Withdrawal of dextropropoxyphene in Australia

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From 1 March 2012, two of the four available dextropropoxyphene-containing products (Capadex and Paradex) will be unavailable in Australia. This follows an announcement from the Therapeutic Goods Administration (TGA) in December 2011 that all analgesics containing dextropropoxyphene will be withdrawn.[1]

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Reasons for withdrawal

The withdrawal follows an extensive review of the safety and efficacy of detropropoxyphene by the TGA. The review was prompted by a recent study that found dextropropoxyphene at therapeutic doses can cause significant changes to the electrical activity of the heart.
Based on this information and other safety data, the TGA decided that the overall risk of serious adverse reactions outweighed any benefits of dextropropoxyphene-containing medicines. Medicine regulators in the United States, Europe, New Zealand and elsewhere, have made similar decisions to remove dextropropoxyphene-containing medicines from the market.

Dextropropoxyphene has effects on the heart's electrical activity, increasing the risk of serious arrhythmias. These effects are more pronounced with high doses or overdoses. Other safety concerns include serious adverse drug reactions (e.g. hepatic reactions, hallucinations, abuse, withdrawal symptoms and hypoglycaemia), possible lethality after overdose, and risk of accumulation in patients with renal failure. The US Food and Drug Administration published new information about the effect of dextropropoxyphene on cardiac electrophysiology (QT interval) in 2010.[2]

There is no evidence that dextropropoxyphene in combination with paracetamol is any more effective than paracetamol alone.

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Recommendations for prescribers of Capadex or Paradex

  • Do not start dextropropoxyphene treatment for any new patients.
  • Inform patients taking Capadex or Paradex that their current analgesic is being withdrawn for safety reasons and that their treatment will need to be reviewed (see Alternatives).
  • Be aware that some patients may experience a withdrawal reaction (nausea, tremor, agitation, insomnia, diaphoresis, fever) if dextropropoxyphene is stopped abruptly — this can be avoided by slowly reducing the daily intake. Seek specialist advice if symptoms occur.
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Alternatives to dextropropoxyphene for analgesia

  • Review analgesic requirements — the need for analgesia may have changed.
  • Consider switching to paracetamol — there is no evidence that dextropropoxyphene in combination with paracetamol is any more effective than paracetamol alone.
  • If maximum daily dose paracetamol is insufficient, a low-dose NSAID (e.g. ibuprofen) may be added or used instead of paracetamol. NSAIDs should be used at the lowest possible dose for the shortest possible duration.
  • If NSAIDs are contraindicated, not tolerated or inadequate, consider a weak opioid (e.g. codeine) added to maximum daily dose paracetamol.
  • Strong opioids (e.g. oxycodone or tramadol) are not recommended as first-line alternatives to dextropropoxyphene.[3,4]
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Status of two remaining dextropropoxyphene containing products

The remaining two products, dextropropoxyphene (Doloxene) and paracetamol with dextropropoxyphene (Di-Gesic), will continue to be available pending an appeal by the supplier with the Australian Administrative Appeals Tribunal (AAT) but with stronger safety warnings and a narrower indication.[5]

The AAT is expected to hear the appeal towards the end of May 2012 and, depending on the result, Doloxene and Di-Gesic may become unavailable soon afterwards. However, as a consequence of the TGA decision the Department of Veterans' Affairs has withdrawn Doloxene from the Repatriation Pharmaceutical Benefits Scheme as of 1 March 2012.

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Recommendations for prescribers of Doloxene or Di-Gesic

  • For patients currently taking Doloxene or Di-Gesic advise that these may be withdrawn from the market at short notice and they may need to take an alternative analgesic.
  • Be aware that some patients may experience a withdrawal reaction (nausea, tremor, agitation, insomnia, diaphoresis, fever) if dextropropoxyphene is stopped abruptly — this can be avoided by slowly reducing the daily intake. Seek specialist advice if symptoms occur.
  • Be aware of the possibility of cardiac conduction abnormalities (prolonged QT, PR, and QRS intervals) and assess patients if they present with any signs or symptoms of arrhythmia.
  • Check renal function at least every 3 months for all patients taking dextropropoxyphene regularly.
  • Perform an electrocardiogram (ECG) at least every 3 months for all patients taking dextropropoxyphene regularly.[6]

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New contraindications for Doloxene and Di-Gesic

  • A history of depression or mental illness.
  • A history of clinically significant cardiovascular disease, heart failure, cardiac hypertrophy, arrhythmia or bradycardia.
  • A predisposition to hypokalaemia and/or hypomagnesaemia (caused by a condition or coadministered drug).
  • Significant hepatic impairment.
  • Prolonged QT interval (congenital or acquired).
  • Age > 70 years.
  • Creatinine clearance < 40 mL/min.
  • Concomitant use of drugs known to prolong QT interval (e.g. sotalol, haloperidol, amitriptyline, clomipramine, chlorpromazine, erthythromycin, clarithromycin, amiodarone) and alcohol.
  • Concomitant use of drugs that inhibit CYP3A4 (e.g. HIV antivirals, clarithromycin, itraconazole, ketoconazole).[6,7]
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More information

See NPS Prescribing Practice Review 35: Analgesic choices in persistent pain for further advice on analgesic selection and NPS Prescribing Practice Review 51: Opioids in chronic non-cancer pain: use a planned approach for updated information about opioid prescribing.

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References

  1. Australian Government Department of Health and Ageing Therapeutic Goods Administration. Australian Public Assessment Report for Vildagliptin (Galvus, Xiliarx). Submission No: PM-2009-00158-3-5. 2010. (accessed 12 May 2011).
  2. US Food and Drug Administration. FDA Drug Safety Communication: FDA recommends against the continued use of propoxyphene. 2010.  (accessed 27 February 2012).
  3. Australian Medicines Handbook, 2012.
  4. UK National Prescribing Center. The withdrawal of co-proxamol: alternative analgesics for mild to moderate pain. MeReC Bulletin 2006; 16. (accessed 27 February 2012).
  5. Therapeutic Goods Administration. Update on TGA decision to cancel four prescription pain-killers. 17 February 2012. (accessed 27 February 2012).
  6. Aspen Pharmacare. Di-Gesic Product Information. 2012. (accessed 5 December 2013).
  7. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine. 2011. (accessed 31 August 2011).