OROS® Hydromorphone

®
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
MA approved in Mar 2014, JUR‐14010215
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, 1992. International Association for the Study of Pain (IASP), 1993.
MA approved in Mar 2014, JUR‐14010215
2
Patients’ quality of life would
be influenced with pain
Brief Pain Inventory- Chinese Version (BPI-C)
for Lung Cancer Patients with Pain
Mean
SD
5.24
1.74
daily activities
7.41
1.89
General activities
7.42
1.98
Mood
7.70
2.13
Walking
7.54
2.06
Working
7.63
1.95
Relations with others
7.09
2.20
Sleeping
7.08
2.29
Enjoyment of life
7.42
2.12
Average pain
Interference with
Ref: Tsui-Hsia Hsu, et. al. Journal of Pain and Symptom Management 26: 835-842, 2003
MA approved in Mar 2014, JUR‐14010215
3
Cancer pain can be managed
effectively through relatively
simple means in up to 90%
of patients
WHO RECOMMEND
MA approved in Mar 2014, JUR‐14010215
4
WHO 3-Step Ladder
Mild
Moderate
Severe
Co-analgesics
Strong Opioids ± Non-Opioids
Ex: Morphine, Hydromorphone, Fentanyl-TTS
Weak Opioids ± Non-Opioids
Ex: Ultracet, Codeine, Tramadol
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. 1996.
MA approved in Mar 2014, JUR‐14010215
5
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 2.2013
MA approved in Mar 2014, JUR‐14010215
6
Good Pain Management Model
NCCN Guideline Version 2.2013.
MA approved in Mar 2014, JUR‐14010215
7
Good Pain Management
NCCN Guideline Version 2.2013.
MA approved in Mar 2014, JUR‐14010215
8
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):1207-1214 .
MA approved in Mar 2014, JUR‐14010215
2. NCCN Practice guidelines in Oncology, V2. 2011
9
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):355-68.
MA approved in Mar 2014, JUR‐14010215
10
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
MA approved in Mar 2014, JUR‐14010215
Jackie , et al ,Pain Practice, Volume 10, Issue 1, 2010 72–77
CNS Drugs. 2010 Apr;24(4):337‐61
Drug Therapy Topics 2006; Vol 35 No 4
11
Hydromorphone
• Not through Cytochrome P450 • Low protein binding rate (<30%)
Decrease risk of drug‐drug interaction of multi‐drug patients
MA approved in Mar 2014,
Jackie , et al ,Pain
JUR‐14010215
Practice, Volume 10, Issue 1, 2010 72–77
Concise Guide to Drug Interaction Principles for Medical Practice
12
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
Hard Shell
Hydromorphone HCl
Osmotic Pump 滲透壓幫浦
(Push layer)
Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S19-24.
硬殼
(clear overcoat, (透明包衣
color overcoat) 有色包衣)
(推送層)
Push Pull™ Osmotic Pump
Semipermeable
Membrane
Delivery
Orifice
Osmotic
Drug Core
Water
Osmotic
Color Overcoat 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。
MA approved in Mar 2014, JUR‐14010215
14
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.
MA approved in Mar 2014, JUR‐14010215
OROS® Hydromorphone: Drug Release
and GI Absorption
Drug intake/ End of drug release
Drug delivery begins
24/0h
2h
>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
MA approved in Mar 2014, JUR‐14010215
16
Cumulative Percent Released (LC)
Release Rate of OROS® hydromorphone
in a Pharmacological Model
100%
90%
80%
70%
60%
50%
40%
OROS® hydromorphone 8 mg
OROS® hydromorphone 16 mg
OROS® hydromorphone 32 mg
OROS® hydromorphone 64 mg
30%
20%
10%
0%
2
4
6
8
10
12 14
Time (hr)
Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S19-24.
MA approved in Mar 2014, JUR‐14010215
16
18
20
22
24
17
Effect of Dose on Pharmacokinetic Profile of
OROS® hydromorphone
6.0
8mg OROS® hydromorphone
16mg OROS® hydromorphone
32mg OROS® hydromorphone
Hydromorphone (ng/mL)
5.0
64mg OROS® hydromorphone
(n=31)
4.0
3.0
2.0
1.0
0
9
18
27
36
45
54
63
72
Time (hr)
Data on file, ALZA Corporation.
MA approved in Mar 2014, JUR‐14010215
18
Pharmacokinetic Profile after Single-dose
IR Hydromorphone vs. OROS® hydromorphone
Hydromorphone (ng/mL)
5.0
8 mg IR HMO
8 mg OROS® hydromorphone
16 mg OROS® hydromorphone
32 mg OROS® hydromorphone
(n=12)
4.0
3.0
2.0
1.0
0
12
24
36
48
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):S19-24.
MA approved in Mar 2014, JUR‐14010215
19
Pharmacokinetic Profile after Multidose
IR Hydromorphone vs. OROS® hydromorphone
Hydromorphone (ng/mL)
2.5
2.0
1.5
1.0
16mg
mgOROS®
OROS®
hydromorphone
t72-96
16
hydromorphone
q24h
4 mg IR hydromorphone q6h
0.5
0.0
72
78
84
90
96
Time (hr)
• Concentrations maintained higher than IR Cmin for 24 hours
• Fluctuations in plasma levels reduced by ~40%
Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S19-24.
MA approved in Mar 2014, JUR‐14010215
20
OROS® hydromorphone Plasma Concentration
after Continuous Dosing
10.00
1.00
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):S19-24.
MA approved in Mar 2014, JUR‐14010215
21
Effect of Food on Absorption of OROS®
hydromorphone
1.2
16 mg OROS® hydromorphone Fasted
Hydromorphone (ng/mL)
16 mg OROS® hydromorphone Fed
1.0
0.8
0.6
0.4
0.2
0
8
16
24
Time (hr)
Gupta S, Sathyan G. J Pain Sympt Manage. 2007;33(2 Suppl):S19-24.
MA approved in Mar 2014, JUR‐14010215
32
40
48
22
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):S19-24.
MA approved in Mar 2014, JUR‐14010215
23
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.
MA approved in Mar 2014, JUR‐14010215
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
Screening
Randomization
Phase I
2 to 9 days
Hanna M, et al. BMC Palliative Care. 2008;7:17.
MA approved in Mar 2014, JUR‐14010215
Phase II
10 to 15 days
IR
IRHydromorphone
Hydromorphone
12
12to
to108
108mg/day
mg/day
OROS®
OROS® hydromorphone
hydromorphoneqd
qd
(16
to
96
mg/day)
(16 to 96 mg/day)
IR
IR Morphine
Morphine
60
60to
to540
540mg/day
mg/day
Morphine
Morphine SR
SR bid
bid
(60
(60to
to540
540mg/day)
mg/day)
25
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.
MA approved in Mar 2014, JUR‐14010215
26
Results: Impact of Pain on Daily Activities at
end of Controlled-release Phase
* P=0.0386 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
MA approved in Mar 2014, JUR‐14010215
Hanna M, et al. BMC Palliative Care. 2008;7:17.
27
Cancer Pain: Once-Daily OROS® Hydromorphone
Improves Pain Relief Compared with Twice-Daily SR
Morphine
Primary Efficacy
Outcome
-1.59
-0.80
• Lower CI limit
lies outside of
the predetermined
equivalence
band
-0.01
Worst Pain
Secondary Efficacy
Outcome
-1.03
-0.38
0.27
Pain AM
-1.49
Pain PM
-0.77
• Equivalence
hypothesis is not
proven
-0.05
-0.51
0.06
0.64
Least Pain
-0.49
0.15
0.79
Average Pain
-2.0
-1.5
-1.0
Favors
OROS® Hydromorphone
Hanna M, et al. BMC Palliative Care. 2008;7:17.
MA approved in Mar 2014, JUR‐14010215
-0.5
0
0.5
1.0
1.5
2.0
Favors
CR Morphine
28
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.
MA approved in Mar 2014, JUR‐14010215
NCCN Guidelines Version 1.2013- Adults Cancer Pain
29
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 2012.
MA approved in Mar 2014, JUR‐14010215
30
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.
MA approved in Mar 2014, JUR‐14010215
31
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, 2014
MA approved in Mar 2014, JUR‐14010215
32
®
Jurnista (OROS® Hydromorphone)
Jackie , et al ,Pain Practice, Volume 10, Issue 1, 2010 72–77. Gupta S, Sathyan G. J Pain Sympt Manage 2007;33(2 Suppl):S19‐24.
Bosilkovska et al, Drugs 2012; 72 (12): 1645‐1669
J Pain Symptom Manage 2004;28:497–504.
MA approved in Mar 2014, JUR‐14010215
33
®
Jurnista (OROS® Hydromorphone)
When Cancer Pain Goes
Around the Clock…
MA approved in Mar 2014, JUR‐14010215
34

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