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 PDA. 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 Long-term outcomes in infants treated with ibuprofen are needed.
• Multiple Courses: Closure rates were 71% (67/94), 40% (11/27), and 35% (5/14) after the first, second, and third courses, respectively, of oral ibuprofen in preterm neonates (mean gestational age, 30.6 weeks (24 to 36 weeks) and birth weight 1220 g (490 to 3000 g)) with hemodynamically significant PDA in a retrospective study (n=97). Adverse events (thrombocytopenia and/or renal function impairment (n=3)) occurred with the first course of ibuprofen.
• Prevention of patent ductus arteriosus (PDA): The risks do not outweigh the shortterm benefits of prophylactic ibuprofen. The incidence of PDA and the need for rescue treatment with cyclo-oxygenase inhibitors or surgical closure were reduced with prophylactic oral or IV ibuprofen compared with placebo or no intervention; however adverse effects (oliguria, increased serum creatinine concentrations, gastrointestinal hemorrhage) increased in a meta-analysis (9 trials; N=1070). Spontaneous closure in the control group was 58% by day 3 or 4. Compared with placebo or no intervention there was no differences for necrotizing colitis, mortality, any grade intraventricular hemorrhage, or chronic lung disease Hemodynamically significant PDA developed in 28% of extremely low birth weight preterm infants (n=46; less than 28 weeks gestational age and less than 1000 g) administered prophylactic oral ibuprofen within 12 to 24 hours after birth compared with 56% in a control group. However, the study was terminated early due to the high adverse event profile with ibuprofen.

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• 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 birth weights were 1.1 kg, 1 kg, and 1.1 kg in the infants treated with acetaminophen, ibuprofen, and indomethacin, respectively.
• High-Dose: In a systematic review and network meta-analysis of ibuprofen, indomethacin, and acetaminophen used in 68 randomized trials in 4,802 preterm infants, high-dose oral ibuprofen (15 to 20 mg/kg orally followed by 7.5 to 10 mg/kg orally every 12 to 24 hours for a total of 3 doses) was more likely to be associated with hemodynamically significant PDA closure compared with standard doses of IV ibuprofen (OR 3.59 (95% credible intervals (CrIs) 1.64 to 8.17)) or IV indomethacin (OR 2.35 (95% CrIs 1.08 to 5.31)) by indirect comparisons. High-dose oral ibuprofen significantly reduced the need for repeat pharmacotherapy compared with standard-dose IV ibuprofen (OR, 0.35) and placebo/no treatment (OR, 0.07) and the need for surgical PDA ligation compared with standard-dose IV ibuprofen (OR, 0.01) and placebo/no treatment (OR, 0). There were no significant differences between high-dose oral ibuprofen and any of the active comparators or placebo/no treatment in neonatal mortality, necrotizing enterocolitis, bronchopulmonary dysplasia, or intraventricular hemorrhage. Standard dosages were 10 mg/kg IV followed by 5 mg/kg IV every 12 to 24 hours for a total of 3 doses for ibuprofen and 0.1 to 0.3 mg/kg IV every 12 to 24 hours for a total of 3 doses for indomethacin.
• Oral vs. IV: Standard doses of oral ibuprofen were more likely to be associated with hemodynamically significant PDA closure compared with the standard-dose IV ibuprofen (OR 2.22 (95% credible intervals (CrIs) 1.44 to 3.4)) and placebo/no treatment (OR 9.93 (95% CrIs 6.23 to 16.08)) in a systematic review and network meta-analysis of ibuprofen, indomethacin, and acetaminophen used in 68 randomized trials in 4,802 preterm infants. Standard doses of oral ibuprofen reduced the need for repeat pharmacotherapy compared with standard-dose IV ibuprofen (OR, 0.39) and placebo/no treatment (OR, 0.08). There were no significant differences between standard doses of oral and IV ibuprofen in the need for surgical patent ductus arteriosus ligation, neonatal mortality, necrotizing enterocolitis, bronchopulmonary dysplasia, or intraventricular hemorrhage. Standard dosages were 10 mg/kg IV or oral followed by 5 mg/kg IV or oral every 12 to 24 hours for a total of 3 doses for IV ibuprofen.
• Ibuprofen vs placebo: In full-term infants (n=51; older than 3 days of life), oral ibuprofen had a higher PDA closure rate compared with placebo (73.3% vs 42.9%).

 

FDA APPROVED INDICATION

• Oral: Oral: Reduction of fever in children 6 months of age and older. Treatment of mild to moderate pain in children 6 months of age and older. Treatment of signs and symptoms of juvenile arthritis.
• Intravenous: Reduction of fever, management of mild to moderate pain, and management of moderate to severe pain as an adjunct to opioid analgesics in children 6 months of age or older.

 

CONTRAINDICATIONS

Contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs; serious, rarely fatal anaphylactic reactions have occurred in these patients.

PRECAUTIONS

Increased risk of myocardial infarction and stroke has been reported in patients with or without heart disease or risk factors for heart disease. Risk of myocardial infarction and stroke can occur as early as the first weeks of therapy and may increase with higher NSAID doses and longer duration of use. Use the lowest effective dose for the shortest possible duration. Increased risk of heart failure. Can cause new hypertension or worsening of existing hypertension. Serious skin reactions (exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis) have been reported. Elevations in liver enzymes may occur in up to 15% of patients. Some of these abnormalities have progressed to hepatitis, liver necrosis, and hepatic failure, including fatal cases. Anemia has occurred. Inhibits platelet aggregation which may increase the bleeding time in some patients. Fluid retention and edema have been reported; use with caution in patients with congestive heart failure or edema. Long-term use has been associated with development of renal papillary necrosis and other renal impairment. In commercially available ibuprofen suspensions in the United States, the osmolality is greater than 2000 mOsm/kg. It is unknown if a small amount of an extremely high osmolal suspension via enteral route may be deleterious to preterm infants.

 

ADVERSE EFFECTS

Gastrointestinal bleeding (n=2), spontaneous intestinal perforation (n=2), and acute kidney failure (n=2) occurred in extremely low birth weight preterm infants (n=46) administered oral ibuprofen within 12 to 24 hours after birth for prevention of patent ductus arteriosus. Spontaneous intestinal perforation, without signs of necrotizing enterocolitis, occurred in 2 very low birth weight infants treated with oral ibuprofen for patent ductus arteriosus. The perforations resolved with Penrose drainage. Compared with placebo, IV ibuprofen substantially altered renal function in infants with birth weight of 1000 g or less and/or gestational age of 26 weeks or less in a randomized, doubleblind trial (n=134). In contrast, renal function was not altered in infants with a birth weight greater than 1000 g and/or gestational age of greater than 26 weeks. Preterm infants administered IV ibuprofen experienced a higher peak total serum bilirubin (9 mg/dL vs 7.3 mg/dL), greater need for phototherapy (95.3% vs 87.2%), and a longer duration of phototherapy (94.3 hours vs 87.2 hours) compared with preterm infants not treated with ibuprofen in a retrospective analysis (n=706 infants; 30 weeks gestational age or less).

 

BLACK BOX WARNING

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may be increased with duration of use, and in patients with cardiovascular disease or risk factors for cardiovascular disease. Ibuprofen is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. NSAIDs can also cause an increased risk of serious gastrointestinal 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.

 

ADMINISTRATION

Intravenous: Administer by intermittent IV infusion at a final concentration of 4 mg/mL or less over 15 minutes. Oral: Ibuprofen may be mixed with 0.5 mL milk and administered via oro-gastric tube.

 

MONITORING

Monitor for signs and symptoms of gastrointestinal bleeding. Monitor blood pressure. Monitor coagulation tests in patients on anticoagulants and those with coagulation disorders. Monitor serum transaminases for liver abnormalities. Carefully monitor renal function.