Food and Drug Administration (FDA) Postmarket Reported Side Effects and Adverse Events Associated with Pulmonary Hypertension Therapy in Pediatric Patients

Abstract

Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.

Sildenafil Stimulates and Dexamethasone Inhibits Pulmonary Vascular Development in Congenital Diaphragmatic Hernia Rat Lungs

“…It will be very important to study short- and long-term adverse effects, dosages, and timing on the fetus and pregnant women before starting sildenafil clinically, including pulmonary, cardiac, vascular, visual, and neurologic evaluations [28]. Recently, Luong et al [16] showed that antenatal sildenafil had no adverse effects on retinal and brain development.…”

Plasma Concentrations of Tadalafil in Children With Pulmonary Arterial Hypertension

“…7 That is, when healthy male subjects received 40 mg tadalafil once a day concomitantly with bosentan at a dose of 125 mg twice a day, the mean area under the curve values of tadalafil after 10 days of repetitive dose decreased by 41.5% compared with tadalafil alone. 7 Because bosentan is frequently coadministered with PDE5 inhibitors in the treatment of children with PAH, 3,5,11 this drug-drug interaction should be of interest to most pediatricians. In addition, it was reported that gender, age, and hepatic impairment have no effect on the pharmacokinetics of tadalafil in adults, although systemic exposure in the elderly was 25% greater than in young subjects.…”

“…1,2 The clinical development of new agents has improved the quality of life and mortality of patients with PAH in the past 2 decades. 3 One such drug class is phosphodiesterase type-5 (PDE5) inhibitors (sildenafil and tadalafil), and this class of therapy has contributed to the improved prognosis of adult PAH patients. 2,3 On the other hand, no therapies are approved for children.…”

“…3 One such drug class is phosphodiesterase type-5 (PDE5) inhibitors (sildenafil and tadalafil), and this class of therapy has contributed to the improved prognosis of adult PAH patients. 2,3 On the other hand, no therapies are approved for children. On the basis of similar clinical characteristics and histopathology, recommendations for the treatment of children have been extrapolated from evidence-based adult guidelines.…”

Update on Pediatric Pulmonary Arterial Hypertension

“…66 The 3 most frequent adverse events were liver dysfunction (62%), cardiac failure (11%), and syncope (8.6%) for bosentan; pulmonary hemorrhage (13.1%), cardiac failure (9.7%), and hemoptysis (8%) for epoprostenol; and cardiac failure (12.4%), hypotension (11.2%), and dyspnea (10.1%) for sildenafil. Serious adverse events not previously reported in the literature (eg, pulmonary hemorrhage, hemoptysis, pneumonia, cardiac arrest, hypoxia) were also reported.…”