BETHESDA, MD 17 August 2012—FDA on Wednesday announced that three children with evidence of ultrarapid codeine metabolism died after undergoing surgery for obstructive sleep apnea syndrome and receiving doses of the morphine precursor "within the typical dose range."

The agency called attention to the particular risk of codeine-related breathing problems and death in children who have undergone tonsillectomy or adenoidectomy for obstructive sleep apnea syndrome and whose cytochrome P-450 isoenzyme (CYP) 2D6 converts codeine to morphine at an ultrarapid rate.

Health care professionals who order codeine-containing drugs for these children, the agency advised, should prescribe the lowest effective dose for the shortest period of time and on an as-needed basis.

FDA also suggested that health care professionals consider prescribing analgesics other than codeine for children who have undergone tonsillectomy or adenoidectomy to treat obstructive sleep apnea syndrome.

Reports on the children at the heart of FDA's announcement first appeared in the medical literature.

In 2009, the New England Journal of Medicine published a letter (PDF) about a two-year-old, 13-kg boy who had undergone adenotonsillectomy to treat sleep apnea and snoring. The instructions for analgesia at home were codeine 10–12.5 mg and acetaminophen 120 mg every four to six hours as needed. On the second evening after the outpatient surgery, the boy had a fever and was wheezing; by morning he was dead. Genotypic analysis provided evidence that the boy was an ultrarapid metabolizer of codeine and other CYP2D6 substrates.

The May 2012 issue of Pediatrics had a case report on four- and five-year-old boys who had undergone adenotonsillectomy at different facilities to treat obstructive sleep apnea syndrome or snoring. For the four-year-old boy, who weighed 27.6 kg, the instruction for analgesia at home was codeine 8 mg up to five times a day. He died two days after discharge from the hospital; he had received four doses of codeine at home. Genotypic analysis revealed he was an ultrarapid metabolizer. For the five-year-old boy, who weighed 29 kg, the instruction for analgesia at home was codeine 12 mg with acetaminophen every four hours. He was dead 24 hours after surgery. Pharmacokinetic modeling of his codeine intake and postmortem codeine and morphine blood concentrations suggested the boy was an ultrarapid metabolizer.

FDA said it was reviewing additional safety-related reports to determine if other children receiving codeine have died or inadvertently overdosed and whether these events occurred after surgery.