FDA seeks input on genotyping for pediatric codeine use

Regulatory NewsRegulatory News | 26 June 2020 |  By 

The US Food and Drug Administration (FDA) is seeking public consultation on whether children under the age of 12 years should be permitted to receive analgesics containing codeine, if they have been cleared from having a genetic tendency to metabolize the drug at potentially toxic levels.
Currently, the use of products containing codeine is contraindicated in children under the age of 12. Codeine, an opioid indicated for relief of mild to moderate pain under some circumstances for adults, is partially metabolized to morphine through the liver’s CYP2D6 pathway. However, individuals vary greatly in their CYP2D6 metabolism of codeine. Those who are poor metabolizers may not receive sufficient analgesia, whereas so-called “ultra-rapid metabolizers” may experience opioid-related toxicity because of rapid elevation in serum morphine levels after administration of codeine.
The request for consultation was prompted by a citizen petition submitted by clinical pharmacologists and pharmacogeneticists who asked that the current contraindication to the use of codeine-containing products for those aged less than 12 years be amended to permit the use of these products in those known to be normal or intermediate CYP2D6 metabolizers.
The petitioners noted that preparations containing codeine and acetaminophen are classified as Schedule III in the Controlled Substances Act and are therefore able to be prescribed by telephone, whereas other opioid analgesics suitable for treating pain in this age group are Schedule II medications, which cannot be prescribed by telephone. “The Petitioners suggest that the current contraindication may cause children under 12 years of age with recurrent acute pain to have decreased access to opioid analgesics, which may result in more emergency department and urgent care visits,” wrote FDA.
The current contraindication was preceded by a 2013 European Medicines Agency (EMA) determination that codeine should not be used in those under 12 years, and should also be avoided for tonsillectomy and/or adenoidectomy in children under 18 years of age, and in breastfeeding women known to be ultra-rapid metabolizers. (RELATED: EU Committee Wants Additional Restrictions on Codeine Use in Children, Regulatory Focus, 16 March 2015)
Following a 2015 joint meeting of its Pulmonary and Allergy Drugs and the Drug Safety and Risk Management Advisory Committees, FDA issued a Safety Labeling Change notification letter advising of the risk of respiratory depression that could be life-threatening in children receiving codeine, or breast-feeding infants whose mothers received codeine. The notification letter contained the contraindication for use of codeine in those under 12 and a warning for children aged 12 to 18 with risk factors for respiratory depression. The supplements submitted in response to the notification letter and updated labeling were approved in August 2017.
In its solicitation of information and commentary from stakeholders, FDA is also asking for commentary on a broader swath of pertinent topics, including factors to consider in prescribing opioid analgesics for children under 12 years of age; which pediatric populations use these medications; the role, if any a codeine-acetaminophen preparation in this age group, and other clinical and prescribing questions. The agency also is seeking input from technical experts and prescribers regarding experience with CYP2D6 genotyping, details of detection of ultra-rapid metabolizers, and clinical utility of the tests. Finally, FDA is asking for information regarding e-prescribing of schedule II opioids, which may afford some opportunity to mitigate the current difficulty in accessing acute pain relief for children without necessitating a clinic or emergency department visit.



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