Annotation of U.S. Food and Drug Administration (FDA) label information
for codeine
and CYP2D6
Summary
The FDA-approved drug label for codeine states in a black box warning that respiratory depression and death have occurred in children who received codeine following a tonsillectomy and/or adenoidectomy and who had evidence of being CYP2D6 ultra-rapid metabolizers. The label also states that deaths have occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were CYP2D6 ultra-rapid metabolizers.
Annotation
On April 20th 2017, the FDA released a safety announcement stating that they are restricting the use of codeine and tramadol in children, and recommending against the use of codeine and tramadol in breastfeeding mothers due to possible harm to their infants. Please refer to the link above for full details on the safety announcement.
Codeine is an opioid analgesic pro-drug, typically used for pain relief. It is metabolized by CYP2D6 into morphine, which is the active drug form.
Excerpts from the codeine drug label:
Respiratory depression and death have occurred in children who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine.
Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing).
Cytochrome P450 2D6 is the major enzyme responsible for conversion of codeine to morphine...
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the codeine drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.