ibuprofen lysine

RECENT MAJOR CHANGES Warnings and Precautions ( 5.6 ) 10/2023

1 INDICATIONS AND USAGE Ibuprofen Lysine Injection is indicated to close a clinically significant patent ductus arteriosus (PDA) in premature infants weighing between 500 and 1500 g, who are no more than 32 weeks gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support, etc.) is ineffective. The clinical trial was conducted among infants with an asymptomatic PDA. However, the consequences beyond 8 weeks after treatment have not been evaluated; therefore, treatment should be reserved for infants with clear evidence of a clinically significant PDA. Ibuprofen Lysine Injection is a nonsteroidal anti-inflammatory drug indicated to close a clinically significant patent ductus arteriosus (PDA) in premature infants weighing between 500 and 1500 g, who are no more than 32 weeks gestational age when usual medical management is ineffective. The clinical trial was conducted among infants with an asymptomatic PDA. However, the consequences beyond 8 weeks after treatment have not been evaluated; therefore, treatment should be reserved for infants with clear evidence of a clinically significant PDA. (1)

2 DOSAGE AND ADMINISTRATION A course of therapy is three doses administered I.V. (2.1) An initial dose of 10 mg/kg (based on birth weight) is followed by two doses of 5 mg/kg each, after 24 and 48 hours (2.1) Do not administer if anuria or marked oliguria (<0.6 mL/kg/hr) is evident at the scheduled time of the second or third dose (2.1) 2.1 Recommended Dose A course of therapy is three doses of Ibuprofen Lysine Injection administered intravenously (administration via an umbilical arterial line has not been evaluated). An initial dose of 10 mg per kilogram is followed by two doses of 5 mg per kilogram each, after 24 and 48 hours. All doses should be based on birth weight. If anuria or marked oliguria (urinary output <0.6 mL/kg/hr) is evident at the scheduled time of the second or third dose of Ibuprofen Lysine Injection, no additional dosage should be given until laboratory studies indicate that renal function has returned to normal. If the ductus arteriosus closes or is significantly reduced 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.

3 DOSAGE FORMS AND STRENGTHS 20 mg/2 mL (10 mg/mL) as a clear sterile preservative-free solution of the L-lysine salt of ibuprofen in a 2 mL single-use vial. 20 mg/2 mL (10 mg/mL) as a clear sterile preservative-free solution of the L-lysine salt of ibuprofen in a 2 mL single-use vial (3)

4 CONTRAINDICATIONS Ibuprofen Lysine Injection is contraindicated in: Preterm infants with proven or suspected infection that is untreated; Preterm infants with congenital heart disease in whom patency of the PDA is necessary for satisfactory pulmonary or systemic blood flow (e.g., pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta); Preterm infants who are bleeding, especially those with active intracranial hemorrhage or gastrointestinal bleeding; Preterm infants with thrombocytopenia; Preterm infants with coagulation defects; Preterm infants with or who are suspected of having necrotizing enterocolitis; Preterm infants with significant impairment of renal function. Ibuprofen Lysine Injection is contraindicated in preterm infants: With proven or suspected infection that is untreated (4) With congenital heart disease in whom patency of the PDA is necessary for satisfactory pulmonary or systemic blood flow (4) With impaired renal function (4) With thrombocytopenia, coagulation defects or who are bleeding (4) With or who are suspected of having necrotizing enterocolitis (4)

6 ADVERSE REACTIONS Most common adverse reactions (≥10%) are sepsis, anemia, intraventricular bleeding, apnea, gastrointestinal disorders, impaired renal function, respiratory infection, skin lesions, hypoglycemia, hypocalcemia, respiratory failure. (6) To report SUSPECTED ADVERSE REACTIONS, contact XGen Pharmaceuticals DJB Inc. at 1-866-390-4411, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The most frequently reported adverse events with Ibuprofen Lysine Injection were as shown in Table 1. Table 1. Adverse Events within 30 Days of Therapy in the Multicenter Study* % Incidence Adverse Event Ibuprofen Lysine Injection Placebo Sepsis 43 37 Anemia 32 25 Total Bleeding** 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 * Within 30 days of therapy, with an event rate greater on Ibuprofen Lysine Injection than on placebo, and greater than 2 events on Ibuprofen Lysine Injection. ** A given subject may have experienced more than one specific event within these adverse event categories. Only the most severe grade of IVH counted for a given subject. 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 Postmarketing 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.

7 DRUG INTERACTIONS Diuretics: Ibuprofen may reduce the effect of diuretics; diuretics can increase the risk of nephrotoxicity of NSAIDs in dehydrated patients. Monitor renal function in patients receiving concomitant diuretics. Amikacin: Ibuprofen may decrease the clearance of amikacin. Diuretics: Increased risk of renal dysfunction. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.4 Pediatric Use Safety and effectiveness have only been established in premature infants.

12.1 Mechanism of Action The mechanism of action through which ibuprofen causes closure of a patent ductus arteriosus (PDA) in neonates is not known. In adults, ibuprofen is an inhibitor of prostaglandin synthesis.

11 DESCRIPTION Ibuprofen Lysine Injection is a clear sterile preservative-free solution of the L-lysine salt of (±)-ibuprofen which is the active ingredient. (±)-Ibuprofen is a nonsteroidal anti-inflammatory agent (NSAID). L-lysine is used to create a water-soluble drug product salt suitable for intravenous administration. Each mL of Ibuprofen Lysine Injection contains 17.1 mg of ibuprofen lysine (equivalent to 10 mg of (±)-ibuprofen) in Water for Injection, USP. The pH is adjusted to 7.0 with sodium hydroxide or hydrochloric acid. The structural formula is: Ibuprofen Lysine Injection is designated chemically as α-methyl-4-(2-methyl propyl) benzeneacetic acid lysine salt. Its molecular weight is 352.48. Its empirical formula is C 19 H 32 N 2 O 4 . It occurs as a white crystalline solid which is soluble in water and slightly soluble in ethanol. Structural Formula

10 OVERDOSAGE The following signs and symptoms have occurred in individuals (not necessarily in premature infants) following an overdose of oral ibuprofen: breathing difficulties, coma, drowsiness, irregular heartbeat, kidney failure, low blood pressure, seizures, and vomiting. There are no specific measures to treat acute overdosage with Ibuprofen Lysine Injection. The patient should be followed for several days because gastrointestinal ulceration and hemorrhage may occur.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Ibuprofen Lysine Injection is dispensed in treated Ibuprofen Lysine Injection is dispensed in a glass vial having a silicon dioxide coating or polymer coating that inhibits the formation of particulates that result from the interaction of the ibuprofen lysine with untreated glass. clear glass single-use vials, each containing 2 mL of sterile solution (NDC 66993-490-84). The solution is not buffered and contains no preservatives. Each milliliter contains 17.1 mg/mL (±)-ibuprofen L-lysine [equivalent to 10 mg/mL (±)-ibuprofen] dissolved in Water for Injection, USP. Ibuprofen Lysine is supplied in a carton (NDC 66993-490-36) containing 3 single-use vials. Storage and Handling Store at 20 – 25°C (68 – 77°F); excursions permitted 15 – 30°C (59 – 86°F) [see USP Controlled Room Temperature]. Protect from light. Store vials in carton until contents have been used.