Hydromorphone Hydrochloride, extended release capsules, 12 mg, 16 mg , 24 mg, and 32 mg, Palladone® XL, July 2005
Public Summary Document for Hydromorphone Hydrochloride, extended release capsules, 12 mg, 16 mg , 24 mg, and 32 mg, Palladone® XL, July 2005.
Page last updated: 24 October 2005
Public Summary Document
Product: Hydromorphone Hydrochloride, extended release capsules, 12 mg, 16 mg , 24 mg, and 32 mg, Palladone® XL
Sponsor: Mundipharma Pty Ltd
Date of PBAC Consideration: July 2005
1. Purpose of Application
This application sought a restricted benefit listing on the Pharmaceutical Benefits
Scheme (PBS) for the treatment of chronic severe disabling pain not responding to
This dosage form of hydromorphone hydrochloride had not been previously considered
by the Pharmaceutical Benefits Advisory Committee (PBAC).
Hydromorphone hydrochloride injection and oral solution (Dilaudid®) were listed on the PBS as unrestricted benefits following a PBAC recommendation at the December 1999 meeting. The recommendation was made on a cost-minimisation basis, with 1 mg hydromorphone hydrochloride accepted as being of similar effectiveness and safety to 5 mg morphine sulfate/hydrochloride/tartrate.
Immediate release (IR) hydromorphone hydrochloride (Dilaudid) oral tablets were PBS listed on 1 November 2001 on a cost-minimisation basis compared with oxycodone hydrochloride, with 1 mg hydromorphone hydrochloride accepted as being of similar effectiveness and safety to 4 mg oxycodone hydrochloride.
3. Registration Status
Hydromorphone hydrochloride extended release capsules (hydromorphone CR) were registered
by the Therapeutic Goods Administration on 20 January 2003 for “the management of
opioid responsive chronic pain of moderate to severe intensity in patients who have
been titrated to a daily dose of 12 mg or more immediate release hydromorphone or
other equivalent opioid”.
4. Listing Requested and PBAC’s View
The submission requested the following listing:
Chronic severe disabling pain not responding to non-narcotic analgesics.
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 where the authority is requested by a specialist; or
(iii) chronic severe disabling pain where the requesting medical practitioner has consulted with another medical practitioner and the clinical need for each authority has been established.
The PBAC considered that the NOTE included in the requested restriction should be replaced with the recently amended NOTE for opioid preparations on the PBS and that the standard caution note applying to other controlled release opioids on the PBS should be included in the listing, viz: ‘the risk of drug dependence is high’.
5. Clinical Place for the Proposed Therapy
A range of different available opioids allows physicians to tailor treatment to individual
requirements, as side effects occur on initiation of opioid therapy in some patients,
and in others, opioid tolerance develops during treatment for extended periods. Hydromorphone
CR offers another once daily pain management option for patients suffering chronic
cancer and non-cancer related pain.
The submission nominated oxycodone controlled release (CR) tablets as the comparator.
The PBAC accepted this as appropriate.
7. Clinical Trials
The submission provided an indirect comparison of hydromorphone CR (Palladone XL)
and oxycodone controlled release (CR) tablets in the treatment of chronic cancer and
non-cancer pain based on the established dose relativity of 1 mg hydromorphone hydrochloride
immediate release (HHIR) being accepted by the PBAC as being of similar effectiveness
and safety to 4 mg immediate release (IR) oxycodone hydrochloride.
Strategy for Submission:
Palladone XL equivalent to CR oxycodone
Evidence for the safety and efficacy of hydromorphone CR was provided by four key
efficacy studies. Two of these studies were short (3-7 day), randomised controlled,
cross-over, equivalence studies comparing hydromorphone CR and IR hydromorphone in
cancer and non-cancer pain. The other two studies were longer term (28 day) randomised,
controlled, parallel-group studies comparing hydromorphone CR and placebo in the treatment
of moderate to severe non-cancer pain. One additional study demonstrating the bioequivalence
of hydromorphone CR and IR hydromorphone was also presented. None of these studies
had been published at the time of submission.
To provide evidence for the equivalence of IR and CR oxycodone the results of 5 studies comparing these two formulations were presented. These studies were all published at the time of submission (in four reports) as follows:
|Stambaugh et al, 2001||Randomised, double-blind comparison of the analgesic and pharmacokinetic profiles of controlled-release oral oxycodone in cancer patients.||Journal of Clinical Pharmacology 41(5):500-6.|
|Hale et al, 1999||Efficacy and safety of controlled-release versus immediate-release oxycodone: randomised, double-blind evaluation in patients with chronic back pain.||Clinical Journal of Pain 15(3):179-83.|
|Salzman et al, 1999||Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release
from for the purposes of titrating to stable pain control?
NOTE: that there are two trials in this paper – one each for cancer and non cancer patients.
|Journal of Pain and Symptom Management 18(4):271-9.|
|Parris et al, 1998||The use of controlled-release oxycodone for the treatment of chronic pain: a randomised, double-blind study.||Journal of Pain and Symptom Management 16(4):205-11|
8. Results of Trials
In the two cross-over trials of hydromorphone, the CR and IR formulations were considered
equivalent in terms of the mean average pain intensity rating. In the two parallel
group studies of hydromorphone CR versus placebo, hydromorphone CR was significantly
better than placebo in the main outcome measures of mean pain intensity or days to
emergence of inadequate analgesia, respectively.
In the oxycodone trials, no significant efficacy differences were seen between the IR and CR formulations.
The toxicity data presented suggested that hydromorphone CR has a similar toxicity profile to that of hydromorphone IR.
9. Clinical Claim
The submission claimed that hydromorphone CR administered once daily has equivalent
analgesic efficacy and similar toxicity to IR hydromorphone, and superior efficacy
to placebo. The submission also claimed that CR oxycodone has equivalent analgesic
efficacy and similar toxicity to IR oxycodone.
Based on the accepted dose relativity of 1 mg IR hydromorphone being equivalent to 4 mg IR oxycodone, the submission claimed that the clinical evidence supported the equivalence of hydromorphone CR and oxycodone CR with a dose relativity of 1:4.
This was considered acceptable by the PBAC.
10. Economic Analysis
A preliminary economic analysis was presented in the form of a cost-minimisation analysis
based on a dose relativity of 1 mg IR hydromorphone being equivalent to 4 mg IR oxycodone.
This was accepted as a reasonable approach by the PBAC.
11. Estimated PBS Usage and Financial Implications
Based on the assumption that hydromorphone CR would not be prescribed for new, opioid
naïve patients, the submission stated that it is not expected to increase the current
opioid market and will therefore not add any additional cost to the PBS.
12. Recommendation and Reasons
The PBAC recommended listing on a cost-minimisation basis, concluding the indirect
comparison involving immediate release hydromorphone as the common reference submitted
indicated hydromorphone hydrochloride controlled release capsules were no worse than
oxycodone hydrochloride controlled release tablets in pain management. The equi-effective
doses are hydromorphone hydrochloride controlled release 1 mg and oxycodone hydrochloride
controlled release 4 mg.
The PBAC noted that the lowest dose of hydromorphone available is a relatively high starting dose compared to other controlled release preparations. The PBAC requested the National Prescribing Service educate prescribers that it was critical for patients to be appropriately commenced on treatment with controlled release hydromorphone.
The risk of drug dependence is high.
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; orii) Chronic severe disabling pain not responding to non-narcotic analgesics where treatment was initiated in a hospital (in-patient or out-patient) prior to 1 April 2005. This criterion will be deleted from the Schedule of Pharmaceutical Benefits on 1 April 2006; or
iii) Chronic severe disabling pain not responding to non-narcotic analgesics where the total duration of narcotic analgesic treatment is less than 12 months; oriv) 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 three months prior to the application for a PBS authority. The full name of the medical practitioner consulted and the date of consultation is to be provided at the time of application; or
v) 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.
|10 (all strengths)
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