Although tramadol-containing products and single-ingredient codeine medications are only approved for use in adults, they are sometimes used off label to treat children. The Food and Drug Administration (FDA) has now revised the labeling of codeine and tramadol products to include new contraindications and warnings to restrict this. Both drugs are now contraindicated for the treatment of pain in children younger than age 12, and codeine is contraindicated for the treatment of cough in this age group.

Two new warnings have also been added to the products' labeling. First, these drugs are not recommended for adolescents between the ages of 12 and 18 who are obese or who have obstructive sleep apnea or compromised respiratory function, as their use in young people with these comorbidities can increase the risk of serious respiratory adverse effects. Second, women who are breastfeeding should avoid taking these drugs because they increase the risk of excessive sedation, respiratory depression, and death in infants. For a list of prescription drugs containing codeine or tramadol, see http://bit.ly/2pkESd5.

These new and revised warnings update previously issued warnings about the two drugs. In 2013, the FDA added a boxed warning to codeine's labeling stating that the drug should not be prescribed to children of any age after tonsillectomy or adenoidectomy because of the risk of respiratory depression and death (see Drug Watch, June 2013). Although this risk only applies to children who are ultrarapid metabolizers of codeine-who convert the drug to morphine too quickly, which can lead to high drug levels in the blood, overdose, and possibly death-all children were included in the boxed warning because it's difficult to determine which children are ultrarapid metabolizers of codeine. Drug Safety Communications were also issued in July and September of 2015 to warn of the serious respiratory adverse effects in children who are ultrarapid metabolizers of codeine or tramadol.

The labeling revisions for codeine- and tramadol-containing products are based on the FDA's review of several decades of adverse events reports. The reports showed that, from January 1969 to May 2015, the use of codeine in children was associated with 64 worldwide cases of respiratory depression, including 24 deaths. Fifty of those cases involved children under the age of 12, 21 of the 24 deaths occurring in this age group. The codeine products mentioned in these reports were acetaminophen with codeine and promethazine with codeine (phenylephrine was also an ingredient in some cases). The FDA also reviewed nine cases of respiratory depression in children under the age of 18 who were taking tramadol; three of the children were under the age of six and died. The three deaths occurred outside the United States.

Mothers who metabolize these drugs normally will produce very low levels of the active narcotic metabolite in their breast milk. Mothers who are ultrarapid metabolizers of these drugs, however, are likely to produce higher than expected drug levels in their breast milk, leading to an increased risk of sedation and serious respiratory effects in their infants. The FDA notes that "numerous reports of respiratory depression and sedation, including one infant death" could be attributed to mothers who were ultrarapid metabolizers of these drugs.

NPs should avoid prescribing products containing codeine and tramadol to children under the age of 12 and use other analgesics and antitussives instead. If, after careful consideration, an NP considers these drugs suitable for adolescents ages 12 to 18 who do not have compromised respiratory status, they should teach the patients and their parents about the risk of opioid toxicity and the signs and symptoms of overdose. The drugs should be stopped immediately and emergency attention sought if the teens exhibit any signs of respiratory depression or excessive sedation. Nurse midwives and NPs who work with breastfeeding mothers should not prescribe codeine or tramadol products. The FDA requests that any health care professional who encounters an adverse event involving codeine or tramadol report it to the FDA MedWatch program: http://bit.ly/1KGErtT. To read the Drug Safety Communication on these two drugs, go to http://bit.ly/2pkESd5.