NEODOSE

INDICATIONS

• Closure of patent ductus arteriosus (PDA): Long-term outcomes are not improved when preterm infants, younger than 14 days, are treated routinely for patent ductus arteriosus. Treatment benefits when administered after 2 weeks of age or in high-risk infants in the first 2 postnatal weeks are unknown. There are risks to NSAIDs and there is a high rate of spontaneous closure; therefore, treatment should be limited to select preterm newborns with symptomatic PDA. At 36 weeks’ postmenstrual age, there was no significant difference in mortality or moderate to severe bronchopulmonary dysplasia between NSAID treatment (initiated 2 to 28 days postnatally) and no treatment in a cohort of 12,018 preterm infants (gestational age 28 weeks or younger) with patent ductus arteriosus. PDA closure rates were similar for IV or oral ibuprofen and IV or oral indomethacin; however, ibuprofen was associated with a reduced duration of ventilator support and reduced risk of necrotizing enterocolitis, oliguria, and elevated serum/plasma creatinine in a meta-analysis of 39 studies (n=2843 infants). Long-term outcomes in infants treated with ibuprofen are needed.

• Acetaminophen vs Ibuprofen vs Indomethacin: Acetaminophen IV is as effective as indomethacin IV and ibuprofen (at standard doses) IV in the closure of PDA in preterm infants (gestational age less than 28 weeks) with hemodynamically significant PDA in a randomized study (n=300). After the first treatment course, the closure rates were 80%, 77%, and 81% for acetaminophen, ibuprofen, and indomethacin, respectively. Adverse effects (increase in serum creatinine and serum BUN and decrease in platelet count and urine output) were significantly more with ibuprofen and indomethacin than acetaminophen. Bilirubin significantly increased with ibuprofen. The mean weights were 1.1 kg, 1 kg, and 1.1 kg in the infants treated with acetaminophen, ibuprofen, and indomethacin, respectively. Infusing indomethacin over a prolonged period may reduce the vasoconstriction and subsequent detrimental effect on the end organs (renal, GIT, and CNS). Infants (n=63) randomized to 36-hour continuous IV infusion of indomethacin 17 mcg/kg/hr (27.8 weeks gestational age, 1100 g birth weight) compared with ibuprofen lysine (27.8 weeks gestational age, 1060 g birth weight) experienced no apparent differences in renal function or renal, mesenteric, or cerebral blood flow (by Doppler measurement); furthermore, PDA closed in 74% vs 59% (p=0.132), respectively . However, the manufacturer recommends against further dilution after reconstitution of the lyophilized powder and the stability and sterility of preservative-free indomethacin are unknown

• Prevention of patent ductus arteriosus (PDA): There are risks to indomethacin and there is a high rate of spontaneous closure (up to 60%); therefore, prophylaxis (in the first>24 hours of life) with indomethacin is not recommended for all preterm infants,>particularly, indomethacin may not be justified for perceived benefits on PDA or an>expectation of better long-term outcomes.
• Prevention of intraventricular hemorrhage (IVH): In settings of high IVH rates, prophylactic indomethacin may be appropriate. Similarly, prophylactic indomethacin may be appropriate if early, severe pulmonary hemorrhage is common. However, indomethacin may not be justified for perceived benefits on PDA or an expectation of better long-term outcomes. A meta-analysis (n=2872; 19 trials) demonstrated short-term benefits including a reduction in frequency of severe intraventricular hemorrhage, the incidence of symptomatic PDA, and surgical ligation of the PDA in preterm infants administered prophylactic indomethacin on the first day after birth. However, long-term benefit on death or neurodevelopment at 18 to 36 months corrected age was not demonstrated. Oliguria/anuria occurred more often in infants on prophylactic indomethacin, but any renal impairment was temporary. Routine use of prophylactic indomethacin has been questioned.

FDA APPROVED INDICATION

IV indomethacin is indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 to 1750 g.

CONTRAINDICATIONS

Contraindicated in active bleeding, significant thrombocytopenia or coagulation defects, necrotizing enterocolitis, untreated proven or suspected infection, and/or significantly impaired renal function.

PRECAUTIONS

If oliguria occurs, observe for hyponatremia and hypokalemia, and consider prolonging the dosing interval of renally excreted drugs (eg, gentamicin). Consider withholding feedings. Concomitant therapy with furosemide may lead to increased hyponatremia and a significant rise in serum creatinine.

ADVERSE EFFECTS

Hypoglycemia is common, usually preventable by increasing the glucose infusion rate by 2 mg/kg per minute. Causes platelet dysfunction. Rapid (less than 5-minute) infusions are associated with reductions in organ blood flow. Gastrointestinal perforations occur frequently if used concurrently with corticosteroids. Renal Effects: Urine output decreased significantly more in indomethacin-treated (41%) compared with ibuprofen-treated (21%) preterm neonates (mean gestational age, 26 weeks; birth weight, less than 1000 g) with clinically significant patent ductus arteriosus (PDA) in a randomized double-blind study (n=144). The difference was significant for day 1, but not days 3, 5, 7, or 14. There was also a significantly greater increase in serum creatinine and decrease in GFR for the first 2 days with indomethacin. Dosages used were ibuprofen lysine 10 mg/kg IV for 1 dose, then 5 mg/kg/dose every 24 hours for 2 doses and indomethacin 0.2 mg/kg IV for 1 dose, then 0.1 mg/kg/dose every 24 hours for 2 doses.

BLACK BOX WARNING

NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. Indomethacin is contraindicated in the setting of CABG surgery. NSAIDs can also cause an increased risk of serious gastrointestinal (GI) adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at a greater risk for serious GI events.

ADMINISTRATION

Infuse the 0.5 to 1 mg/mL solution over 20 to 30 minutes.

MONITORING

Monitor urine output, serum electrolytes, glucose, creatinine and BUN, and platelet counts. Assess murmur, pulse pressure. Assess for gastrointestinal bleeding by gastric and fecal occult blood testing. Observe for prolonged bleeding from puncture sites.