Decentralised Procedure. Public Assessment Report

Decentralised Procedure Public Assessment Report Hydromorphon Develco 1 x täglich Hydromorphon Aristo long Hydromorphon-neuraxpharm 1 x täglich 4 / 8 / 16 / 32 mg Retardtabletten Hydromorphone hydrochloride DE/H/3737, 3761, 3762/001-004/DC Applicant: Develco Pharma GmbH Reference Member State DE

TABLE OF CONTENTS I INTRODUCTION 4 II EXECUTIVE SUMMARY 4 II.1 PROBLEM STATEMENT 4 II.2 ABOUT THE PRODUCT 4 II.3 GENERAL COMMENTS ON THE SUBMITTED DOSSIER 5 II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES. 5 III SCIENTIFIC OVERVIEW AND DISCUSSION 5 III.1 QUALITY ASPECTS 5 III.2 NON CLINICAL ASPECTS 6 III.3 CLINICAL ASPECTS 6 IV BENEFIT RISK ASSESSMENT 10 Public AR Page 2/10

ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS Name of the drug substance (INN name): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number(s) for the Decentralised Procedure Reference Member State: Concerned Member States: Applicant (name and address) Hydromorphon Develco 1 x täglich 4/8/16/32 mg Retardtabletten Hydromorphon Aristo long 4/8/16/32 mg Retardtabletten Hydromorphon-neuraxpharm 1 x täglich 4/8/16/32 mg Retardtabletten Hydromorphone hydrochloride N02AA03 prolonged release tablet DE/H/3737, 3761-62/001-004/DC DE DE/H/3737: LU DE/H/3761-62/001-004/DC: LU withdrawn Develco Pharma GmbH Grienmatt 42 79650 Schopfheim, Germany Public AR Page 3/10

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Hydromorphone hydrochloride once daily XL tablets, proposed to be used for the relief of severe and very severe pain, is approved. II EXECUTIVE SUMMARY II.1 Problem statement This decentralised procedure concerns an application for prolonged release (PR) hydromorphone hydrochloride available as 4 mg, 8 mg, 16 mg, and 32 mg tablets (further referred to as Hydromorphone hydrochloride 4, 8, 16, 32 mg prolonged release tablets XL) intended for once daily administration. As the newly developed Hydromorphone hydrochloride 4, 8, 16, 32 mg prolonged release tablets XL are not generic to the approved twice daily hydromorphone PR formulation, this application is filed in accordance with Article 10.3 of Directive 2001/83/EC with reference to hydromorphone-containing medicinal products for twice daily administration already on the EU market (e.g. under the trade names Palladone SR capsules, Napp Pharmaceuticals Ltd. in the UK and Palladon retard 4 mg, 8 mg, 16 mg, and 24 mg Hartkapseln, Mundipharma GmbH in Germany). The newly developed hydromorphone hydrochloride PR tablets XLare proposed to be used for the relief of severe and very severe pain. Apart from the reference hydromorphone hydrochloride PR capsules for twice daily administration, Jurnista 4,8,16,32,64 mg PR tablets were approved for once daily administration following MR procedure DK/H/869 (Janssen-Cilag). Both the reference hydromorphone hydrochloride b.i.d. PR capsules and the o.d. Jurnista PR tablets are approved for the treatment of severe pain. The Jurnista dossier is still under data protection impeding a generic application based on demonstration of bioequivalence at present. With Germany as the Reference Member State in this Decentralized Procedure, Develco Pharma GmbH is applying for the Marketing Authorisations for Hydromorphone hydrochloride PR tablets XLin LU. However, the applicant in DE/H/3761-62/001-004/DC decided to withdraw the application in LU. II.2 About the product The semi-synthetic hydromorphone hydrochloride, a hydrogenated ketone of morphine, is a potent opioid analgesic known since the 1920 s. Like morphine, hydromorphone exerts its primary effects as an agonist of μ (mu) receptors and to a lesser extent of δ receptors in the central nervous system. Through slight structural modifications of the morphine molecule a higher analgesic potency is achieved. Hence, the oral analgesic potency ratio of hydromorphone to morphine is estimated about 5-10:1 thereby allowing for reduction of nominal doses when a patient is switched from morphine to hydromorphone. Hydromorphone hydrochloride PR Tablets XL are intended for once daily administration as opposed to the reference product Palladon retard that is intended for twice daily administration. Therefore, the newly developed once daily PR product does fulfil the criteria of essential similarity and is not generic to the approved PR formulation for twice daily administration. Due to the differences between both products (additional strength, different formulation) and consequential differences in Cmax and Tmax, bioequivalence in the literal sense cannot be established. In view of the expected differences between the once and twice daily formulations, the applicant has characterised the pharmacokinetics of the new once daily product in comparison to the approved twice daily product and has investigated the dose-proportionality of the new product. Owing to the expected differences in the pharmacokinetic profile, the applicant submits a Phase III efficacy and safety/tolerability study in patients with chronic pain in comparison to the reference product for twice daily administration. Public AR Page 4/10

II.3 General comments on the submitted dossier The clinical phase I and phase III study programme was discussed within two EMA Scientific Advice procedures. During the first SA procedure (March 2011), the Applicant s initial plan to file the application based on Art. 8(3) was discussed. The revised study programme, intending to base the future MAA on Art. 10(3) (so-called hybrid application), was discussed within a follow-up SA procedure (June 2011). The advice given by the CHMP was taken into consideration within the assessment report. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. 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 this product. 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. PK study sites All studies were assured to be performed in accordance with GCP and audited SOPs. The clinical study site was the same in all pharmacokinetic studies. The site was also audited by the Austrian Authority for one bioequivalence study in 2011, by the German Authority for three bioequivalence studies in 2006, and by the French Authority for one bioequivalence study in 2003. Clinical sites Study 1824/DEV (EudraCT-Nr. 2011-004471-37) was conducted at regular ambulatories or hospital facilities. III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Hydromorphone hydrochloride is a well-known substance and sufficiently characterized in the Ph. Eur. monograph. The quality of the drug substance hydromorphone hydrochloride is controlled in compliance with the corresponding monograph of the European Pharmacopoeia (Ph. Eur.). The suitability of the monograph to test the drug substance has been verified by EDQM for the substance from all manufacturers. A re-test period of 3 years is mentioned on the CEP for the drug substance supplied by manufacturer A. A re-test period of 2 years is mentioned on the CEP for the drug substance supplied by manufacturer B. In addition, the drug substance supplied by manufacturer C is covered by an ASMF. Letter of access has been provided. Stability data covering the re-test period of 36 months have been provided which are considered acceptable. Drug Product The company has developed an oral prolonged release tablet formulation of hydromorphone hydrochloride that provides prolonged drug release allowing for once daily administration. This hydromorphone hydrochloride tablet is a multiple-unit pellet formulation and will be available in multiple strengths, i.e. prolonged-release tablets containing 4 mg, 8 mg, 16 mg and 32 mg hydromorphone hydrochloride. All relevant quality characteristics of the drug substance and the drug product (release and shelf-life) are specified. The proposed limits are accepted. The description of the analytical methods used to analyse the drug substance and drug product are adequate, the validation results are mainly plausible. Compliance certificates and expert opinions for the primary packaging (round and oblong cavities) regarding child resistance and senior friendliness have been provided. A shelf life of 24 months without storage precaution is accepted. Public AR Page 5/10

III.2 Non clinical aspects Pharmacology, pharmacokinetics, toxicology Pharmacodynamic, pharmacokinetic and toxicological properties of hydromorphone are well known. As hydromorphone is a widely used, well-known active substance, the applicant has not provided additional non-clinical studies and further non-clinical studies are not required. Overview based on literature review is, thus, appropriate. The provided non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. Environmental Risk Assessment (ERA) Since Hydromorphone hydrochloride 4, 8, 16, 32 mg prolonged release tablets XL are intended for substitution of existing hydromorphone formulations, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.3 Clinical aspects To support the application, the applicant has conducted four phase I studies to characterise the pharmacokinetic profile of the new o.d. formulation in conjunction with one phase III non-inferiority comparing the efficacy and safety of hydromorphone hydrochloride PR tablets XL with the reference Palladon retard Hartkapseln in chronic pain patients. PK studies of Hydromorphone hydrochloride 8, 16, 32 mg prolonged release tablets XL: Comparative bioavailability study of hydromorphone after single doses of Hydromorphone hydrochloride 8 mg PR Tablets XL and single dose administration two times daily of Palladon retard 4 mg Hartkapseln (Mundipharma GmbH, Germany) under fasting conditions in 12 healthy subjects (Study ID 191B11, pilot study) Food interaction study after single doses of Hydromorphone hydrochloride 8 mg PR Tablets XL (test) and comparative bioavailability study of Hydromorphone hydrochloride 8 mg PR Tablets XL (test) administered as a single dose and Palladon retard 4 mg Hartkapseln (reference) given twice daily in fasted state in 12 healthy subjects (Study Code 105B12) Comparative bioavailability study of hydromorphone after multiple dose administration (fasting conditions) of Hydromorphone hydrochloride 8 mg PR Tablets XL and Palladon retard 4 mg Hartkapseln (Mundipharma GmbH, Germany) in 12 healthy subjects (Study ID 136B12) Dose proportionality study of hydromorphone after single oral administration of Hydromorphone hydrochloride 8 mg PR Tablets XL, Hydromorphone hydrochloride 16 mg PR Tablets XL and Hydromorphone hydrochloride 32 mg PR Tablets XL under fasting conditions in 36 healthy subjects (Study ID 615B10) Dose proportionality study of hydromorphone after single oral administration of Hydromorphone hydrochloride 4 mg PR tablets XL, Hydromorphone hydrochloride 8 mg PR tablets XL, Hydromorphone hydrochloride 16 mg PR tablets XL and Hydromorphone hydrochloride 32 mg PR tablets XL under fasting conditions in 30 healthy subjects (Study ID 445B12) In study 191B11 equivalent extent of absorption (AUC) was demonstrated after once daily administration of one hydromorphone hydrochloride 8 mg PR tablet XL vs twice daily administration of Palladon 4 mg retard Hartkapseln under fasting conditions. Blood levels after 24 hours (pre-dose levels on the morning of the second day of treatment) were almost identical between the once daily and twice daily formulation. Study 105B12 revealed that ingestion of a standardized high-fat, high-calorie meal before administration of the newly developed once daily formulation does not change the plasma concentration of hydromorphone hydrochloride to a clinically relevant degree. Like in the case of the reference Palladon retard Hartkapseln, no particular dosing recommendation as regards intake before / after meal are required for the new once daily tablet. Public AR Page 6/10

In the multiple dose study 136B12 steady state plasma concentrations were achieved after the third administration of the once daily formulation. While borderline compliance with the 80-125% acceptance range was obtained for AUC0-τ (point estimator 113.94), plateau plasma concentrations under steady state conditions are higher and flatter for the once daily formulation. This is reflected by the considerable difference in geometric mean PTF value that was lower with the test product (65.20%) than the reference product (90.31%) and the fact that CIs for Cmin,ss,24h exceeded the upper acceptance limit (point estimator 122.25; CIs 106.58-140.21). Dose proportionality study 615B10 was conducted to demonstrate dose linearity across the 8-32 mg range. The 4 mg formulation was not included. In terms of guideline provisions, pharmacokinetics is considered to be linear if the difference in dose-adjusted mean AUCs is no more than 25% when comparing the studied strength and the strength for which a waiver is considered. However, according to the advice given by the CHMP within the preceding scientific advice procedure dose linearity with regard to extent and rate of absorption of hydromorphone should be demonstrated via dose-normalized AUC and Cmax results. Dose proportionality in terms of AUC was demonstrated in terms of guideline provisions. Cmax values, however, were evidently not proportional across the dose strengths. The Cmax values obtained from the 35 subjects participating in study 615B10 for the 8 mg and the 16 mg strength were largely similar / almost overlapping. This unexpected finding is to be seen in the context that the compositions of the four once daily formulations are composed of two dose-proportional pairs (4/8 mg and 16/32 mg). Furthermore, in-vitro dissolution data revealed decreased dissolution rates with increasing dose strength. The Applicant conducted a second dose proportionality study (445B12) that covered the entire dose range from 4 mg to 32 mg. Comparative in-vitro dissolution across the four biobatches used in the second dose proportionality study showed similar, yet not superimposable, dissolution profiles. The tendency of the higher 32 mg strength to demonstrate slower in-vitro dissolution (already observed with the biobatches used in the first dose proportionality study) was confirmed. The largest difference in vitro dissolution between the 4 mg and the 32 mg dose strength, observed between 600 and 960 min after the start, amounts to about 15%. Accordingly, in some cases f2 values calculated across strengths fail to reach 50 as the formal criterion for similarity. The newly conducted second dose proportionality study 445B12 demonstrated dose proportional increases in AUC across the entire 4 mg -32 mg dose range. Like already observed in the preceding dose proportionality study 615B10, Cmax values do not increase proportionally across the four dose strengths. Cmax values are completely doubled when the 4 mg and 8 mg formulation (the composition of the 4 and 8 mg tablets are dose weight multiples) are compared. Similarly almost doubled peak plasma concentrations are obtained when comparing the 16 and 32 mg tablets (the composition of the 16 and 32 mg tablets are dose weight multiples). According to guideline stipulations dose proportionality has been demonstrated across the entire 4, 8, 16, 32 mg dose range and thus, extrapolation of in vivo results obtained for the 8 mg tablet to the lower 4 mg tablet formulation is justified. However, lower than proportional Cmax value increases are observed between the 8 mg and 16 mg tablet (0.9 ng/ml versus 1.3 ng/ml). Thus, strengths are not interchangeable, i.e. largely different maximum plasma concentrations are to be expected after administration of two 8 mg tablets as compared to administration of one 16 mg tablet. The dose recommendations have been adapted accordingly. Pharmacodynamics The pharmacodynamic action of the drug substance hydromorphone is well established and was not further elucidated within the present MAA. The PK studies as well as the phase III non-inferiority study were intended to examine formulation-related differences between the established twice-daily capsule and the newly developed once-daily tablet. Public AR Page 7/10

Clinical efficacy Phase III non-inferiority study: Randomised, double-blind, cross-over Phase III study to investigate the efficacy and safety of hydromorphone after once daily administration of Hydromorphone hydrochloride PR tablets XL in comparison to twice daily administration of Palladon retard Hartkapseln in patients with chronic severe cancer or non-cancer pain (Study ID 1824) On top of pharmacokinetic studies the Applicant conducted a phase III, randomised, double-blind, cross-over non-inferiority study to investigate the efficacy and safety of hydromorphone after once daily administration of Hydromorphone hydrochloride PR tablets XL in comparison to twice daily administration of Palladon retard Hartkapseln in patients with chronic severe cancer or non-cancer. The primary objective was to demonstrate that once daily administration of Hydromorphone hydrochloride PR tablets XL is at least as effective as twice daily administration of Palladon retard Hartkapseln at the same daily dosage. During a titration/stabilisation period (maximum 14 d), the patients were treated with the reference product (4 mg, 8 mg or 16 mg) twice daily at the individually determined total daily dose (TDD). Patients not taking hydromorphone at the screening visit were switched to hydromorphone at the start of the titration period. The patients were randomised to double-blind treatment when adequate and stable analgesia was attained, i.e. mean current pain intensity per day of 40 mm on a 100-mm VAS (mean of pain intensity at 8:00, 11:00, 14:00, 17:00, and 20:00 h was 40 mm on each of the last three consecutive days), stable maintenance dose of hydromorphone hydrochloride ( 8 mg to 32 mg hydromorphone hydrochloride per day), and not more than two doses/d of the rescue medication for the last three consecutive days. The study followed a crossover design of two twelve-day double-blind treatment periods without wash-out period. The overall current pain intensity (mean current pain intensity over all time points of the last five treatment days of both periods) was the primary efficacy endpoint. An unblinded interim analysis was performed. The adaptation rule was clearly pre-specified. The interim analysis demonstrated the non-inferiority of once daily Hydromorphone hydrochloride PR tablets XL to twice daily Palladon retard Hartkapseln. Following the recommendation of the IDMC, the sponsor decided to terminate the study due to early success. 37 patients who required continuous opioid treatment for chronic cancer (N=3) or non-cancer (N=34) pain were treated with once daily Hydromorphone hydrochloride PR tablets XL and twice daily Palladon retard Hartkapseln. There were no significant differences in demographics between sequences. Efficacy PPS: Non-inferiority of the test product in the primary efficacy endpoint was confirmed in the PPS: The difference in overall "current" PI between test and reference was -0.89 mm VAS (difference in least square [LS] means) with a 95% CI between -4.15 mm and 2.37 mm. FAS: Non-inferiority of the test product in the primary efficacy endpoint was confirmed also in the FAS: The difference in overall "current" PI between test and reference was 0.10 mm VAS (difference in LS means) with a 95% CI between -3.12 mm and 3.32 mm (one-sided p-value for non- inferiority <.0001). Clinical Safety The study results did not point to a difference in the safety profile of both formulations. In-vitro dissolution in the presence of 5-40% ethanol in 0.1 N HCl It has been adequately demonstrated that ethanol does not compromise the prolonged release characteristics of the newly developed tablet formulation to a clinically relevant degree. Public AR Page 8/10

User Testing User Readability Test An user readability test has been conducted according to the current requirements regarding the testing of the readability of package leaflets with the German PL of Hydromorphon Develco 4 mg Retardtabletten. The interviewed population (25 participants in total) of both genders between 17 and 72 years of age is acceptable. The number of 15 content-related questions plus 5 structure-related questions for each round is sufficient. The questions cover significant safety issues. The interview was conducted in well structured manner. The length of the interview is acceptable (approx. 20 minutes without explanations). A pilot phase with 5 participants has been conducted, afterwards, 2 rounds of testing with 10 participants in each round were performed. During the first round, information was found by 99% of the subjects for all 14 questions. 100% of the participants gave the correct answers and understood the answers. No amendments have been made to the PL. During the second round, correct information was found by all test readers. 100% of the subjects gave the correct answers and understood the answers. No revisions to the PL were made as no significant problems could be detected. The PL has been successfully user tested and no additional testing or changes are required to the existing PL. Bridging report The compared PLs have the same indication, the same route of administration and the same active substances with three common dose strengths (4 mg, 8 mg, 16 mg) and an additional different one (24 mg versus 32 mg). Many of the differences observed are of formal nature, i.e. due to the revised QRD-template, and there are only few differences in the content resulting mainly from the new formulation and the reduced intake frequency of once daily in the daughter PL compared to twice daily in the parent PL. With a comparable layout of the daughter PL, the navigation and findability of information can be considered as comparably good for the patient. Sumarized, the PL for 'Hydromorphone HCl OID 4mg prolonged release tablets XL' is completely in line with article 59(3) of Council Directive 2001/83/EC (as amended from 2004/27 EC). Further, the results are transferable to the three related PLs Hydromorphone HCl OID 8 mg, 16 mg, 32 mg prolonged release tablets XL' so that the conclusion of this bridging report also holds true for these three PLs. Pharmacovigilance system (DDPS) Aristo Pharma GmbH The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable. Develco Pharma GmbH The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable. neuraxpharm Arzneimittel GmbH The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable. Public AR Page 9/10

Risk Management Plan The RMP lists the following safety concerns: Important identified risks: o Respiratory depression o Drug dependence and withdrawal o Abuse, misuse and diversion Important potential risks: o Accidental exposure o Medication errors o Overdose Important missing information: o Safety and efficacy in children o Safety and efficacy of use during pregnancy and lactation No additional pharmacovigilance or risk minimization activities are being proposed. Periodic Safety Update Report (PSUR) The PSUR cycle should follow the (EURD-list). The EURD-list states a submission frequency of 3 years with a 30.11.2015 as DLP. It should be noted that no PSURs are required for products referred to in Articles 10(1), 10a, 14, 16a of Directive 2001/83/EC as amended. IV BENEFIT RISK ASSESSMENT The application concerns four dose strengths (4 / 8 / 16 / 32 mg) of a new once-daily formulation of hydromorphone hydrochloride tablets. The PK program was descriptively designed to compare the newly developed once daily tablet with the approved twice daily reference prolonged release comparator. The newly conducted second dose proportionality study 445B12 demonstrated dose proportional increases in AUC across the entire 4 mg -32 mg dose range. Formally, extrapolation of the results of the food-effect study as well as the multiple-dose study conducted with 8 mg to the other strengths is appropriate. However, lower than proportional Cmax value increases are observed between the 8 mg and 16 mg tablet (0.9 ng/ml versus 1.3 ng/ml). Thus, strengths are not interchangeable and this information have been addressed within the product information. The phase III study provides additional data confirming therapeutic equivalence between the test and the reference product in terms of the overall "current" PI. In-vitro dissolution data in the presence of increasing ethanol concentrations (5, 10, 20, 40%) were provided that demonstrate that no dose dumping occurs in case of concomitant consumption of alcoholic beverages. Overall, the benefit-risk-balance for the new once-daily formulation of hydromorphone hydrochloride PR tablets is positive. The application is approved. For intermediate amendments see current product information. Public AR Page 10/10