Buprenorphine, transdermal patch, 5 mg, 10 mg and 20 mg (releasing 5 micrograms, 10 micrograms and 20 micrograms per hour respectively), Norspan®, July 2005

Public Summary Document for Buprenorphine, transdermal patch, 5 mg, 10 mg and 20 mg (releasing 5 micrograms, 10 micrograms and 20 micrograms per hour respectively), Norspan®, July 2005.

Page last updated: 24 October 2005

Public Summary Document
Product: Buprenorphine, transdermal patch, 5 mg, 10 mg and 20 mg (releasing 5 micrograms, 10 micrograms and 20 micrograms per hour respectively), Norspan®
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 chronic severe disabling pain not responding to non-narcotic analgesics.

2. Background

At the March 2001 meeting, the Pharmaceutical Benefits Advisory Committee (PBAC) recommended the Section 100 listing of buprenorphine sublingual tablets for the treatment of opiate dependence including maintenance and detoxification (withdrawal) within a framework of medical, social and psychological treatment.

Buprenorphine transdermal patches have not previously been considered by the PBAC.

3. Registration Status

Buprenorphine 5 mg, 10 mg and 20 mg patches were registered by the Therapeutic Goods Administration on 9 May 2005 for the ‘management of moderate to severe pain’.

4. Listing Requested and PBAC’s View

The sponsor requested the following listing:

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 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 which came into effect 19 April 2005.

5. Clinical Place for the Proposed Therapy

Buprenorphine transdermal patches are intended to treat patients with chronic severe disabling pain, both cancer and non-cancer related. They may be used as an alternative in patients taking lower doses of opioids (up to 90 mg of morphine-equivalents a day) and combination analgesics.

6. Comparator

The submission nominated oxycodone controlled release (CR) as the main comparator. This was considered appropriate by the PBAC.

7. Clinical Trials

Five key randomised trials formed two indirect comparisons to show the equivalence of transdermal buprenorphine and oxycodone CR. One indirect comparison used oxycontin immediate release (IR)/paracetamol as the common reference, and the other used placebo as the common reference

In addition, two randomised trials comparing transdermal buprenorphine with sublingual buprenorphine and hydromorphone /paracetamol respectively, and 5 randomised trials comparing oxycontin CR with oxycontin IR, were provided as supporting trials.

Six of the total of 12 studies had been published at the time of submission, as follows: (Note: one publication, Salzman (1999), reports the results of two separate studies).

Trial/first author	Protocol title	Publication citation
Caldwell	Treatment of osteoarthritis pain with controlled-release oxycodone or fixed-combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double-blind, randomised, multicenter, placebo-controlled trial.	Journal of Rheumatology, 1999, 26(4):862-9.
Stambaugh	Double-blind, randomised comparison of the analgesic and pharmacokinetic profiles of controlled-release oral oxycodone in cancer patients.	Journal of Clinical Pharmacology, 2001, 41(5):500-6.
Hale	Efficacy and safety of controlled-release versus immediate-release oxycodone: randomised, double-blind evaluation in patients with chronic back pain.	Clinical Journal of Pain, 1999, 15(3):179-83.
Salzman	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?	Journal of Pain and Symptom Management, 1999, 18(4):271-9.
Parris	The use of controlled-release oxycodone for the treatment of chronic pain: a randomised, double-blind study.	Journal of Pain and Symptom Management, 1998, 16(4):205-11.

 

8. Results of Trials

The outcomes that were common to the majority of the trials were ‘pain on average’ (measured at 30 days) and ‘pain right now’ (also at 30 days).

The pain intensity reduction compared with baseline, either assessed ‘on average’ or ‘right now’, was similar across the transdermal buprenorphine versus oxycontin IR/paracetamol and the oxycodone CR versus oxycontin IR/paracetamol trials.

In trials with placebo as the common reference, statistically significant differences were identified in pain reduction ‘on average’ in pooled transdermal buprenorphine results, and the oxycodone CR study.

In the indirect comparison with oxycontin IR/paracetamol as the common reference, the adverse events observed were those typically associated with opioids. No significant difference was identified across any compared arm. Transdermal buprenorphine and oxycodone CR have similar toxicity profiles. No unexpected safety concerns were raised in any of the trials. The percent of patients with adverse events associated with transdermal wear was similar among all treatment groups including placebo, suggesting these reactions were due to the transdermal system itself and not to the buprenorphine that was being released from the transdermal system.

9. Clinical Claim

The submission claimed that transdermal buprenorphine is equivalent to oxycodone CR in pain management, based on the indirect comparisons concluding that transdermal buprenorphine is equivalent to the common comparator oxycontin IR/paracetamol, and therefore oxycodone CR.

The PBAC considered that this may be reasonable, although it is based on indirect comparisons and therefore should be interpreted with caution.

10. Economic Analysis

The submission presented a cost-minimisation analysis with transdermal buprenorphine 5mg, 10mg, 20mg every seven days and oxycodone CR 10mg, 20mg, 40mg twice daily, respectively, claimed to be equivalent.

The PBAC considered that although the relativity of equi-effective doses is consistent with the evidence for the two lower strengths of transdermal buprenorphine, the key trial evidence most directly supports equi-effectiveness across buprenorphine 20mg every seven days and oxycodone CR 30mg twice daily. The PBAC considered that the claimed relativity of transdermal buprenorphine 20 mg every 7 days to oxycodone hydrochloride controlled release 40 mg twice daily was not demonstrated.

11. Estimated PBS Usage and Financial Implications

The submission estimated the additional cost to the PBS to be < $10 million per year in the first two years of listing.

12. Recommendation and Reasons

The PBAC recommended listing on a cost-minimisation basis, concluding that the indirect comparisons involving immediate release oxycodone/paracetamol and placebo as the common references, indicated buprenorphine transdermal patches were similar to oxycodone hydrochloride controlled release tablets in terms of pain management. The equi-effective doses are transdermal buprenorphine 5 mg, 10 mg and 20 mg every seven days and oxycodone hydrochloride controlled release 10 mg, 20 mg and 30 mg twice daily, respectively.

Recommendation
List

BUPRENORPHINE, transdermal patches, 5 mg, 10 mg and 20 mg (releasing 5 micrograms, 10 micrograms and 20 micrograms per hour respectively)

CAUTION: The risk of drug dependence is high.

Restriction:	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 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; or (iv) 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.
Maximum quantity Repeats:	2 (all strengths) Nil

 

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