Sildenafil (Revatio and Viagra): reports of persistent pulmonary hypertension of the newborn (PPHN) following in-utero exposure in a clinical trial on intrauterine growth restriction

Sildenafil is not authorised for use in pregnancy for the treatment of intrauterine growth restriction. The STRIDER clinical trial, which was studying the use of sildenafil in pregnancy for intrauterine growth restriction, has been prematurely discontinued due to a higher incidence of persistent pulmonary hypertension of the newborn (PPHN) and neonatal mortality in the sildenafil arm of the study.

Advice for healthcare professionals:

  • data from an independent clinical trial has shown potential harm, including increased risk of persistent pulmonary hypertension of the newborn (PPHN) and increased mortality, when used in pregnancy for early-onset intrauterine growth restriction (IUGR)
  • sildenafil (Revatio and Viagra) is not authorised for the treatment of IUGR (see indication below)
  • Revatio for the treatment of pulmonary arterial hypertension (PAH) is not recommended in pregnancy unless strictly necessary; Viagra is not authorised for use in women
  • report suspected adverse drug reactions to sildenafil on a Yellow Card

Data from Dutch STRIDER study

Interim data from an independent clinical trial, the Dutch STRIDER (Sildenafil TheRapy in Dismal prognosis Early-onset fetal growth Restriction) study, suggest an increased risk of persistent pulmonary hypertension of the newborn (PPHN) and neonatal mortality when sildenafil was used in pregnancy for intrauterine (fetal) growth restriction compared with placebo. The group assigned to sildenafil had an incidence of 17 cases of PPHN in 64 babies (27%), including 11 deaths before discharge. In the placebo group, 3 of 58 babies (5%) had PPHN, with no reported deaths before discharge. These findings occurred in the absence of any benefit shown on the primary endpoint of neonatal survival until term age.

The Dutch STRIDER study was one of 5 independent studies by an international collaboration investigating the use of sildenafil for this unauthorised use. The 5trials in the STRIDER Consortium were undertaken in the UK, Ireland, The Netherlands, New Zealand/Australia, and Canada. Pregnant women were randomised to generic sildenafil or placebo. Sildenafil was given in a dose of 25 mg three times a day to pregnant women for the treatment of severe intrauterine (fetal) growth restriction.

Details of the interim analysis of the Dutch STRIDER study are not yet available and the analysis by the STRIDER consortium of studies is awaited. A letter has been sent to relevant healthcare professionals to inform them of this information and that sildenafil should not be used in intrauterine (fetal) growth restriction.

UK arm of STRIDER study

The UK arm of the STRIDER trial, with a sample size of 135 women and a primary outcome of prolongation of pregnancy by 1 week, has completed and the results have been published. 1 The results of the UK STRIDER showed no difference in the median randomisation to delivery interval between women assigned to sildenafil (17 days [IQR 7–24]) and women assigned to placebo (18 days [IQR 8–28]; p=0·23).

In the UK STRIDER trial, although not significant, higher percentages of neonatal death, neonatal morbidity, oxygen dependency, and surfactant use were observed among the sildenafil group compared to placebo.1 No benefit in terms of longer interval until delivery was observed in the UK STRIDER. Although no significant difference in PPHN or neonatal mortality was identified in this arm of the trial, the smaller sample size has implications for the power of this study to identify an increase in these outcomes. The effects of the sildenafil in this unauthorised indication require further review of the full datasets from the STRIDER Studies, once these become available.

At this point, the benefit-risk balance of Sildenafil in the authorised indication of pulmonary artery hypertension remains unchanged for women who are pregnant (see below); however, this will be kept under review as further data emerge.

Background

Sildenafil is the active substance of the medicinal products Revatio and Viagra.

Revatio, and associated generic products, is authorised for the treatment of adults and children aged 1 to 17 years with pulmonary arterial hypertension (PAH). The product information for Revatio states that due to lack of data, Revatio should not be used in pregnant women unless strictly necessary. Viagra, and associated generic products, are used in the treatment of men with erectile dysfunction. It is not indicated for use in women.

Report suspected adverse drug reactions in pregnancy

Report to the Yellow Card Scheme any suspected adverse reactions associated with medicines taken during pregnancy experienced by women or the baby or child. Your report is essential to improve our understanding of medicines effects during pregnancy and ensure that healthcare professionals have up-to-date information on risks.

You can report on the Yellow Card website, through some clinical IT systems, or the free Yellow Card app. Download the app today via iTunes Yellow Card for iOS devices or via PlayStore Yellow Card for Android devices.

MHRA may request more detailed information and follow-up about the outcomes of the pregnancy as necessary. Therefore, when reporting, please provide sufficient contact information to allow for this. For more information, see Drug Safety Update, July 2018.

Article citation: Drug Safety Update volume 12, issue 4: November 2018: 3.

Published 14 November 2018