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Common Clinical and Practical Questions on the Use of Intravenous

9.13.2018 | Christian Lawman

13) to the percentage of infants (25%) receiving a second course of ibuprofen treatment (surrogate for rescue) in 2 separay published active-controlled treatment trials. No placebo-controlled trials with ibuprofen for the treatment of PDA have been published; however, the pooled rescue rate from the 2 treatment trials reviewed above is similar (P =. 10, 11.

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In order to estimate a placebo or no-treatment effect, the active-controlled trial submission included a post-hoc group of infants who were not treated. 6 This trial was also re-examined for the primary outcome of percentage of patients requiring rescue so that its results could be pooled with a third pivotal clinical trial. 1, 8.

4 Since that time, ibuprofen lysine has been well studied in humans and was approved for use in the United States (US) in 2006 (NeoProfen, Ovation Pharmaceuticals, Deerfield, IL). 5. It is currently FDA-approved for the closure of a clinically significant PDA in premature infants who weigh between 500 g and 1,500 g and who are no more than 32 weeks GA, when usual medical management has been ineffective. Intravenous (IV) indomethacin (Indocin IV, Ovation Pharmaceuticals, Deerfield, IL) has been the sole therapy approved by the Food and Drug Administration (FDA) for the treatment of PDA during the last 20 years. IV ibuprofen, which has been used in various forms in other countries, was first demonstrated to be effective for ductal closure in animals in 1979. Cyclooxygenase inhibitors have become the mainstay of pharmacologic therapy for a PDA because normal closure of the ductus is primarily mediated by homeostatic down-regulation of prostaglandins.

The results of recently completed but unpublished tests on stability and compatibility with commonly used drugs in the neonatal setting are also reviewed. Three major trials served as the approval basis for the safety and efficacy of ibuprofen lysine. Ibuprofen lysine now represents an alternative pharmacological option to surgery for the treatment of PDA. Intravenous indomethacin has been the only approved treatment for PDA available in the United States for the past 20 years. The armamentarium has recently been expanded with the approval of intravenous ibuprofen lysine in 2006. Many practical questions regarding the drug, including dosing, administration, and storage are addressed. This review addresses common questions about ibuprofen lysine, summarizes the available literature, and discusses the data submitted to the Food and Drug Administration (FDA) in support of its approval. Ibuprofen lysine has been used for years in Europe, and the author reviews the extensive published literature. The author has summarized these studies and, where appropriate, presents pooled results from additional analyses that have not been previously published. Cyclooxygenase inhibitors have proven efficacy in the treatment of patent ductus arteriosus (PDA).

21. 21 The review authors found that in comparison to placebo or no treatment there was a significant increase in serum creatinine levels on day 3 in the ibuprofen-treated patients, with no differences in mortality, intraventricular hemorrhage, chronic lung disease, necrotizing enterocolitis, or gastrointestinal hemorrhage or perforation. The serum creatinine rise occurred in only 1 study, 13 which was stopped prematurely because of hypoxemia reported in 3 of 65 infants who received ibuprofen. A Cochrane meta-analysis evaluated ibuprofen for the prevention of PDA in 2003 and found a closure rate at day 3 of 84% for ibuprofen and 55% for placebo. 00001, RR = 0.37, NNT = 3), in the need for rescue treatment with cyclooxygenase inhibitors (P <. The formulation used in this study (ibuprofen trishydroxyamino-methane or THAM [Pedea, Orphan Europe S.a.r.l., Paris, France]) is different from the formulation available in the US (ibuprofen lysine). 00001, RR = 0.17, NNT = 4), and in the need for surgical ligation (P =. 20 An update of this analysis published in 2006 concluded there was a statistically significant decrease in the incidence of PDA on day 3 in the ibuprofen group (P <. The Cochrane meta-analysis authors concluded that ibuprofen reduces the incidence of PDA, the need for rescue therapy, and surgical closure; however, with the high spontaneous rate of closure (60%) in the target infant population, they did not recommend exposing a large proportion of infants to prophylactic therapy. 02, RR = 0.34, NNT = 25).

How do you mix iv indomethacin?
Common Clinical and Practical Questions on the Use of Intravenous

8, 9 Similar results were obtained in the re-analysis of the active-controlled treatment study in the ibuprofen-treated vs. In the pivotal trial, ibuprofen lysine was significantly more effective than placebo for the treatment of PDA. A statistically significantly lower proportion of infants treated with ibuprofen lysine required rescue, died, or dropped out vs. 01). 51.9%, P <. 01). 53%, P =. 6, 8, 9. 005). the no-treatment group (34% vs. those receiving placebo (30.9% vs. 50%, P =. 6, 9 When these results are pooled, a significantly lower proportion of infants who received ibuprofen lysine required rescue treatment, died, or dropped out of the study prior to study day 14 compared to those who received placebo or no treatment (32.4% vs.

IV ibuprofen lysine was approved under the Orphan Drug Act in April 2006. 6, 7 One was a randomized, prospective, active-controlled multicenter PDA treatment trial. The sponsor submitted results of 3 controlled clinical trials in support of efficacy and safety. Two of the trials were reanalyses of completed trials from Europe. 7 The data from these 2 trials were fully adjudicated and validated before submission to the FDA. 6 and the second a double-blind, randomized, placebo-controlled PDA prophylaxis trial.

001) and vs. the active-controlled study (1,230 g, P <. The ibuprofen-treated infants in the pivotal trial had a significantly younger GA (26.1 weeks) vs. those in the prevention study (28.1 weeks, P <. 001). 6, 7, 8 Birth weights for the ibuprofen-treated infants were also significantly lower in the pivotal trial (798.5 g) vs. In each of the trials, there was no difference in demographic or baseline characteristics within the study groups. 52%). 001) and vs. 7, 8. those in the active-controlled study (29.1 weeks, P <. 001). the prevention study (1,048 g, P <. When the 2 treatment groups were pooled, there were similar percentages of males in the placebo/no-treatment group and the ibuprofen lysine group (56% vs.

0164). Additional support for this conclusion comes from pooling the data from the 2 treatment trials, which indicates that there was no statistically significant difference in the ibuprofen-lysine-treated infants and the placebo group in regard to change from baseline to worst serum creatinine value (0.19 and 0.24, respectively). 5, 6, 8, 9. 5, 6, 8, 9 Furthermore, there was a significantly higher serum creatinine change from baseline to last value in the placebo group compared to the ibuprofen group (0.03 versus −0.06, P =.

018) between the ibuprofen and indomethacin treatment groups favoring ibuprofen, with regard to the highest relationship of study drug to the serious adverse event (possibly related: 16.7% ibuprofen vs. 23.3% indomethacin; probably not related: 11.1% ibuprofen vs. 40% indomethacin). 36.7% indomethacin; not related: 72.2% ibuprofen vs. In the active-controlled study, 6 148 infants with evidence of PDA were randomized to ibuprofen lysine or indomethacin. Of the infants who experienced treatment-emergent serious adverse events, there was a statistically significant difference (P =.

Ibuprofen has been shown to have neuroprotective effects in animal models and to enhance cerebral autoregulation without affecting cerebral blood flow, cerebral metabolism or intestinal or renal hemodynamics. 17, 30. 25–29 Mosca et al. have demonstrated in premature infants that, unlike indomethacin, ibuprofen widens the upper limit of autoregulated cerebral blood flow.

2 Spontaneous closure can occur in up to 40% of premature neonates, but up to 70% of those weighing less than 1,000 g or of less than 28 weeks gestational age require intervention due to significant hemodynamic symptoms. Patent ductus arteriosus (PDA) is a condition seen in premature infants with an incidence as high as 60% in infants of less than 28 weeks gestational age (GA). 1 Approximay 45% of neonates weighing less than 1,750 g and nearly 80% of those weighing less than 1,000 g present with a PDA. 3.

In all trials submitted to the FDA, there were no statistically significant differences between treatment groups in renal function, as measured by mean change in blood urea nitrogen (BUN) from baseline to worst value and last value. 6, 7, 8 However, a higher percentage of infants in the ibuprofen lysine group (7.4%) than in the placebo group (4.4 %) had an increase in BUN values from a less severe baseline value, although this was not statistically significant (P =. 22). 7, 8.

21, 31. 21, 31 In a systematic review of trials comparing indomethacin with ibuprofen, whether for prevention or treatment of a PDA, no differences were noted in the onset incidence of IVH between indomethacin and ibuprofen or between ibuprofen and placebo. A number of studies have captured the onset incidence of IVH with intravenous cyclooxygenase inhibitor therapy; however, most of these trials were not designed specifically to study IVH, and many of them excluded infants who had IVH.

0001), need for rescue treatment (7% vs. The pooled results from these studies indicate a statistically significant favorable difference in closure of PDA at day 3 (84% vs. 33%, P <. 0001), and need for surgery (1.6% vs. Five controlled and 4 uncontrolled published trials have investigated IV ibuprofen for the prevention of PDA. 5.3%, P =. 57%, P <. Based on this analysis, approximay 30% of the untreated group would be expected to benefit from prophylactic therapy with ibuprofen, where benefit is defined as a closed PDA by day 3 or lack of need for rescue therapy or surgery ( Table 3 ). 7, 12–19 The 5 controlled studies were analyzed in an attempt to calculate an early treatment benefit ( Table 3 ). 008) with ibuprofen lysine compared to placebo or control group.

6, 8, 9 This analysis demonstrates comparable efficacy across all age groups studied. Table 1 provides further detail of the pooled data from the 2 treatment trials by GA categories and rescue rates. Table 2 provides detail on specific weight categories and rescue rates as observed in the pooled data from the 2 treatment trials. 6, 8, 9 The overall rescue rate was significantly lower with ibuprofen (and indomethacin) vs. placebo, and most individual weight categories showed significantly lower rescue rates with ibuprofen as well (individual probability values are listed in Table 2 ). There were too few patients in the lower (400–700g) and higher (> 1,600 g) weight ranges for meaningful analyses.

10 In a study comparing treatments for PDA, the incidence of progressive IVH was similar in patients randomized to indomethacin and ibuprofen. 6. 6 Eight patients in the indomethacin group progressed at least 1 grade category, and 5 patients in the ibuprofen group progressed from grade 0 to 1 or greater (P =. 6, 10, 32 Lago et al. 38). Two randomized, placebo-controlled studies of ibuprofen lysine that used IVH as a primary outcome measure in premature infants with PDA reported no statistically significant difference between the placebo and ibuprofen groups in regard to the incidence of any stage of IVH. In 3 trials in which this was a secondary measure, no difference was seen in the incidence of IVH (11% with ibuprofen vs. 7, 15 No controlled trial has compared ibuprofen lysine to indomethacin with IVH as the primary outcome variable. noted that the incidence of IVH in both the indomethacin and ibuprofen groups was lower than in the overall population within their unit. 87). 13% with indomethacin, P =.

05). 6, 8, 9 This was primarily driven by a smaller number of cases of “hyperbilirubinemia neonatal,” anemia, sepsis, jaundice, respiratory distress, and necrotizing enterocolitis (NEC) reported with ibuprofen lysine. 92%, P ≤. 05). Hyperbilirubinemia, jaundice, and NEC were individually statistically significantly different from the placebo/no-treatment group (P <. 6, 8, 9. In an analysis of the combined treatment studies, significantly fewer “common significant but not serious treatment emergent adverse effects” were reported in infants receiving ibuprofen than in infants receiving placebo (79% vs.

6, 8, 9 In addition, no serious adverse events were reported in a substantially different percentage of infants receiving ibuprofen lysine or placebo (i.e., difference of at least 5 percentage points), including outcomes of special interest such as retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), periventricular leukomalacia (PVL), and death. 5, 8, 9 No statistically significant differences between treatment groups were observed in the incidence of serious adverse events in the pivotal study or when the results were pooled from the 2 treatment studies submitted to the FDA. The most common side effects reported in the pivotal trial are summarized in Table 4. No statistically significant differences between treatment groups were observed for mean cumulative urine output during the studies.

Given that it would be unethical to perform a placebo-controlled study including infants with symptomatic PDA, asymptomatic premature infants with echocardiographically-documented ductal shunting were randomly assigned to placebo or ibuprofen lysine and followed for the need to treat (rescue) a symptomatic PDA. 1, 8 Infants were randomized to receive either a 3-treatment course of IV ibuprofen lysine or placebo. This study was designed to determine whether early treatment with ibuprofen lysine would reduce the need for rescue therapy (i.e., indomethacin or surgery) in infants at risk for a symptomatic PDA. In these 3 trials a total of 357 infants received ibuprofen lysine, 349 received placebo or no treatment, and 73 received indomethacin. This study enrolled 136 infants of less than 30 weeks GA, with birth weights between 500 g and 1000 g. The pivotal trial, a multicenter, randomized, double-blind, placebo-controlled study, served as the primary data source for the safety and efficacy evaluation of ibuprofen lysine.

These events were captured without regard to presumed causality. In the PDA prevention study 7, 433 infants were randomized to ibuprofen or placebo within 6 hours of birth. 05). Statistically significant differences were reported in the percentage of infants experiencing apnea (ibuprofen less than placebo, P <. 05) and hypotension (ibuprofen greater than placebo, P <.

As has been pointed out by Van Overmeire et al., the efficacy of PDA closure is not correlated with improved IVH outcomes, and other pharmacologic effects of cyclooxygenase inhibitors may play a greater role in more favorable neurodevelopmental outcomes. 7 Others have concluded that although ibuprofen has an improved safety profile, especially in regard to renal and gastrointestinal function, the lack of demonstrated efficacy in IVH prophylaxis makes its use in this setting unsubstantiated. 1. 1 With no other alternative for IVH prophylaxis, the risks and benefits of IV indomethacin should be considered.

6–9. 6–9 In pooled data from these 3 trials submitted to the FDA, no individual event classified as possibly or probably drug related was reported statistically more often in the treatment group compared to the placebo/no-treatment group. In conclusion, the percentage of infants in whom the study drug was discontinued due to adverse events was small (2.5% in both ibuprofen and placebo groups and 4.1% in the indomethacin group) and did not differ between groups.

8, 9 There were no statistically significant differences (P >. Furthermore, pivotal trial results indicate that in patients less than 28 weeks GA and weighing less than 750 g, significantly more infants required rescue with placebo (11/22) than with ibuprofen lysine (5/22, P =. Therefore, ibuprofen lysine can be said to be effective in all age and weight groups studied. 045). In regression analyses performed in the pivotal trial, no correlations were found between GA or weight and rescue rate. 05) in rescue rates between those who started ibuprofen lysine at less than 24 hours of age (21%), 24 to 48 hours of age (28%), or greater than 48 hours of age (23%).

6–9 Although these studies were not powered to address this issue and the number of events was small in each group, there was a statistically significant difference in the number of infants reported to have possibly experienced a drug-related adverse event in the treatment group (ibuprofen lysine or indomethacin) vs. 01). The most common events reported were IVH (all grades) and NEC/perforation, which represented over 50% of events. In all trials submitted to the FDA, 47 infants (placebo/no treatment 2.3%, ibuprofen lysine 8.9%, and indomethacin 9.58%) experienced a total of 58 adverse events that were considered possibly or probably related to the study drug. However, none of the individual events deemed to be drug related were statistically significantly more frequent in either of the treatment groups vs. 6–9. the placebo/no-treatment group. the placebo or no-treatment group (P <.

The following summary reviews the most commonly asked questions about ibuprofen lysine in the management of PDA. With a focus on clinical and practical applications, this summary is meant to help health care practitioners better understand the place of ibuprofen lysine in the armamentarium of treatment strategies for PDA.

23 Ohlsson has argued that the positive effects of indomethacin on short-term reduction of IVH may be outweighed by its longer-term effects on reducing cerebral blood flow. 24. 22, 23 The long-term sequelae on neurodevelopment, however, have not been shown to be negatively or positively affected. Previous studies and systematic reviews have confirmed that another non steroidal anti-inflammatory drug (NSAID), indomethacin, when used prophylactically for PDA, can reduce the incidence of IVH.

7. Perforation occurred more often in the ibuprofen group, although at a low frequency (2.3% vs. Of the events considered possibly or probably related to study drug, 22 infants experienced 29 treatment-emergent serious adverse events. 03).7 Reports of IVH were not statistically significantly different (P =. 7 The most commonly reported events were IVH and perforation. 0%, P =. 3) between the ibuprofen lysine-treated patients (2.3%) and those receiving placebo (1%).

5, 8, 9 This probably represented the deleterious action of the rescue medication (indomethacin) within the placebo group because there were no differences noted prior to day 9, and fluid intake and diuretic use were not different within the study groups. 02 in both). The findings that the ibuprofen group had a slightly higher starting serum creatinine than the placebo group (1.03 vs. There were no differences between placebo and ibuprofen lysine in BUN during any study day. 0.94 mg/dL), with slightly higher values noted among the ibuprofen-lysine-treated infants (P =. 019). Differences in serum creatinine were noted on study day 3 (1.03 mg/dL vs. In the pivotal trial, mean urinary output as measured over days of life was significantly higher in the ibuprofen group than in the placebo group on day 9 of life (P =. 0.98 mg/dL) and study day 4 (1.07 mg/dL vs. 5, 8, 9. 1.01) on the first day of therapy and that values on study days 5 and 6 were not significantly different indicate that these serum creatinine changes are clinically insignificant.

How do you mix iv indomethacin?