Codeine in children — deaths prompt new safety warnings

Published in Health News and Evidence

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Practice points | New international guidance for codeine in children | Codeine not recommended for children under 12 years | FDA safety review identifies 10 fatal cases of respiratory depression | Ultra-rapid metabolisers — increased risk but difficult to identify | NSAIDs safe to use after tonsillectomy | TGA reviewing Australian data | The tip of the iceberg? | References


Safety concerns have arisen over use of codeine and codeine-containing medicines in children after reports of respiratory depression, including some fatalities. New guidelines and contraindications have been issued by international regulatory bodies, including the FDA, EMA and MHRA following safety reviews. The TGA is aware of the actions of other regulators and is continuing to review the available information to determine whether any action is required in Australia.

Practice points

When prescribing codeine, consider the following new international guidance.

  • Do not use codeine to treat pain in children aged under 18 after tonsillectomy and/or adenoidectomy. Consider alternative analgesics.1–4
  • Only use codeine to treat moderate pain of short duration in children over 12 years and only if it cannot be relieved by other analgesics such as paracetamol or ibuprofen.1,2
  • Do not use codeine in adults or children known to be ultra-rapid metabolisers of codeine.1,2
  • If codeine is prescribed, use the lowest dose for the shortest time possible.1 Avoid round-the-clock dosing.5
  • If codeine is prescribed, advise parents or carers to monitor for signs of morphine toxicity (such as unusual sleepiness, confusion, small pupils, nausea or vomiting, constipation, lack of appetite or difficult or noisy breathing) and seek immediate medical attention if these occur.2,5
  • Report adverse events to the TGA.

New international guidance for codeine in children

Respiratory depression and death are adverse events that cause the most concern when considering opioid use.6 To ensure codeine is only used when the benefits outweigh the risks, new guidance has been issued by international regulatory bodies, including the FDA, EMA and MHRA.1,2,4 This guidance follows safety reviews prompted by case reports of deaths and near fatal respiratory depression after the use of codeine in children and nursing babies.1,4,7–9

Updated guidance from FDA, EMA and MHRA

  • The EMA and MHRA have contraindicated codeine for all children under 12 and for children up to 18 years for pain relief after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome.1,2
  • Due to uncertainty about which children may be most affected, the FDA has contraindicated the use of these medicines in children under 18 undergoing tonsillectomy and/or adenoidectomy for any cause.3,4
  • If prescribing codeine-containing medicines for children aged 12–18 use the lowest effective dose for the shortest period of time.1 Treat for a maximum of 3 days and if no effective pain relief is observed, review management.2
  • These medicines are not recommended in any child whose respiratory function may be compromised (such as those with neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections) and they are contraindicated in patients known to be codeine (CYP2D6 substrate) ultra-rapid metabolisers.1,2
  • The efficacy of codeine for pain relief is not significantly better than that of non-opioid pain killers such as paracetamol or ibuprofen;1 because of the identified risks other analgesics should be used when possible.10

Codeine not recommended for children under 12 years

The EMA safety review concluded that codeine and codeine-containing medicines should only be used to treat moderate pain of short duration in children over 12 years of age, and only if the pain cannot be relieved by other painkillers such as paracetamol or ibuprofen.1

This recommendation reflects limited data about the pharmacokinetic profile of codeine in children.1 Data reviewed by the EMA suggests that children under 12 have a reduced ability to metabolise codeine and that while morphine-associated adverse events could affect people of any age, children under 12 appear to be at the greatest risk.1

In children aged 12–18 the MHRA recommend a maximum daily codeine dose of 240 mg, which can be taken in divided doses up to four times a day at 6-hour intervals.2 Current Australian guidance advises up to 240 mg/day at intervals of 4–6 hours.11

FDA safety review identifies 10 fatal cases of respiratory depression

The FDA safety review identified 13 cases of respiratory depression in children aged from 21 months to 9 years — 10 fatal cases and three life-threatening cases. 9 Eight of the 13 cases occurred after adenotonsillectomy, while three occurred in children treated for a respiratory tract infection.9 One nursing infant whose mother was an ultra-rapid codeine metaboliser also died.4

Obstructive sleep apnoea is the most common form of sleep breathing disorder.11 It is commonly diagnosed in overweight middle aged men but is estimated to affect about 1–4% of children.11

As children who require tonsillectomy for obstructive sleep apnoea have breathing problems3 they may be particularly sensitive to codeine-related respiratory adverse effects.3,12

Ultra-rapid metabolisers — increased risk but difficult to identify

The level of analgesia from codeine varies considerably from person to person due to variability in expression of the enzyme CYP2D6, which converts codeine to morphine.12

Ultra-rapid metabolisers convert more codeine into morphine and are at increased risk of adverse events such as morphine toxicity.1,9,11 Indeed, many international children's hospitals have removed codeine from their formularies because of the risks of adverse events in ultra-rapid metabolisers.11

Many, but not all, of the published and/or reviewed cases of fatal and life-threatening respiratory depression occurred in children who were shown, or suspected, to be ultra-rapid codeine metabolisers.1,3,4,7–9,12,13 Most patients will not know, and it is difficult to determine, which children are ultra-rapid metabolisers.5

Extensive (normal) codeine metabolisers are also at risk of respiratory depression.9,12 Therefore the contraindications should apply to all children under 18 years requiring pain management after tonsillectomy and/or adenoidectomy, and alternate analgesics are recommended for these children.1–3

NSAIDs safe to use after tonsillectomy

Guidelines advise that ibuprofen can be used safely for pain control after tonsillectomy.14

Despite concerns that use of NSAIDs increases the risk of bleeding after tonsillectomy, a recent Cochrane Review showed that there was no evidence for withholding NSAIDs (as a class of drugs) after this procedure.15

NSAIDs do not increase clinically significant bleeding after tonsillectomy but reduce nausea and vomiting compared with placebo or other analgesics.15

TGA reviewing Australian data

Current Australian guidance does not reflect the new international recommendations; guidance for use of prescription only codeine and codeine-containing medicines available in Australia is summarised in Table 1.

Table 1. Guidance for use in children of prescription-only codeine and codeine-containing medicines available in Australia16–28

Brand name

Guidance for use in children

Actacode codeine linctus*

Not recommended for use in children without medical supervision; not suitable for children under 12

Codeine Phosphate*

Not suitable for use in children
under 12

Paracetamol/Codeine 500/30, Codapane Forte, Comfarol Forte, Codalgin Forte tablets, Dolaforte tablets, Panadeine Forte, Prodeine 15, Prodeine Forte

Can be given in reduced doses to children over age 7; not suitable for children under 7

Mersyndol Forte tablets

Not recommended for children
under 12

* Codeine phosphate
† Paracetamol and codeine phosphate
‡ Paracetamol, codeine phosphate and doxylamine succinate

In Australia a number of codeine-containing medicines are also available over the counter, including Painstop for Children Day-Time Pain Reliever Syrup and Painstop for Children Night-Time Pain Reliever Syrup (approved for ages ≥ 2 years).
(See for a complete list.)

In Australia opioids, including codeine, are indicated for treatment of moderate pain not adequately relieved by paracetamol and/or NSAIDs.11 The Australian Medicines Handbook does not recommend codeine use and suggests that if an opioid is needed, morphine may be more appropriate.29

In Australia codeine use in children is usually initiated or recommended by a specialist.29

Australia's Database of Adverse Event Notifications (DEAN) contains 14 cases of respiratory depression in people taking a codeine-containing medicine, including five fatal cases.§30

The TGA has confirmed they have received no reports of fatalities in children under 18 in Australia due to respiratory depression after taking codeine or a codeine-containing medicine, but have received one report of a 16-year-old boy who experienced non-fatal respiratory depression after taking codeine.

The TGA is aware of the actions of other regulators and is continuing to review the available information to determine whether any action is required in Australia.

Use of cough and cold medicines (including those containing codeine) is contraindicated in children under 6 and these medicines should only be given to children aged 6–11 on the advice of a doctor, pharmacist or nurse practitioner.31

Read more about the recommendations for cough and cold medicines in children.

§ Three of the 14 cases involved a single suspected medicine.

The tip of the iceberg?

Globally, reported cases may represent the tip of the iceberg for estimating the prevalence of opioid-induced respiratory depression in children, as most case studies do not reach the medical literature.12 The reported cases only represent very serious cases in which, without intervention, all the children would have died.12

Report adverse events to the TGA online or by using the 'Blue Card' distributed once a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website. Health professionals should also encourage patients to report adverse events.

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  2. Medicines and Healthcare Products Regulatory Agency. Drug safety update Codeine for analgesia: restricted use in children because of reports of morphine toxicity. 2013. (accessed 20 July 2013).
  3. U.S. Food and Drug Administration. FDA Drug Safety Communication: Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. 2013. (accessed 9 July 2013).
  4. U.S. Food and Drug Administration. Codeine Product Labeling Changes Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER). 2013. (accessed 10 July 2013).
  5. U.S. Food and Drug Administration. FDA Drug Safety Communication: Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death. 2012 (accessed 10 July 2013).
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  10. Medicines and Healthcare Products Regulatory Agency. Press release: MHRA confirms codeine not to be used in children under 12 years old. 2013. (accessed 9 July 2013).
  11. eTG complete [online]. Therapeutic Guidelines: Analgesics. Revised October 2012.
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  13. Goldman JL, Baugh RF, Davies L, et al. Mortality and major morbidity after tonsillectomy: etiologic factors and strategies for prevention. Laryngoscope 2013(Apr 17);doi:10.1002/lary.23926. [Epub ahead of print]. [PubMed]
  14. Baugh RF, Archer SM, Mitchell RB, et al. Clinical practice guideline: tonsillectomy in children. Otolaryngol Head Neck Surg 2011;144[1.Suppl):S1–30. doi:10.1177/0194599810389949. [PubMed]
  15. Cardwell M, Siviter G, Smith A. Non-steroidal anti-inflammatory drugs and perioperative bleeding in paediatric tonsillectomy updated 23 August 2010. Cochrane Database Syst Rev 2005:CD003591. [PubMed]
  16. Alphapharm Pty Ltd. Codapane Forte Product Information, updated 29 April 2013. (accessed 16 July 2013).
  17. Apotex Pty Ltd. Apo-paracetamol/codeine 500/30 (Paracetamol/Codeine 500/30) Product Information, updated 19 October 2012. (accessed 16 July 2013).
  18. Aspen Pharma Pty Ltd. Actacode codeine linctus (Actacode) Product Information, updated 20 February 2008. (accessed 16 July 2013).
  19. Aspen Pharma Pty Ltd. Codeine phosphate Product Information, updated 16 May 2012. (accessed 16 July 2013).
  20. Chemists' Own Pty Ltd. Dolaforte tablets Product Information, updated 30 November 2007. (accessed 16 July 2013).
  21. Fawns & McAllan Pty Ltd. Codalgin Forte tablets Product Information, updated 16 November 2012. (accessed 16 July 2013).
  22. Sanofi-aventis Australia Pty Ltd. Prodeine Forte Product Information, updated 18 July 2012. (accessed 16 July 2013).
  23. Sanofi-aventis Australia Pty Ltd. Prodeine 15 Product Information, updated 18 July 2012. (accessed 16 July 2013).
  24. Sanofi-aventis Australia Pty Ltd. Panadeine Forte Product Information updated 18 July 2012. (accessed 16 July 2013).
  25. Sanofi-aventis Australia Pty Ltd. Mersyndol Forte tablets Product Information, 18 July 2012. (accessed 16 July 2013).
  26. Sanofi-aventis Australia Pty Ltd. Comfarol forte Product Information 18 July 2012. (accessed 16 July 2013).
  27. Aspen Pharma Pty Ltd. Actacode linctus (Actacode) Consumer Medicine Information Updated October 2011. (accessed 30 July 2013).
  28. Aspen Pharma Pty Ltd. Codeine phosphate Consumer Medicine Information updated May 2012. (accessed 30 July 2013).
  29. Rossi S (ed). Australian Medicines Handbook, 2013. Adelaide: Australian Medicines Handbook Pty Ltd, 2013.
  30. Therapeutic Goods Administration Department of Health and Ageing. Database of Adverse Event Notifications. 2013. Available at: (accessed 18 July 2013).
  31. Therapeutic Goods Administration. Cough and cold medicines for children – changes. 26 November 2012. Australian Government, 2012. (accessed 24 May 2013).