Indocin IV

DESCRIPTION

注射用无菌消炎痛®输液(消炎痛)for intravenous administration is lyophilized indomethacin for injection. Each vial contains indomethacin for injection equivalent to 1 mg indomethacin as a white to yellow lyophilized powder or plug. Variations in the size of the lyophilized plug and the intensity of color have no relationship to the quality or amount of indomethacin present in the vial.

Indomethacin for injection is designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H吲哚3 -acetic acid, sodium salt, trihydrate. Its molecular weight is 433.82. Its empirical formula is C₁₉H₁₅ClNNaO₄•3H₂O and its structural formula is:

INDICATIONS

INDOCIN I.V. is indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1750 g when after 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support, etc.) is ineffective. Clear-cut clinical evidence of a hemodynamically significant patent ductus arteriosus should be present, such as respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly and pulmonary plethora on chest x-ray.

DOSAGE AND ADMINISTRATION

FOR INTRAVENOUS ADMINISTRATION ONLY.

Dosage recommendations for closure of the ductus arteriosus depend on the age of the infant at the time of therapy. A course of therapy is defined as three intravenous doses of INDOCIN I.V. given at 12-24 hour intervals, with careful attention to urinary output. 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 INDOCIN I.V., no additional doses should be given until laboratory studies indicate that renal function has returned to normal (see警告,Renal Effects).

Dosage according to age is as follows:

AGE at 1st dose	DOSAGE (mg/kg)
Less than 48 hours	1st 0.2	2日0.1	3rd 0.1
2-7 days	0.2	0.2	0.2
over 7 days	0.2	0.25	0.25

If the ductus arteriosus closes or is significantly reduced in size after an interval of 48 hours or more from completion of the first course of INDOCIN I.V., no further doses are necessary. If the ductus arteriosus re-opens, a second course of 1-3 doses may be given, each dose separated by a 12-24 hour interval as described above.

If the neonate remains unresponsive to therapy with INDOCIN I.V. after 2 courses, surgery may be necessary for closure of the ductus arteriosus. If severe adverse reactions occur, STOP THE DRUG.

使用说明

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

的reconstituted solution is clear, slightly yellow and essentially free from visible particles.

的solution should be preparedonlywith 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection.Benzyl alcohol as a preservative has been associated with toxicity in neonates. Therefore, all diluents should be preservative-free. If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL. Any unused portion of the solution should be discarded because there is no preservative contained in the vial. A fresh solution should be prepared just prior to each administration. Once reconstituted, the indomethacin solution may be injected intravenously. While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20-30 minutes.

INDOCIN I.V. is not buffered. Further dilution with intravenous infusion solutions is not recommended.

HOW SUPPLIED

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

NDC67386-511-51.

Storage

Store at 20-25°C (68-77°F). See USP controlled room temperature. Protect from light. Store container in carton until contents have been used.

Manufactured by: Hollister-Stier Laboratories, LLC, Spokane, WA 99207, U.S.A. Revised: Mar 2021

SIDE EFFECTS

In a double-blind, placebo-controlled trial of 405 premature infants weighing less than or equal to 1750 g with evidence of large ductal shunting, in those neonates treated with indomethacin (n=206), there was a statistically significantly greater incidence of bleeding problems, including gross ormicroscopicbleeding into thegastrointestinal tract, oozing from the skin afterneedle stick, pulmonaryhemorrhage和弥散性血管内凝血病。的re was no statistically significant difference between treatment groups with reference to intracranial hemorrhage.

的neonates treated with indomethacin for injection also had a significantly higher incidence of transientoliguriaand elevations of serum creatinine (greater than or equal to 1.8 mg/dL) than did the neonates treated with placebo.

的incidences of retrolental fibroplasia (grades III and IV) andpneumothoraxin neonates treated with INDOCIN I.V. were no greater than in placebo controls and were statistically significantly lower than in surgically-treated neonates.

的following additional adverse reactions in neonates have been reported from the collaborative study, anecdotal case reports, from other studies usingrectal, oral, or intravenous indomethacin for treatment ofpatent ductus arteriosusor in marketed use. The rates are calculated from a database which contains experience of 849 indomethacin-treated neonates reported in the medical literature, regardless of the route of administration. One year follow-up is available on 175 neonates and shows no long-termsequelaewhich could be attributed to indomethacin. In controlled clinical studies, onlyelectrolyteimbalance and renal dysfunction (of the reactions listed below) occurred statistically significantly more frequently after INDOCIN I.V. than after placebo. Reactions marked with a single asterisk (*) occurred in 3-9 percent of indomethacin-treated neonates; those marked with a double asterisk (**) occurred in 3-9 percent of both indomethacinand placebo-treated neonates. Unmarked reactions occurred in less than 3 percent of neonates. Renal: renal failure, renal dysfunction in 41 percent of neonates, including one or more of the following: reduced urinary output; reduced urine sodium, chloride, orpotassium, urine osmolality, free water clearance, orglomerularfiltration rate; elevated serum creatinine orBUN;uremia.

Cardiovascular:intracranial bleeding**,肺hypertension.

Gastrointestinal:gastrointestinalbleeding*, vomiting, abdominaldistention, transientileus,gastricperforation, localized perforation(s) of the small and/orlarge intestine, necrotizing enterocolitis. Metabolic:hyponatremia*, elevated serum potassium*, reduction in blood sugar, includinghypoglycemia, increased weight gain (fluid retention).

Coagulation:decreasedplatelet aggregation(seePRECAUTIONS).

的following adverse reactions have also been reported in neonates treated with indomethacin, however, a causal relationship to therapy with INDOCIN I.V. has not been established:

Cardiovascular:bradycardia.

Respiratory:apnea, exacerbation of pre-existing pulmonary infection.

Metabolic:acidosis/alkalosis.

Hematologic:disseminated intravascularcoagulation,thrombocytopenia.

Ophthalmic:retrolental fibroplasia.**

Dermatologic:drug reaction witheosinophiliaand systemic symptoms (DRESS)

To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck Inc. at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Since renal function may be reduced by INDOCIN I.V., consideration should be given to reduction in dosage of those medications that rely on adequate renal function for their elimination. Because the half-life of digitalis (given frequently to pre-term infants withpatent导管动susand associated cardiac failure) may be prolonged when given concomitantly with indomethacin, theneonateshould be observed closely; frequent ECGs and serum digitalis levels may be required to prevent or detect digitalis toxicity early. Furthermore, in one study of premature infants treated with INDOCIN I.V. and also receiving either gentamicin or amikacin, both peak and trough levels of these aminoglycosides were significantly elevated.

的rapy with indomethacin may blunt thenatriureticeffect of furosemide. This response has been attributed to inhibition ofprostaglandinsynthesis by non-steroidal anti-inflammatory drugs. In a study of 19 premature infants withpatent ductusarteriosus treated with either INDOCIN I.V. alone or a combination of INDOCIN I.V. and furosemide, results showed that neonates receiving both INDOCIN I.V. and furosemide had significantly higher urinary output, higher levels of sodium and chloride excretion, and higher glomerular filtration rates than did those receiving INDOCIN I.V. alone. In this study, the data suggested that therapy with furosemide helped to maintain renal function in the premature infant when INDOCIN I.V. was added to the treatment of patentductusarteriosus.

Indomethacin usually does not influence the hypoprothrombinemia produced by anticoagulants. When indomethacin is added to anticoagulants,prothrombin timeshould be monitored closely. In post marketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and INDOCIN I.V. Caution should be exercised when INDOCIN I.V. and anticoagulants are administered concomitantly.

In some patients with compromised renal function, the co-administration of anNSAIDand an ACE inhibitor orangiotensinIIantagonistmay result in further deterioration of renal function, including possibleacute renal failure, which is usually reversible.

警告

Gastrointestinal Effects

In the collaborative study, major gastrointestinal bleeding was no more common in those neonates receiving indomethacin than in those neonates on placebo. However, minor gastrointestinal bleeding (i.e., chemical detection of blood in the凳子) was more commonly noted in those neonates treated with indomethacin. Severe gastrointestinal effects have been reported in adults with various arthritic disorders treated chronically with oral indomethacin. [For further information, see package insert for Capsules INDOCIN^®(Indomethacin).]

Central Nervous System Effects

Prematurityper se, is associated with an increased incidence of spontaneousintraventricularhemorrhage. Because indomethacin may inhibit platelet aggregation, the potential for intraventricular bleeding may be increased. However, in the large multicenter study of INDOCIN I.V. (seeCLINICAL PHARMACOLOGY), the incidence of intraventricular hemorrhage in neonates treated with INDOCIN I.V. was not significantly higher than in the control neonates.

Renal Effects

INDOCIN I.V. may cause significant reduction in urine output (50 percent or more) with concomitant elevations ofblood urea nitrogenand creatinine, and reductions in glomerular filtration rate and creatinine clearance. These effects in most neonates are transient, disappearing with cessation of therapy with INDOCIN I.V. However, because adequate renal function can depend upon renal prostaglandin synthesis, INDOCIN I.V. may precipitate renal insufficiency, including acute renal failure, especially in neonates with other conditions that may adversely affect renal function (e.g.,extracellularvolume depletion from any cause,congestive heart failure,sepsis, concomitant use of anynephrotoxicdrug, hepatic dysfunction). When significant suppression of urine volume occurs after a dose of INDOCIN I.V., no additional dose should be given until the urine output returns to normal levels.

INDOCIN I.V. in pre-term infants may suppress water excretion to a greater extent than sodium excretion. When this occurs, a significant reduction in serum sodium values (i.e., hyponatremia) may result. Neonates should have serum electrolyte determinations done during therapy with INDOCIN I.V. Renal function and serum electrolytes should be monitored (seeDRUG INTERACTIONSandDOSAGE AND ADMINISTRATION).

PRECAUTIONS

General

INDOCIN (Indomethacin) may mask the usual signs and symptoms of infection. Therefore, the physician must be continually on the alert for this and should use the drug with extra care in the presence of existing controlled infection.

Severe hepatic reactions have been reported in adults treated chronically with oral indomethacin for arthritic disorders. [For further information, see package insert for Capsules INDOCIN (Indomethacin).] If clinical signs and symptoms consistent withliver diseasedevelop in the neonate, or if systemic manifestations occur, INDOCIN I.V. should be discontinued.

INDOCIN I.V. may inhibit platelet aggregation. In one small study, platelet aggregation was grossly abnormal after indomethacin therapy (given orally to premature infants to close the ductus arteriosus). Platelet aggregation returned to normal by the tenth day. Premature infants should be observed for signs of bleeding.

的drug should be administered carefully to avoid extravascular injection or leakage as the solution may be irritating to tissue.

Neonatal Effects

In rats and mice, oral indomethacin 4.0 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 neuronalnecrosisin the diencephalon in the live-born fetuses was observed. At 2.0 mg/kg/day, no increase in neuronal necrosis was observed as compared to the control groups. Administration of 0.5 or 4.0 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 2.0 mg/kg/day and 4.0 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 pulmonaryhypertensionof the neonate.

OVERDOSE

No Information Provided

CONTRAINDICATIONS

INDOCIN I.V. is contraindicated in: neonates with proven or suspected infection that is untreated; neonates who are bleeding, especially those with active intracranial hemorrhage or gastrointestinal bleeding; neonates with thrombocytopenia; neonates with coagulation defects; neonates with or who are suspected of having necrotizing enterocolitis; neonates with significant impairment of renal function; neonates withcongenital heart diseasein whom patency of the ductus arteriosus is necessary for satisfactory pulmonary or systemic blood flow (e.g., pulmonaryatresia, severetetralogy of Fallot, severecoarctation of the aorta).

CLINICAL PHARMACOLOGY

Although the exact mechanism of action through which indomethacin causes closure of a patent ductus arteriosus is not known, it is believed to be through inhibition of prostaglandin synthesis. Indomethacin has been shown to be a potent inhibitor of prostaglandin synthesis, bothin vitroandin vivo. In human newborns with certaincongenitalheart malformations, PGE 1 dilates the ductus arteriosus. In fetal and newborn lambs, E type prostaglandins have also been shown to maintain the patency of the ductus, and as in human newborns, indomethacin causes its constriction.

Studies in healthy young animals and in premature infants with patent ductus arteriosus indicated that, after the first dose of intravenous indomethacin, there was a transient reduction in cerebral blood flow velocity and cerebral blood flow. Similar decreases in mesenteric blood flow and velocity have been observed. The clinical significance of these effects has not been established.

In double-blind, placebo-controlled studies of INDOCIN I.V. in 460 small pre-term infants, weighing 1750 g or less, the neonates treated with placebo had a ductus closure rate after 48 hours of 25 to 30 percent, whereas those treated with INDOCIN I.V. had a 75 to 80 percent closure rate. In one of these studies, a multicenter study, involving 405 pre-term infants, later reopening of the ductus arteriosus occurred in 26 percent of neonates treated with INDOCIN I.V., however, 70 percent of these closed subsequently without the need for surgery or additional indomethacin.

制药公司cokinetics And Metabolism

的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: 3-60 hours, n=18). In neonates older than 7 days, the mean plasma half-life of indomethacin was 12 hours (range: 4-38 hours, n=10). Grouping the neonates by weight, mean plasma half-life in those weighing less than 1000 g was 21 hours (range: 9-60 hours, n=10); in those neonates weighing more than 1000 g, the mean plasma half-life was 15 hours (range: 3-52 hours, n=18).

Following intravenous administration in adults, indomethacin is eliminated via renal excretion,metabolism, andbiliaryexcretion. Indomethacin undergoes appreciable enterohepaticcirculation. 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 theblood-brain barrier和胎盘。

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 bilirubinencephalopathy(kernicterus).

PATIENT INFORMATION

No information provided. Please refer to the警告andPRECAUTIONSsections.