title: Implications of the U.S. Food and Drug Administration warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.
authors.affiliation: Department of Pediatrics, Pediatric Pulmonary Hypertension Network, University of Colorado School of Medicine, 13123 East 16th Avenue, Aurora, CO 80045, USA. steven.abman@ucdenver.edu
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
authors.forename: John P
authors.initials: JP
authors.lastname: Kinsella
authors.forename: Erika B
authors.initials: EB
authors.lastname: Rosenzweig
authors.forename: Usha
authors.initials: U
authors.lastname: Krishnan
authors.forename: Thomas
authors.initials: T
authors.lastname: Kulik
authors.forename: Mary
authors.initials: M
authors.lastname: Mullen
authors.forename: David L
authors.initials: DL
authors.lastname: Wessel
authors.forename: Robin
authors.initials: R
authors.lastname: Steinhorn
authors.forename: Ian
authors.initials: I
authors.lastname: Adatia
authors.forename: Brian
authors.initials: B
authors.lastname: Hanna
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Feinstein
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fineman
authors.forename: Usha
authors.initials: U
authors.lastname: Raj
authors.forename: Tilman
authors.initials: T
authors.lastname: Humpl
mesh_terms: D018450:Disease Progression; D016903:Drug Monitoring; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D011358:Product Surveillance, Postmarketing; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D014481:United States; D014486:United States Food and Drug Administration; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate