Safety Alerts

Overseas recommendations on the use of codeine-containing products for pain relief in paediatric patients

Audiences

Healthcare professional

Industry member

Product type

Therapeutic Products

29 August 2014

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HSA would like to provide an interim update on the new contraindication and precautionary recommendations issued by the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and Health Canada on the use of codeine-containing products in paediatric patients for pain relief. EMA is also separately reviewing the use of codeine-containing preparations used for cough or cold in children,¹ and its recommendations are expected at the end of 2014. HSA is currently reviewing the use of codeine-containing preparations in children in totality, covering both pain relief as well as cough suppression for the relief of unproductive cough and will advise our healthcare professionals on the recommendations relevant to our local context in due course.

Background

In August 2012, the US FDA reviewed the use of codeine following reports of three deaths and a case of severe respiratory depression in young children (aged 2 to 5 years old) who received codeine following tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome.² These children had evidence of being “ultra-rapid metabolisers” of substrates of CYP2D6, which include codeine, and they may have been particularly sensitive to the respiratory depressant effects resulting from the increased conversion of codeine to morphine. Data from the US FDA’s Adverse Event Reporting System database, from 1999-2012, identified a further 10 cases of paediatric death and three cases of drug overdose associated with codeine use. Of these, three were ultra-rapid metabolisers, three were extensive metabolisers and one was a likely ultra-rapid metaboliser. Eight of the cases involved adenotonsillectomy.³ In August 2007, the US FDA reported the death of a healthy breast-fed 13-day-old baby, whose mother was taking a low dose of codeine for episiotomy pain. The mother was found to be an ultra-rapid metaboliser of codeine and the baby was shown to have high blood levels of morphine which was consumed through breast milk.⁴

Recommendations by US FDA and other regulatory authorities

Following its review of the safety profile of codeine, the US FDA enhanced the label warnings regarding the use of codeine in paediatric patients. Subsequently, other regulatory agencies such as the EMA and Health Canada announced similar recommendations on restricting the use of codeine for pain relief in children. Table 1 summarises the new label recommendations by the US FDA, EMA and Health Canada.

Table 1. New label recommendations by overseas agencies

Table caption

	US FDA³	EMA⁵	Health Canada⁶
Post-operative pain after tonsillectomy and/or adenoidectomy	Contraindicated in all children (≤ 17 years old)	Contraindicated in patients < 18 years old	Not recommended in patients < 12 years old regardless of clinical setting
General management of other types of pain	Use only if benefits outweigh risks	≤ 12 years old: Not recommended >12 years old: Restrict to treatment of acute moderate pain not relieved by other analgesics (e.g., paracetamol, ibuprofen)
Other recommendations	Closely monitor children for signs of morphine overdose (e.g., unusual sleepiness, confusion, difficult or noisy breathing), and seek medical attention immediately if these signs are observed	Children with breathing problems should not use codeine Codeine should not be used by nursing mothers Codeine should not be used by people of any age who are known to be ultra-rapid metabolisers	Caution is advised when codeine is administered to nursing mothers

US FDA³

EMA⁵

Health Canada⁶

Post-operative pain after tonsillectomy and/or adenoidectomy

Contraindicated in all children (≤ 17 years old)

Contraindicated in patients < 18 years old

Not recommended in patients < 12 years old regardless of clinical setting

General management of other types of pain

Use only if benefits outweigh risks

≤ 12 years old: Not recommended

>12 years old: Restrict to treatment of acute moderate pain not relieved by other analgesics (e.g., paracetamol, ibuprofen)

Other recommendations

Closely monitor children for signs of morphine overdose (e.g., unusual sleepiness, confusion, difficult or noisy breathing), and seek medical attention immediately if these signs are observed

Children with breathing problems should not use codeine

Codeine should not be used by nursing mothers

Codeine should not be used by people of any age who are known to be ultra-rapid metabolisers

Caution is advised when codeine is administered to nursing mothers

Local situation

To date, HSA has not received any local adverse event report of respiratory depression associated with the use of codeine in children. HSA is embarking on a review of codeine-containing preparations in Singapore for pain relief as well as the relief of cough symptoms in children, taking into account the recommendations made by international regulatory agencies. In the meantime, healthcare professionals are advised to exercise caution when codeine is administered to paediatric patients. HSA will provide an update on the outcome of our review when it is completed.

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Overseas recommendations on the use of codeine-containing products for pain relief in paediatric patients

Background

Recommendations by US FDA and other regulatory authorities

Table 1. New label recommendations by overseas agencies

Local situation

References

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