s after treatment have not been evaluated; therefore, treatment should be reserved for infants with clear evidence of a clinically significant pda. (1)

ntinually on the alert and should use the drug with extra care in the presence of controlled infection and in infants at risk of infection. 5.3 platelet aggregation ibuprofen lysine injection, like other non-steroidal anti-inflammatory agents, can inhibit platelet aggregation. preterm infants should be observed for signs of bleeding. ibuprofen has been shown to prolong bleeding time (but within the normal range) in normal adult subjects. this effect may be exaggerated in patients with underlying hemostatic defects (see contraindications ). 5.4 bilirubin displacement ibuprofen has been shown to displace bilirubin from albumin binding-sites; therefore, it should be used with caution in patients with elevated total bilirubin. 5.5 administration ibuprofen lysine injection should be administered carefully to avoid extravascular injection or leakage, as solution may be irritating to tissue.

educed in size after completion of the first course of ibuprofen lysine injection, no further doses are necessary. if during continued medical management the ductus arteriosus fails to close or reopens, then a second course of ibuprofen lysine injection, alternative pharmacological therapy, or surgery may be necessary. 2.2 directions for use for intravenous administration only. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. do not use ibuprofen lysine injection if particulate matter is observed. after the first withdrawal from the vial, any solution remaining must be discarded because ibuprofen lysine injection contains no preservative. for administration, ibuprofen lysine injection should be diluted to an appropriate volume with dextrose or saline. ibuprofen lysine injection should be prepared for infusion and administered within 30 minutes of preparation and infused continuously over a period of 15 minutes. the drug should be administered via the iv port that is nearest the insertion site. after the first withdrawal from the vial, any solution remaining must be discarded because ibuprofen lysine injection contains no preservative. since ibuprofen lysine injection is potentially irritating to tissues, it should be administered carefully to avoid extravasation. ibuprofen lysine injection should not be simultaneously administered in the same intravenous line with total parenteral nutrition (tpn). if necessary, tpn should be interrupted for a 15-minute period prior to and after drug administration. line patency should be maintained by using dextrose or saline.

grade of ivh counted for a given subject. 32 29 intraventricular hemorrhage, grades 1/2 15 13 intraventricular hemorrhage, grades 3/4 15 10 other bleeding 6 13 intraventricular hemorrhage, all grades 29 24 apnea 28 26 gastrointestinal disorders non-necrotizing enterocolitis 22 18 total renal events 21 15 renal failure 1 3 renal insufficiency, impairment 6 4 urine output reduced 3 1 blood creatinine increased 3 1 blood urea increased with hematuria 1 1 blood urea increased 7 4 respiratory infection 19 13 skin lesion/irritation 16 6 hypoglycemia 12 6 hypocalcemia 12 9 respiratory failure 10 4 urinary tract infection 9 4 adrenal insufficiency 7 1 hypernatremia 7 4 edema 4 0 atelectasis 4 1 6.2 renal function compared to placebo, there was a small decrease in urinary output in the ibuprofen group on days 2-6 of life, with a compensatory increase in urine output on day 9. in other studies, adverse events classified as renal insufficiency including oliguria, elevated bun, elevated creatinine, or renal failure were reported in ibuprofen treated infants. 6.3 additional adverse events the adverse events reported in the multicenter study and of unknown association include tachycardia, cardiac failure, abdominal distension, gastroesophageal reflux, gastritis, ileus, inguinal hernia, injection site reactions, cholestasis, various infections, feeding problems, convulsions, jaundice, hypotension, and various laboratory abnormalities including neutropenia, thrombocytopenia, and hyperglycemia. 6.4 post-marketing experience because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency, or establish a causal relationship to drug exposure. the following adverse reactions have been identified from spontaneous post-marketing reports or published literature: gastrointestinal perforation, necrotizing enterocolitis, drug reaction with eosinophilia and systemic symptoms (dress), and pulmonary hypertension.

ividual variability in clearance and volume of distribution were 55% and 14%, respectively. in general, the half-life in infants is more than 10 times longer than in adults. the metabolism and excretion of ibuprofen in premature infants have not been studied. in adults, renal elimination of unchanged ibuprofen accounts for only 10-15% of the dose. the excretion of ibuprofen and metabolites occurs rapidly in both urine and feces. approximately 80% of the dose administered orally is recovered in urine as hydroxyl and carboxyl metabolites, respectively, as a mixture of conjugated and unconjugated forms. ibuprofen is eliminated primarily by metabolism in the liver where cyp2c9 mediates the 2- and 3-hydroxylations of r- and s-ibuprofen. ibuprofen and its metabolites are further conjugated to acyl glucuronides. in neonates, renal function and the enzymes associated with drug metabolism are underdeveloped at birth and substantially increase in the days after birth.

e not been studied. in adults, renal elimination of unchanged ibuprofen accounts for only 10-15% of the dose. the excretion of ibuprofen and metabolites occurs rapidly in both urine and feces. approximately 80% of the dose administered orally is recovered in urine as hydroxyl and carboxyl metabolites, respectively, as a mixture of conjugated and unconjugated forms. ibuprofen is eliminated primarily by metabolism in the liver where cyp2c9 mediates the 2- and 3-hydroxylations of r- and s-ibuprofen. ibuprofen and its metabolites are further conjugated to acyl glucuronides. in neonates, renal function and the enzymes associated with drug metabolism are underdeveloped at birth and substantially increase in the days after birth.

uprofen lysine injection (10 mg/kg on the first dose and 5 mg/kg at 24 and 48 hours). mean birth age was 1.5 days (range: 4.6 – 73.0 hours), mean gestational age was 26 weeks (range: 23 – 30 weeks), and mean weight was 798 g (range: 530 – 1015 g). all infants had a documented pda with evidence of ductal shunting. as shown in table 2, 25% of infants on ibuprofen lysine injection required rescue therapy versus 48% of infants on placebo (p=0.003 from logistic regression controlling for site). table 2. summary of efficacy results, n (%) ibuprofen lysine injection n=68 placebo n=68 required rescue through study day 14 total 17 (25) 33 (48) by age at treatment birth to < 24 hours 3/14 (21) 8/16 (50) 24-48 hours 9/32 (28) 16/37 (43) > 48 hours 5/22 (23) 9/15 (60) echocardiographically proven pda prior to rescue 17 (100) 32 (97) reasons for rescue hemodynamically significant pda per neonatologist 14 (82) 25 (76) bounding pulse 6 (35) 12 (36) systolic murmur 6 (35) 15 (45) pulmonary edema 3 (18) 5 (15) hyperdynamic precordium 2 (12) 3 (9) increased cardiac silhouette 1 (6) 5 (15) of the infants requiring rescue within the first 14 days after the first dose of study drug, no statistically significant difference was observed between the ibuprofen lysine injection and placebo groups for mean age at start of first rescue treatment (8.7 days, range 4-15 days, for the ibuprofen lysine injection group and 6.9 days, range 2-15 days, for the placebo group). the groups were similar in the number of deaths by day 14, the number of patients on a ventilator or requiring oxygenation at day 1, 4 and 14, the number of patients requiring surgical ligation of their pda (12%), the number of cases of pulmonary hemorrhage and pulmonary hypertension by day 14, and bronchopulmonary dysplasia at day 28. in addition, no significant differences were noted in the incidences of stage 2 and 3 necrotizing enterocolitis, grades 3 and 4 intraventricular hemorrhage, periventricular leukomalacia and retinopathy of prematurity between groups as determined at 36±1 weeks adjusted gestational age. two supportive studies also determined that ibuprofen, either prophylactically (n=433, weight range: 400 – 2165 g) or as treatment (n=210, weight range: 400 – 2370 g), was superior to placebo (or no treatment) in preventing the need for rescue therapy for a symptomatic pda.