Long-Term Adverse Drug Reactions in Pediatrics: Overview from MUSiC Project

Background: Detection of adverse reactions occurring long after start of drug therapy in pediatrics is challenging in clinical trials due to reduced sample size and length of follow-up. Objectives: We explored pattern of adverse drug reaction (ADR) reports in pediatrics in relation to the lag time between start of treatment and onset of event across different drug classes and age categories. Methods: Suspected ADR reports in population younger than 18 years were retrieved from Italian Pharmacovigilance Network (IPhN). Time to event was calculated for all reports including start date of drug therapy (classified by ATC code) and date of event occurrence (coded as MedDRA SOC-PT). Long-term adverse event was identified if occurred after at least 6 months from start therapy. Long-term ADRs were analyzed overall, by age-categories, implicated drug and suspected event. Proportions of ADRs reported within vs. after 6 months were compared. Results: All reports of ADRs have been retrieved from the IPhN up to May 31, 2016 (N = 335,864), except reports from literature. After exclusion of all reports concerning adults or with missing or inconsistent dates, 53,404 reports have been analyses. Among them, 98% (N = 52.436) were reported within 6 months, mainly after the first week of treatment (42,780, 80%), while only 2% (N = 968) after 6 months. This proportion slightly increased (N = 831; 5%) after excluding vaccines. The proportion of ADRs after long term use increased significantly with age, ranged from 1.4% (N = 12) among neonates to almost 50% (N = 407) among adolescents. In terms of SOCs, ‘Investigations’ (long vs. short: 12% vs. 2.2%), ‘Metabolism/nutrition disorders’ (7.0% vs. 1.4%) and ‘Nervous system disorders’ (11.6% vs. 8.4%) were more often reported after long-term use. Drugs for which long-term ADRs were mostly reported included Risperidone (N = 134), Somatotropin (N = 85) and Valproic acid (N = 42). Conclusions: Pattern of ADRs in relation to lag time between treatment start and time of onset significantly differed across age categories and type of event. The much larger frequency of long-term ADR reporting among adolescents could be due to increased exposure to of chronic therapy as compared to neonates and toddlers. Skin and gastrointestinal adverse reactions are expected to rapidly occur, mainly within few hours/days after start therapy, while increase of liver enzymes (reported among ‘Investigations’ SOC) usually occurs after long-term treatment, emphasizing the inability to be detected in (short-term) clinical trials.