Safety Alerts

Restrictions on the use of codeine-containing products in children and adolescents

Audiences

Healthcare professional

Industry member

Product type

Therapeutic Products

20 December 2016

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Background

HSA first issued an interim safety update in 2014 to healthcare professionals which summarised the overseas recommendations on the use of codeine-containing products for pain relief in paediatric patients. It also informed healthcare professionals that HSA would be conducting a comprehensive review of such products in Singapore for pain relief and for the relief of cough symptoms in children.¹ Subsequently, a Dear Healthcare Professional Letter was issued in July 2016 regarding new restrictions on the use of codeine-containing products in order to reduce the risk of death and respiratory depression in infants and children.² This article serves as a reminder on the restrictions for the use of codeine-containing products.

Codeine has been registered in Singapore since 1989 for the treatment of pain and the relief of cough and cold. Locally, there are seven registered codeine-containing products indicated for pain and 22 codeine-containing products indicated for the relief of cough and cold in children and adolescents. They are available in various dosage forms such as tablets, syrups and injections.

International regulatory actions

In February 2013, the US Food and Drug Administration (US FDA) issued its recommendation to contraindicate the use of codeine for postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy. The US FDA also strengthened the product information with warnings regarding deaths and respiratory depression, following a safety review of codeine. The review considered reports of deaths and respiratory depression in young children aged 2 to 5 years old who had received codeine following tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome.³ It found that these children had evidence of being “ultra-rapid metabolisers” of substrates of CYP2D6, including codeine, and might have been particularly sensitive to the respiratory depressant effects of codeine, due to increased conversion of codeine to morphine, and especially as they already had underlying breathing problems. However, the contraindication applies to all children below 18 years old undergoing tonsillectomy and/or adenoidectomy because it is not easy to identify ultra-rapid metabolisers of codeine. In June 2013, the European Medicines Agency (EMA) contraindicated the use of codeine for postoperative pain management in children and adolescents below 18 years of age who have undergone tonsillectomy and/or adenoidectomy.⁴

In April 2015, following further review of the use of codeine-containing products for relief of cough and cold in children, the EMA contraindicated the use of codeine-containing products for cough and cold in children under 12 years old in view of the serious adverse events such as deaths and respiratory depression, and limited efficacy data in this age group.⁵Evaluation of the use of codeine-containing products for relief of cough and cold in children by the US FDA is still ongoing.⁶

In July 2016, Health Canada announced that codeine is contraindicated in patients under 18 years old for the treatment of post-surgical pain following tonsillectomy and adenoidectomy due to the increased risk of serious breathing problems. Codeine is already not recommended for children younger than 12 years old.⁷

HSA’s benefit-risk assessment and advisory

To date, HSA has received five local reports of respiratory adverse events (AE) such as dyspnoea and bronchospasm in children between 9 to 16 years old associated with the use of codeine-containing cough products. No death or severe respiratory depression has been reported locally.

Taking into consideration the current available scientific evidence, input from local clinical experts, local and overseas AE reports, the potential for serious and fatal AEs in the local population and international regulatory actions, HSA has reviewed the benefits versus the risks of codeine and is recommending the following restrictions on the use of codeine-containing products in Singapore:

Codeine is not recommended for the treatment of post-operative pain following surgical procedures such as tonsillectomy/adenoidectomy in children and adolescents below 18 years old due to the increased risk of respiratory depression.
For treatment of unproductive cough and treatment of acute moderate pain not relieved by analgesics, codeine remains indicated for those 12 years old and above. The lowest effective dose should be used for the shortest possible duration.
Caution is advised when codeine is used in children with underlying respiratory conditions, including those with asthma and other chronic breathing problems.
Parents and caregivers should be advised on the possible signs and symptoms of respiratory depression in their children, such as unusual sleepiness, confusion and difficult or noisy breathing, and to seek immediate medical attention if these are observed.
Nursing mothers should also be advised to exercise caution when taking codeine as codeine’s metabolite (morphine) may subsequently be found in the breast milk. If the infant shows signs of increased sleepiness, difficulty when breastfeeding, breathing difficulties or limpness, immediate medical attention should be sought.

HSA is working with the companies of codeine-containing products to update their local package inserts with the new restrictions.

Healthcare professionals are encouraged to take into consideration the above recommendations when prescribing codeine. They are also encouraged to report any suspected serious adverse events related to codeine to the Vigilance and Compliance Branch of HSA.

Restrictions on the use of codeine-containing products in children and adolescents

Background

International regulatory actions

HSA’s benefit-risk assessment and advisory

References

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