 Suspension FOR injection ( morphine SULPHATE PENTAHYDRATE) PL 13621/0041 Depodur 20MG/2ML Suspension FOR injection ( morphine SULPHATE PENTAHYDRATE) PL 13621/0042 UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific discussion Page 3 Steps taken for assessment Page 78 Steps taken after authorisation summary Page 79 Summary of Product Characteristics Page 80 Product Information Leaflet Page 106 Labelling Page 112 Depodur Suspension for injection PL 13621/0040-2 - 2 - Depodur Suspension FOR injection PL

2 13621/0040-2 LAY SUMMARY The MHRA granted SkyePharma PLC Marketing Authorisations (licences) for the medicinal product Depodur 10mg/1ml Suspension for injection (PL 20334/0002), Depodur 15 Suspension for injection (PL 20334/0003) and Depodur 20mg/2ml Suspension for injection (PL 20334/0004) on the 20th April 2006. This is a prescription only medicine (POM), for the relief of post-operative pain following major orthopaedic, abdominal or pelvic surgery. Depodur Suspension for injection is for epidural administration only. It contains the active ingredient morphine sulphate pentahydrate which is a natural opioid alkaloid and is used to provide relief from pain. Depodur Suspension for injection is an aqueous Suspension of lipid-based particles, from which the active drug ( morphine ) is released gradually over a number of hours in order to achieve a long duration of pain relief.

3 The applicant has supplied scientific literature to demonstrate that the active substance in Depodur Suspension for injection has been in well-established medicinal with acceptable levels of effectiveness and safety. The clinical data presented to the MHRA, pre licensing, demonstrated the safety and effectiveness of Depodur Suspension for injection given as a single epidural injection to provide a sustained-release pain-killer. There were no significant safety concerns, provided that patients are closely monitored for 48 hours following administration of the product. It was therefore judged that the benefits of using Depodur Suspension for injection outweigh the risks. Hence Marketing Authorisations have been granted. Following the grant of a Change of Ownership on 19th May 2008, these licences were transferred to Flynn Pharma Limited (PL 13621/0040-2).

4 The licences for Depodur 15 Suspension for injection (PL 13621/0041) and Depodur 20mg/2ml Suspension for injection (PL 13621/00042) were subsequently cancelled on 26th November 2008. Depodur Suspension for injection PL 13621/0040-2 - 3 - Depodur Suspension FOR injection PL 13621/0040-2 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 4 Pharmaceutical assessment Page 5 Note regarding consideration by Chemistry, Pharmacy and Standards Sub-committee Page 18 Preclinical assessment Page 19 Clinical assessment (including statistical assessment) Page 24 Committee on Safety of Medicines initial recommendation Page 59 Clinical assessment of applicant s response Page 59 Committee on Safety of Medicines final recommendation Page 74 Clinical assessment of applicant s response Page 74 Overall conclusions and risk benefit assessment Page 77 Depodur Suspension for injection PL 13621/0040-2 - 4 - INTRODUCTION Based on the review of the data on quality, safety and efficacy the UK granted marketing authorisations for the medicinal products Depodur Suspension for injection (PL 20334/0002-4) to SkyePharma PLC on 20th April 2006.

5 The products are Prescription Only Medicines (POM), available on special prescription. The application was submitted as a bibliographic application , under article 10(a) [formerly (a) (ii)] of Directive 2001/83/EC. The scientific literature demonstrated that the active substance in Depodur Suspension for injection has been in well-established medicinal use with acceptable efficacy and safety. Clinical data supplied showed that the safety and effectiveness of the new product Depodur Suspension for injection given as a single epidural injection was satisfactory, provided that patients receive high dependency monitoring for 48 hours following administration of the product. Depodur Suspension for injection is a sustained-release formulation containing the active ingredient morphine sulphate pentahydrate, a natural opium alkaloid, and is indicated for the relief of post-operative pain for up to 48 hours,when given as a single epidural injection .

6 These applications for Depodur Suspension for injection (10mg/1ml, 15 and 20mg/2ml) were submitted at the same time and were assessed concurrently. Consequently, all sections of this Scientific Discussion refer to all products. Following the grant of a Change of Ownership on 19th May 2008, these licences were transferred to Flynn Pharma Limited (PL 13621/0040-2). The licences for Depodur 15 Suspension for injection (PL 13621/0041) and Depodur 20mg/2ml Suspension for injection (PL 13621/00042) were subsequently cancelled on 26th November 2008. Depodur Suspension for injection PL 13621/0040-2 - 5 - PHARMACEUTICAL ASSESSMENT Note: This assessment report has been updated to incorporate the information provided by the applicant, in response to queries raised by the assessor and/or the UK Advisory Committee.

7 All queries were answered satisfactorily. 1. INTRODUCTION These national abridged applications are for suspensions for injection containing 10mg/ml morphine sulfate pentahydrate in 1ml, and 2ml glass vials, for epidural use only. The applicant has proposed that the products are indicated for the relief of post-operative pain for up to 48 hours. All references in this report to morphine sulfate or morphine sulphate refer to the pentahydrate, unless otherwise specified. These applications have been made under Article 10(a) [formerly article (a)(ii)] of Directive 2001/83/EC (so called bibliographic application ). This legal basis is acceptable. These products will only be available on a special prescription (CD) in accordance with Article 71 of Directive 2001/83/EC.

8 Formal Scientific Advice was provided by CPMP and by the UK, France, The Netherlands and Ireland on pharmaceutical, pre-clinical and clinical strategy prior to submitting these applications. Copies of relevant documentation from meetings/requests have been included in the dossiers. The proposed products have not been authorised to the applicant or to a related company in any other European Union (EU) member state. The products have been authorised in the USA since May 2004. 2. COMMON TECHNICAL DOCUMENT SUMMARIES INTRODUCTION A brief but satisfactory introduction has been provided. QUALITY OVERALL SUMMARY (QOS) A satisfactory Quality Overall Summary has been provided. 3. ACTIVE SUBSTANCE GENERAL INFORMATION Nomenclature Depodur Suspension for injection PL 13621/0040-2 - 6 - INN: morphine sulfate morphine sulfate pentahydrate morphine Sulphate Ph Eur morphine Sulfate USP Chemical names: (i) 7,8-Didehydro-4,5 -epoxy-17-methylmorphinan-3,6 -diol sulfate (2:1) (salt), pentahydrate (ii) Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl, (5 , 6 )-, sulfate (2:1) (salt), pentahydrate CAS Number: 6211-15-0 Structure (C17H19NO3) MW: General Properties Fine, odourless, white powder that may yellow slightly with age.

9 Soluble in water (1g in ), very slightly soluble in ethanol (1g in 565ml) at 25 C, practically insoluble in toluene. The pH of an aqueous 15mg/ml solution is approximately Water of hydration is lost between 100-130 C. The anhydrous form melts with decomposition at approximately 250 C. The pKa for morphine are and MANUFACTURE Manufacturer A copy of a letter of access dated 09 October 2003 and the Applicant s Part of the EDMF have been provided for the specified source of active substance. This version is identical to that supplied direct to the MHRA by the DMF holder. Manufacturing process description and process controls Details of the manufacturing process have been provided. No organic solvents (including those described in the USP as organic volatile impurities) are used in the process.

10 Control of materials Confirmation has been provided that morphine sulfate is a natural product of vegetable origin. No TSE risk is associated with this active substance. Depodur Suspension for injection PL 13621/0040-2 - 7 - CHARACTERISATION Elucidation of structure and other characteristics morphine possesses 5 chiral centres, although as the bridge system must be cis, only 8 pairs of enantiomers are possible. Only 1 enantiomer is derived from natural sources. Specific rotation is -107 to at 25 C (20mg/ml solution in water, on anhydrous basis) The structure of morphine sulfate pentahydrate has been confirmed by IR, C-NMR and H-NMR. Copies of spectra have been provided.