Ibuprofen Lysine

IBUPROFEN LYSINE- ibuprofen lysine solution
XGen Pharmaceuticals DJB, Inc.

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.

2 DOSAGE AND ADMINISTRATION

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.

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.

5 WARNINGS AND PRECAUTIONS

5.1 General

There are no long-term evaluations of the infants treated with ibuprofen at durations greater than the 36 weeks post-conceptual age observation period. Ibuprofen’s effects on neurodevelopmental outcome and growth as well as disease processes associated with prematurity (such as retinopathy of prematurity and chronic lung disease) have not been assessed.

5.2 Infection

Ibuprofen Lysine Injection may alter the usual signs of infection. The physician must be continually 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.

6 ADVERSE REACTIONS

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 *

* 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.
	% 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