Hydromorphone hydrochloride, prolonged release tablets, 8 mg, 16 mg, 32 mg, 64 mg, Jurnista®, November 2008
Public Summary Document for Hydromorphone Hydrochloride, prolonged release tablets, 8 mg, 16 mg, 32 mg, and 64 mg Jurnista®, November 2008
Page last updated: 25 March 2009
Public summary Document
Product: Hydromorphone hydrochloride, prolonged
release tablets, 8 mg, 16 mg, 32 mg, 64 mg,
Jurnista®
Sponsor: Janssen-Cilag Pty Ltd.
Date of PBAC Consideration: November 2008
1. Purpose of Application
To seek a Restricted Benefit listing in the General and Dental
Schedules for chronic severe disabling pain not responding to
non-narcotic analgesics.
An Authority Required listing in the Palliative Care Schedule was
also requested for palliative care patients with chronic severe
disabling pain not responding to non-narcotic analgesics.
2. Background
This was the first submission requesting listing of this
hydromorphone hydrochloride prolonged release tablet
formulation.
At the July 2005 meeting the PBAC recommended the listing of
hydromorphone hydrochloride extended release capsules
(Palladone® XL) as a restricted benefit for the
treatment of chronic severe disabling pain not responding to
non-narcotic analgesics, noting the benefits of having a range of
different opioids available to allow physicians to tailor treatment
to individual requirements. The product was withdrawn later in 2005
due to a potential dose-dumping effect if used concomitantly with
alcohol.
3. Registration Status
Hydromorphone hydrochloride prolonged release tablets were
registered by the Therapeutic Goods Administration on 29 July 2008
for the treatment of moderate to severe pain, to be used in
patients requiring continuous analgesia.
4. Listing Requested and PBAC’s View
General Schedule:
Caution:
The risk of drug dependence is high.
Restricted Benefit
Chronic severe disabling pain not responding to non-narcotic analgesics.
Note:
Authorities for increased maximum quantities and/or repeats will be granted only for:
i. chronic severe disabling pain associated with proven malignant neoplasia; or
ii. chronic severe disabling pain not responding to non-narcotic analgesics where the total duration of narcotic analgesic treatment is less than 12 months; or
iii. first application for treatment beyond 12 months of chronic severe disabling pain not responding to non-narcotic analgesics where the patient's pain management has been reviewed through consultation by the patient with another medical practitioner, and the clinical need for continuing narcotic analgesic treatment has been confirmed. The date of the consultation must be no more than 3 months prior to the application for a PBS authority. The full name of the medical practitioner consulted and the date of consultation are to be provided at the time of application; or
iv. subsequent application for treatment of chronic severe disabling pain not responding to non-narcotic analgesics where a PBS authority prescription for treatment beyond 12 months has previously been issued for this patient.
Dental Schedule:
Caution:
The risk of drug dependence is high.
Restricted Benefit:
Chronic severe disabling pain not responding to non-narcotic analgesics.
Note:
Prescribing of drugs of addiction by dentists is not permitted in some States/Territories.
The PBAC deemed that a listing in the Palliative Care Schedule would be inappropriate
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Hydromorphone prolonged release tablets offer an additional
treatment option in the management of chronic pain.
6. Comparator
The submission nominated oxycodone controlled release (CR) tablets
as the comparator. The PBAC accepted this as appropriate.
7. Clinical Trials
The submission presented one direct randomised comparative trial
(unpublished) and one supplementary randomised comparative trial
(Hale 07) comparing OROS hydromorphone and oxycodone CR in patients
with chronic pain due to non-cancer causes.
The submission also presented an indirect comparison of one direct
randomised trial of OROS hydromorphone (unpublished) and three
direct randomised trials of oxycodone CR with morphine sustained
release (SR) (Mucci 98, Heisk 97 and Brue 98) as the common
comparator in the treatment of chronic pain due to cancer.
Details of the studies published at the time of the submission are
presented in the table below.
| Trial ID | Protocol title/Publication title | Publication citation |
| Hale 07 | Efficacy and tolerability of once-daily OROS (registered trademark) hydromorphone and twice-daily extended-release oxycodone in patients with chronic, moderate to severe osteoarthritis pain: Results of a 6-week, randomized, open-label, noninferiority analysis. | Hale M, et al . Clinical Therapeutics 2007; 29(5):874-888. |
| Mucci 98 | Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomised, double-blind, parallel-group study. | Mucci-LoRusso P, et al. European Journal of Pain 1998; 2(3): 239-249 |
| Brue 98 | Randomised, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. | Bruerea E, et al. Journal of Clinical Oncology 1998; 16(10): 3222-3229 |
| Heisk 97 | Controlled-release oxycodone and morphine in cancer related pain. Morphine or oxycodone in cancer pain? | Heiskanen T et al. Pain 1997; 73: 37-45 Heiskanen T et al. Acta Oncologica 2000; 39(8): 941-47 |
8. Results of Trials
The submission presented two efficacy analyses: in non-cancer pain
(direct) and in cancer pain (indirect).
In the non-cancer pain trial ANA3001, OROS hydromorphone and
oxycodone CR were considered to be equivalent in terms of change
from baseline to endpoint in mean brief pain inventory (BPI) pain
severity sub-score ‘pain right now’ for both ITT and PP
analyses. This was based on the pre-specified equivalence criterion
where the upper boundary of the confidence interval is below the
non-inferiority margin of 1.0.
From the cancer pain trials, OROS hydromorphone and morphine SR
were considered equivalent (95% two-sided CI for the difference
between the adjusted means lies within -1.5 to 1.5), in terms of
change from baseline to endpoint in the mean of the last two
recorded scores for “worst pain” both in the ITT and PP
analysis during the immediate release phase.
It was noted that overall, the primary outcomes in the trials for
treatment of non-cancer and cancer pain vary between the
trials.
The results of two indirect comparisons based on standardised mean
difference and normalisation of the rating scale to a common scale
of 11 points were provided. Based on the standardised mean
difference methodology, OROS hydromorphone and oxycodone CR are
considered equivalent. Based on the normalised score methodology,
however, OROS hydromorphone was considered superior to oxycodone CR
(95 % two-sided CI for the difference between the adjusted means
lies within -1.5 to 1.5).
In the direct non-cancer pain trial, the most common adverse events
were nausea, constipation, vomiting, fatigue and hyperhidrosis, in
both treatment groups. In Hale 07, the most common adverse events
were nausea, constipation, vomiting and somnolence. The incidence
of constipation was higher in patients taking OROS hydromorphone
compared to oxycodone CR in both trials, however the differences
were not statistically significant.
In the unpublished cancer pain trial, the event rate of
constipation and headache was higher in OROS hydromorphone than in
morphine SR patients. The rate of nausea, vomiting and dizziness
was higher in morphine SR patients. In Mucci 98, more patients in
the oxycodone CR group reported adverse events compared to the
morphine SR group. In Heisk 97, constipation was significantly more
common with oxycodone CR, while vomiting occurred significantly
more with morphine SR.
For PBAC’s comments on these results, see Recommendation
and Reasons.
9. Clinical Claim
The submission claimed OROS hydromorphone was non-inferior in terms
of comparative effectiveness and comparative safety to oxycodone
CR.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost-minimisation analysis claiming the
equi-effective doses to be OROS hydromorphone 26.4 mg and oxycodone
CR 74 mg, giving a ratio of 1 : 2.80. This was accepted by the
PBAC.
The submission calculated the weighted average dose used for OROS
hydromorphone and oxycodone CR in chronic pain (due to cancer and
non-cancer causes) based on the trial data.
11. Estimated PBS Usage and Financial Implications
The submission estimated the number of prescriptions per year to be
greater than 200,000 in Year 5 with net savings to the PBS of less
than $10 million per year over the first 5 years of listing.
12. Recommendation and Reasons
The PBAC recommended the listing of hydromorphone hydrochloride prolonged release
tablets on the PBS in the General and Dental schedules for the treatment of chronic
severe disabling pain not responding to non-narcotic analgesics on a cost minimisation
basis to oxycodone controlled release (CR) tablets. The equi-effective doses are 26.4
mg hydromorphone hydrochloride prolonged release to 74 mg oxycodone hydrochloride
controlled release, giving a ratio of 1: 2.8.
The PBAC considered the evidence presented supported the claim of non-inferior clinical
efficacy of hydromorphone PR compared to oxycodone CR for both non-cancer and cancer
related chronic pain, with results possibly favouring hydromorphone in the treatment
of cancer related pain.
The comparative safety data presented supported the claim of non-inferior safety of
hydromorphone PR tablets compared to oxycodone CR tablets, however the Committee was
very concerned with likelihood of serious toxicity if the product is crushed and injected
intravenously. The PBAC requested its DUSC employ their relationship with the National
Drug and Alcohol Research Centre (NDARC) to be alerted if NDARC becomes aware of issues
with illicit use of hydromorphone PR tablets. The PBAC also requested that the National
Prescribing Service (NPS) educate prescribers of the potential serious toxicity of
the hydromorphone PR tablet product and remind prescribers of the potential for diversion
of opioids from the PBS. The Committee also requested that the ADRAC alert it if it
becomes aware of reports of toxicity related to hydromorphone PR tablets.
The PBAC did not recommend the application for listing in the Palliative Care Schedule
as the Committee deemed the listing would be inappropriate considering the use of
hydromorphone PR tablets in the treatment of chronic pain is not specific to the palliative
care setting. The PBAC noted that prescribers would be able to access hydromorphone
PR tablets through the General Schedule for their palliative care patients, consistent
with the listing of other opioids on the PBS for the treatment of chronic pain.
Recommendation
HYDROMORPHONE HYDROCHLORIDE, prolonged release tablets, 8 mg, 16 mg, 32 mg, and 64
mg, Jurnista®
Restriction: General Schedule:
Caution:
The risk of drug dependence is high.
Restricted Benefit
Chronic severe disabling pain not responding to non-narcotic analgesics.
Note:
Authorities for increased maximum quantities and/or repeats will be granted only for:
i. chronic severe disabling pain associated with proven malignant neoplasia; or
ii. chronic severe disabling pain not responding to non-narcotic analgesics where the total duration of narcotic analgesic treatment is less than 12 months; or
iii. first application for treatment beyond 12 months of chronic severe disabling pain not responding to non-narcotic analgesics where the patient's pain management has been reviewed through consultation by the patient with another medical practitioner, and the clinical need for continuing narcotic analgesic treatment has been confirmed. The date of the consultation must be no more than 3 months prior to the application for a PBS authority. The full name of the medical practitioner consulted and the date of consultation are to be provided at the time of application; or
iv. subsequent application for treatment of chronic severe disabling pain not responding to non-narcotic analgesics where a PBS authority prescription for treatment beyond 12 months has previously been issued for this patient.
Dental Schedule:
Caution:
The risk of drug dependence is high.
Restricted Benefit:
Chronic severe disabling pain not responding to non-narcotic analgesics.
Note:
Prescribing of drugs of addiction by dentists is not permitted in some States/ Territories.Maximum
quantity: 10
Number of repeats: 0
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor welcomes the PBAC’s recommendation as the
availability of hydromorphone prolonged release tablets will allow
physicians to tailor treatment to individual requirements by
rotating different long acting opioids when side effects or
treatment tolerance occurs.
