Oxycodone hydrochloride with naloxone hydrochloride dihydrate, controlled release tablet, 5 mg-2.5 mg, 10 mg-5 mg, 20 mg-10 mg and 40 mg-20 mg, Targin®
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controlled release tablet, 5 mg-2.5 mg, 10 mg-5 mg, 20 mg-10 mg and 40 mg-20 mg, Targin®
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Product: Oxycodone hydrochloride with naloxone
hydrochloride dihydrate, controlled release tablet, 5 mg-2.5 mg, 10
mg-5 mg, 20 mg-10 mg and 40 mg-20 mg, Targin®
Sponsor: Mundipharma Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought a Restricted Benefit listing for patients
with chronic severe disabling pain not responding to non-narcotic
analgesics.
2. Background
At the July 2010 meeting, the PBAC rejected the submission for oxycodone with naloxone
for patients with chronic severe disabling pain not responding to non-narcotic analgesics
on the basis of an uncertain and high cost-effectiveness ratio.
Full details are available in the July 2010 Public Summary Document are available.
3. Registration Status
Oxycodone with naloxone was TGA registered on 12 May 2010 for the
management of moderate to severe chronic pain unresponsive to
non-narcotic analgesia. The naloxone component in a fixed
combination with oxycodone is indicated for the therapy and/or
prophylaxis of opioid-induced constipation.
4. Listing Requested and PBAC’s View
Restricted benefit
Chronic severe disabling pain not responding to non-narcotic
analgesics.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Chronic pain occurs in up to 70% of patients with advanced cancer
and in approximately 65% of patients suffering from terminal
non-malignant disease. Opioids are the current mainstay of pain
management for patients with moderate-to-severe cancer pain and are
increasingly being used for the treatment of chronic non-cancer
pain. Opioid-induced bowel dysfunction (OIBD) comprises a range of
different side effects of which opioid-induced constipation (OIC)
is the most frequently reported. Prophylactic treatment of OIC with
laxatives is recommended in opioid treatment best practice
guidelines.
The proposed place in therapy of oxycodone with naloxone is as an
alternative pain management therapy to opioids alone or in
conjunction with prophylactic laxatives. It may also potentially
reduce the risk of intravenous or intranasal misuse by individuals
dependent on opioid agonists such as heroin, morphine or methadone,
as oxycodone with naloxone tablets are expected to produce marked
withdrawal symptoms due to the opioid receptor antagonist
characteristics of naloxone.
6. Comparator
The re-submission nominated oxycodone controlled release, without
prophylactic laxatives, as the comparator. This is the same as in
the previous submission.
To support using this comparator rather than oxycodone plus
prophylactic laxatives as previously suggested by the PBAC, the
submission presented Bettering the Evaluation and Care of Health
(BEACH) data on the co-prescribing of laxatives by general
practitioners when prescribing sustained release opioids.
The re-submission stated that the BEACH data analysis indicated
that there was a low rate of co-prescribing of laxatives in
patients receiving prescriptions for opioids. The submission stated
that for chronic conditions there is a greater degree of laxatives
being co-prescribed but that in general GPs are not commencing
laxative treatment until patients require such intervention despite
opioid treatment best practice guidelines.
The submission stated that the conclusion from the BEACH data
analysis supports the GP and Specialists survey presented in the
original submission in terms of laxative co-prescribing estimates
and therefore confirms the appropriate comparator is oxycodone
without prophylactic laxatives.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The re-submission presented further information on the key clinical
studies (OXN3401, OXN3001 and OXN3006) to clarify the relative
importance of the study outcomes and rank the various analyses
based on published data.
Publication details of these studies have been previously reported
in the July 2010 Public Summary Document.
8. Results of Trials
The re-submission stated that studies OXN3001 and OXN3006 were designed to primarily
assess bowel function and powered to show superiority of oxycodone with naloxone over
oxycodone alone in the mean bowel function index (BFI) score (at 4 weeks), compared
with low oxycodone dose ranges (OXN3001) and high oxycodone dose ranges (OXN3006).
Whereas, study OXN3401 was designed and powered to show superiority in pain control
of oxycodone with naloxone over oxycodone alone only. All bowel function outcomes
from this study, including the BFI, were assessed as exploratory efficacy variables
and therefore provided preliminary data only on the impact of treatment on constipated
patients.
The re-submission presented statistical analyses in which the proportion of patients
using laxatives as rescue medication showed no statistically significant difference
between constipated and not constipated patients at baseline (ratio of relative risk
1.31 [95% CI: 0.79, 2.18] p=0.3). The same conclusion was shown for the proportion
of patients who achieved a BFI<28.8 (i.e. not constipated) at 12 weeks (ratio of relative risk 1.29 [95% CI: 0396,
1.73] p=0.087). The submission claimed that this demonstrated that oxycodone with
naloxone is efficacious in both constipated and non-constipated patients or no less
efficacious in non-constipated patients for these key variables.
The PBAC noted that in the previous submission, the three clinical trials pooled meta-analysis
results for BFI at week 4 and week 12 showed borderline clinical significance however
did not reach the minimum clinically important difference, which was defined as a
change of greater than 12 points. The re-submission stated that the cut-off point
of 12 was used to provide rigorous response criteria to determine patients that are
responding or not responding to treatment. The sponsor also noted that Rentz et al
(Validation of Bowel Function Index to detect clinical meaningful changes in opioid-induced
constipation. Journal of Medical Economics 2009; 12(4) 371-383) suggests that patients may have
a clinically significant change in bowel function when the change of BFI score is
between 7.5 and 9 points. Therefore, the re-submission claimed that the pooled meta-analysis
mean differences of -11.5 and -11.86 were still clinically meaningful.
9. Clinical Claim
The submission described oxycodone with naloxone as superior in
terms of comparative effectiveness (in terms of bowel function
only) and equivalent in terms of comparative safety over oxycodone
alone. The PBAC had previously considered this was reasonable,
given the evidence.
10. Economic Analysis
The economic model presented was unchanged from the July 2010 submission, however the following key parameters, previously identified by PBAC as areas of uncertainty, were addressed and amended:
Price;
Different base case risk ratio of response - proportion of patients not constipated (at 12 weeks);
Incorporation of abuse potential of the comparator. The abuse potential of oxycodone with naloxone was assumed to be negligible;
Incorporation of effectiveness of prophylactic laxatives in preventing opioid induced constipation (OIC); and
Revised base case average daily dose (ADD) based on BEACH data.
The revised base case incremental cost-effectiveness ratio (ICER)
was in the range of $15,000 to $45,000 per quality adjusted life
year (QALY) (higher than in the previous submission, but within the
same range).
Several one-way sensitivity analyses were conducted to address some
of the PBAC’s concerns regarding the previous model. These
included the analysis of the costs and disutilities of
complications, a higher average daily dose above 50 mg/day,
adjustment of the risk ratio to 1.42, adjustment of laxative
co-prescribing to 11.11% and opioid abuse at 2%. The resulting ICER
was increased to between $45,000 and $75,000 per QALY at daily
doses in excess of 50 mg/day.
11. Estimated PBS Usage and Financial Implications
The re-submission estimated the likely number of patients to be in
the range of 50,000 to 100,000 in year 5 of listing (compared with
between 10,000 and 50,000 in the previous submission).
The re-submission estimated the financial cost to the PBS to be
less than $10 million in year 5 of listing (but higher than in the
previous submission). The re-submission estimated MBS savings
through reduced cost of OIC diagnosis, testing and treatment,
resulting in a net cost to the Government health budget of less
than $10 million in year 5 (and lower than in the previous
submission).
12. Recommendation and Reasons
The PBAC recommended the listing of oxycodone with naloxone on the PBS as a Restricted
Benefit for chronic severe disabling pain on the basis of an acceptable cost-effectiveness
ratio compared with oxycodone controlled release, without prophylactic laxatives.
The PBAC noted that although the price of the combination product had been reduced,
there was still a price premium over oxycodone controlled release (OxyContin®). The PBAC also noted that the comparator was oxycodone controlled release, without
prophylactic laxatives, the same as in the July 2010 submission. At the July 2010
meeting, the PBAC considered that oxycodone alone was not the appropriate comparator
as there was evidence suggesting a significant proportion of patients were likely
to receive prophylactic laxatives, consistent with current clinical guidelines, particularly
patients with chronic pain on long term opioid therapy and that the more appropriate
comparator was oxycodone plus prophylactic laxatives.
To support using oxycodone alone as the comparator rather than oxycodone plus prophylactic
laxatives as suggested by the PBAC, the re-submission presented BEACH data on the
co-prescribing of laxatives by GPs when prescribing sustained release opioids. The
PBAC noted that the BEACH data analysis indicated that there was a low rate of co-prescribing
of laxatives in patients receiving prescriptions for opioids. The PBAC also noted
that in general GPs are not commencing laxative treatment until patients require such
intervention despite opioid treatment best practice guidelines. Additionally, the
PBAC also noted that many people purchase over the counter laxatives for this purpose.
The re-submission presented further information on the key clinical studies (OXN3401,
OXN3001 and OXN3006 – considered at the July 2010 meeting) to clarify the relative
importance of the study outcomes and rank the various analyses based on published
data. The PBAC noted that Studies OXN3001 and OXN3006 were designed to primarily assess
bowel function and powered to show superiority of oxycodone with naloxone over oxycodone
in the mean bowel BFI score (at 4 weeks), compared to low oxycodone dose ranges (OXN3001)
and high oxycodone dose ranges (OXN3006). Study OXN3401 was designed and powered to
show superiority in pain control of oxycodone with naloxone over oxycodone only. All
bowel function outcomes from this study, including the BFI, were assessed as exploratory
efficacy variables and therefore provided preliminary data only on the impact of treatment
on constipated patients.
The PBAC noted that a statistical analysis of the sponsor’s preferred study outcome
of the proportion of patients using laxatives as rescue medication showed no statistically
significant difference between constipated and not constipated patients at baseline
(RR = 1.31 [95% CI: 0.79, 2.18; P=0.3]). The same conclusion was shown for the proportion
of patients achieving a bowel function index<28.8 (i.e. not constipated) at 12 weeks (RR = 1.29 [95% CI: 0.96, 1.73; P=0.087]).
The PBAC accepted that oxycodone with naloxone is efficacious in both constipated
and non-constipated patients or no less efficacious in non-constipated patients for
these key variables. It was noted that Rentz et al (2009) suggested that patients
may have a clinically significant change in bowel function when the change of BFI
score is between 7.5 and 9 points and that the pooled meta-analysis mean differences
of -11.15 and -11.86 are still clinically meaningful. However, the PBAC noted that
the article abstract actually states that “data indicate that a BFI score change of
greater or equal to 12 points represents a clinically meaningful change in constipation”.
The PBAC noted that the economic model presented was unchanged from that considered
in July 2010, however, the following parameters used in the model were amended: price;
different base case risk ratio of response - proportion of patients not constipated
(at 12 weeks) based on a BFI<28.8 (RR=1.30) (previous submission used proportion of patients who used laxatives
as rescue medication, RR=1.50); incorporation of abuse potential of the comparator,
3.8% based on Australian Institute of Health and Welfare (AIHW) data, (negligible
for oxycodone/naloxone); incorporation of effectiveness of prophylactic laxatives
in preventing OIC based upon the GP survey results for the ratio of OIC with laxatives/OIC
without laxatives; and revised base case average daily dose (ADD) based on BEACH data,
median dose 40 mg/day (compared with 38.71 mg/day in the previous submission).
The PBAC noted that the revised base case ICER was in the range of $15,000 to $45,000
per QALY (higher than in July 2010). The PBAC also noted that several one-way sensitivity
analyses were presented to address some of the PBAC’s concerns regarding the previous
model. These included the analysis of the costs and disutilities of complications,
a higher average daily dose above 50 mg/day, adjustment of the risk ratio to 1.42,
adjustment of laxative co-prescribing to 11.11% and opioid abuse at 2%. The resulting
ICER increased to between $45,000 and $75,000 per QALY at daily doses in excess of
50 mg/day.
The re-submission presented revised estimates of patient numbers and the financial
implications on government expenditure which allowed for 37% of 80 mg presentations
to utilise oxycodone with naloxone (2 x 40/20 mg), removed the potential cost savings
from reduced abuse potential, included under-copayment 20 mg scripts and increased
the projected uptake/switching rate of oxycodone with naloxone (from oxycodone) from
60% to 80%. The PBAC noted that although predicted utilisation increased in terms
of prescriptions dispensed compared with the July 2010 submission, the net costs to
PBS of remain lower than those provided by the Drug Utilisation Sub-Committee Secretariat
in June 2010.
The PBAC considered that it was appropriate to list oxycodone with naloxone on the
PBS as the availability of this product is likely to increase prophylactic management
of OIC, the cost of the product is similar to oxycodone plus an over-the-counter laxative,
the product may prevent constipation and not cause diarrhoea, and it may also reduce
diversion.
The PBAC recommended that the Safety Net 20 day rule should not apply.
The PBAC recommended that oxycodone with naloxone fixed dose combination is suitable
for inclusion in the PBS medicines for prescribing by nurse practitioners within collaborative
arrangements as a shared care model.
Recommendation:
OXYCODONE HYDROCHLORIDE with NALOXONE HYDROCHLORIDE DIHYDRATE, controlled release
tablet, 5 mg–2.5 mg, 10 mg–5 mg, 20 mg–10 mg and
40 mg–20 mg
Restriction: 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.
NOTE:
Shared Care Model: For prescribing by nurse practitioners where care of a patient is shared between a nurse practitioner and medical practitioner in a formalised arrangement with an agreed management plan. Further information can be found in the Explanatory Notes for Nurse Practitioners.
Maximum quantity: 20 (change to 28 when pack size becomes available)
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 has no comment.
