IBUPROFEN LYSINE (Generic for NEOPROFEN)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-For intravenous infusion administration only. Do NOT administer by IM injection or by IV bolus.
-Administration via an umbilical arterial line has not been evaluated.
Intravenous Administration
Reconstitution
-Each ml contains 10 mg/ml of ibuprofen (17.1 mg of ibuprofen lysine salt); dosing is based on ibuprofen content. Dilute with dextrose 5% or 0.9% NaCl to an appropriate volume for administration.
-Do not use ibuprofen lysine if particulate matter is observed.

-Discard any remaining solution after the initial withdrawal from the vial; this product is preservative free.

Intermittent IV Infusion
-Administer within 30 minutes of preparation.
-Administer via the IV port that is nearest the insertion site.
-Infuse over 15 minutes.
-Avoid extravasation, as the drug may be irritating to extravascular tissue.
-Do not simultaneously administer in the same intravenous line with Total Parenteral Nutrition (TPN). TPN should be interrupted for a 15-minute period before and after drug administration. Maintain line patency by using dextrose or saline.

In a multicenter trial of 68 premature neonates, adverse renal events were more common in the ibuprofen lysine group (21%) when compared to the placebo group (15%) ; however, data suggest that ibuprofen lysine causes fewer adverse renal effects than indomethacin. The specific incidences of adverse renal events for ibuprofen lysine vs. placebo, respectively include renal impairment or insufficiency (6% vs. 4%), reduction in renal output (3% vs. 1%), increase in blood creatinine (3% vs. 1%), hyperuricemia (7% vs. 4%), and hyperuricemia with hematuria (1% vs. 1%). Renal failure (unspecified) occurred in fewer ibuprofen lysine patients than placebo (1% vs. 3%). 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. Edema was reported in 4% of ibuprofen lysine-treated neonates and in none of the placebo group. The degree of ibuprofen-induced reduction in renal perfusion may be inversely related to kidney maturity, which is a function of both birth age and gestational age. In other studies, adverse events classified as renal insufficiency including oliguria, elevated BUN, elevated creatinine, or renal failure were reported in ibuprofen-treated infants. Ibuprofen lysine is contraindicated for use in preterm infants with significant impairment of renal function.

Intraventricular hemorrhage (IVH) occurred in 20/68 (29.4%) of patients treated with ibuprofen lysine and in 16/68 (23.5%) of patients treated with placebo in a multicenter trial; grades 3 and 4 IVH accounted for 15% and 10% of the events in the ibuprofen lysine group and placebo group, respectively. Other bleeding events (unspecified) occurred less frequently in the ibuprofen lysine treated group (4/68) than in the placebo group (9/68). Thirty-two percent of patients treated with ibuprofen lysine in this trial experienced at least 1 bleeding episode. Ibuprofen-induced changes in platelet aggregation may contribute to prolonged bleeding time. Monitor all patients receiving ibuprofen lysine closely for signs and symptoms of bleeding.

Gastrointestinal adverse events, particularly the development of necrotizing enterocolitis (NEC), are a major concern associated with NSAID use for PDA closure. Necrotizing enterocolitis has been reported during post-marketing use of ibuprofen lysine ; however, results of a meta-analysis found ibuprofen to lower the risk of necrotizing enterocolitis when compared to indomethacin (RR 0.68 [95% CI, 0.47-0.99]). Gastrointestinal disorders such as non-necrotizing enterocolitis were reported in 15/68 (22%) of patients treated with ibuprofen lysine and in 12/68 (18%) of patients treated with placebo in a multicenter trial. No significant differences were noted in the incidence of stage 2 or 3 necrotizing enterocolitis between the ibuprofen lysine and placebo groups. Gastrointestinal perforation has been reported during the postmarketing surveillance period. Two cases of spontaneous GI perforation (intestinal) without signs of necrotizing enterocolitis also occurred after treatment of PDA with oral ibuprofen in 2 patients (gestational ages 29 and 30 weeks). Abdominal distension, gastroesophageal reflux, gastritis, and ileus have been reported in patients treated with ibuprofen lysine; a causal relationship has not been established. Gastrointestinal events may be the result of prostaglandin synthesis suppression and bleeding time prolongation due to changes in platelet aggregation. Concomitant use of anticoagulants or oral corticosteroids and duration of NSAID use are known to increase the risk of severe GI events in adults. Consider alternate therapies in patients with gastrointestinal abnormalities or GI perforation.

Possible respiratory adverse effects of ibuprofen lysine are not yet clearly defined. In a multicenter trial of 68 neonates, the following adverse events occurred at a higher rate in the ibuprofen lysine group compared to placebo: apnea (28% vs. 26%), respiratory failure (10% vs. 4%), and atelectasis (4% vs. 1%). In clinical practice, there has been concern regarding a possible association between ibuprofen lysine use and pulmonary hypertension based on case reports. In these case reports, severe pulmonary hypertension developed shortly after the second or third dose of ibuprofen. In addition, in a meta-analysis, ibuprofen lysine was associated with an approximately 30% greater risk of chronic lung disease compared to indomethacin (RR 1.28 [95% CI 1.03-1.60]).

Dermatologic reactions, including skin ulcer and skin irritation (unspecified), were reported in 16% of 68 patients treated with ibuprofen lysine and in 6% of 68 patients treated with placebo. Extravasation of ibuprofen lysine injection may lead to skin irritation or an injection site reaction. Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported during postmarketing experience. NSAIDS, including ibuprofen, can cause serious skin reactions which can be fatal. Reported NSAID induced allergic reactions include anaphylactoid reactions such as anaphylactic shock, pruritus, rash, urticaria, exfoliative dermatitis, erythema nodosum, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis (AGEP). Discontinue ibuprofen at the first appearance of skin rash or any other sign of hypersensitivity.

Ibuprofen lysine is known to displace bilirubin from albumin binding sites; hyperbilirubinemia may result. In a retrospective comparison of neonates < 30 weeks gestational age, the ibuprofen lysine cohort (n = 418) had higher peak total serum bilirubin concentrations compared to neonates not exposed to ibuprofen (n = 288) (9 +/- 2.5 vs. 7.3 +/- 3.3 mg/dl). Additionally, the ibuprofen group had more need for phototherapy (398 infants [95%] vs. 254 [87.6%]) and a longer phototherapy duration (94.3 +/- 43.6 vs. 87.2 +/- 38.6 hours). The rates of exchange transfusions were similar between the 2 groups. Of note, the non-ibuprofen group was treated between 1993 and 1999; the ibuprofen group was treated between 2000 and 2007. Competitive inhibition between ibuprofen and bilirubin in the hepatic glucuronidation pathway may have contributed to the hyperbilirubinemia. NSAIDs have been associated with hepatotoxicity such as hepatitis or jaundice in other patient populations. In the multicenter study of ibuprofen lysine, jaundice and cholestasis were reported, although the association of the events with ibuprofen lysine is unknown.

In a multicenter trial of 68 neonates, anemia occurred in 32% of patients treated with ibuprofen lysine and in 25% of patients treated with placebo. Neutropenia and thrombocytopenia were also reported in patients treated with ibuprofen lysine; a causal relationship was not established.

Treatment-emergent adverse events were assessed in a double-blind, multicenter clinical study comparing ibuprofen lysine to placebo therapy in 136 premature neonates within a 30 day follow-up period. Hypoglycemia and hypocalcemia occurred in 8/68 (12%) of neonates and hypernatremia occurred in 7%. Sinus tachycardia, heart failure, inguinal hernia, feeding problems, seizures, hypotension, and hyperglycemia were reported, although the association of these events with ibuprofen lysine is unknown. Ibuprofen's long term safety and effects on neurodevelopmental outcome, neurological disease, and growth, as well as disease processes associated with neonatal prematurity such as retinopathy of prematurity and chronic lung disease, have not been assessed.

The incidence of infections reported in 68 patients treated with ibuprofen lysine compared to 68 patients treated with placebo include sepsis (43% vs. 37%), respiratory infection (19% vs. 13%), and urinary tract infection (9% vs. 4%). Ibuprofen may mask the signs and symptoms of an infection; monitor patients carefully.

Ibuprofen lysine is contraindicated in patients with patent ductus arteriosus (PDA)-dependent congenital heart disease (e.g., pulmonary atresia, severe tetralogy of Fallot, severe aortic coarctation). In these patients, patency of the PDA is necessary for satisfactory pulmonary or systemic blood flow, and PDA closure could result in devastating consequences. Typically, clinical trials involving ibuprofen lysine have excluded neonates with hypertension. In general, conditions such as congestive heart failure or hypertension can be exacerbated with NSAID use.

Ibuprofen lysine is contraindicated in patients with coagulopathy or thrombocytopenia and in patients who are actively bleeding, especially those with intracranial bleeding or GI bleeding. Ibuprofen lysine, like other nonsteroidal anti-inflammatory agents, can inhibit platelet aggregation. This effect may be exaggerated in patients with underlying hemostatic defects. Monitor all neonates who receive ibuprofen lysine for signs and symptoms of bleeding. Ibuprofen has been shown to prolong bleeding time (but within the normal range) in normal adult subjects. Use with caution in patients expected to undergo surgery; if surgery is required in a patient who has recently received ibuprofen lysine, alert operating room staff and nursing personnel. Anemia also may be exacerbated with the use of NSAIDs. Monitor hemoglobin values; premature neonates have a baseline risk for developing anemia.

Ibuprofen lysine is contraindicated in preterm neonates with an untreated suspected or proven infection. NSAIDs may mask the signs of infection; neonates must be monitored closely during therapy. Caution should be exercised when this drug is used in patients with an active controlled infection or in neonates at risk of infection.

Ibuprofen lysine use is contraindicated in preterm neonates with severe renal impairment or renal failure. Use with caution in neonates with mild to moderate renal impairment; if anuria or marked oliguria (urinary output < 0.6 ml/kg/hr) is evident at the time of a scheduled dose of ibuprofen lysine, dosage should be held until laboratory studies indicate that renal function has returned to normal. In a clinical trial in neonates 24-32 weeks gestational age, ibuprofen lysine caused significantly less renal failure/oliguria than indomethacin. A meta-analysis also found that ibuprofen lysine has less negative effects on renal function when compared to indomethacin.

Ibuprofen lysine has been shown to displace bilirubin from albumin binding-sites; therefore, use with caution in patients with elevated total bilirubin, as indicated by jaundice or laboratory result. In a retrospective comparison of neonates < 30 weeks gestational age, the ibuprofen lysine cohort (n = 418) had a higher mean peak total serum bilirubin concentration, increased need for phototherapy, and prolonged phototherapy duration compared to the non-ibuprofen cohort (n = 288). Of note, the non-ibuprofen group was treated between 1993 and 1999; the ibuprofen group was treated between 2000 and 2007.

Ibuprofen lysine is contraindicated in preterm neonates with, or who are suspected of having, necrotizing enterocolitis. Ibuprofen may alter mesenteric hemodynamics, and a decrease in blood flow to the bowel in susceptible patients may result in intestinal tissue death and perforation. Patients with gastrointestinal malformations, GI perforation, or impaired intestinal circulation are not good candidates for pharmacologic closure of PDA. In a meta-analysis, ibuprofen was found to reduce the risk of necrotizing enterocolitis when compared to indomethacin. Ibuprofen has less COX 1 inhibition compared to indomethacin, resulting in less vasoconstrictive side effects.

Ibuprofen lysine should be administered via intravenous infusion only; avoid subcutaneous administration and intramuscular administration. Administer carefully to prevent extravasation, as the solution may be irritating to tissue.

Description: Ibuprofen lysine was developed for the treatment of patent ductus arteriosus (PDA) in premature infants. It is an injectable l-lysine salt of ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID) of the propionic acid chemical class. L-lysine is used to create a water-soluble solution suitable for intravenous administration. In clinical studies, ibuprofen lysine has been shown to be as effective as intravenous indomethacin in closing PDA of premature infants with a success rate of approximately 75%. Ibuprofen appears to be the drug of choice for closing a PDA due to its lower risk of necrotizing enterocolitis (NEC) and transient renal insufficiency compared to indomethacin. Indomethacin is known to result in a marked decrease in blood flow to the cerebral, mesenteric, and renal circulation; echocardiographic study of animal models and preterm infants treated with ibuprofen lysine showed no significant reductions. However, decreases in renal function in some ibuprofen lysine treated neonates were seen in subsequent studies. Long term survival and effect on neurodevelopment have not been assessed. Ibuprofen lysine is FDA approved to close clinically significant patent ductus arteriosus in infants weighing 500-1500 grams who are no more than 32 weeks gestational age when usual medical management is ineffective.

For treatment of a clinically significant patent ductus arteriosus (PDA) in premature infants when usual medical management is ineffective:
NOTE: Ibuprofen lysine is FDA-approved for use in premature neonates weighing 500-1500 g.
Intravenous dosage:
Premature neonates <= 32 weeks gestation: 10 mg/kg IV followed by 2 doses of 5 mg/kg/dose IV at 24 and 48 hours after the initial dose. Base all doses on birth weight. If oliguria (urine output < 0.6 ml/kg/hour) or anuria is evident at the scheduled time for the second or third dose, no additional doses should be given until renal function returns to normal. If the ductus arteriosus closes or significantly reduces in size after the first dose, the remaining doses may be omitted. If the ductus arteriosus fails to close or reopens, a second course of ibuprofen lysine, alternative pharmacological therapy, or surgical closure may be necessary.

Maximum Dosage Limits:
-Neonates
Neonates > 32 weeks gestational age: Safety and efficacyhave not been established.
Premature neonates (<= 32 weeks gestation): 10 mg/kg/day IV for initial dose; 5 mg/kg/day for remaining doses.
-Infants
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Adolescents
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Ibuprofen may, however, displace bilirubin; therefore, it should be used with caution in patients with elevated bilirubin.

Patients with Renal Impairment Dosing
Use is contraindicated in neonates with significant renal impairment. Do not administer to patients who are anuric or with marked oliguria (urine output < 0.6 ml/kg/hour).

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: The exact mechanism by which ibuprofen lysine causes closure of a patent ductus arteriosus (PDA) in neonates is not known. It is thought that the inhibition of prostaglandin synthesis is relevant. Local release of prostaglandins results in the dilation of, and may delay the closure of, the ductus. Ibuprofen blocks arachidonate binding resulting in competitive inhibition of both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, which in turn limits the COX-1 and COX-2 catalyzed conversion of arachidonic acid to prostaglandin G2 (PGG2) and subsequent prostaglandin and thromboxane synthesis. Based on in vitro information, ibuprofen has about equal inhibitory effects on COX-1 and COX-2.

Pharmacokinetics: Ibuprofen lysine is administered as an intravenous infusion. Ibuprofen lysine has only been studied in neonates, but in adults, ibuprofen is highly protein bound. It is metabolized via hepatic oxidation by cytochrome P450 2C9 to two inactive metabolites then excreted in the urine. Approximately 80% of an oral dose of ibuprofen is excreted in the urine as metabolites and 10-15% as unchanged drug. Some biliary excretion also occurs.

Affected cytochrome P450 isoenzymes: CYP2C9
Ibuprofen is a substrate of the hepatic cytochrome isoenzyme CYP2C9. Drug interactions of ibuprofen lysine in neonates have not been assessed. However, ibuprofen lysine is the l-lysine salt of ibuprofen.


-Special Populations
Pediatrics
Premature Neonates
In premature neonates, approximately 95% of ibuprofen is protein bound. Ibuprofen lysine pharmacokinetic data were obtained from 54 premature infants (< 30 weeks gestational age, weighing 500-1000 g) that exhibited asymptomatic PDA with echocardiographic documentation of ductal shunting. Average clearance and volume of distribution values at birth were 3 ml/kg/hour and 0.32 L/kg, respectively. Clearance increased rapidly with postnatal age (an average increase of approximately 0.5 ml/kg/hour per day). Inter-individual variability in clearance and volume of distribution were 55% and 14%, respectively. The volume of distribution in 13 preterm neonates (gestational age: 28.7 +/- 1.3 weeks) was 0.244 +/- 0.084 L/kg on day of life 3 and 0.171 +/- 0.077 L/kg on day of life 5. The half-life was 43.1 +/- 26.1 hours on day 3 of life (after the 1st ibuprofen dose) and was 26.8 +/- 23.6 hours on day 5 of life (after the 3rd ibuprofen dose). The half-life in 21 neonates (gestational age: 22-31 weeks, administered within 3 hours of life) was 30.5 +/- 4.2 hours. In general, the half-life of ibuprofen in infants is more than 10 times longer than in adults. The prolonged half-life reflecting the slow metabolism may be due, in part, to reduced or deficient activity of the hepatic cytochrome P450 enzyme complex and UDP-glucuronyl transferase isoforms. Renal function and the enzymes associated with drug metabolism, in general, are underdeveloped at birth and substantially increase in the days after birth. No pharmacokinetic data are available in neonates with either renal or hepatic impairment.