Evaluation of the quality and value of data sources for postmarket surveillance of the safety of cough and cold medications in children

Green, Jody L.; Reynolds, Kate M.; Banner, William; Bond, G. Randall; Kauffman, Ralph E.; Palmer, R.B.; Paul, Ian M.; Dart, Richard C.

doi:10.1186/s12874-018-0626-3

Cited by 7 publications

(11 citation statements)

References 8 publications

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“…We attempted to capture all existing cases of pediatric oral OTC CCM cases by utilizing multiple sources, including the National Poison Data System (NPDS) of the American Association of Poison Control Centers (AAPCC), FDA Adverse Event Reporting System (AERS), news and media reports, English language medical literature, and participating manufacturer safety reports ( Figure 1). To be included in this study, reports had to meet all of the following criteria [10]: child <12 years of age, oral exposure to one or more of eight index CCM ingredients (brompheniramine, chlorpheniramine, dextromethorphan, DPH, doxylamine, guaifenesin, phenylephrine, pseudoephedrine), report of a significant adverse event, and the exposure occurred in the U.S. Duplicate cases from multiple sources were identified using the Guideline on Detection and Management of Duplicate Individual Cases and Individual Case Safety Reports standards and were combined into a single case record, preserving all available case records [11].…”

Section: Study Design and Settingmentioning

confidence: 99%

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Adverse events associated with diphenhydramine in children, 2008–2015

Palmer

Reynolds

Banner³

et al. 2019

Clinical Toxicology

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Introduction: Diphenhydramine (DPH) exposures in children may be the result of accidental unsupervised ingestions, caregiver error, and intentional misuse of DPH-containing cough and cold medications (CCM). We sought to understand the nature of pediatric ingestions of DPH, particularly the toxicity and outcome of a single product, single ingredient DPH (DPH-only) exposures, in order to derive ingredient-specific information about the clinical effects and course of such cases. Methods: As part of a U.S. multi-year safety surveillance program to assess the safety of over-thecounter (OTC) medications used in cough and cold preparations in children <12 years of age, an expert panel reviewed cases involving symptomatic adverse events potentially related to oral exposures to these medications. After individual review, the cases were categorized by causal relationship of the reported ingredients to the adverse event, exposure intent (therapeutic, non-therapeutic, unknown intent), and dose (therapeutic, supratherapeutic, or unknown). Following panel review, any disagreement on classification was discussed until a consensus was reached. The data were then analyzed with respect to descriptive findings. Results: The panel reviewed 6618 eligible cases and determined 2802 were at least potentially related to oral exposure to DPH. Of these, 2028 were DPH-only cases (39.1% of all cases judged at least potentially related to a cough and cold medication). The majority (79.5%) of DPH-only cases occurred in children 2 to <4 years of age and involved accidental unsupervised ingestions (74.7%). Liquid pediatric formulations were the most common (51.7%) products reported followed by solid pediatric formulations (24.0%). The most common adverse events were tachycardia (53.4%), hallucinations (46.5%), somnolence (34.7%), agitation (33.9%), and mydriasis (26.3%). Seizures occurred in only 5.5% of cases. Five (0.2%) deaths were reported; in the death cases, the DPH dose was judged supratherapeutic in one and unknown in the other four. Child abuse was reported in four of the five death cases and three of the five deaths were homicides. Conclusions: Exposures to DPH-only products were the most common type of exposure detected in our study of adverse events associated with CCM in children. The majority of the DPH-only cases were the result of accidental unsupervised ingestions. Most adverse events were relatively mild self-limited anticholinergic effects and few deaths occurred. Deaths involving DPH were often associated with child abuse or homicide. Interventions targeting the prevention of accidental unsupervised are likely to be impactful in preventing morbidity associated with DPH-only exposure.

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Section: Study Design and Settingmentioning

confidence: 99%

“…causes of the exposure. The causal relationship between each adverse event and CCM ingredient was assigned to one of four categories [10]: related, potentially related, unlikely related, and unable to determine ( Table 1). Exact dose often could not be determined from information in the case narrative.…”

Section: Outcome Measuresmentioning

confidence: 99%

Adverse events associated with diphenhydramine in children, 2008–2015

Palmer

Reynolds

Banner³

et al. 2019

Clinical Toxicology

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“…Fatalities in children <12 years old associated with CCM exposure were identified by the Pediatric Cough and Cold Safety Surveillance System, which has been described previously. 6,7 In brief, the system collected data from 5 sources: the National Poison Data System (NPDS) of the American Association of Poison Control Centers, the FDA Adverse Event Reporting System, news or media reports, Englishlanguage medical literature, and safety reports made to participating CCM manufacturers. Cases were collected from January 1, 2008, to March 31, 2017, based on the report date.…”

Section: Methodsmentioning

confidence: 99%

“…The panel reviewed fatality cases to determine if the causal relationship between each CCM ingredient mentioned and death was related, potentially related, unlikely related, or unable to determine using established definitions. 7 Cases judged related or potentially related were further categorized by intent (therapeutic, nontherapeutic, or unknown intent) and by dose (therapeutic, supratherapeutic, or unknown dose). Therapeutic intent was defined as use for a labeled indication, and nontherapeutic intent was defined as use for any other purpose, including off-label use, accidental exploratory ingestions, and malicious use.…”

Section: Methodsmentioning

confidence: 99%

Pediatric Fatalities Associated With Over-the-Counter Cough and Cold Medications

et al. 2021

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BACKGROUND AND OBJECTIVES: In 2008, over-the-counter cough and cold medications (CCMs) underwent labeling changes in response to safety concerns, including fatalities, reported in children exposed to CCMs. The objective of this study is to describe fatalities associated with exposures to CCMs in children <12 years old that were detected by a safety surveillance system from 2008 to 2016.METHODS: Fatalities in children <12 years old that occurred between 2008 and 2016 associated with oral exposure to one or more CCMs were identified by the Pediatric Cough and Cold Safety Surveillance System. An expert panel reviewed all cases to determine the causal relationship between the exposure and death, if the intent of exposure was therapeutic, and if the dose was supratherapeutic. Other contributing factors related to the child's death were also identified as part of a root cause analysis.RESULTS: Of the 180 eligible fatalities captured during the study period, 40 were judged by the expert panel to be either related or potentially related to the CCM. Of these, the majority (n 5 24; 60.0%) occurred in children <2 years old and involved nontherapeutic intent (n 5 22; 55.0%). The most frequently involved index ingredient was diphenhydramine (n 5 28; 70.0%). In 6 cases (n 5 6; 15.0%), the CCM was administered to murder the child. In another 7 cases (n 5 7; 17.5%), death followed the intentional use of the CCM to sedate the child.CONCLUSIONS: Pediatric fatalities associated with CCMs occurred primarily in young children after deliberate medication administration with nontherapeutic intent by a caregiver.

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“…The Pediatric Cough and Cold Safety Surveillance System methods have been described elsewhere [4,5]. In brief, we collected data from five national data sources (National Poison Data System, medical literature, FDA Adverse Event Reporting System, news/media reports, manufacturer safety reports) from 2009 to 2016 [4,5].…”

Section: Methodsmentioning

confidence: 99%

Trends in adverse events and related health-care facility utilization from cough and cold medication exposures in children

Wang

Green

Reynolds

et al. 2020

Clinical Toxicology

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Introduction: Initial research following regulatory changes addressing the pediatric safety of cough and cold medications (CCMs) demonstrated decreases in adverse events (AEs). Using a national multisource surveillance system, we studied subsequent CCM-related AE case rate trends and associated health-care facility (HCF) evaluation in children. Methods: Data were collected from 2009 to 2016. Case eligibility included: age <12 years; exposure to an over-the-counter product containing !1 CCM pharmaceutical ingredient; !1 significant AE that occurred in the United States. Results: About 4756 (72.6%) cases were determined at least potentially related to an index ingredient. Accidental unsupervised ingestions (AUIs; 3134; 65.9%) were the most common case type. Nearly half of AE cases involved children 2 to <4 years old (2,159; 45.4%). The AE case rate did not change significantly over time (p ¼ 0.22). The proportion of AE cases resulting in HCF admission increased from 32.4% (207) in 2009 to 43.4% ( 238) in 2016 (p < 0.01). Exposures to diphenhydramine (1,305; 67.3%) and/or dextromethorphan (591; 30.5%) were involved in the majority of HCF admissions. Conclusions: The proportion of AE cases resulting in HCF admission increased from 2009 to 2016. Efforts to prevent AUIs such as packaging innovation and engineering controls, particularly for diphenhydramine and dextromethorphan-containing products, should be pursued.

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Evaluation of the quality and value of data sources for postmarket surveillance of the safety of cough and cold medications in children

Cited by 7 publications

References 8 publications

Adverse events associated with diphenhydramine in children, 2008–2015

Adverse events associated with diphenhydramine in children, 2008–2015

Pediatric Fatalities Associated With Over-the-Counter Cough and Cold Medications

Trends in adverse events and related health-care facility utilization from cough and cold medication exposures in children

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