Sildenafil for the treatment of pulmonary hypertension in children

Abstract

Pulmonary hypertension, including pulmonary arterial hypertension (PAH), is a serious disease in children, but few clinical studies have been conducted to evaluate treatment regimens in this population. Currently, treatment of children with PAH is mostly based on clinical studies conducted in adults and a few dedicated pediatric studies. Sildenafil, a phosphodiesterase type 5 inhibitor, has an established efficacy and safety profile for the treatment of adults with PAH. In May 2011, sildenafil received approval for the treatment of pediatric patients aged 1–17 years in the EU; however, pediatric use is not approved in the USA. This systematic literature review summarizes the clinical data available on the use of sildenafil to treat children with PAH and pulmonary hypertension.

Keywords::

• adolescent
• child
• clinical trial
• nitric oxide
• phosphodiesterase type 5 inhibitor
• pulmonary arterial hypertension
• pulmonary hypertension
• sildenafil

Financial & competing interests disclosures

M Beghetti has served as consultant and/or advisory board member for Actelion, Bayer-Schering, Lilly, GlaxoSmithKline, Novartis and Pfizer Inc. and has received investigator-initiated research funding from Actelion and Bayer-Schering. S Merali is a former employee of Pfizer Inc. Editorial support was provided by Tiffany Brake, Susan DeRocco, Janet E. Matsuura and Deborah Campoli-Richards at Complete Healthcare Communications, Inc., and funded by Pfizer Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Similar to adult, patients pediatric patients with chronic pulmonary arterial hypertension (PAH) have improved outcomes (including hemodynamic parameters) with sildenafil treatment.

• Because of concerns about the use of high-dose sildenafil in pediatric patients with PAH, doses higher than those approved by the EMA (10 mg three times daily for children 8–20 kg and 20 mg three times daily for children >20 kg) should be avoided.

• The US FDA did not approve sildenafil treatment in children and recommended against its use in pediatric PAH patients aged 1–17 years; however, the FDA later clarified the warning to note that there may be situations in which the benefit–risk profile of sildenafil may be acceptable in individual children (e.g., when other treatment options are limited and sildenafil can be used with close monitoring) [53].

• In children, pharmacokinetic studies have assessed sildenafil monotherapy, while an increasing number of children now receive combined therapy [57–59]; further pharmacokinetic investigation is warranted.

• Key limitations of the STARTS-2 study data (upon which the FDA decision was based) were identified by PAH experts [51]; these limitations highlight the need for further research in this population.

• Sildenafil is associated with improved oxygenation in newborns with persistent pulmonary hypertension of the newborn, although it is not approved by any regulatory agency for this indication.

• In exploratory studies in acute PAH, sildenafil can facilitate inhaled nitric oxide withdrawal and prevent rebound pulmonary hypertension; however, effects on systemic vasculature and ventilation/perfusion mismatch are possible.

• Sildenafil treatment is generally well tolerated in pediatric PAH patients.

• Although there are substantial barriers to designing and conducting trials in this population, further research of sildenafil in children is necessary to identify optimal therapeutic treatment.

Notes