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Efficacy and tolerability of enteral formulations of ibuprofen in the treatment of patent ductus arteriosus in preterm infants
Clinical Therapeutics/Volume 32, Number 10, 2010
Commentary
Efficacy and Tolerability of Enteral Formulations of Ibuprofen in the Treatment of Patent Ductus Arteriosus in Preterm Infants Jean-Bernard Gouyon, MD1; and Yves Kibleur, MD2 1Service
de Réanimation et Médecine Néonatales, Centre d’Investigation Clinique du CHU de Dijon, Dijon, France; and 2Orphan–Europe, Paris, France
ABSTRACT Background: The persistence of a patent ductus arteriosus (PDA) in preterm infants complicates their clinical course and may contribute to increased morbidity. Intravenous preparations of ibuprofen constitute one of the standard therapies for closure of a PDA. However, the unavailability of intravenous ibuprofen in certain regions of the world and the availability of inexpensive oral preparations has led to off-label nasogastric administration of oral ibuprofen in preterm infants with PDA. Objective: This article reviews and comments on the evidence for the enteral use of oral formulations of racemic ibuprofen for PDA closure in preterm infants, with a focus on the risk of necrotizing enterocolitis (NEC). Methods: MEDLINE, Current Contents, and Google Scholar were searched in April 2010 for trials of enteral ibuprofen in the treatment of PDA in preterm or lowbirth-weight infants using the terms treatment, pharmacokinetics, ibuprofen, oral, enteral, patent ductus arteriosus, PDA, preterm, premature, low birth weight, infant, and newborn. Relevant congress Web sites were also searched for relevant abstracts. Results: The literature search identified 2 pharmacokinetic studies involving 32 infants and 13 clinical efficacy studies involving 306 infants treated with enteral ibuprofen. The clinical studies reported some benefit for enteral ibuprofen relative to the comparators. However, these studies had methodologic limitations, including small numbers of subjects, lack of blinding, inclusion of preterm infants with a higher gestational age, customized treatment regimens, and second-order statistical error that prevented conduct of a systematic review. When the results of all studies were pooled, NEC was reported in a total of 46 of 281 infants (16%) receiving enteral ibuprofen and 21 of 83 infants (25%) receiving 1740
indomethacin. This rate of NEC with enteral ibuprofen was twice that reported for intravenous ibuprofen in a recent meta-analysis (27/356 [8%]). Conclusions: The evidence supporting the off-label use of enteral ibuprofen for PDA in preterm infants is weak. Well-designed, appropriately powered pharmacologic and controlled clinical studies are needed before use of enteral ibuprofen can be recommended. In countries where an intravenous formulation of racemic ibuprofen is approved, off-label use of enteral racemic ibuprofen cannot be supported. (Clin Ther. 2010; 32:1740–1748) © 2010 Excerpta Medica Inc. Key words: ibuprofen, preterm infant, PDA, methodology, enteral, NEC, cost.
INTRODUCTION In neonatal intensive care units (NICUs), intravenous formulations of ibuprofen constitute one of the standard therapies for closure of a hemodynamically significant patent ductus arteriosus (HsPDA) in preterm infants. HsPDA has been reported to occur in up to 65% of infants born at <28 weeks of gestation, particularly those with respiratory disease.1–3 The ductus arteriosus is a physiologic vessel that shunts the pulmonary blood flow during fetal life. In full-term infants, this vessel closes spontaneously within the first hours of life; in preterm infants, it may remain open for many days.4 Because a portion of the blood that should flow through the aorta returns to the lungs, PDA may lead to hemodynamic disturbances related to the degree of left-to-right shunting. HsPDA may promote Accepted for publication August 2, 2010. doi:10.1016/j.clinthera.2010.08.011 0149-2918/$ - see front matter © 2010 Excerpta Medica Inc. All rights reserved.
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J.-B. Gouyon and Y. Kibleur an increase in pulmonary blood flow, cardiac overload, a drop in diastolic blood pressure with systemic hypotension, and a decrease in organ perfusion (ie, diversion of blood from the cerebral and peripheral [renal, mesenteric] circulation).5 HsPDA may be complicated by such severe clinical conditions as intraventricular hemorrhage, worsening of respiratory distress syndrome, bronchopulmonary dysplasia, renal insufficiency, and necrotizing enterocolitis (NEC), a syndrome of inflammation and necrosis of the small and large intestines5–7 that has been reported to occur in ~5% to 10% of very-lowbirth-weight infants.8 HsPDA may be treated with the NSAIDs ibuprofen or indomethacin,2,3 administered intravenously to avoid the digestive complications (NEC, bowel perforation) that have been associated with enteral administration of indomethacin.9–11 Oral formulations of ibuprofen, which have been available for other indications for some 40 years,12 have been reported to be directly harmful to the digestive mucosa compared with placebo in healthy adult volunteers.13,14 Two well-designed randomized, double-blind, controlled trials in preterm infants (148 with a gestational age of <33 weeks and 175 with a gestational age of <35 weeks) reported comparable rates of HsPDA closure with the use of intravenous ibuprofen and intravenous indomethacin (70% and 73%, respectively, in one study and 66% and 70% in the other).2,3 In some cases, the use of commercially available enteral formulations of ibuprofen (ie, administered by the gastric route) in infants with HsPDA has been justified by the unavailability of an intravenous formulation.15–29 Unexpectedly, this off-label use of enteral ibuprofen appears to be increasing in Europe; a recent survey found that 29% of NICUs employed this therapeutic strategy.30 An intravenous formulation of ibuprofen was specifically developed for the treatment of preterm infants with HsPDA and was approved in Europe in 2004.31 The recommended course of intravenous ibuprofen for this indication is 10 mg/kg, followed by 5 mg/kg administered 24 and 48 hours later.31 The intravenous formulation of ibuprofen has been reported to have good gastrointestinal tolerability in preterm infants, with no impairment of mesenteric blood flow.2,3,32 The present review evaluated the evidence for the enteral use of oral formulations of racemic ibuprofen for PDA closure in preterm infants, with a focus on the risk of NEC. September 2010
PATIENTS AND METHODS A search of MEDLINE, Current Contents, and Google Scholar was conducted in April 2010 for trials of enteral ibuprofen in the treatment of PDA in preterm or lowbirth-weight infants using the terms treatment, pharmacokinetics, ibuprofen, oral, enteral, patent ductus arteriosus, PDA, preterm, premature, low birth weight, infant, and newborn. Relevant congress Web sites (Pediatric Academic Societies, European Society for Paediatric Research, and the Journées Francophones de Recherche en Néonatalogie) were also searched for relevant abstracts. There were no limitations as to date of publication, type of publication, or language. All reports of randomized or open-label studies comparing enteral ibuprofen with intravenous ibuprofen, placebo, no intervention, or the reference comparator (indomethacin) in the closure of PDA, diagnosed either clinically or by echocardiographic criteria, in preterm and/or low-birth-weight infants were selected for review. Publications had to report pharmacokinetic parameters or mean and/or individual data on patients’ clinical condition after a first partial and/or complete course of enteral ibuprofen for closure of PDA (primary outcome). When available, data were extracted on the methods used to diagnose PDA, the ibuprofen regimen, the number of patients overall and per group, the comparator regimen (including mode of administration), efficacy results for the first course of treatment with enteral ibuprofen, adverse events, and statistical analysis. The limited data made it impossible to perform a systematic review and meta-analysis.33 No statistical analysis of efficacy could be performed using odds ratios; therefore, only pooled rates of PDA closure and NEC were reported.
RESULTS Pharmacokinetics of Enteral Ibuprofen in Preterm Infants Only 2 studies were identified that reported on the pharmacokinetics of enteral ibuprofen in preterm infants. In a well-described study, Sharma et al34 evaluated the pharmacokinetics of a single dose of enteral ibuprofen 10 mg/kg, administered between 4 and 72 hours after birth, in 20 preterm infants with a gestational age ranging from 26 to 32 weeks (mean [SD] gestational age, 30.5 [1.5] weeks; mean birth weight, 1262 [248] g). The mean Cmax was 20 (14.9) μg/mL, the mean Tmax was 3 (1) hours, and the mean plasma elimination t1/2 was 16 (17) hours. 1741
Clinical Therapeutics Barzilay et al35 presented an abstract of a study in which a single dose of enteral ibuprofen 10 mg/kg was administered between 24 and 72 hours after birth in 12 preterm infants with a PDA (mean [SD] gestational age, 27.8 [2.4] weeks; mean birth weight, 1052 [443] g). The mean Cmax was 38 (22) μg/mL; Tmax and t1/2 were provided only graphically.
Clinical Studies of Enteral Ibuprofen in Preterm Infants With HsPDA The literature search identified 13 clinical efficacy studies (most of them pilot studies) in which a total of 306 preterm infants with HsPDA were treated with various oral formulations of ibuprofen (Table).15–27 These studies had various methodologic limitations, including small sample sizes and lack of statistical power,15–24,27 lack of a control group,16,18,23,26 unrecorded regimen or timing of administration of ibuprofen or the comparator,16,17,20,22,24,26,27 and, most important, inclusion primarily of infants with a favorable prognosis (ie, higher gestational age and/or birth weight).15–17,19,21–24,26 All comparative studies suggested an efficacy benefit for enteral ibuprofen over indomethacin, with pooled PDA closure rates of 88% (269/306) and 77% (64/83), respectively. Only the study by Cherif et al25 directly compared enteral and intravenous ibuprofen. This study found a significant benefit of enteral versus intravenous ibuprofen (closure rate, 84% vs 63%, respectively; P = 0.04). However, the study was limited by an inadequate sample size and categorization of digestive complications according to their time of occurrence. Overall, there were 17 cases of gastrointestinal hemorrhage in infants receiving oral ibuprofen.15,20,23,25 Feeding intolerance was reported in 48 of the 80 infants (60%) receiving oral ibuprofen in one study.26 When the results of all studies were pooled, NEC was reported in a total of 46 of 281 patients (16%) receiving enteral ibuprofen, compared with 21 of 83 patients (25%) receiving indomethacin by the oral or intravenous route.
DISCUSSION Two large randomized controlled studies found ibuprofen to be better tolerated than intravenous indomethacin in the closure of PDA in preterm infants, with comparable efficacy.2,3 Data from these and other studies supported the recent registration of intravenous ibuprofen in both Europe31 and the United States.36 The off-label use of enteral ibuprofen for the closure of PDA in some countries may be explained by the unavailability 1742
of intravenous formulations. However, although intravenous ibuprofen is commercially available for the closure of PDA in European countries, off-label use of enteral ibuprofen has been reported in 29% of NICUs,30 the most probable reason being the relatively low cost of enteral ibuprofen. The standard course of intravenous ibuprofen treatment for HsPDA is 10, 5, and 5 mg/kg administered 24 hours apart (ie, a total of 20 mg/kg body weight), for a cost of approximately €200/kg in Europe31 and approximately €300/kg in the United States.36 On the other hand, the cost of oral ibuprofen syrup for the newborn is approximately €0.17/mg in Europe; therefore, a full course of treatment for PDA would cost €3.4/kg, 60 to 75 times less than the cost of a full course of intravenous ibuprofen. However, the choice of treatment must be guided by an understanding of the pharmacokinetics, efficacy, and safety profile of enteral ibuprofen. Pharmacokinetic studies of ibuprofen in healthy adults have not reported any difference in bioavailability between oral and intravenous formulations.37 In studies of oral ibuprofen in children with cystic fibrosis38 and in febrile children,39 ibuprofen pharmacokinetics were reported to be unaffected by age. A pharmacokinetic study of intravenous ibuprofen in preterm infants reported a mean (SD) t1/2 of 43 (26) hours and a Cmax of 43.5 (11.2) mg/L.40 In studies of enteral ibuprofen, the elimination t1/2 was numerically shorter and the Cmax was both numerically lower and delayed.34,35 The plasma t1/2 after intravenous administration of ibuprofen was numerically longer in lowergestational-age infants40 compared with that after the same dose (corrected in mg/kg) in less premature infants.34 The longer t1/2 after intravenous administration in the lower-gestational-age infants may be explained by less active metabolism in these infants.40 The ibuprofen Cmax was numerically lower with administration by the enteral route compared with the intravenous route.34 The occurrence of reduced bioavailability, a gestational age–related decrease in volume of distribution, and a gestational age–related increase in ibuprofen metabolism may also be hypothesized. Despite the weak relationship between NSAID Cmax and the closure of PDA,41 use of the enteral formulation of ibuprofen over the intravenous formulation is not supported by its low and delayed Cmax. The clinical trials of enteral ibuprofen in preterm infants with HsPDA were investigator initiated and were limited by methodologic weaknesses (Table). This Volume 32 Number 10
September 2010 Oral ibuprofen 10, 5, and 5 mg/kg, 12 h apart
13 Infants; gestational age, 28–35 wk; birth weight, 1100–2300 g
18 Infants; gestational age, <34 wk; mean (SD) birth weight, 1450 (500) g
22 Infants; gestational age, 24–31 wk; birth weight, 380–1500 g
30 Infants; gestational age, <34 wk; mean (SD) birth weight, 1400 (400) g
Hariprasad et al16 (India)
Supapannachart et al17 (Thailand)
Heyman et al18 (Israel)
Chotigeat et al19 (Thailand)
3 Doses of oral ibuprofen, 24 h apart (n = 15) 3 Doses of IV indomethacin, 12 h apart (n = 15)
Oral ibuprofen 10 mg/kg (n = 14) Oral ibuprofen 10 and 5 mg/kg, 24 h apart (n = 6) Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 2)
Oral ibuprofen 10, 10, and 10 mg/kg, 24 h apart (n = 9) IV indomethacin 0.2, 0.2, and 0.2 mg/kg, 12 h apart (n = 9)
Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 12) IV indomethacin 0.2, 0.2, and 0.2 mg/kg, 12 h apart (n = 11)
Regimens
23 Infants; gestational age, 28–34 wk; birth weight, 1050–2000 g
Patient Population
Akısü et al15 (Turkey)
Authors (Country)
6 (40%) ibuprofen vs 9 (60%) indomethacin (P = NS)
21 (95%)
7 (78%) ibuprofen vs 8 (89%) indomethacin (P = NS)
11 (85%)
10 (83%) ibuprofen vs 8 (73%) indomethacin (P = NS)
Rate of PDA Closure
NEC: 6 (40%) ibuprofen and 10 (67%) indomethacin
NEC: 1
NEC: 1 ibuprofen and 3 indomethacin
Not reported
No NEC; GI hemorrhage: 2 (17%) ibuprofen and 1 (9%) indomethacin
GI Adverse Events
(continued)
Small sample size; regimens not specified
Small sample size; only 2 infants received fulldose regimen; no control group
Small sample size; ibuprofen regimen double the recommended maintenance dose via the IV route
Small sample size; no control group; retrospective design; doses given at half the recommended time interval; letter to editor
Small sample size; available in English only as an abstract
Study Limitations
Table. Studies of enteral ibuprofen in the treatment of preterm infants with hemodynamically significant patent ductus arteriosus (PDA).
J.-B. Gouyon and Y. Kibleur
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1744
36 Infants; mean (SD) gestational age, 31.2 (1.7) wk; mean birth weight, 1590 (372) g
40 Infants; gestational age, 25– 31.5 wk; birth weight, 630–1770 g
Fakhraee et al22 (Iran)
Cherif et al23 (Tunisia) Oral ibuprofen 10 mg/kg (n = 24) Oral ibuprofen 10 and 5 mg/kg, 24 h apart (n = 10) Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 6)
Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 18) Oral indomethacin 0.2, 0.2, and 0.2 mg/kg, 24 h apart (n = 18)
21 Infants; gestational Oral ibuprofen 10, 5, and age, 27–35 wk; mean 5 mg/kg, 24 h apart (SD) birth weight, (n = 12) 1702 (440) g IV indomethacin 0.2, 0.2, and 0.2 mg/kg, 12 h apart (n = 9)
Aly et al21 (Egypt)
Oral ibuprofen 10, 10, and 10 mg/kg, 24 h apart (n = 22) Orange-starch suspension, 3 doses 24 h apart (n = 20)
Regimens
42 Infants; gestational age, 28–32 wk; mean (SD) birth weight, 1280 (80) g
Patient Population
Sangtawesin et al20 (Thailand)
Authors (Country)
Table (continued).
38 (95%)
18 (100%) ibuprofen vs 15 (83%) indomethacin (P = NS)
10 (83%) ibuprofen vs 7 (78%) indomethacin (P = NS)
21 (95%) vs 13 (65%) orange-starch suspension (P < 0.01)
Rate of PDA Closure
NEC: 8 (20%); GI hemorrhage: 2 (5%)
NEC: 0 ibuprofen and 3 indomethacin
No NEC or GI hemorrhage in either group
NEC: 8 (36%) ibuprofen and 6 (30%) orangestarch suspension; GI hemorrhage: 12 (55%) and 6 (30%), respectively
GI Adverse Events
(continued)
Only 6 infants received full-dose regimen; no control group
Comparator regimen given at twice the recommended time interval; use of oral indomethacin
Small sample size
Small sample size; ibuprofen regimen was double the recommended maintenance dose via the IV route
Study Limitations
Clinical Therapeutics
Volume 32 Number 10
September 2010 Oral ibuprofen 10, 5, 5, 5, 5, and 5 mg/kg, 24 h apart
80 Infants; gestational age, <32 wk; birth weight, 500–2000 g
41 Infants; mean (SD) gestational age, 27.7 (2.6) wk; mean birth weight, 1073 (640) g
Manjunath and Hariram26 (India)
Salama et al27 (Qatar)
NEC = necrotizing enterocolitis; GI = gastrointestinal.
Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 21) IV indomethacin 0.2, 0.2, and 0.2 mg/kg, 24 h apart (n = 20)
Oral ibuprofen 10 mg/kg (n = 11) Oral ibuprofen 10 and 5 mg/kg, 24 h apart (n = 8) Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 13) IV ibuprofen 10, 5, and 5 mg/kg (n = 32)
64 Infants; gestational age, 25.0–31.5 wk; birth weight, 630– 1470 g
Cherif et al25 (Tunisia)
Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 10) Oral indomethacin 0.2, 0.2, and 0.2 mg/kg, 24 h apart (n = 10)
Regimens
20 Infants; mean (SD) gestational age, 32.1 (3.7) wk; mean birth weight, 1790 (516) g
Patient Population
Pourarian et al24 (Iran)
Authors (Country)
Table (continued).
14 (67%) ibuprofen vs 10 (50%) indomethacin
68 (85%)
27 (84%) oral ibuprofen vs 20 (63%) IV ibuprofen (P = 0.04)
8 (80%) ibuprofen vs 7 (70%) indomethacin (P = NS)
Rate of PDA Closure
NEC: 2 (10%) ibuprofen and 5 (25%) indomethacin
NEC: 14 (18%); feeding intolerance: 48 (60%)
NEC: 6 (19%) oral ibuprofen and 4 (13%) IV ibuprofen; GI hemorrhage: 1 (3%) and 0, respectively
No NEC or GI hemorrhage in either group
GI Adverse Events
Small sample size; comparator regimen given at twice the recommended time interval
No control group; use of longer-than-recommended regimen; available in English only as an abstract
Lack of statistical power; small sample size received full-dose regimen of oral ibuprofen; use of IV ibuprofen as backup treatment if oral ibuprofen failed
Small sample size; only the first patient was randomized; comparator regimen given at twice the time interval; use of oral indomethacin
Study Limitations
J.-B. Gouyon and Y. Kibleur
1745
Clinical Therapeutics becomes particularly evident when these trials are compared with the 2 main efficacy studies of intravenous ibuprofen and intravenous indomethacin,2,3 which employed comparable methods, had large sample sizes, and reached consistent conclusions. Most of the reviewed studies involved limited numbers of patients and were therefore subject to statistical bias.15–24,27 (In one study, only 2 of 22 infants received a full course of therapy.18) Moreover, 9 of the 13 studies included preterm infants of greater gestational age and/or birth weight (ie, with a good clinical prognosis and high likelihood of spontaneous closure of PDA).15–17,19,21–24,26 Four studies had no control group.16,18,23,26 The dosing regimens used were either unspecified19 or were used at half the recommended dosing interval for ibuprofen (12 rather than 24 hours apart),16 twice the recommended dosing interval for the comparator (24 rather than 12 hours apart),20,22,24 double the recommended maintenance dose (10 rather than 5 mg/kg),17,20 or for a prolonged duration (5 rather than 2 maintenance doses).26 One of the studies was retrospective.16 Despite the 95% rate of PDA closure reported in a pilot study of enteral ibuprofen,23 a related study lacked statistical power and used the intravenous formulation as a backup treatment if enteral ibuprofen failed.25 Based on these limitations, the current perception of the efficacy of enteral ibuprofen for closure of PDA in preterm infants may be misguided. The assessment of adverse events in retrospective studies or in prospective studies with small sample sizes is unreliable and of poor methodologic quality. When the results of the 13 studies were pooled, NEC was reported in a total of 46 of 281 infants receiving enteral ibuprofen (16%), comparable to the rate with indomethacin (21/83 [25%]). In one study, rates of immediate and secondary NEC with enteral and intravenous ibuprofen were 19% and 13%, respectively.25 These rates of NEC with enteral ibuprofen were twice the overall rate reported for intravenous ibuprofen (27/356 [8%]) in a recent meta-analysis of studies in preterm infants with HsPDA.42 In adults, enteral ibuprofen has been associated with increases in intestinal permeability in proportion to its cyclooxygenase-inhibitory potency through disruption of the intestinal barrier at the level of intercellular junctions.13 Moreover, the hyperosmolarity of most currently available oral formulations of ibuprofen (mean [SD] osmolarity, 1495 [39]–4222 [136] mOsm/kg H2O) may be an additional risk factor for NEC, making these formulations inappropriate for 1746
enteral administration in preterm infants, particularly without dilution.43 In regions where intravenous formulations are available for the closure of PDA in preterm infants, off-label use of enteral ibuprofen cannot be recommended. In regions where no intravenous formulations are available, a registry of preterm infants treated with enteral ibuprofen could improve understanding of the efficacy and safety profile of this regimen.
CONCLUSIONS This commentary highlights the lack of strong evidence supporting the use of enteral ibuprofen in preterm infants with HsPDA in countries where an intravenous formulation is available. Well-designed and appropriately powered pharmacologic and controlled clinical studies are needed before enteral ibuprofen can be recommended for this indication.
ACKNOWLEDGMENTS Dr. Gouyon serves as a consultant for Orphan–Europe and has been involved in the preparation of reports supporting the European authorization of intravenous ibuprofen. Dr. Kibleur is an employee of Orphan– Europe. The authors have indicated that they have no other conflicts of interest with regard to the content of this article. Both authors contributed equally to the writing and review of the manuscript.
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in premature infants. J Clin Pharmacol. 2003;43:968–973. Barzilay B, Batash D, Keidar R, et al. Oral ibuprofen maintains therapeutic levels for longer time compared to intravenous ibuprofen in preterm infants. Presented at: 50th Annual Meeting of the European Society for Paediatric Research; October 9–12, 2009; Hamburg, Germany. Poon G. Ibuprofen lysine (NeoProfen) for the treatment of patent ductus arteriosus. Proc (Baylor Univ Med Cent). 2007;20:83–85. Davies NM. Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin Pharmacokinet. 1998;34:101– 154. Konstan MW, Hoppel CL, Chai BL, Davis PB. Ibuprofen in children with cystic fibrosis: Pharmacokinetics and adverse effects. J Pediatr. 1991; 118:956–964. Nahata MC, Durrell DE, Powell DA, Gupta N. Pharmacokinetics of ibuprofen in febrile children. Eur J Clin Pharmacol. 1991;40:427–428. Van Overmeire B, Touw D, Schepens PJ, et al. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther. 2001;70:336–343. Clyman RI. Medical treatment of patent ductus arteriosus in premature infants. In: Long WA, ed. Fetal and Neonatal Cardiology. Philadelphia, Pa: WB Saunders; 1990:64– 75. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2010; (4):CD003481. Pereira-da-Silva L, Pita A, Virella D, Serelha M. Oral ibuprofen for patent ductus arteriosus closure in preterm infants: Does high osmolality matter? Am J Perinatol. 2008;25: 319–320.
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Address correspondence to: Prof. Dr. Jean-Bernard Gouyon, Service de Réanimation et Médecine Néonatales, Centre d’Investigation Clinique du CHU de Dijon, CHU du Bocage, 1 Boulevard Jeanne d’Arc, 21000 Dijon, France. E-mail: [email protected] Volume 32 Number 10
Commentary
Efficacy and Tolerability of Enteral Formulations of Ibuprofen in the Treatment of Patent Ductus Arteriosus in Preterm Infants Jean-Bernard Gouyon, MD1; and Yves Kibleur, MD2 1Service
de Réanimation et Médecine Néonatales, Centre d’Investigation Clinique du CHU de Dijon, Dijon, France; and 2Orphan–Europe, Paris, France
ABSTRACT Background: The persistence of a patent ductus arteriosus (PDA) in preterm infants complicates their clinical course and may contribute to increased morbidity. Intravenous preparations of ibuprofen constitute one of the standard therapies for closure of a PDA. However, the unavailability of intravenous ibuprofen in certain regions of the world and the availability of inexpensive oral preparations has led to off-label nasogastric administration of oral ibuprofen in preterm infants with PDA. Objective: This article reviews and comments on the evidence for the enteral use of oral formulations of racemic ibuprofen for PDA closure in preterm infants, with a focus on the risk of necrotizing enterocolitis (NEC). Methods: MEDLINE, Current Contents, and Google Scholar were searched in April 2010 for trials of enteral ibuprofen in the treatment of PDA in preterm or lowbirth-weight infants using the terms treatment, pharmacokinetics, ibuprofen, oral, enteral, patent ductus arteriosus, PDA, preterm, premature, low birth weight, infant, and newborn. Relevant congress Web sites were also searched for relevant abstracts. Results: The literature search identified 2 pharmacokinetic studies involving 32 infants and 13 clinical efficacy studies involving 306 infants treated with enteral ibuprofen. The clinical studies reported some benefit for enteral ibuprofen relative to the comparators. However, these studies had methodologic limitations, including small numbers of subjects, lack of blinding, inclusion of preterm infants with a higher gestational age, customized treatment regimens, and second-order statistical error that prevented conduct of a systematic review. When the results of all studies were pooled, NEC was reported in a total of 46 of 281 infants (16%) receiving enteral ibuprofen and 21 of 83 infants (25%) receiving 1740
indomethacin. This rate of NEC with enteral ibuprofen was twice that reported for intravenous ibuprofen in a recent meta-analysis (27/356 [8%]). Conclusions: The evidence supporting the off-label use of enteral ibuprofen for PDA in preterm infants is weak. Well-designed, appropriately powered pharmacologic and controlled clinical studies are needed before use of enteral ibuprofen can be recommended. In countries where an intravenous formulation of racemic ibuprofen is approved, off-label use of enteral racemic ibuprofen cannot be supported. (Clin Ther. 2010; 32:1740–1748) © 2010 Excerpta Medica Inc. Key words: ibuprofen, preterm infant, PDA, methodology, enteral, NEC, cost.
INTRODUCTION In neonatal intensive care units (NICUs), intravenous formulations of ibuprofen constitute one of the standard therapies for closure of a hemodynamically significant patent ductus arteriosus (HsPDA) in preterm infants. HsPDA has been reported to occur in up to 65% of infants born at <28 weeks of gestation, particularly those with respiratory disease.1–3 The ductus arteriosus is a physiologic vessel that shunts the pulmonary blood flow during fetal life. In full-term infants, this vessel closes spontaneously within the first hours of life; in preterm infants, it may remain open for many days.4 Because a portion of the blood that should flow through the aorta returns to the lungs, PDA may lead to hemodynamic disturbances related to the degree of left-to-right shunting. HsPDA may promote Accepted for publication August 2, 2010. doi:10.1016/j.clinthera.2010.08.011 0149-2918/$ - see front matter © 2010 Excerpta Medica Inc. All rights reserved.
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J.-B. Gouyon and Y. Kibleur an increase in pulmonary blood flow, cardiac overload, a drop in diastolic blood pressure with systemic hypotension, and a decrease in organ perfusion (ie, diversion of blood from the cerebral and peripheral [renal, mesenteric] circulation).5 HsPDA may be complicated by such severe clinical conditions as intraventricular hemorrhage, worsening of respiratory distress syndrome, bronchopulmonary dysplasia, renal insufficiency, and necrotizing enterocolitis (NEC), a syndrome of inflammation and necrosis of the small and large intestines5–7 that has been reported to occur in ~5% to 10% of very-lowbirth-weight infants.8 HsPDA may be treated with the NSAIDs ibuprofen or indomethacin,2,3 administered intravenously to avoid the digestive complications (NEC, bowel perforation) that have been associated with enteral administration of indomethacin.9–11 Oral formulations of ibuprofen, which have been available for other indications for some 40 years,12 have been reported to be directly harmful to the digestive mucosa compared with placebo in healthy adult volunteers.13,14 Two well-designed randomized, double-blind, controlled trials in preterm infants (148 with a gestational age of <33 weeks and 175 with a gestational age of <35 weeks) reported comparable rates of HsPDA closure with the use of intravenous ibuprofen and intravenous indomethacin (70% and 73%, respectively, in one study and 66% and 70% in the other).2,3 In some cases, the use of commercially available enteral formulations of ibuprofen (ie, administered by the gastric route) in infants with HsPDA has been justified by the unavailability of an intravenous formulation.15–29 Unexpectedly, this off-label use of enteral ibuprofen appears to be increasing in Europe; a recent survey found that 29% of NICUs employed this therapeutic strategy.30 An intravenous formulation of ibuprofen was specifically developed for the treatment of preterm infants with HsPDA and was approved in Europe in 2004.31 The recommended course of intravenous ibuprofen for this indication is 10 mg/kg, followed by 5 mg/kg administered 24 and 48 hours later.31 The intravenous formulation of ibuprofen has been reported to have good gastrointestinal tolerability in preterm infants, with no impairment of mesenteric blood flow.2,3,32 The present review evaluated the evidence for the enteral use of oral formulations of racemic ibuprofen for PDA closure in preterm infants, with a focus on the risk of NEC. September 2010
PATIENTS AND METHODS A search of MEDLINE, Current Contents, and Google Scholar was conducted in April 2010 for trials of enteral ibuprofen in the treatment of PDA in preterm or lowbirth-weight infants using the terms treatment, pharmacokinetics, ibuprofen, oral, enteral, patent ductus arteriosus, PDA, preterm, premature, low birth weight, infant, and newborn. Relevant congress Web sites (Pediatric Academic Societies, European Society for Paediatric Research, and the Journées Francophones de Recherche en Néonatalogie) were also searched for relevant abstracts. There were no limitations as to date of publication, type of publication, or language. All reports of randomized or open-label studies comparing enteral ibuprofen with intravenous ibuprofen, placebo, no intervention, or the reference comparator (indomethacin) in the closure of PDA, diagnosed either clinically or by echocardiographic criteria, in preterm and/or low-birth-weight infants were selected for review. Publications had to report pharmacokinetic parameters or mean and/or individual data on patients’ clinical condition after a first partial and/or complete course of enteral ibuprofen for closure of PDA (primary outcome). When available, data were extracted on the methods used to diagnose PDA, the ibuprofen regimen, the number of patients overall and per group, the comparator regimen (including mode of administration), efficacy results for the first course of treatment with enteral ibuprofen, adverse events, and statistical analysis. The limited data made it impossible to perform a systematic review and meta-analysis.33 No statistical analysis of efficacy could be performed using odds ratios; therefore, only pooled rates of PDA closure and NEC were reported.
RESULTS Pharmacokinetics of Enteral Ibuprofen in Preterm Infants Only 2 studies were identified that reported on the pharmacokinetics of enteral ibuprofen in preterm infants. In a well-described study, Sharma et al34 evaluated the pharmacokinetics of a single dose of enteral ibuprofen 10 mg/kg, administered between 4 and 72 hours after birth, in 20 preterm infants with a gestational age ranging from 26 to 32 weeks (mean [SD] gestational age, 30.5 [1.5] weeks; mean birth weight, 1262 [248] g). The mean Cmax was 20 (14.9) μg/mL, the mean Tmax was 3 (1) hours, and the mean plasma elimination t1/2 was 16 (17) hours. 1741
Clinical Therapeutics Barzilay et al35 presented an abstract of a study in which a single dose of enteral ibuprofen 10 mg/kg was administered between 24 and 72 hours after birth in 12 preterm infants with a PDA (mean [SD] gestational age, 27.8 [2.4] weeks; mean birth weight, 1052 [443] g). The mean Cmax was 38 (22) μg/mL; Tmax and t1/2 were provided only graphically.
Clinical Studies of Enteral Ibuprofen in Preterm Infants With HsPDA The literature search identified 13 clinical efficacy studies (most of them pilot studies) in which a total of 306 preterm infants with HsPDA were treated with various oral formulations of ibuprofen (Table).15–27 These studies had various methodologic limitations, including small sample sizes and lack of statistical power,15–24,27 lack of a control group,16,18,23,26 unrecorded regimen or timing of administration of ibuprofen or the comparator,16,17,20,22,24,26,27 and, most important, inclusion primarily of infants with a favorable prognosis (ie, higher gestational age and/or birth weight).15–17,19,21–24,26 All comparative studies suggested an efficacy benefit for enteral ibuprofen over indomethacin, with pooled PDA closure rates of 88% (269/306) and 77% (64/83), respectively. Only the study by Cherif et al25 directly compared enteral and intravenous ibuprofen. This study found a significant benefit of enteral versus intravenous ibuprofen (closure rate, 84% vs 63%, respectively; P = 0.04). However, the study was limited by an inadequate sample size and categorization of digestive complications according to their time of occurrence. Overall, there were 17 cases of gastrointestinal hemorrhage in infants receiving oral ibuprofen.15,20,23,25 Feeding intolerance was reported in 48 of the 80 infants (60%) receiving oral ibuprofen in one study.26 When the results of all studies were pooled, NEC was reported in a total of 46 of 281 patients (16%) receiving enteral ibuprofen, compared with 21 of 83 patients (25%) receiving indomethacin by the oral or intravenous route.
DISCUSSION Two large randomized controlled studies found ibuprofen to be better tolerated than intravenous indomethacin in the closure of PDA in preterm infants, with comparable efficacy.2,3 Data from these and other studies supported the recent registration of intravenous ibuprofen in both Europe31 and the United States.36 The off-label use of enteral ibuprofen for the closure of PDA in some countries may be explained by the unavailability 1742
of intravenous formulations. However, although intravenous ibuprofen is commercially available for the closure of PDA in European countries, off-label use of enteral ibuprofen has been reported in 29% of NICUs,30 the most probable reason being the relatively low cost of enteral ibuprofen. The standard course of intravenous ibuprofen treatment for HsPDA is 10, 5, and 5 mg/kg administered 24 hours apart (ie, a total of 20 mg/kg body weight), for a cost of approximately €200/kg in Europe31 and approximately €300/kg in the United States.36 On the other hand, the cost of oral ibuprofen syrup for the newborn is approximately €0.17/mg in Europe; therefore, a full course of treatment for PDA would cost €3.4/kg, 60 to 75 times less than the cost of a full course of intravenous ibuprofen. However, the choice of treatment must be guided by an understanding of the pharmacokinetics, efficacy, and safety profile of enteral ibuprofen. Pharmacokinetic studies of ibuprofen in healthy adults have not reported any difference in bioavailability between oral and intravenous formulations.37 In studies of oral ibuprofen in children with cystic fibrosis38 and in febrile children,39 ibuprofen pharmacokinetics were reported to be unaffected by age. A pharmacokinetic study of intravenous ibuprofen in preterm infants reported a mean (SD) t1/2 of 43 (26) hours and a Cmax of 43.5 (11.2) mg/L.40 In studies of enteral ibuprofen, the elimination t1/2 was numerically shorter and the Cmax was both numerically lower and delayed.34,35 The plasma t1/2 after intravenous administration of ibuprofen was numerically longer in lowergestational-age infants40 compared with that after the same dose (corrected in mg/kg) in less premature infants.34 The longer t1/2 after intravenous administration in the lower-gestational-age infants may be explained by less active metabolism in these infants.40 The ibuprofen Cmax was numerically lower with administration by the enteral route compared with the intravenous route.34 The occurrence of reduced bioavailability, a gestational age–related decrease in volume of distribution, and a gestational age–related increase in ibuprofen metabolism may also be hypothesized. Despite the weak relationship between NSAID Cmax and the closure of PDA,41 use of the enteral formulation of ibuprofen over the intravenous formulation is not supported by its low and delayed Cmax. The clinical trials of enteral ibuprofen in preterm infants with HsPDA were investigator initiated and were limited by methodologic weaknesses (Table). This Volume 32 Number 10
September 2010 Oral ibuprofen 10, 5, and 5 mg/kg, 12 h apart
13 Infants; gestational age, 28–35 wk; birth weight, 1100–2300 g
18 Infants; gestational age, <34 wk; mean (SD) birth weight, 1450 (500) g
22 Infants; gestational age, 24–31 wk; birth weight, 380–1500 g
30 Infants; gestational age, <34 wk; mean (SD) birth weight, 1400 (400) g
Hariprasad et al16 (India)
Supapannachart et al17 (Thailand)
Heyman et al18 (Israel)
Chotigeat et al19 (Thailand)
3 Doses of oral ibuprofen, 24 h apart (n = 15) 3 Doses of IV indomethacin, 12 h apart (n = 15)
Oral ibuprofen 10 mg/kg (n = 14) Oral ibuprofen 10 and 5 mg/kg, 24 h apart (n = 6) Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 2)
Oral ibuprofen 10, 10, and 10 mg/kg, 24 h apart (n = 9) IV indomethacin 0.2, 0.2, and 0.2 mg/kg, 12 h apart (n = 9)
Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 12) IV indomethacin 0.2, 0.2, and 0.2 mg/kg, 12 h apart (n = 11)
Regimens
23 Infants; gestational age, 28–34 wk; birth weight, 1050–2000 g
Patient Population
Akısü et al15 (Turkey)
Authors (Country)
6 (40%) ibuprofen vs 9 (60%) indomethacin (P = NS)
21 (95%)
7 (78%) ibuprofen vs 8 (89%) indomethacin (P = NS)
11 (85%)
10 (83%) ibuprofen vs 8 (73%) indomethacin (P = NS)
Rate of PDA Closure
NEC: 6 (40%) ibuprofen and 10 (67%) indomethacin
NEC: 1
NEC: 1 ibuprofen and 3 indomethacin
Not reported
No NEC; GI hemorrhage: 2 (17%) ibuprofen and 1 (9%) indomethacin
GI Adverse Events
(continued)
Small sample size; regimens not specified
Small sample size; only 2 infants received fulldose regimen; no control group
Small sample size; ibuprofen regimen double the recommended maintenance dose via the IV route
Small sample size; no control group; retrospective design; doses given at half the recommended time interval; letter to editor
Small sample size; available in English only as an abstract
Study Limitations
Table. Studies of enteral ibuprofen in the treatment of preterm infants with hemodynamically significant patent ductus arteriosus (PDA).
J.-B. Gouyon and Y. Kibleur
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1744
36 Infants; mean (SD) gestational age, 31.2 (1.7) wk; mean birth weight, 1590 (372) g
40 Infants; gestational age, 25– 31.5 wk; birth weight, 630–1770 g
Fakhraee et al22 (Iran)
Cherif et al23 (Tunisia) Oral ibuprofen 10 mg/kg (n = 24) Oral ibuprofen 10 and 5 mg/kg, 24 h apart (n = 10) Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 6)
Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 18) Oral indomethacin 0.2, 0.2, and 0.2 mg/kg, 24 h apart (n = 18)
21 Infants; gestational Oral ibuprofen 10, 5, and age, 27–35 wk; mean 5 mg/kg, 24 h apart (SD) birth weight, (n = 12) 1702 (440) g IV indomethacin 0.2, 0.2, and 0.2 mg/kg, 12 h apart (n = 9)
Aly et al21 (Egypt)
Oral ibuprofen 10, 10, and 10 mg/kg, 24 h apart (n = 22) Orange-starch suspension, 3 doses 24 h apart (n = 20)
Regimens
42 Infants; gestational age, 28–32 wk; mean (SD) birth weight, 1280 (80) g
Patient Population
Sangtawesin et al20 (Thailand)
Authors (Country)
Table (continued).
38 (95%)
18 (100%) ibuprofen vs 15 (83%) indomethacin (P = NS)
10 (83%) ibuprofen vs 7 (78%) indomethacin (P = NS)
21 (95%) vs 13 (65%) orange-starch suspension (P < 0.01)
Rate of PDA Closure
NEC: 8 (20%); GI hemorrhage: 2 (5%)
NEC: 0 ibuprofen and 3 indomethacin
No NEC or GI hemorrhage in either group
NEC: 8 (36%) ibuprofen and 6 (30%) orangestarch suspension; GI hemorrhage: 12 (55%) and 6 (30%), respectively
GI Adverse Events
(continued)
Only 6 infants received full-dose regimen; no control group
Comparator regimen given at twice the recommended time interval; use of oral indomethacin
Small sample size
Small sample size; ibuprofen regimen was double the recommended maintenance dose via the IV route
Study Limitations
Clinical Therapeutics
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September 2010 Oral ibuprofen 10, 5, 5, 5, 5, and 5 mg/kg, 24 h apart
80 Infants; gestational age, <32 wk; birth weight, 500–2000 g
41 Infants; mean (SD) gestational age, 27.7 (2.6) wk; mean birth weight, 1073 (640) g
Manjunath and Hariram26 (India)
Salama et al27 (Qatar)
NEC = necrotizing enterocolitis; GI = gastrointestinal.
Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 21) IV indomethacin 0.2, 0.2, and 0.2 mg/kg, 24 h apart (n = 20)
Oral ibuprofen 10 mg/kg (n = 11) Oral ibuprofen 10 and 5 mg/kg, 24 h apart (n = 8) Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 13) IV ibuprofen 10, 5, and 5 mg/kg (n = 32)
64 Infants; gestational age, 25.0–31.5 wk; birth weight, 630– 1470 g
Cherif et al25 (Tunisia)
Oral ibuprofen 10, 5, and 5 mg/kg, 24 h apart (n = 10) Oral indomethacin 0.2, 0.2, and 0.2 mg/kg, 24 h apart (n = 10)
Regimens
20 Infants; mean (SD) gestational age, 32.1 (3.7) wk; mean birth weight, 1790 (516) g
Patient Population
Pourarian et al24 (Iran)
Authors (Country)
Table (continued).
14 (67%) ibuprofen vs 10 (50%) indomethacin
68 (85%)
27 (84%) oral ibuprofen vs 20 (63%) IV ibuprofen (P = 0.04)
8 (80%) ibuprofen vs 7 (70%) indomethacin (P = NS)
Rate of PDA Closure
NEC: 2 (10%) ibuprofen and 5 (25%) indomethacin
NEC: 14 (18%); feeding intolerance: 48 (60%)
NEC: 6 (19%) oral ibuprofen and 4 (13%) IV ibuprofen; GI hemorrhage: 1 (3%) and 0, respectively
No NEC or GI hemorrhage in either group
GI Adverse Events
Small sample size; comparator regimen given at twice the recommended time interval
No control group; use of longer-than-recommended regimen; available in English only as an abstract
Lack of statistical power; small sample size received full-dose regimen of oral ibuprofen; use of IV ibuprofen as backup treatment if oral ibuprofen failed
Small sample size; only the first patient was randomized; comparator regimen given at twice the time interval; use of oral indomethacin
Study Limitations
J.-B. Gouyon and Y. Kibleur
1745
Clinical Therapeutics becomes particularly evident when these trials are compared with the 2 main efficacy studies of intravenous ibuprofen and intravenous indomethacin,2,3 which employed comparable methods, had large sample sizes, and reached consistent conclusions. Most of the reviewed studies involved limited numbers of patients and were therefore subject to statistical bias.15–24,27 (In one study, only 2 of 22 infants received a full course of therapy.18) Moreover, 9 of the 13 studies included preterm infants of greater gestational age and/or birth weight (ie, with a good clinical prognosis and high likelihood of spontaneous closure of PDA).15–17,19,21–24,26 Four studies had no control group.16,18,23,26 The dosing regimens used were either unspecified19 or were used at half the recommended dosing interval for ibuprofen (12 rather than 24 hours apart),16 twice the recommended dosing interval for the comparator (24 rather than 12 hours apart),20,22,24 double the recommended maintenance dose (10 rather than 5 mg/kg),17,20 or for a prolonged duration (5 rather than 2 maintenance doses).26 One of the studies was retrospective.16 Despite the 95% rate of PDA closure reported in a pilot study of enteral ibuprofen,23 a related study lacked statistical power and used the intravenous formulation as a backup treatment if enteral ibuprofen failed.25 Based on these limitations, the current perception of the efficacy of enteral ibuprofen for closure of PDA in preterm infants may be misguided. The assessment of adverse events in retrospective studies or in prospective studies with small sample sizes is unreliable and of poor methodologic quality. When the results of the 13 studies were pooled, NEC was reported in a total of 46 of 281 infants receiving enteral ibuprofen (16%), comparable to the rate with indomethacin (21/83 [25%]). In one study, rates of immediate and secondary NEC with enteral and intravenous ibuprofen were 19% and 13%, respectively.25 These rates of NEC with enteral ibuprofen were twice the overall rate reported for intravenous ibuprofen (27/356 [8%]) in a recent meta-analysis of studies in preterm infants with HsPDA.42 In adults, enteral ibuprofen has been associated with increases in intestinal permeability in proportion to its cyclooxygenase-inhibitory potency through disruption of the intestinal barrier at the level of intercellular junctions.13 Moreover, the hyperosmolarity of most currently available oral formulations of ibuprofen (mean [SD] osmolarity, 1495 [39]–4222 [136] mOsm/kg H2O) may be an additional risk factor for NEC, making these formulations inappropriate for 1746
enteral administration in preterm infants, particularly without dilution.43 In regions where intravenous formulations are available for the closure of PDA in preterm infants, off-label use of enteral ibuprofen cannot be recommended. In regions where no intravenous formulations are available, a registry of preterm infants treated with enteral ibuprofen could improve understanding of the efficacy and safety profile of this regimen.
CONCLUSIONS This commentary highlights the lack of strong evidence supporting the use of enteral ibuprofen in preterm infants with HsPDA in countries where an intravenous formulation is available. Well-designed and appropriately powered pharmacologic and controlled clinical studies are needed before enteral ibuprofen can be recommended for this indication.
ACKNOWLEDGMENTS Dr. Gouyon serves as a consultant for Orphan–Europe and has been involved in the preparation of reports supporting the European authorization of intravenous ibuprofen. Dr. Kibleur is an employee of Orphan– Europe. The authors have indicated that they have no other conflicts of interest with regard to the content of this article. Both authors contributed equally to the writing and review of the manuscript.
REFERENCES 1. Eichenwald EC, Stark AR. Management and outcomes of very low birth weight. N Engl J Med. 2008;358:1700– 1711. 2. Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med. 2000;343:674–681. 3. Lago P, Bettiol T, Salvadori S, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: A randomised controlled trial. Eur J Pediatr. 2002;161:202–207. 4. Clyman RI, Mauray F, Roman C, et al. Factors determining the loss of ductus arteriosus responsiveness to prostaglandin E. Circulation. 1983;68:433–436. 5. Hammerman C, Kaplan M. Patent ductus arteriosus in the premature neonate: Current concepts in pharmacological management. Paediatr Drugs. 1999;1:81–92. 6. Ryder RW, Shelton JD, Guinan ME. Necrotizing enterocolitis: A prospective multicenter investigation. Am J Epidemiol. 1980;112:113–123.
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J.-B. Gouyon and Y. Kibleur 7. Cassady G, Crouse DT, Kirklin JW, et al. A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N Engl J Med. 1989;320:1511– 1516. 8. Fanaroff AA, Stoll BJ, Wright LL, et al, for the NICHD Neonatal Research Network. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol. 2007;196:147.e1–147.e8. 9. Nagaraj HS, Sandhu AS, Cook LN, et al. Gastrointestinal perforation following indomethacin therapy in very low birth weight infants. J Pediatr Surg. 1981;16:1003–1007. 10. Alpan G, Eyal F, Vinograd I, et al. Localized intestinal perforations after enteral administration of indomethacin in premature infants. J Pediatr. 1985;106:277–281. 11. Shorter NA, Liu JY, Mooney DP, Harmon BJ. Indomethacin-associated bowel perforations: A study of possible risk factors. J Pediatr Surg. 1999; 34:442–444. 12. Adams SS, McCullough KF, Nicholson JS. The pharmacological properties of ibuprofen, an antiinflammatory, analgesic and antipyretic agent. Arch Int Pharmacodyn Ther. 1969;178:115–129. 13. Müller P, Simon B. Effects of ibuprofen lysinate and acetylsalicylic acid on gastric and duodenal mucosa. Randomized single-blind placebo-controlled endoscopic study in healthy volunteers. Arzneimittelforschung. 1994;44:840–843. 14. Bjarnason I, Williams P, Smethurst P, et al. Effect of non-steroidal antiinflammatory drugs and prostaglandins on the permeability of the human small intestine. Gut. 1986; 27:1292–1297. 15. Akısü M, Özyürek AR, Dorak C, et al. Enteral ibuprofen versus indomethacin in the treatment of PDA in preterm newborn infants [in Turkish]. Çocuk Saglıgı ve Hastalıkları Dergisi. 2001;44:56–60.
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16. Hariprasad P, Sundarrajan V, Srimathy G, et al. Oral ibuprofen for closure of hemodynamically significant PDA in premature neonates. Indian Pediatr. 2002;39:99–100. 17. Supapannachart S, Limrungsikul A, Khowsathit P. Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: A randomized trial at Ramathibodi Hospital. J Med Assoc Thai. 2002;85(Suppl 4):S1252–S1258. 18. Heyman E, Morag I, Batash D, et al. Closure of patent ductus arteriosus with oral ibuprofen suspension in premature newborns: A pilot study. Pediatrics. 2003;112:e354. 19. Chotigeat U, Jirapapa K, Layangkool T. A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants. J Med Assoc Thai. 2003;86(Suppl 3):S563–S569. 20. Sangtawesin V, Sangtawesin C, Raksasinborisut C, et al. Oral ibuprofen prophylaxis for symptomatic patent ductus arteriosus of prematurity. J Med Assoc Thai. 2006;89: 314–321. 21. Aly H, Lotfy W, Badrawi N, et al. Oral Ibuprofen and ductus arteriosus in premature infants: A randomized pilot study. Am J Perinatol. 2007;24:267–270. 22. Fakhraee SH, Badiee Z, Mojtahedzadeh S, et al. Comparison of oral ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Zhongguo Dang Dai Er Ke Za Zhi. 2007;9:399–403. 23. Cherif A, Jabnoun S, Khrouf N. Oral ibuprofen in early curative closure of patent ductus arteriosus in very premature infants. Am J Perinatol. 2007;24:339–345. 24. Pourarian S, Pishva N, Madani A, Rastegari M. Comparison of oral ibuprofen and indomethacin on closure of patent ductus arteriosus in preterm infants. East Mediterr Health J. 2008;14:360–365. 25. Cherif A, Khrouf N, Jabnoun S, et al. Randomized pilot study comparing
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Address correspondence to: Prof. Dr. Jean-Bernard Gouyon, Service de Réanimation et Médecine Néonatales, Centre d’Investigation Clinique du CHU de Dijon, CHU du Bocage, 1 Boulevard Jeanne d’Arc, 21000 Dijon, France. E-mail: [email protected] Volume 32 Number 10