FDA Warns About Pediatric Codeine-Related Deaths

The Food and Drug Administration issued a warning on Aug. 15 about the risk of death in children who receive codeine for postoperative pain, particularly after tonsillectomy and/or adenoidectomy, based on three deaths and a nonfatal case of life-threatening respiratory depression.

The three children who died had evidence of being ultrarapid metabolizers of codeine, and the fourth case was in a child with evidence of being an "extensive" metabolizer, the FDA said in a statement announcing the warning. All four children, aged 2-5 years, underwent a tonsillectomy and/or adenoidectomy for treating obstructive sleep apnea syndrome, and received codeine within the typical dose range.

"The FDA is currently conducting a review of adverse event reports and other information to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occur during treatment of other kinds of pain, such as postoperative pain following other types of surgery or procedures," Dr. Bob Rappaport, director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.

For now, the FDA is advising health care professionals and parents to be aware of the risks of codeine in children, "particularly in those who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome," and – when they prescribe medications that contain codeine to children – to use "the lowest effective dose for the shortest time on an as-needed basis." Parents and caregivers should stop codeine and get immediate medical attention if a child who has been receiving codeine after surgery has any symptoms of an overdose.

CYP2D6 (cytochrome P450 2D6) metabolizes codeine to morphine. Ultrametabolizers of codeine have a genetic variation in this enzyme and are more likely to have abnormally high levels of morphine after taking codeine, and therefore are at greater risk of related adverse events and death.

The four children started to show signs of morphine toxicity within 1-2 days of starting the codeine, and in the three children who died, postmortem morphine levels were "substantially higher" than the normal therapeutic range, according to the FDA. The four cases were also described in Pediatrics (2012;129:e1343-7).

An estimated 1%-7% of the general population are ultrarapid metabolizers, but the rate is much higher in certain ethnic groups, with the highest prevalence (29%) reported for people of Ethiopian descent. The reported prevalence is 6% in the Greek population, 3.4%-6.5% among the African American population, 3.6% in whites, and 1%-2% in northern Europeans.

When the FDA review is completed, the agency plans to provide an update.

The risk of morphine overdose in nursing infants whose mothers are taking codeine and who are ultrarapid metabolizers was recognized several years ago. In 2007, a year after the first case report was described in the Lancet (2006;368:704), the FDA issued a warning about this risk.

The FDA has also posted a consumer update on its website.

The full alert is available, and possible cases should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.

The Food and Drug Administration issued a warning on Aug. 15 about the risk of death in children who receive codeine for postoperative pain, particularly after tonsillectomy and/or adenoidectomy, based on three deaths and a nonfatal case of life-threatening respiratory depression.

The three children who died had evidence of being ultrarapid metabolizers of codeine, and the fourth case was in a child with evidence of being an "extensive" metabolizer, the FDA said in a statement announcing the warning. All four children, aged 2-5 years, underwent a tonsillectomy and/or adenoidectomy for treating obstructive sleep apnea syndrome, and received codeine within the typical dose range.

"The FDA is currently conducting a review of adverse event reports and other information to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occur during treatment of other kinds of pain, such as postoperative pain following other types of surgery or procedures," Dr. Bob Rappaport, director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.

For now, the FDA is advising health care professionals and parents to be aware of the risks of codeine in children, "particularly in those who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome," and – when they prescribe medications that contain codeine to children – to use "the lowest effective dose for the shortest time on an as-needed basis." Parents and caregivers should stop codeine and get immediate medical attention if a child who has been receiving codeine after surgery has any symptoms of an overdose.

CYP2D6 (cytochrome P450 2D6) metabolizes codeine to morphine. Ultrametabolizers of codeine have a genetic variation in this enzyme and are more likely to have abnormally high levels of morphine after taking codeine, and therefore are at greater risk of related adverse events and death.

The four children started to show signs of morphine toxicity within 1-2 days of starting the codeine, and in the three children who died, postmortem morphine levels were "substantially higher" than the normal therapeutic range, according to the FDA. The four cases were also described in Pediatrics (2012;129:e1343-7).

An estimated 1%-7% of the general population are ultrarapid metabolizers, but the rate is much higher in certain ethnic groups, with the highest prevalence (29%) reported for people of Ethiopian descent. The reported prevalence is 6% in the Greek population, 3.4%-6.5% among the African American population, 3.6% in whites, and 1%-2% in northern Europeans.

When the FDA review is completed, the agency plans to provide an update.

The risk of morphine overdose in nursing infants whose mothers are taking codeine and who are ultrarapid metabolizers was recognized several years ago. In 2007, a year after the first case report was described in the Lancet (2006;368:704), the FDA issued a warning about this risk.

The FDA has also posted a consumer update on its website.

The full alert is available, and possible cases should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.

The Food and Drug Administration issued a warning on Aug. 15 about the risk of death in children who receive codeine for postoperative pain, particularly after tonsillectomy and/or adenoidectomy, based on three deaths and a nonfatal case of life-threatening respiratory depression.

The three children who died had evidence of being ultrarapid metabolizers of codeine, and the fourth case was in a child with evidence of being an "extensive" metabolizer, the FDA said in a statement announcing the warning. All four children, aged 2-5 years, underwent a tonsillectomy and/or adenoidectomy for treating obstructive sleep apnea syndrome, and received codeine within the typical dose range.

"The FDA is currently conducting a review of adverse event reports and other information to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occur during treatment of other kinds of pain, such as postoperative pain following other types of surgery or procedures," Dr. Bob Rappaport, director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.

For now, the FDA is advising health care professionals and parents to be aware of the risks of codeine in children, "particularly in those who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome," and – when they prescribe medications that contain codeine to children – to use "the lowest effective dose for the shortest time on an as-needed basis." Parents and caregivers should stop codeine and get immediate medical attention if a child who has been receiving codeine after surgery has any symptoms of an overdose.

CYP2D6 (cytochrome P450 2D6) metabolizes codeine to morphine. Ultrametabolizers of codeine have a genetic variation in this enzyme and are more likely to have abnormally high levels of morphine after taking codeine, and therefore are at greater risk of related adverse events and death.

The four children started to show signs of morphine toxicity within 1-2 days of starting the codeine, and in the three children who died, postmortem morphine levels were "substantially higher" than the normal therapeutic range, according to the FDA. The four cases were also described in Pediatrics (2012;129:e1343-7).

An estimated 1%-7% of the general population are ultrarapid metabolizers, but the rate is much higher in certain ethnic groups, with the highest prevalence (29%) reported for people of Ethiopian descent. The reported prevalence is 6% in the Greek population, 3.4%-6.5% among the African American population, 3.6% in whites, and 1%-2% in northern Europeans.

When the FDA review is completed, the agency plans to provide an update.

The risk of morphine overdose in nursing infants whose mothers are taking codeine and who are ultrarapid metabolizers was recognized several years ago. In 2007, a year after the first case report was described in the Lancet (2006;368:704), the FDA issued a warning about this risk.

The FDA has also posted a consumer update on its website.

The full alert is available, and possible cases should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.