Di-Gesic and Doloxene decision: safety implications for health professionals

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Practice points | TGA cancellation overturned after lengthy appeal | Dextropropoxyphene safety concerns | The AAT and the Australian regulatory actions | Information for patients | References


After a lengthy appeal against the TGA's decision to cancel dextropropoxyphene-containing analgesics from the ARTG, the Australian Administrative Tribunal (AAT) has concluded that Di-Gesic and Doloxene should remain on the register subject to new conditions.

Prescribers and patients should be aware of the the safety concerns associated with dextropropoxyphene, including the risk of arrhythmic disorders and possible death after overdose.

New conditions imposed by the AAT will require prescribers to complete a Prescriber Confirmation form acknowledging that these risks have been mitigated. Pharmacists will be required to sight the completed form before the first dispensing of Di-Gesic or Doloxene.

Practice points

  • Dextropropoxyphene-containing products have been associated with cardiac conduction abnormalities (prolonged QT, PR and QRS intervals) that may lead to life threatening arrythmias.
  • They are contraindicated in older people and those with known abnormal QT interval, a history of cardiovascular disease, decreased kidney function or history of depression or mental illness.1,2
  • Only two dextropropoxyphene-containing analgesics are registered in Australia — Di-Gesic and Doloxene.
  • From early 2014 a first-time prescription of Di-Gesic or Doloxene will require completion of a Prescriber Confirmation form indicating that adequate pain relief cannot be provided by an alternative analgesic, and that both the prescriber and patient understand the risks associated with dextropropoxyphene-containing analgesics.3
  • Pharmacists must sight this signed form before dispensing a first supply of dextropropoxyphene-containing analgesics.3
  • Monitor patients undergoing chronic treatment with a dextropropoxyphene-containing analgesic with a kidney function test and ECG at baseline and periodically at least every 3 months.1,2 Immediately stop dextropropoxyphene if there is significant decline in kidney function and/or abnormal ECG results are observed.1,2
  • For patients currently using dextropropoxyphene-containing products, review analgesic requirements. If analgesia is still required consider switching treatment with alternative analgesia. (See the NPS fact sheet Alternatives to dextropropoxyphene for analgesia.)
  • If stopping dextropropoxyphene, be aware that some patients may experience a withdrawal reaction (nausea, tremor, agitation, insomnia, diaphoresis, fever) — this can be avoided by slowly reducing the daily intake. Seek specialist advice if symptoms occur.

TGA cancellation overturned after lengthy appeal

In December 2011 the TGA announced a decision to withdraw all analgesics containing dextropropoxyphene from the ARTG, after finding the safety and efficacy of such medicines to be unacceptable.4 Accordingly, in March 2012 two products containing dextropropoxyphene, Capadex and Paradex, became unavailable in Australia.5

However, the manufacturer of two other dextropropoxyphene-containing analgesics, Di-Gesic (dextropropoxyphene with paracetamol) and Doloxene (dextropropoxyphene), lodged an appeal against the TGA decision with the Administrative Appeals Tribunal (AAT) based on the assertion that these were suitable to treat a small number of people not adequately managed on other analgesics.3

Since the initial announcement in December 2011, the TGA has twice reaffirmed its assessment that dextropropoxyphene-containing products pose unacceptable risks.3,6

In April 2013 the AAT concluded that the quality, safety and efficacy of Di-Gesic and Doloxene were not unacceptable, provided that additional conditions and monitoring arrangements are imposed.3 New prescribing and supply processes are expected to be in place in early 2014.7

Dextropropoxyphene safety concerns

The TGA's decision to cancel dextropropoxyphene-containing analgesics from the ARTG followed similar decisions by US, European and New Zealand regulators.4

Concerns about risk of overdose and suicide prompted withdrawal of dextropropoxyphene-containing medicines in the UK in 20058 and in the EU in 2009.9

The decision to withdraw dextropropoxyphene-containing analgesics from the US and Australian markets followed the emergence of additional data of an effect of dextropropoxyphene on cardiac conduction abnormalities, increasing the risk of arrhythmia.10

A US study, requested by the FDA10 and performed in healthy subjects, reported that dextropropoxyphene administered at the maximum approved dose was sufficient to cause significant QT-interval prolongations at a level considered to be pro-arrhythmic. Dose-dependent prolongation of the PR and QRS intervals was also observed.

Older people and those with declining kidney function are considered to be particularly susceptible to these pro-arrhythmic effects due to reduced clearance of dextropropoxyphene and its metabolites.10

Dextropropoxyphene in acute overdosage is highly toxic; the difference between a therapeutic amount and a potentially fatal dose is smaller than for most other medicines.3,7 Furthermore, dextropropoxyphene in combination with alcohol, tranquillisers, sedative–hypnotics, antidepressants and other CNS depressants is known to have additive depressant effects.1,2

A UK study assessing suicide due to poisoning in the period following withdrawal of the dextropropoxyphene-containing drug co-proxamol suggested a reduction in deaths due to dextropropoxyphene poisoning that did not result in increased deaths due to poisoning with other drugs.11

(See Contraindications for Di-Gesic and Doloxene.)

There is no evidence that dextropropoxyphene is any more effective for pain relief than paracetamol alone.12,13 Therefore the safety risks associated with use of dextropropoxyphene are considered to outweigh any benefits.

The AAT and the Australian regulatory actions

After the TGA's announcement in late 2011 that all dextropropoxyphene-containing analgesics would be cancelled from the ARTG, the pharmaceutical sponsor responsible for marketing in Australia two of the products subject to the cancellation decision, Di-Gesic and Doloxene, launched an appeal with the AAT.

In February 2012, the AAT granted a stay on the cancellation of Di-Gesic and Doloxene,3 conditional on changes made to Product Information and Consumer Medicines Information.6 These included:

  • strong warnings that patients should not be started on these products
  • a description of the safety risks
  • a narrowed indication for use to 'relief of mild to moderate pain in patients who do not respond adequately to other analgesics'.6

After hearing the appeal in May 2012 the AAT referred the decision back to the TGA to attempt to reach an agreement between the TGA and the sponsor. However, after subsequent review the TGA confirmed its position that the safety and efficacy of dextropropoxyphene-containing products was unacceptable, and found the sponsor's proposals to address the safety issues to be unsatisfactory.5

After further review in April 2013, the AAT issued a determination that the safety and efficacy of Di-Gesic and Doloxene were not unacceptable, provided that their availability is subject to certain prescribing and monitoring arrangements.3

These conditions were formalised by AAT in an announcement on 12 September 2013 and took effect from 10 October 2013. The new processes are expected to be in place in early 2014; that is, 60 days after the new PI is approved.3

How the conditions around Di-Gesic and Doloxene affect health professionals3

Australian prescribers will be supplied a Prescriber Confirmation form, which must be signed by the prescriber, acknowledging the following:

  • the drug is only approved for use in patients who are not able to be adequately treated with other mild analgesics
  • the contraindications outlined in the PI have been considered
  • any recent changes to the patient's clinical presentation and biochemical status have been considered
  • the patient has been warned about appropriate use of the product
  • the patient's history does not indicate that the patient is at risk of accidental or intentional self-harm.

By ordering Di-Gesic or Doloxone, Australian pharmacies opt-in to a supply arrangement with the sponsor that requires them to:

  • sight a signed Prescriber Confirmation form before first-time dispensing of these products (but not for repeats).
  • provide documentation to the sponsor on request, as part of periodic audits, demonstrating that the dispensing conditions have been met.

An updated CMI will be included in each pack. Printed copies of the CMI and a separate Patient Information leaflet will be provided to pharmacies by the sponsor on request.

Information for patients

Di-Gesic and Doloxene are only approved for use by a small number of patients who do not achieve adequate relief with other painkillers.

Do not take more than the recommended dose, as even a small overdose can be fatal. Do not combine Di-Gesic or Doloxene with alcohol, antidepressants, tranquillisers, sedative–hypnotics or other central nervous system depressants.

Products containing dextropropoxyphene have been associated with abnormal heart rhythms. Do not take these products if you have a heart condition.

Do not take Di-Gesic or Doloxene if you are older than 70, have kidney problems, or a history of depression or mental illness, or have in the past had thoughts of suicide.

If you experience any of the following symptoms while taking either Di-Gesic or Doloxene, stop the medicine and seek medical assistance:3,14,15

  • fainting
  • dizziness with shoulder pain
  • chest pain
  • light-headedness
  • irregular heart beats or palpitations
  • jaundice, yellowing of the skin or eyes
  • fits
  • psychoses, abnormal thought processes.
  1. Aspen Pharmacare. Di-Gesic Product Information. 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06769-3 (accessed 25 September 2013).
  2. Aspen Pharmacare. Doloxene Product Information. 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-07775-3 (accessed 25 September 2013).
  3. Administrative Appeals Tribunal of Australia. Aspen Pharmacare Australia Pty Ltd and Minister for Health and Ageing [2013] AATA 649. 2013. http://www.austlii.edu.au/au/cases/cth/aat/2013/649.html (accessed 19 September 2013).
  4. Australian Government Department of Health and Ageing, Therapeutic Goods Administration. TGA to cancel four prescription pain-killers from 1 March 2012. 2011. http://www.tga.gov.au/newsroom/media-2011-dextropropoxyphene-111122.htm (accessed 19 September 2013).
  5. Australian Government Department of Health and Ageing, Therapeutic Goods Administration. Update on TGA decision to cancel prescription pain-killers, 8 November 2012. 2012. http://www.tga.gov.au/newsroom/media-2012-dextropropoxyphene-121108.htm (accessed 25 September 2012).
  6. Australian Government Department of Health and Ageing, Therapeutic Goods Administration. Update on TGA decision to cancel four prescription pain-killers, 17 February 2012. 2012. http://www.tga.gov.au/newsroom/media-2012-dextropropoxyphene-120217.htm (accessed 25 September 2013).
  7. Australian Government Department of Health and Ageing, Therapeutic Goods Administration. Update on TGA decision to cancel prescription pain-killers, 19 September 2013. http://www.tga.gov.au/newsroom/media-2013-dextropropoxyphen-130919.htm (accessed 25 September 2013).
  8. Medicines and Healthcare Products Regulatory Agency (MHRA). MHRA withdraws the pain killer co-proxamol. 2005. http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON002065 (accessed 30 September 2013).
  9. Medicines and Healthcare Products Regulatory Agency (MHRA). European Medicines Agency (EMEA) recommends withdrawal of dextropropoxyphene-containing medicines (including co-proxamol). 2009. http://www.mhra.gov.uk/NewsCentre/CON049300 (accessed 25 September 2013).
  10. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA recommends against the continued use of propoxyphene. 2010. http://www.fda.gov/Drugs/DrugSafety/ucm234338.htm (accessed 25 September 2013).
  11. Hawton K, Bergen H, Simkin S, et al. Six-year follow-up of impact of co-proxamol withdrawal in England and Wales on prescribing and deaths: time-series study. PLoS Med 2012;9:e1001213. [PubMed]
  12. Li Wan Po A, Zhang WY. Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. BMJ 1997;315:1565–71. [PubMed]
  13. Thompson IM, Jr, Goodman PJ, Tangen CM, et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med 2013;369:603–10. [PubMed]
  14. Aspen Pharmacare. Di-Gesic Consumer Medicine Information. 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-CMI-06768-3 (accessed 25 September 2013).
  15. Aspen Pharmacare. Doloxene Consumer Medicine Information. 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-CMI-07776-3 (accessed 25 September 2013).