The six participating pediatric hospitals contributed 241 eligible patients administered oral azithromycin and 367 patients administered IV/IM fentanyl (Tables 1, 2, 4).
Exposure to Oral Azithromycin and Serious Adverse Events
Of the 241 children exposed to oral azithromycin, 106 (44%) were female, while the median patient age was 6 years (range 0–20) and the most commonly reported race was black (100, 42%). The most common comorbidities were those affecting the respiratory system (121, 50%), congenital/chromosomal disorders (63, 26%), and diseases of blood and immune disorders (47, 20%). There were 17 patients in the azithromycin cohort who were 16–20 years of age. Only three of these 17 adolescents had an SAE.
The median maximum daily dose for azithromycin was 10 mg/kg (range 2.2–21.8), with the median cumulative dose at 25 mg/kg (range 4–170.5) (Table 2).
Ninety-three patients (39%) in the azithromycin cohort were administered the drug off-label, with most off-label use being by indication only (65, 27% of all patients), but the specific indications for off-label use were not determined. A total of 21 patients (9%) experienced at least one of the identified 32 SAEs. Thirteen patients that were on-label experienced an SAE and eight that were off-label. Prolonged diarrhea/loose stool, noted in six individuals (2% of the cohort) was the most common SAE (Table 2). All of the patients with diarrhea on azithromycin were taking the drug on-label.
For the azithromycin regression analysis, five confounders were deemed eligible: sex, Asian race/ethnicity, total comorbidities, having a blood or immune system related comorbidity, and total concomitant medications. The logistical regression model included 235 individuals with complete data once the confounders were included. Off-label use was not a significant predictor of SAEs (p = 0.81), though females, Asian patients, and the number of concomitant medications administered to the patient were associated significantly with SAE risk (Table 3).
The sensitivity analysis showed that when the correlation coefficient cut-off was reduced from |r| ≥ 0.1 to |r| ≥ 0.05 for eligible confounders, the azithromycin regression model included six additional confounders: black and Hispanic race/ethnicity, maximum daily dose, cumulative dose, specific comorbidities (infectious and parasitic disease, congenital malformations and chromosomal mutations) (ESM Table 1). However, off-label use of oral azithromycin was still not significantly associated with risk of any SAE (p = 0.83).
A Kaplan–Meier plot was generated to characterize how the risk of any SAE changed over the course of therapy with azithromycin (ESM Fig. 1). In addition, a Cox proportional hazards regression was used to compare time to event (first SAE reported) in on-label compared with off-label groups. The Cox proportional hazards assumption was fulfilled for the analysis (p = 0.90). In this regression, the off-label group was associated with reduced risk of any SAE, but this was not statistically significant [hazard ratio (HR) 0.83, 95% CI 0.31–2.23; p = 0.71]. Female and Asian patients as well as the number of concomitant medications administered to the patient were still associated significantly with SAE risk.
Exposure to IV/IM Fentanyl and Serious Adverse Events
Of the 367 children exposed to fentanyl, 149 were female (41%), while median patient age was 2 months (range 0–18 years) and the most commonly reported race/ethnicity was white (134, 37%). The most common comorbidities were congenital/chromosomal disorders (142, 39%), followed by those affecting the circulatory system (120, 33%) and respiratory system (101, 28%). There were 16 patients in the fentanyl cohort who were 16–20 years of age. Only two of 16 16- to 20-year-olds had an SAE. The median maximum daily dose for fentanyl excluding patients with PRN dosing was 2.1 mcg/kg (n = 211, range 0.1–156), and the median cumulative dose over the entire hospitalization was 2.0 mcg/kg (n = 180, range 0.1–1884) (Table 4). Patients in this study had a variety of dosing regimens, including continuous infusion, single-dose bolus, and doses given at different times. These were standardized into a cumulative dose given for the day and then expanded to a cumulative dose per hospital stay. The sample size in this metric is lower because it excludes patients with dosing recorded as PRN at some point during hospitalization, with the exact amount administered not recorded. There were also four patients where fentanyl dosing was not adequately reported, so we were unable to calculate a weight-based dose.
It is important to note that fentanyl dosing regimens included a mix of continuous infusions, boluses, and single injections. One patient may have received all three types of administration during their hospitalization. Patients in our fentanyl cohort had up to eight different regimens during hospitalization, though it should be noted only three patients had four or more different regimens. There are also some outlier cumulative doses for fentanyl. For instance, nine patients had a cumulative dose of over 100 mcg/kg per stay, with three of these patients administered over 500 mcg/kg. The highest recorded was a cumulative dose of 1884 mcg/kg over the course of a 52-day hospital stay (24 days of fentanyl administered). This patient was administered a changing regimen of fentanyl continuous infusion with 108 mcg/kg/day at the highest level. This patient had no SAEs reported.
Off-label use of fentanyl (287, 78%) was predominant and involved mostly off-label use by both age and indication (129, 35% of all patients) and off-label use by age only (131, 36% of all patients). Of the 367 children exposed to fentanyl, a total of 95 patients (26%) (15 on-label and 80 off-label) experienced at least one SAE. The most common SAEs were respiratory depression (37, 10%) (ventilator use not captured in this study), death (30, 8%), and circulatory depression (29, 8%) (Table 4). Only two patients who had respiratory depression were on-label, while 35 patients who had respiratory depression were off-label.
For the logistic regression, five variables were identified as eligible confounders for the outcome of any SAE reported with exposure to fentanyl: total comorbidities, specific comorbidities (nervous system disease, respiratory disease, and perinatal disease), and total concomitant medications. Off-label use of fentanyl by both age and indication was associated with increased risk for any SAE, but was not significant (OR 1.99; 95% CI 0.94–4.19; p = 0.07) (Table 5). A sub-analysis for the association of respiratory depression with off-label use of fentanyl included two eligible confounders: respiratory disease and perinatal disease. Adjusting for these confounders, off-label use of fentanyl by both age and indication was associated with a higher risk of respiratory depression (n = 24; OR 5.05; 95% CI 1.08–23.56, p = 0.04) (Table 5).
For our first sensitivity analysis, the criterion for eligible confounders was broadened from |r| ≥ 0.1 to |r| ≥ 0.05. The association of off-label use of fentanyl by both age and indication with any SAE increased significantly (OR 2.53; 95% CI 1.13–5.65; p = 0.02). When the eligible confounders were broadened for the outcome of respiratory depression only, off-label use of fentanyl by both age and indication (OR 5.05; 95% CI 1.05–24.27; p = 0.04) remained significant (ESM Table 2).
When the dosing variables were included in the fentanyl regression model, the sample size decreased to 178 as patients with any PRN dosing were excluded from the analysis. Only 180 patients had complete drug regimen information that did not include any PRN dosing and an additional six patients were missing race/ethnicity, with an overlap of four with the group above. In this analysis, off-label use of fentanyl by both age and indication (n = 41) was not significantly associated with the risk of any SAE (OR 3.38; 95% CI 0.93–12.28; p = 0.06). In addition, cumulative dose was not associated with the risk of any SAE (ESM Table 3).
Kaplan–Meier plots were generated to characterize how the risk of any SAE or the risk of respiratory depression by itself changed over the course of therapy with fentanyl, with a focus on off-label use by both age and indication (Fig. 1, ESM Fig. 2). Cox proportional hazards regression was used to compare time to event (first SAE reported or respiratory depression reported) in on-label compared with off-label groups. The Cox proportional hazards assumption was fulfilled for the analysis of any SAE (p = 0.31) and respiratory depression alone (p = 0.35). For the risk of any SAE over time, off-label use by age only (HR 1.10; 95% CI 0.56–2.14; p = 0.78), indication only (HR 0.54; 95% CI 0.18–1.66; p = 0.29), and off-label by both age and indication (HR 1.28; 95% CI 0.67–2.45; p = 0.46) were all not significant. For the risk of respiratory depression over time, off-label use by age only (HR 1.85; 95% CI 0.39–8.79; p = 0.44), indication only (HR 1.13; 95% CI 0.10–12.65; p = 0.92), and off-label by both age and indication (HR 3.64; 95% CI 0.81–16.42; p = 0.09) were also not significant.