Fentanyl citrate, lozenge with integral applicator, 200 microgram, 400 microgram, 600 microgram, 800 microgram, 1200 microgram and 1600 microgram, Actiq, November 2007
Public summary document for Fentanyl citrate, lozenge with integral applicator, 200 microgram, 400 microgram, 600 microgram, 800 microgram, 1200 microgram and 1600 microgram, Actiq, November 2007
Page last updated: 29 February 2008
Public Summary Document
Product:Fentanyl citrate, lozenge with integral applicator, 200 microgram, 400 microgram,
600 microgram, 800 microgram, 1200 microgram and 1600 microgram, Actiq
Sponsor: Orphan Australia Pty Ltd
Date of PBAC Consideration: November 2007
1. Purpose of Application
The submission requested an authority required ‘palliative care’ listing for all registered strengths of fentanyl lozenges for the treatment of breakthrough pain in palliative care patients who are receiving opioids for their underlying persistent cancer pain where morphine is contraindicated due to renal impairment or adverse reactions which require cessation or change of therapy.
2. Background
At the June 2003 PBAC meeting, the PBAC rejected a submission seeking a Section 100
listing of fentanyl lozenges for the management of breakthrough cancer pain in patients
with malignancies who meet certain criteria because of a lack of evidence in the proposed
patient group with resulting uncertain clinical benefit and uncertain cost-effectiveness.
At the July 2004 PBAC meeting, the PBAC considered an application for an authority
required ‘palliative care’ listing for the management of breakthrough cancer pain
by specialists in palliative care patients who are receiving opioids for their underlying
persistent cancer pain and where morphine and one other opioid are each precluded
from use due to certain circumstances. The PBAC rejected the application because of
uncertain clinical benefit and the resulting uncertain and unfavourable cost effectiveness.
3. Registration Status
Actiq was TGA registered on 15 November 2002 for the management of breakthrough cancer
pain in patients with malignancies who are already receiving and are tolerant to opioid
therapy for their underlying persistent cancer pain.
As stated in the approved PI, use of oral transmucosal fentanyl citrate is contraindicated
in opioid naﶥ patients. Patients considered opioid tolerant are those who are taking
at least 60 mg morphine/day, 50 microgram transdermal fentanyl/hour, or an equianalgesic
dose of another opioid for a week or longer.
4. Listing Requested and PBAC’s View
Authority required
For the treatment of breakthrough pain in palliative care patients who are receiving
opioids for their underlying persistent cancer pain where morphine is contraindicated
due to:
(1) Renal impairment defined as estimated glomerular filtration rate (eGFR) of less
than 50 mL/min/1.73 m2; or
(2) Adverse reactions which require cessation or change of therapy, and defined in
the National Cancer Institute of the National Institute of Health Common Terminology
Criteria for Adverse Events (CTCAE) (2003) as follows:
Nausea (Grade 2) – persisting after 2 to 3 doses despite adequate trials of antinauseants;
or Vomiting (Grade 2) – persisting after 2 to 3 doses despite adequate trials of antinauseants;
or Constipation (Grade 2) – persisting for up to a week despite adequate trials of
laxatives, or Depressed level of consciousness (Grade 2) - persisting after 2 - 3
doses, or Confusion (Grade 3) – persisting for more than 24 hours, or Hypersensitivity
(Grade 2) – defined as rash, flushing, dyspnoea and drug fever ≥ 38˚C
Maximum Quantity: 3 (Initiation pack of 3), 20 (Maintenance pack of 3). Repeats: Nil
For PBAC’s view of the requested restriction, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Fentanyl has a number of advantages in patients with renal impairment in that it is
metabolised in the liver to inactive metabolites and has a short half-life. For patients
with renal impairment, accumulation of active metabolites of other opioids may contribute
to the adverse effects of opioids.
The Sponsor has agreed to initiate an extensive best practice education program on
correct prescribing to limit fentanyl lozenges to the patient population as intended
in the restriction and on correct titration to achieve optimum results.
6. Comparator
The submission nominated placebo as the comparator in the proposed PBS population. This was previously accepted by the PBAC.
7. Clinical Trials
No new clinical data was presented in the submission. The pivotal trial, AC 200/013,
used in support of this submission was the same as that in the previous submissions.
This study has been published as follows:
|
Trial ID |
Protocol title/ Publication title |
Publication citation |
|---|---|---|
|
Farrar J et al |
Oral transmucosal fentanyl citrate: randomised, double-blind, placebo-controlled trial for treatment of breakthrough pain in cancer patients. |
Journal of the National Cancer Institute 90(8):611-6,1998 |
|
Farrar JT |
Clinically important changes in acute pain outcome measures: a validation study. |
Journal of Pain & Symptom Management 25(5):406-11, 2003 |
8. Results of Trials
The key results are summarised in the table below.
Relative risk of responder (pain intensity difference of ≥33% at 30 mins) in Trial AC 200/013
|
Fentanyl N=556 |
Placebo N=245 |
Relative risk (95%CI) |
Risk difference (95%CI) |
NNT (95%CI) |
|---|---|---|---|---|
|
351 (63.1%) |
89 (36.3%) |
1.74 (1.46, 2.08) |
0.27 (0.19, 0.34) |
4 (3, 6) |
Efficacy of fentanyl lozenges across all scales using the optimal cut-off points in Trial AC 200/013 (secondary outcomes)
|
Trial AC 200/013 |
Scale |
Cut-off point |
Relative risk (95% CI) |
|---|---|---|---|
|
% Max TOTPAR**(at 60 min) |
0-100 |
33% |
1.66 (1.36-2.03) |
|
Pain relief (at 30 min) |
0-4 |
0-1 vs. 2-4 |
1.64 (1.40-1.92) |
|
PID(absolute change at 30 min) |
0-10 |
0-1 vs. 2-10 |
1.78 (1.49-2.13) |
|
SPID (sum of PID/h over 60 min) |
0-10 |
0-2 vs. 3-10 |
1.74 (1.45-2.13) |
|
Global performance (at 60 min) |
0-4 |
0-1 vs. 2-4 |
1.83 (1.53-2.17) |
PID = Pain Intensity Difference, TOTPAR = Total Pain Relief; SPID = Sum of Pain Intensity
Difference
Pain Intensity measured on an 11-point scale (0=no pain, 10=worst pain)
Pain Relief measured on 5-point scale (0=no relief, 4=complete relief)
Global Performance and Global Satisfaction Rating measured on a 5-point scale (0=poor,
4=excellent)
No new toxicity data was presented in the submission.
9. Clinical Claim
The submission claimed that fentanyl lozenge is statistically significantly superior to placebo for all measures of pain relief in cancer breakthrough pain. The PBAC noted that fentanyl lozenges produce greater pain relief compared to placebo, but have more toxicity.
10. Economic Analysis
An updated preliminary economic evaluation was presented. A cost effectiveness analysis
on a per patient basis was presented as well as a cost utility analysis. Two arms
were considered, the responder and non-responder arm. The relative risk was used for
both arms, using the definition of a patient achieving equal to or greater than 33%
reduction in pain intensity difference at 30 minutes as a responder.
The submission calculated the trial-based incremental cost/extra responder to be less
than $15,000.
No modelled economic evaluation was presented. The economic evaluation involved a
trial based incremental cost per QALY approach. The base case modelled incremental
cost/extra QALY was calculated to be in the range $45,000 - $75,000.
11. Estimated PBS Usage and Financial Implications
The net cost to the PBS of listing fentanyl lozenges was estimated to be less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of fentanyl lozenge on the Palliative Care Section
of PBS for the treatment of breakthrough pain in palliative care patients with cancer
who are receiving opioids for their persistent cancer pain and where further escalation
in the dose of morphine for breakthrough pain results in intolerable adverse effects
on the basis of a high but acceptable cost-effectiveness ratio.
The PBAC noted that renal function is not routinely monitored in palliative care patients
and that this measure was therefore inappropriate to be one of the criteria for the
restriction.
The PBAC considered that the utility gain of 0.7 for a responder over a non-responder
was high but plausible for the identified patients with uncontrolled pain in the palliative
care setting of a terminal illness. The PBAC also recognised the high clinical need
of these patients.
The PBAC considered that the utilisation predictions by the submission were an underestimate
and that the proposed risk sharing agreement would limit the increase in costs to
the PBS due to usage outside the recommended restriction.
Recommendation
Restriction:
Caution: The risk of drug dependence is high.
Authority required
Initial supply for dose titration for breakthrough pain in palliative care patients
with cancer who are receiving opioids for their persistent pain and where further
escalation in the dose of morphine for breakthrough pain results in intolerable adverse
effects.
Note: No applications for increased repeats will be authorised.
Maximum quantity: 3 x finished packs of 3 units
Repeats: Nil
Authority required
1st continuing supply (for up to 3 months) for breakthrough pain in palliative care
patients with cancer who are receiving opioids for their persistent pain and where
further escalation in the dose of morphine for breakthrough pain results in intolerable
adverse effects.
NOTE: No applications for increased repeats will be authorised.
Telephone approvals are limited to 1 month’s therapy.
Maximum quantity: 20 x finished packs of 3 units
Repeats: 2
Authority required
Second and subsequent continuing supply (for up to 3 months) for breakthrough pain
in palliative care patients with cancer who are receiving opioids for their persistent
pain and where further escalation in the dose of morphine for breakthrough pain results
in intolerable adverse effects, where consultation with a palliative care specialist
or service has occurred.
NOTE: No applications for increased repeats will be authorised.
Telephone approvals are limited to 1 month’s therapy.
Maximum quantity: 20 x finished packs of 3 units
Repeats: 2
Authority required
Second and subsequent continuing supply (for up to one month) for breakthrough pain
in palliative care patients with cancer who are receiving opioids for their persistent
pain and where further escalation in the dose of morphine for breakthrough pain results
in intolerable adverse effects.
NOTE: No applications for increased repeats will be authorised.
Maximum quantity: 20 x finished packs of 3 units
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
Orphan welcomes this recommendation by the PBAC to list a treatment option for breakthrough cancer pain in palliative care patients who cannot receive further dose escalation of morphine because of intolerable side effects.
