Regulatory Focus™ > News Articles > FDA Finalizes Boxed Warning for Codeine Product Associated with Pediatric Deaths

FDA Finalizes Boxed Warning for Codeine Product Associated with Pediatric Deaths

Posted 20 February 2013 | By Alexander Gaffney, RAC

US regulators have announced that prescription codeine will now be required to contain a boxed warning contraindicating its use in children who have just undergone a tonsillectomy procedure, saying that deaths and injuries have occurred after some children ultra-rapidly metabolized the drug into morphine.

FDA's 20 February 2013 warning follows a preliminary one made in August 2012, in which it said that the drug has been associated with the deaths of at least three children in post-operative settings.

Those deaths were preliminarily attributed to how the drug is broken down in the bodies of some children, regulators said.

"The agency is warning the public that this danger exists for some children whose livers convert codeine to morphine in higher than normal amounts," FDA wrote. FDA said it estimated between one and seven in every 100 children is a so-called "ultra-rapid metabolizer," but estimates vary depending on the ethnic group involved. An estimated 29% of Ethiopian children are ultra-rapid metabolizers, while just 1-2% of northern European children are.

Genetic testing is available to determine if a child is an ultra-rapid metabolizer, and FDA has cleared several such tests through its 510(k) premarket notification pathway.

But the new warning answers what wasn't known at the time: what actions FDA would take to mitigate the drug's risks in this population. The answer: a new Boxed Warning.

The warning, FDA's strongest without resorting to more restrictive control schemes under Risk Evaluation and Mitigation Strategies (REMS), will also be supported by updated information regarding the drug's contraindications, pediatric use, and patient counseling information.

In addition, products containing codeine will now be restricted from having so-called "reminder ads," which are sometimes used to implore people to, "Ask your doctor about [drug name]." Those ads omit any safety or efficacy warnings about the drug, and are therefore not appropriate, FDA said.

Health care professionals are being advised by FDA to prescribe other analgesics for post-operative pain.


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