Thank you for the opportunity to speak today. My name is Dr. Tracy Rupp: I was previously a clinical pharmacist and pediatric nutritionist at Duke University Medical Center and am now the Director of Public Health Policy Initiatives at the National Center for Health Research. Our research center analyzes scientific and medical data and provides objective health information to patients, providers and policy makers. We do not accept funding from the drug or medical device industry and I have no conflicts of
interest.
We strongly support access to safe and effective medications for children. Codeine is one of the most widely prescribed opioids and is frequently chosen because it is perceived to have a wide margin of safety. Over the past decade, however, serious concerns have been raised about its safety in children.
As we have heard today, the safety risks with codeine are largely due to the substantial variability in how it is metabolized. One study found oral codeine led to a 20-fold higher morphine exposure in extensive metabolizers, the most common genetic variation, compared to poor metabolizers.[1] Ultrametabolizers experience the highest risk of harm from codeine, since they can have morphine levels almost 50% higher than extensive metabolizers.[2] Children who are ultra-metabolizers can convert too much of their codeine dose to morphine, with catastrophic consequences, including death. Unfortunately, physicians usually don’t know how fast a child will metabolize codeine before prescribing it.
From the information presented today, we have learned that the risks of codeine outweigh the benefits for children. A review of the FDA Adverse Event Report System found that most cases of respiratory depression and 21 of 24 deaths occurred in children less than 12 years of age. Cough and pain were two of the most common reasons for use of codeine in these children.
Since the safety and effectiveness of codeine is unpredictable in children, even when prescribed correctly:
- The World Health Organization has removed codeine from its list of essential
medicines for pain in children. They note that acetaminophen or ibuprofen may be
just as effective for musculoskeletal pain but without the same risks. - The AAP cautions about the lack of evidence for the safety and effectiveness
of opioids like codeine for cough; and the American College of Chest Physicians
states that children may experience significant morbidity and mortality with the
use of cough suppressants. - The European Medicines Agency has stated that codeine is contraindicated
for cough and pain in children less than 12 years of age and in women who are
breastfeeding.
We strongly urge the FDA to require labeling that states that codeine is contraindicated for cough and pain in children less than 12 years of age.
We also strongly urge the FDA to remove codeine from the OTC monograph. To be marketed as an OTC drug, a drug must be generally recognized as safe and effective. Nearly half of the states already recognize that codeine is not safe enough for over-the-counter status. The children in the other states deserve the same protection by removing codeine from the OTC monograph.
Lastly, we strongly urge the FDA to require prescription codeine labeling to state that codeine is contraindicated in women who are breastfeeding. Codeine is currently one of the most commonly prescribed opioids for women after cesarean section births. Many providers appear to be unaware of the risks of prescribing codeine to these women. At least one infant has died after receiving a lethal dose of opioid from his mother’s breast milk. Many other safer pain relief options are available. Thank you for the opportunity to comment today and for consideration of our views.
References
- Yue QY, Hasselstrom J, Svensson JO, Sawe J. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers; comparisons between extensive and poor hydroxylators of debrisoquine. British Journal of Clinical Pharmacology 1991; 31(6):635- 642.
- Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. The Pharmacogenomics Journal 2007; 7(4):257-265.