Pulmonary hypertension in neonates: sildenafil, Guidance and guidelines, NICE

Pulmonary hypertension in neonates: sildenafil.
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Key points from the evidence.
The content of this evidence summary was up-to-date in March 2016 . See summaries of product characteristics (SPCs), British national formulary (BNF), BNF for children (BNFc) or the MHRA or NICE websites for up-to-date information.
There is evidence from small, short‑term randomised controlled trials (RCTs) in resource‑limited settings where nitric oxide is not available that oral sildenafil reduces mortality and improves physiological parameters of oxygenation compared with placebo in term or near‑term neonates with persistent pulmonary hypertension of the newborn (PPHN). However, there is very little evidence of sildenafil use for PPHN in settings such as the UK where inhaled nitic oxide is available. In a small RCT in premature neonates at risk of bronchopulmonary dysplasia (BPD) sildenafil was not beneficial, and it remains unclear if sildenafil leads to improved outcomes in premature neonates with BPD‑associated pulmonary hypertension. The long‑term safety of sildenafil in neonates with pulmonary hypertension is not known.
Regulatory status: off‑label. This topic was prioritised following a request for an evidence review from the Neonatal and Paediatric Pharmacists Group because the use of sildenafil for pulmonary hypertension in neonates varies across centres in the UK.
In neonates with PPHN not receiving nitric oxide:
A Cochrane review of 3 placebo‑controlled RCTs (total n=77) found oral sildenafil statistically significantly reduced mortality (3 deaths in the sildenafil group [n=40] and 16 deaths in the placebo group [n=37]) and improved the oxygenation index and partial pressure of oxygen.
An RCT comparing oral sildenafil with intravenous magnesium sulphate (n=72) found no difference in mortality; there were statistically significant improvements in the time to an adequate clinical response, the duration of ventilation and the number of neonates requiring inotropic drugs with sildenafil.
In a dose‑escalation study of intravenous sildenafil in 36 neonates with PPHN (29 also receiving nitric oxide), the oxygenation index improved after sildenafil treatment. One neonate died and 1 required extracorporeal membrane oxygenation.
In premature neonates at risk of BPD:
a placebo‑controlled RCT (n=20) found oral sildenafil did not improve any short‑term respiratory outcomes and did not reduce the length of invasive or non‑invasive ventilation. There were 3 deaths in the sildenafil group (n=10) and 1 death in the placebo group (n=10).
Sildenafil is contraindicated in combination with nitrates, guanylate cyclase stimulators, potent CYP3A4 inhibitors, severe hepatic impairment, recent history of stroke or myocardial infarction, severe hypotension and non‑arteritic anterior ischaemic optic neuropathy (Revatio 10 mg/ml powder for oral suspension summary of product characteristics).
The safety and efficacy of sildenafil in children below 1 year of age has not been established. Doses higher than the recommended doses should not be used in children with pulmonary hypertension (Revatio 10 mg/ml powder for oral suspension summary of product characteristics).
In most studies, sildenafil was given orally via an orogastric tube.
Data on tolerability from studies of sildenafil in neonates with pulmonary hypertension are limited and relate mainly to hypotension.
The cost of sildenafil as Revatio 10 mg/ml powder for oral suspension is £186.75 for 112 ml. Revatio tablets cost £4.96 per 20 mg tablet and generic sildenafil tablets cost £0.24 per 25 mg tablet (MIMS and Drug Tariff February 2016, all costs excluding VAT).
Most studies of sildenafil in neonates with pulmonary hypertension have been carried out in resource‑limited settings where inhaled nitric oxide was not available.
Introduction and current guidance.
Pulmonary hypertension in neonates represents a heterogeneous group of diagnoses, including PPHN, which are associated with a 10% to 20% mortality rate (Perez and Laughon 2015). Pulmonary hypertension can also occur in premature neonates with BPD.
In term or near‑term neonates with pulmonary hypertension, the pulmonary vasodilator, inhaled nitric oxide, is considered the mainstay of treatment. The role of inhaled nitric oxide in premature neonates is less clear (Shah and Ohlsson 2011). Other treatments that can be used include epoprostenol, sildenafil, magnesium sulfate, milrinone and bosentan. However, none of these are specifically licensed for treating pulmonary hypertension in neonates.
Product overview.
Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cGMP. PDE5 is present in the pulmonary vasculature. Sildenafil therefore increases cGMP within pulmonary vascular smooth muscle cells, resulting in relaxation. This can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilation the systemic circulation in people with pulmonary arterial hypertension (Revatio 10 mg/ml powder for oral suspension summary of product characteristics).
Sildenafil, as Revatio 10 mg/ml powder for oral suspension and Revatio 20 mg tablets, is licensed for treating children aged 1 year and over with pulmonary arterial hypertension. These products are not licensed for use in children less than 1 year of age; therefore the use of sildenafil for pulmonary hypertension in neonates is an off‑label use. Sildenafil is also available as Revatio solution for injection, which is licensed for treating adults with pulmonary arterial hypertension, and generic 25 mg, 50 mg and 100 mg tablets, which are licensed for treating erectile dysfunction.
There is a paediatric investigation plan for Revatio in the treatment of pulmonary arterial hypertension. This covers neonates from birth to less than 1 month of age with PPHN and children from 1 month to less than 18 years of age with pulmonary arterial hypertension. The plan includes a 7‑day open‑label, multicentre pharmacokinetic study of intravenous sildenafil in neonates with PPHN (Steinhorn et al. 2009) and an ongoing, placebo‑controlled RCT, which is investigating the efficacy and safety of intravenous sildenafil plus inhaled nitric oxide for the treatment of neonates with PPHN or hypoxic respiratory failure at risk for PPHN (NCT01720524).
Evidence review.
This evidence summary is based on a Cochrane review and a further systematic review of several small RCTs of sildenafil use in neonates with pulmonary hypertension. The largest observational studies of sildenafil use in this condition are also included. The majority of the evidence is for oral sildenafil use in term or near‑term neonates with PPHN. There is also a small amount of evidence for oral sildenafil use in premature neonates with or at risk of BPD.
The Cochrane review (Shah and Ohlsson 2011) included 3 placebo‑controlled RCTs (total n=77) of sildenafil use in neonates with PPHN. All 3 were single‑centre trials in resource‑limited settings where inhaled nitric oxide, high‑frequency ventilation and extracorporeal membrane oxygenation (ECMO) were not available. Sildenafil was given orally via an orogastric tube in all 3 RCTs, at doses of: 1 mg/kg (which could be doubled to 2 mg/kg) every 6 hours to a maximum of 8 doses or until the oxygenation index improved to less than 20; 2 mg/kg every 6 hours for 72 hours; or 3 mg/kg every 6 hours until the oxygenation index was less than 10.
Sildenafil statistically significantly reduced mortality compared with placebo, with 3 deaths in the sildenafil group (n=40) and 16 deaths in the placebo group (n=37). The typical relative risk (RR) was 0.20; 95% confidence interval (CI) 0.07 to 0.57; typical risk difference (RD) −0.38, 95% CI −0.60 to −0.16; and number needed to treat (NNT) 3, 95% CI 2 to 6.
Physiological parameters of oxygenation suggested a steady improvement after the first dose of sildenafil. The mean oxygenation index after 24 hours of treatment was between 11 and 25 in the sildenafil group (n=39), and between 36 and 52 in the placebo group (n=30). After 24 hours of treatment, the mean partial pressure of oxygen (Pa02) in the sildenafil group (n=32) was 70 to 85 mmHg and 56 to 62 mmHg in the placebo group (n=25).
For sildenafil use in term or near‑term neonates with PPHN, the systematic review (Perez and Laughon 2015) included the same 3 RCTs as the Cochrane review plus Soliz et al. 2009 (a multicentre, placebo‑controlled RCT of oral sildenafil 2 mg/kg every 6 hours in 3 centres where inhaled nitric oxide was not available; abstract only [n=49]).
Using mortality data from the same 3 trials as the Cochrane review (no mortality data were available from Soliz et al. 2009), the systematic review reported similar mortality rates. A statistically significant improvement in oxygenation index was reported for all 4 RCTs. The duration of mechanical ventilation was shorter with sildenafil compared with placebo in 2 RCTs, no difference in 1 RCT and not reported in 1 RCT.
Oral sildenafil was compared with intravenous magnesium sulfate in an RCT in 72 term and near‑term neonates with PPHN in a single centre without facilities for inhaled nitric oxide, high‑frequency ventilation or ECMO (Uslu et al. 2011). The dose of sildenafil was 0.5 mg/kg (which could be doubled to a maximum of 2 mg/kg) via an orogastric tube every 6 hours. There was no difference in the mortality rate between the 2 groups (1 death in the sildenafil group [3.2%] and 2 deaths in the magnesium sulfate group [5.9%], p=0.96). However, the time to an adequate clinical response, the duration of ventilation and the number of neonates requiring inotropic drugs were all statistically significantly improved in the sildenafil group.
A multicentre, open‑label dose escalation study of intravenous sildenafil in 36 term and near‑term neonates with PPHN was conducted in 6 centres in the US, France and the UK where nitric oxide was available (Steinhorn et al. 2009). For all 36 neonates (including 29 also receiving nitric oxide), the oxygenation index improved from a mean of 28 before sildenafil treatment to a mean of 11 after 24 hours of sildenafil treatment (p<0.0001). One neonate died and 1 required ECMO. For the 7 neonates not receiving inhaled nitric oxide, the oxygenation index improved from a mean of 25 before sildenafil treatment to a mean of 15 after 4 hours (p=0.0088).
A retrospective study of oral sildenafil and inhaled iloprost use in 47 neonates with PPHN in a single centre where inhaled nitric oxide and ECMO was not used has been published (Kahveci et al. 2014). The dose of sildenafil was 0.5 mg/kg (doubled to a maximum of 2 mg/kg) via an orogastric tube every 6 hours. In the sildenafil group, 4/27 neonates died compared with 3/20 in the iloprost group. The authors present a statistical analysis comparing the sildenafil and iloprost groups suggesting that iloprost was more effective than sildenafil in terms of inotropic agent use, magnesium sulfate use, mean time to an adequate response and mean duration of mechanical ventilation. However, this was an observational study and there are inherent limitations with the study and therefore the interpretation of the results.
The systematic review (Perez and Laughon 2015) included a single‑centre, placebo‑controlled RCT of oral sildenafil use in 20 premature neonates at risk of BPD (Konig et al. 2014). Neonates receiving nitric oxide were excluded. Sildenafil, at a dose of 1 mg/kg every 8 hours via an orogastric tube for 4 weeks, did not improve any short‑term respiratory outcomes, and did not reduce the length of invasive (median 29 days versus 9 days) or non‑invasive (median 67 days versus 59 days) ventilation compared with placebo. There were 3 deaths in the sildenafil group and 1 death in the placebo group. More neonates in the sildenafil group required postnatal steroid treatment but this was not statistically significant (p=0.091). No controlled trials evaluating the use of sildenafil in premature neonates with BPD‑associated pulmonary hypertension were found.
In a retrospective study of oral sildenafil use in 23 premature neonates with BPD‑associated pulmonary hypertension, oral sildenafil resulted in echocardiographic improvement in 15/21 neonates (71%), but there was clinical improvement in only 8/23 neonates (35%), mostly in the first 48 hours (Trottier-Boucher et al. 2015). Sildenafil was started at a median chronological age of 106 days at an initial dose of 1 mg/kg/day (median dose 4.4 mg/kg/day) for a median of 71 days. Most neonates (21/23) also received inhaled nitric oxide.
In a further retrospective investigation of 19 premature neonates with BPD‑associated pulmonary hypertension, pulmonary hypertension resolved in 10/14 neonates (71%) treated with oral sildenafil and 2/5 neonates (40%) not treated with sildenafil (Wardle et al. 2015). Two babies (14%) treated with sildenafil died at a median of 845 days post diagnosis, and 2 babies (40%) not treated with sildenafil died at a median of 388 days post diagnosis. Sildenafil was given at a dose of 0.5 mg/kg 4 times daily, starting at a median chronological age of 69 days and continuing for a median of 78 days.
The Revatio 10 mg/ml powder for oral suspension summary of product characteristics states that the safety and efficacy of sildenafil in children below 1 year of age has not been established. In a long‑term paediatric extension study of children aged 1–17 years with primary pulmonary hypertension or pulmonary arterial hypertension secondary to congenital heart disease (STARTS-2), an increase in deaths was observed in children given doses higher than the recommended dose, and the summary of product characteristics recommends that doses higher than the recommended doses should not be used in children with pulmonary hypertension.
Data on adverse events from studies of sildenafil in neonates with pulmonary hypertension are limited. The Cochrane review (Shah and Ohlsson 2011) of sildenafil use in a total of 77 neonates with PPHN states that no clinically important adverse effects were identified. A review of the safety of sildenafil in infants was published in 2014 (Samiee-Zafarghandy et al. 2014). This included pharmacokinetic studies of sildenafil in neonates and infants, where higher volumes of distribution, longer serum half‑lives and intra- and interpatient variability in plasma concentrations of sildenafil were seen. In the open‑label dose escalation study of intravenous sildenafil in 36 term and near‑term neonates with PPHN by Steinhorn et al. 2009, 6 treatment‑related adverse events were reported (1 patent ductus arteriosus and 5 reports of hypotension or blood pressure lability). In the placebo‑controlled RCT of oral sildenafil use in 20 premature neonates with evolving BPD by Konig et al. 2014, 1 neonate in the sildenafil group developed hypotension severe enough to require withdrawal from the study. In the retrospective study by Trottier-Boucher et al. 2015, of 23 premature neonates with BPD‑associated pulmonary hypertension who were treated with oral sildenafil, the main adverse event seen was transient hypotension in 10 neonates.
The quality of the evidence for sildenafil use in neonates with pulmonary hypertension is limited. The controlled RCTs in neonates with PPHN are mainly single‑centre, short‑term trials, which enrolled small numbers of patients in resource‑limited settings where inhaled nitric oxide was not available. They provide no information on long‑term efficacy or safety and may not be applicable to UK practice, where standard treatments such as inhaled nitric oxide are routinely available. The other evidence presented in this evidence summary also has limitations being either from small, short‑term controlled trials, an open‑label study with no control group or small, retrospective studies with inherent risks of bias and confounding.
Context and estimated impact for the NHS.
Nitric oxide is considered the mainstay of treatment for pulmonary hypertension in neonates. It is licensed for use in newborn infants of at least 34 weeks’ gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need for ECMO. Other treatments that can be used for pulmonary hypertension in neonates include epoprostenol (which is licensed for use in adults but not children with pulmonary hypertension), sildenafil (which is licensed for children aged 1 and over with pulmonary arterial hypertension, but not children under 1 year), magnesium sulfate (which is not licensed for use in adults or children with pulmonary hypertension), milrinone (which is not licensed for use in adults or children with pulmonary hypertension) and bosentan (which is licensed for children aged 1 year and over with pulmonary arterial hypertension; the summary of product characteristics states that in neonates with PPHN the benefit of bosentan has not been shown in the standard‑of‑care treatment and no recommendation on a posology can be made).
The use of sildenafil for pulmonary hypertension in neonates varies across centres in the UK. A survey of sildenafil use for the treatment of PPHN in tertiary neonatal intensive care units in England and Wales was carried out in December 2013 and January 2014 (Murphy et al. 2014). Sildenafil was used frequently (in more than 5 neonates per year) in 12% of units, infrequently (in between 1 and 5 neonates per year) in 23% of units and rarely (in less than 1 neonate per year) in 51% of units.
The cost of sildenafil as Revatio 10 mg/ml powder for oral suspension is £186.75 for 112 ml. Revatio tablets cost £4.96 per 20 mg tablet and generic sildenafil tablets cost £0.24 per 25 mg tablet (MIMS and Drug Tariff February 2016, all costs excluding VAT). The costs of some of the drugs used for pulmonary hypertension in neonates are given in the full text of this evidence summary.
Information for the public.
A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non‑technical language and may be especially helpful for parents or carers of neonates with pulmonary hypertension who are being treated with sildenafil.
About this evidence summary.
‘Evidence summaries: unlicensed or off‑label medicines’ summarise the published evidence for selected unlicensed or off‑label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies.
The summaries support decision‑making on the use of an unlicensed or off‑label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.
The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance .
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