Indomethacin (Page 3 of 3)

12.3 Pharmacokinetics

The disposition of indomethacin following intravenous administration (0.2 mg/kg) in pre-term neonates with patent ductus arteriosus has not been extensively evaluated. Even though the plasma half-life of indomethacin was variable among premature infants, it was shown to vary inversely with postnatal age and weight. In one study, of 28 neonates who could be evaluated, the plasma half-life in those less than 7 days old averaged 20 hours (range: 3 to 60 hours, n=18). In neonates older than 7 days, the mean plasma half-life of indomethacin was 12 hours (range: 4 to 38 hours, n=10). Grouping the neonates by weight, mean plasma half-life in those weighing less than 1,000 g was 21 hours (range: 9 to 60 hours, n=10); in those neonates weighing more than 1,000 g, the mean plasma half-life was 15 hours (range: 3 to 52 hours, n=18).

Following intravenous administration in adults, indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean plasma half-life of indomethacin is 4.5 hours. In the absence of enterohepatic circulation, it is 90 minutes. Indomethacin has been found to cross the blood-brain barrier and the placenta.

In adults, about 99 percent of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. The percent bound in neonates has not been studied. In controlled trials in premature infants, however, no evidence of bilirubin displacement has been observed as evidenced by increased incidence of bilirubin encephalopathy (kernicterus).

13 NONCLINICAL TOXICOLOGY

In rats and mice, oral indomethacin 4 mg/kg/day given during the last three days of gestation caused a decrease in maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses was observed. At 2 mg/kg/day, no increase in neuronal necrosis was observed as compared to the control groups. Administration of 0.5 or 4 mg/kg/day during the first three days of life did not cause an increase in neuronal necrosis at either dose level.

Pregnant rats, given 2 mg/kg/day and 4 mg/kg/day during the last trimester of gestation, delivered offspring whose pulmonary blood vessels were both reduced in number and excessively muscularized. These findings are similar to those observed in the syndrome of persistent pulmonary hypertension of the neonate.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Sterile Indomethacin for Injection is a lyophilized white to yellow powder or plug supplied as single dose vials containing indomethacin for injection, equivalent to 1 mg indomethacin.

Product No.	NDC No.
NP605903	63323-659-09	1 mg per vial, Packaged individually.

The container closure is not made with natural rubber latex.

16.2 Storage

Store at 25°C (77°F) with excursions permitted to 15° to 30°C (59° to 86°F). Protect from light. Store container in carton until contents have been used.

Novaplus is a registered trademark of Vizient, Inc.

Manufactured by:

Fresenius Kabi

Lake Zurich, IL 60047
www.fresenius-kabi.com/us

451358B

novoplus

PACKAGE LABEL — PRINCIPAL DISPLAY — Indomethacin for Injection 1 mg Vial Label

NDC 63323-659-09 NP605903

Indomethacin For Injection
1 mg per vial

FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS

Sterile Rx only

Single Dose Vial — Discard unused portion

PACKAGE LABEL — PRINCIPAL DISPLAY — Indomethacin for Injection 1 mg Carton Panel

NDC 63323-659-09 NP605903

Indomethacin For Injection

1 mg per vial

For Intravenous Use Only

FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS

Rx only

One vial

Single Dose Vial — Discard any unused portion immediately.

INDOMETHACIN indomethacin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63323-659 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INDOMETHACIN (INDOMETHACIN) INDOMETHACIN 1 mg in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM PHOSPHATE, MONOBASIC 0.29 mg in 1 mL SODIUM PHOSPHATE, DIBASIC 0.41 mg in 1 mL SODIUM HYDROXIDE

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:63323-659-09 1 VIAL in 1 CARTON contains a VIAL 1 1 mL in 1 VIAL This package is contained within the CARTON (63323-659-09)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022536 03/19/2010

Labeler — Fresenius Kabi USA, LLC (608775388)

Establishment
Name	Address	ID/FEI	Operations
Fresenius Kabi USA, LLC		840771732	ANALYSIS (63323-659), MANUFACTURE (63323-659)

Revised: 06/2023 Fresenius Kabi USA, LLC