The impetus to drive this change was the adverse effects (including death) from CC products observed in very young children. However, information is lacking as to the effect of this revised labeling on pediatric deaths.
The Pediatric Cough and Cold Safety Surveillance System collects data from five sources, including the National Poison Data System of the American Association of Poison Control Centers, the FDA Adverse Event Reporting System, news and media reports, the medical literature, and manufacturer safety reports. In this database analysis, deaths in children younger than age 12 years that occurred between January 1, 2008, and December 31, 2016, were reviewed.
The investigators analyzed cases involving oral ingestion of eight index ingredients, including brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, or pseudoephedrine.
Autopsy reports and interpretation of postmortem drug concentrations were reviewed to determine if the death was related, potentially related, unlikely related, or undeterminable as to a possible relationship with the index drug. Cases that were deemed related or potentially related were further categorized by intent—i.e., therapeutic, nontherapeutic, or unknown intent—as well as by dose—i.e., therapeutic, suprathrerapeutic, or unknown dose.
Therapeutic intent was defined as use for a labeled indication, and nontherapeutic meant that the drug was being used for any other purpose, including off-label, accidental, or malicious use with the purpose of causing harm. In the case of unknown intent, neither a therapeutic nor a nontherapeutic intent could be determined. For cases referred through the national poison control system, therapeutic intent was determined by exposure reason.
Investigators found that of the 7,983 cases of adverse events involving CC medications, there were 188 deaths (2.4%), of which 40 deaths were considered at least potentially related to the CC medicine. Sixty percent of these 40 cases (n = 24) involved children under age 2 years and 65% involved boys. Only 7.5% (n = 3) of cases were due to accidental ingestion. Forty percent of the fatal doses had been administered by a parent.
Of these 40 cases, it was determined that 55% were nontherapeutic and 15% were therapeutic, with the rest administered with unknown intent. Although the estimated dose could not be determined for 80% of the overdoses, in 20% the dose was supratherapeutic. A total of 50 CC products were involved in the 40 deaths.
Diphenhydramine was the index drug in 70% of potentially related deaths, which differed from earlier analyses in which pseudoephedrine was the drug implicated in most deaths. In 17 deaths, both an index drug and a nonindex drug were involved, with the most common nonindex drug being an opioid in almost 70% of cases. Deaths due to child self-administration involved solid dosage forms of diphenhydramine.
Surprisingly, in six cases (15%), a root cause analysis revealed that the child was murdered, and in approximately another 18% of cases, the CC product was being used for sedation.
Pharmacists are instrumental in educating parents on the proper use of CC medications in pediatric patients. They must also have a high index of suspicion in identifying inappropriate CC product administration for malicious intent.
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