Jurnista 釋通緩釋錠. OROS Hydromorphone Prolonged-Release Tablets 嬌生公司楊森藥廠林子琪 7/8/2014. MA approved in Mar 2014, JUR

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1 Jurnista OROS Hydromorphone Prolonged-Release Tablets 釋通緩釋錠 嬌生公司楊森藥廠林子琪 7/8/2014

2 Clinical Definition of Pain An unpleasant sensory and subjective sensory emotional experience associated with actual or potential tissue damage -IASP Painting : Sharp Pain by Baruch Elron American Pain Society, International Association for the Study of Pain (IASP),

3 Patients quality of life would be influenced with pain Brief Pain Inventory- Chinese Version (BPI-C) for Lung Cancer Patients with Pain Mean Average pain Interference with daily activities SD General activities Mood Walking Working Relations with others Sleeping Enjoyment of life Ref: Tsui-Hsia Hsu, et. al. Journal of Pain and Symptom Management 26: ,

4 Cancer pain can be managed effectively through relatively simple means in up to 90% of patients WHO RECOMMEND 4

5 WHO 3-Step Ladder Co-analgesics Severe Strong Opioids ± Non-Opioids Ex: Morphine, Hydromorphone, Fentanyl-TTS Moderate Weak Opioids ± Non-Opioids Ex: Ultracet, Codeine, Tramadol Mild Non-Opioids Ex: ASS, Ibuprofen, Diclofenac, Cox 2-inhibitors, Paracetamol, Metamizol, Flupirtin Adapted from World Health Organization. Cancer Pain Relief, with a Guide to Opioid Availability

6 NCCN Guidelines Converting from short-acting opioids to long-acting opioids when 24h opioids requirement is stable Used immediaterelease opioids for breakthrough pain 10% 25% (1/6) of 24-h dose Increase rescue dose proportional to long-acting NCCN Guideline Version

7 Good Pain Management Model NCCN Guideline Version

8 Good Pain Management NCCN Guideline Version

9 Hydromorphone Introduction Hydromorphone hydrochloride 易溶於水 Hydromorphone 主要為 μ- 接受體的致效劑, 與中樞神經系統 (CNS) 的 μ- 接受體結合後便會產生止痛效果 口服 hydromorphone 的效力約為 morphine 的五倍 ( 以體重計算 ) 且具有較短的作用時間 為臨床治療指引建議之選擇藥物之一 1. Expert Opin. Pharmacother. (2010) 11(7): NCCN Practice guidelines in Oncology, V

10 Hydromorphone is 5 Times More Potent than Morphine OROS Hydromorphone 8mg = Morphine 40mg/day Equianalgesic dose of oral morphine [mg] to oral hydromorphone [mg] 5:1 Palangio M et al. J Pain and Symptom Manage. 2002;23(5):

11 Hydromorphone Long clinical history µ-opioid receptor agonist 5 times more potent than morphine Low relative histamine release low protein binding(<30%) Metabolism P450 route is minor M6G isn t found in its metabolites Jackie, et al,pain Practice, Volume 10, Issue 1, CNS Drugs Apr;24(4): Drug Therapy Topics 2006; Vol 35 No 4 11

12 Hydromorphone Not through Cytochrome P450 Low protein binding rate (<30%) Decrease risk of drug drug interaction of multi drug patients MA approved Jackie in Mar, 2014, et al,pain JUR Practice, Volume 10, Issue 1, Concise Guide to Drug Interaction Principles for Medical Practice 12

13 Cross-Sectional View of an OROS hydromorphone Tablet Laser-Drilled Hole 雷射小孔 (point of drug release) ( 藥物釋出點 ) 速率控制膜 Rate-Controlling Membrane Hydromorphone HCl Hard Shell (clear overcoat, color overcoat) 硬殼 ( 透明包衣有色包衣 ) Osmotic Pump (Push layer) 滲透壓幫浦 ( 推送層 ) Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S19-24.

14 Push Pull Osmotic Pump Semipermeable Membrane Delivery Orifice Osmotic Drug Core Water Color Overcoat Osmotic Push Compartment Before Operation Expanded Push Compartment During Operation 在胃腸道中, 滲透壓使水分吸入錠劑核心 水分進入核心後, 會被推動層吸收 推動層膨脹後便將藥物從圓頂的小孔釋放出錠劑, 提供 24 小時的連續釋出藥物 14

15 Advances in the Long-Term Management of Chronic Pain: Recent Evidence with OROS Hydromorphone, a Novel, Once-Daily, Long-Acting Opioid Analgesic Providing Constant Analgesia with OROS Hydromorphone Suneel Gupta and Gayatri Sathyan. J Pain Symptom Manage 2007;33:S19-24.

16 OROS Hydromorphone: Drug Release and GI Absorption Drug intake/ End of drug release 24/0h 2h Drug delivery begins >90% of the active substance has been released 18h 24 h clock Prolongation of GI transit time does not result in overdose Adapted from: Gupta et al. J Pain Symptom Manage. 2007;33:S19-S24 16

17 Release Rate of OROS hydromorphone in a Pharmacological Model Cumulative Percent Released (LC) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Time (hr) OROS hydromorphone 8 mg OROS hydromorphone 16 mg OROS hydromorphone 32 mg OROS hydromorphone 64 mg Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S

18 Effect of Dose on Pharmacokinetic Profile of OROS hydromorphone Hydromorphone (ng/ml) mg OROS hydromorphone 16mg OROS hydromorphone 32mg OROS hydromorphone 64mg OROS hydromorphone (n=31) Time (hr) Data on file, ALZA Corporation. 18

19 Pharmacokinetic Profile after Single-dose IR Hydromorphone vs. OROS hydromorphone Hydromorphone (ng/ml) mg IR HMO 8 mg OROS hydromorphone 16 mg OROS hydromorphone 32 mg OROS hydromorphone (n=12) Time (hr) Peak concentration achieved at ~13-16 hrs Plasma concentrations at 80% of peak achieved by ~6 hrs Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S

20 Pharmacokinetic Profile after Multidose IR Hydromorphone vs. OROS hydromorphone 2.5 Hydromorphone (ng/ml) mg mg OROS hydromorphone q24h t mg IR hydromorphone q6h Time (hr) Concentrations maintained higher than IR C min for 24 hours Fluctuations in plasma levels reduced by ~40% Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S

21 OROS hydromorphone Plasma Concentration after Continuous Dosing Actual hydromorphone plasma concentrations (log) simulated hydromorphone plasma concentrations (log) 0.10 OROS Hydromorphone Intake 0.01 Time (hr) Plasma levels of hydromorphone with the OROS system stabilize within 48 hours of continuous dosing Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S

22 Effect of Food on Absorption of OROS hydromorphone Hydromorphone (ng/ml) mg OROS hydromorphone Fasted 16 mg OROS hydromorphone Fed Time (hr) Gupta S, Sathyan G. J Pain Sympt Manage. 2007;33(2 Suppl):S

23 Summary The OROS technology significantly changes the drug profile of hydromorphone Constant drug delivery providing 24-hour analgesia with reduced peak-trough fluctuation Steady-state concentrations achieved after 2 days of dosing with no significant effect from food Dose-proportional pharmacokinetics over all doses Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S

24 Double-blind Assessment of OROS hydromorphone vs. Morphine SR in Patients with Moderate to Severe Chronic Cancer Pain DO-118, Pivotal Cancer Pain Trial Hanna M, et al. BMC Palliative Care. 2008;7:17.

25 Methodology Objective To assess the safety and efficacy of OROS hydromorphone and morphine SR in the treatment of severe chronic pain Design Randomized, double-blind, double-dummy, active-control study Population Patients with chronic cancer pain in 7 European countries and Canada Phase I 2 to 9 days Phase II 10 to 15 days Screening Randomization IR IR Hydromorphone to to 108 mg/day IR IR Morphine to to 540 mg/day OROS hydromorphone qd qd (16 to to mg/day) Morphine SR bid (60 to to 540 mg/day) Hanna M, et al. BMC Palliative Care. 2008;7:17. 25

26 Clinical Efficacy Outcomes Clinical equivalence to morphine SR measured by: Primary Brief Pain Inventory (Worst Pain) Secondary Brief Pain Inventory (BPI; Other Scales) Physician and Patient Global Assessment Eastern Cooperative Oncology Group (ECOG) Performance Scale Mini-Mental State Examination Time to OROS hydromorphone dose stabilization Breakthrough pain medication use Hanna M, et al. BMC Palliative Care. 2008;7:17. 26

27 Results: Impact of Pain on Daily Activities at end of Controlled-release Phase * P= VS IR morphine * Mean Brief Pain Inventory (BPI) interference scores at baseline, end of immediate release (IR) phase, and end of sustained release (SR) phase Brief Pain Inventory scored as: 0 = no interference to 10 = complete interference Hanna M, et al. BMC Palliative Care. 2008;7:17. 27

28 Cancer Pain: Once-Daily OROS Hydromorphone Improves Pain Relief Compared with Twice-Daily SR Morphine Primary Efficacy Outcome Worst Pain Secondary Efficacy Outcome Pain AM Pain PM Least Pain Average Pain Lower CI limit lies outside of the predetermined equivalence band Equivalence hypothesis is not proven Favors OROS Hydromorphone Favors CR Morphine Hanna M, et al. BMC Palliative Care. 2008;7:17. 28

29 Adverse Events The adverse events profiles of hydromorphone and morphine were similar in this study. NCCN Guidelines recommended: Adverse effects to opioids are common, should be anticipated, and should be managed aggressively. Adapted from: Hanna M, et al. BMC Palliative Care. 2008;7:17. NCCN Guidelines Version Adults Cancer Pain 29

30 Safety and Tolerability: Pooled Analysis at 11 Clinical Studies AEs ( 5% of patients) and treatment-related AEs. OROS hydromorphone was generally safe and well tolerated in 1251 opioid-tolerated patients with chronic cancer and non-cancer pain. Srinivas R et al. J Pain Sympt Manage

31 Conclusions The primary endpoint 'worst pain, pain now PM' scores were significantly lower for those taking OROS hydromorphone at the end of the SR phase. Treatment-related adverse events for both OROS hydromorphone and morphine SR were similar and typical for long-acting opioid analgesics Hanna M, et al. BMC Palliative Care. 2008;7:17. 31

32 How to prescribe Jurnista When: 可以口服之癌症疼痛病患, 其已使用口服 morphine, 且劑量穩定不再變動至少二週, 而有更換其他鴉片類藥物止痛的需求者 1 How: Hydormorphone 效力等同口服 morphine 之 5 倍, 一天口服 morphine 劑量接近 40 mg 即可轉換到一天一次 Jurnista 8mg Jurnista 8mg 同時給予口服短效 morphine 10mg PRN 作為突發性疼痛用藥 劑量增加的頻率不應超過每兩天一次 Jurnista, Package Insert,

33 Jurnista (OROS Hydromorphone) Jackie, et al,pain Practice, Volume 10, Issue 1, Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S Bosilkovska et al, Drugs 2012; 72 (12): J Pain Symptom Manage 2004;28:

34 Jurnista (OROS Hydromorphone) When Cancer Pain Goes Around the Clock 34