INDOMETHACIN (Generic for INDOCIN)

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

Route-Specific Administration

Oral Administration
-Administer orally with milk, antacids, or food to minimize GI irritation.
Oral Solid Formulations
-Extended-release capsules: Do not chew, crush, or open; administer intact.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Reconstitution:
-Do not use diluents containing preservatives for reconstitution.
-Reconstitute 1 mg with 1 or 2 ml of sterile water for injection or NS injection to give an IV solution containing 1 or 0.5 mg/ml, respectively. Do not dilute further.
-Administer immediately after preparation.

Intermittent IV Infusion Administration:
-Do NOT administer by IV bolus or infuse via an umbilical artery catheter (UAC).
-Infuse over 20-35 minutes.
-Avoid extravasation as intravenous indomethacin may be irritating to extravascular tissue.

Renal dysfunction can occur during both short- and long-term therapy with indomethacin. A significant reduction in urine output (UOP) is experienced by 50% or more of premature neonates who receive indomethacin for PDA closure. In a clinical trial involving 405 neonates, those treated with indomethacin had a significantly higher incidence of transient oliguria and elevations of serum creatinine (> 1.8 mg/dl) than did infants treated with placebo. In another trial evaluating 421 neonates with PDA, transient renal dysfunction was observed in the indomethacin group during the 36 hours after initial infusion. The mean BUN was significantly higher, as compared to that in neonates receiving placebo (15.7 +/- 8.9 mg/dl vs. 14.5 +/- 8.1 mg/dl). Serum creatinine concentrations were also increased in the treatment group (1.09 +/- 0.45 mg/dl vs. 0.99 +/- 0.33 mg/dl) and urine output was significantly lower in the treatment group (32.6 +/- 22 ml vs. 41.2 +/- 25.2 ml). Concurrent administration of a loop diuretic (e.g., furosemide) increases the risk of renal impairment. Additionally, data suggest that indomethacin causes more adverse renal effects than ibuprofen lysine. Renal function must be monitored closely in all neonates who receive indomethacin. In contrast, the reported incidence of renal and metabolic effects in adults treated with indomethacin is < 1%; the following events have been reported in adults receiving oral indomethacin: proteinuria, nephrotic syndrome, interstitial nephritis, elevated BUN (azotemia), renal insufficiency including renal failure (unspecified), peripheral edema, weight gain, and fluid retention. Rarely renal papillary necrosis has been reported in patients receiving NSAIDs.

According to the manufacturer, combined data suggest that GI bleeding (all severities) occurs in 3-9% of premature neonates who receive intravenous indomethacin. One study reported a similar occurrence of GI bleeding in premature infants treated with indomethacin and those not treated; however, minor GI bleeding, as evidenced by occult blood in feces, occurred more frequently in the neonates treated with indomethacin. Abdominal distention, transient ileus, GI perforation, and necrotizing enterocolitis occurs in < 3% of premature neonates. The concurrent use of indomethacin and corticosteroids increases the risk of GI perforation. Because of the adverse effects of indomethacin on mesenteric blood flow, there is concern for an increased risk of necrotizing enterocolitis (NEC). It has been speculated that a synergistic effect of a ductal-mediated decrease in local perfusion further exacerbated by treatment-induced vasoconstriction may contribute to intestinal ischemia and increase the risk. A cautious feeding regimen and consideration of a lower threshold for discontinuation of feeds has been recommended. Results from a meta-analysis found ibuprofen to lower the risk of NEC when compared to indomethacin (RR 0.68 [0.47-0.99]). Another meta analysis of 5 trials (combined n = 431) compared prolonged indomethacin regimens to short course (<= 3 doses) and found no statistically significant difference in successful PDA closure, need for ligation, reopening or re-treatment; however, there was an increased incidence of NEC with the prolonged course. GI bleeding and perforation may also occur as a result of chronic oral indomethacin use. In adult patients, upper GI ulcers and GI bleeding or perforation occur in approximately 1% of patients treated with NSAIDs for 3-6 months and in 2-4% of patients treated > 1 year. To minimize the risk of serious adverse GI effects from chronic use, the lowest effective dose should be used for the shortest possible duration. All patients, regardless of age or indication, should be monitored for signs and symptoms of GI bleeding while receiving indomethacin therapy.

Metabolic adverse reactions may occur with indomethacin use; assess electrolyte and glucose concentrations prior to and during intravenous indomethacin therapy. Combined data from clinical trials and case reports suggest that hyponatremia and elevated serum potassium (including hyperkalemia) occur in 3-9% of indomethacin-treated premature neonates. Increases in serum potassium concentrations have been reported in patients without renal impairment. Other metabolic adverse reactions reported in neonates treated with indomethacin include acidosis/alkalosis, increased weight gain (fluid retention), and hypoglycemia. In one of the early studies identifying hypoglycemia as an adverse effect, 55 premature neonates received indomethacin for PDA; plasma glucose concentrations were significantly lower in the indomethacin group at 24 and 28 hours compared to the controls. Three neonates had a plasma glucose concentrations < 40 mg/dl. Some experts suggest that an increase in glucose infusion rate (GIR) by 2 mg/kg/min may prevent hypoglycemic episodes. Hyponatremia and hyperkalemia have also been reported with oral indomethacin in adult populations.

Indomethacin causes platelet dysfunction (inhibition); monitor patients for signs and symptoms of bleeding. In a double-blind, placebo-controlled trial of 405 premature neonates, those that received indomethacin (n = 206) experienced a statistically significantly higher incidence of bleeding problems. Gross and microscopic GI bleeding, oozing after a needle stick, pulmonary hemorrhage, and disseminated intravascular coagulation (DIC) were the types of bleeding reported. There was no statistically significant difference between groups with reference to intracranial hemorrhage. Unlike aspirin, the platelet inhibition caused by NSAIDs is shorter and reversible. Patients receiving chronic oral indomethacin therapy should be counseled to report any signs and symptoms of bleeding (e.g., bleeding from gums, unusual bruising, etc.).

In addition to effects on platelet aggregation and bleeding time, other hematologic adverse effects reported in fewer than 1% of adult patients receiving indomethacin include hemolytic anemia, aplastic anemia, pancytopenia, agranulocytosis, leukopenia, thrombotic thrombocytopenic purpura (TTP), and thrombocytopenia.

The most common GI effects reported with oral indomethacin therapy in adults (> 1%, unless otherwise specified) include nausea (3-9%), vomiting, dyspepsia (3-9%), pyrosis, epigastric pain, diarrhea, abdominal pain/distress (gastritis), and constipation. Symptoms of GI distress can be lessened by administration of the oral dose with or immediately after food, or with antacids. Severe GI effects occur with a frequency of less than 1% and include gastric ulceration with or without GI bleeding, peptic ulcer disease, or GI perforation. These severe adverse reactions often occur in the absence of early GI manifestations. Patients should be advised of the signs and symptoms of GI bleeding. The risk of severe GI events is increased by the presence of the following factors: history of peptic ulcer disease or GI bleed, smoking, alcohol usage, concomitant usage of anticoagulants or oral corticosteroids, poor general health status, and NSAID duration of use. GI bleeding or erosive gastritis can be minor or life-threatening and may result from a combination of direct irritant action on the stomach mucosa and a prolonged bleeding time, due to changes in platelet aggregation. Rarely, intestinal ulceration has been associated with stenosis and intestinal obstruction. Preexisting gastric or intestinal lesions can be reactivated by indomethacin. Increased abdominal pain in ulcerative colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur rarely. Other GI adverse reactions include anorexia, flatulence, and melena. Acute pancreatitis has been reported, but a casual relationship to indomethacin has not been established.

Rare cases of esophagitis have been reported in adult patients receiving NSAIDs like indomethacin. NSAID-induced esophagitis is characterized by sudden onset odynophagia, pyrosis (heartburn), retrosternal pain, and dysphagia. Severe complications such as esophageal ulceration, esophageal stricture, bleeding, and perforation have been reported rarely. Risk factors for NSAID-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication.

NSAIDs have been associated with hepatotoxicity such as elevated hepatic enzymes, hepatitis, or jaundice. Usually, this is an infrequent occurrence, but patients should be monitored closely if elevated hepatic enzymes are observed during therapy. Fatal cases of hepatitis and jaundice have been reported in patients treated with indomethacin; overall incidence of these effects in patients treated with indomethacin is < 1%.

Pulmonary hypertension and bradycardia have been reported with intravenous indomethacin use in premature neonates. Cardiac adverse effects reported with other formulations of indomethacin in adult patients include chest pain (unspecified), congestive heart failure, hypertension, hypotension, bradycardia, sinus tachycardia, and palpitations. In adult patients, the use of NSAIDs may increase the risk of serious cardiovascular thromboembolism, myocardial infarction, and stroke, which can be fatal; it is not known whether this risk also applies to pediatric patients. The risk may increase with increased exposure, as measured in dose or duration. Significant cardiovascular risk has been observed within days to weeks of NSAID initiation. The relative increase in cardiovascular thrombotic events over baseline appears to be similar in patients with or without cardiovascular disease or risk factors for cardiovascular disease; however, patients with known cardiovascular disease or risk factors may be at greater risk because of a higher baseline risk of events. Inform patients of the signs and symptoms of a cardiovascular thrombotic event, and advise them to seek medical help immediately if such signs or symptoms occur.

Various nervous system adverse effects, mainly headache (at least 10%, but has been estimated as high as 25% to 50%), dizziness (3% to 9%), and somnolence, vertigo, depression, tinnitus, and fatigue/malaise (1% to 3%) have been attributed to indomethacin use in adults. Adverse nervous system effects may be dose-related, but if severe reactions persist, discontinue indomethacin. Headache is more common in the morning and can be severe. Additional symptoms accompanying indomethacin-induced headache include frontal throbbing, apparent swelling of the temporal vessels, vomiting, tinnitus, ataxia, tremor, dizziness, insomnia, and vertigo. If the headache persists despite reduction in dosage, discontinue indomethacin. The mechanism of indomethacin-induced headache is vasoconstriction in carotid area, with subsequent reduction of cerebral blood flow. After withdrawal of the drug or within 24 hours of a single dose of indomethacin, compensatory vasoconstriction occurs resulting in headache.

Apnea and exacerbation of pulmonary infection have been reported in 1-3% of premature neonates receiving indomethacin. The frequency of pneumothorax in indomethacin-treated neonates has been similar to that in neonates not receiving the drug and less than that in neonates undergoing surgical ligation of the ductus.

According to the manufacturer, retinopathy of prematurity (retrolental fibroplasia) and intraventricular hemorrhage have occurred in 3-9% of premature neonates receiving indomethacin; however, these conditions are also risks of prematurity itself. A large multicenter study of intravenous indomethacin found that the incidence of intraventricular hemorrhage in neonates treated with intravenous indomethacin was not significantly higher than the control group. In addition, low-dose indomethacin is used off-label for the prevention of intraventricular hemorrhage in premature neonates. Ophthalmic toxicity in adults, including blurred vision, intraepithelial corneal deposits, and corneal and retinal disturbance, has been reported in fewer than 1% of patients.

Allergic and dermatologic reactions to indomethacin occur in less than 1% of patients in the general population. Although rare, these reactions can be serious. Reactions reported include anaphylactoid reactions, including anaphylactic shock, angioedema, pruritus, rash, urticaria, exfoliative dermatitis, erythema nodosum, Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis. Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported during postmarketing experience. Extravasation of indomethacin injection may lead to skin irritation. Fulminant necrotizing fasciitis, which may be fatal and is usually associated with group A beta-hemolytic streptococcal infection has been reported rarely in patients receiving NSAIDs, including indomethacin. Patients and caregivers should be instructed to discontinue the medication and contact their health care provider if erythema, rash, blisters, or related skin reactions develop.

Aseptic meningitis has been reported rarely in adult patients receiving NSAID therapy like indomethacin. Ibuprofen has been the most common NSAID implicated in this adverse reaction; however, cases have been reported with sulindac, naproxen, tolmetin, diclofenac, ketoprofen, rofecoxib, and piroxicam. Aseptic meningitis from one NSAID does not preclude use of another NSAID; most patients can be treated with another drug without incident. However, one adult patient with Sjogren's syndrome experienced aseptic meningitis after receipt of naproxen, ibuprofen, and rofecoxib at different times; aseptic meningitis developed about a week after each drug exposure, and the symptoms abated roughly 2 days after each drug cessation. The occurrence of aseptic meningitis is not related to NSAID chemical class or prostaglandin inhibition. A Type III or IV immunological hypersensitivity reaction is the proposed mechanism of action. Drug-induced aseptic meningitis usually occurs shortly after drug initiation but can occur after years of drug usage. Although NSAID-induced aseptic meningitis is primarily reported in patients with systemic lupus erythematosus (SLE), healthy patients and patients with other disease states such as ankylosing spondylitis, connective tissue disease, osteoarthritis, and rheumatoid arthritis have developed NSAID-induced aseptic meningitis. Symptoms of aseptic meningitis include confusion, drowsiness, general feeling of illness, severe headache, nausea, nuchal rigidity, and photophobia. As aseptic meningitis is a diagnosis of exclusion, the suspected drug should be discontinued and not restarted unless a rechallenge is desired.

Indomethacin is contraindicated in patients with a known hypersensitivity to indomethacin or any of its drug product components. Indomethacin is also contraindicated in patients with salicylate hypersensitivity or NSAID hypersensitivity who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactoid reactions have been reported in such patients. A subpopulation of patients with asthma may have aspirin-sensitive asthma or the aspirin triad, characterized by chronic rhinosinusitis and nasal polyps, acute bronchospasm, and/or aspirin or other NSAID intolerance. Indomethacin should not be used in these patients because of the potential for cross-sensitivity. When indomethacin is used in patients with preexisting asthma (with no known aspirin sensitivity), monitor for changes in the signs and symptoms of asthma. The use of NSAIDs, including indomethacin, may cause serious and potentially fatal skin reactions including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. These events may occur without warning. Instruct patients to discontinue the medication and contact their health care provider if erythema, rash, blisters, or related skin reactions develop.

Intravenous indomethacin is contraindicated in neonates with proven or suspected untreated infection. Indomethacin can mask the usual signs of infection; monitor patients carefully for subtle signs of possible infection.

Indomethacin is contraindicated in neonates who are bleeding, especially intracranial bleeding or gastrointestinal bleeding and in neonates with coagulopathy or thrombocytopenia. Indomethacin should be used cautiously in any any patient with preexisting hematological disease (e.g., coagulopathy, hemophilia) or thrombocytopenia due to the effect of the drug on platelet function and vascular response to bleeding. While indomethacin's inhibitory effect on platelet aggregation is shorter than aspirin's, bleeding can still occur in these patient groups. Indomethacin should also be used with caution in patients undergoing surgery when a high degree of hemostasis is required. NSAIDs should be used with caution in patients with immunosuppression or neutropenia. NSAIDs may mask the signs of infection such as fever or pain in patients with bone marrow suppression.

Indomethacin is contraindicated in neonates with GI bleeding and in neonates with necrotizing enterocolitis. The concurrent use of indomethacin and corticosteroid therapy has been shown to increase the risk of GI perforation in premature neonates. In a meta-analysis, ibuprofen lysine was found to reduce the risk of necrotizing enterocolitis when compared to indomethacin. Chronic use of indomethacin, such as for juvenile idiopathic arthritis, can result in gastritis, ulceration with or without GI perforation, and/or GI bleeds, which can occur at any time, often without preceding symptoms. Use all forms of indomethacin with caution in patients with a history of or active GI disease. Avoid use in high risk patients including those with a history of peptic ulcer disease and/or GI bleeding unless the benefits are expected to outweigh the risks. Other factors that increase the risk of NSAID-induced GI bleeding include advanced liver disease, bleeding disorders, poor general health status, and concomitant use of myelosuppressive chemotherapy, corticosteroid therapy, anticoagulant therapy, or selective serotonin reuptake inhibitor (SSRI) therapy. Tobacco smoking and alcohol use also increase the risk for GI adverse events; discuss the risks of these behaviors with adolescents who use chronic indomethacin therapy. To minimize the risk of GI events, use the lowest effective dosage for the shortest possible duration and avoid the concomitant use of multiple NSAIDs. Routinely monitor patients for potential GI ulceration and bleeding. If a serious event is suspected, discontinue indomethacin and promptly evaluate and treat the patient.

Indomethacin is contraindicated in neonates 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. Indomethacin, like all NSAIDs, may exacerbate hypertension and congestive heart failure. In adults, the use of NSAIDs may cause an increased risk of serious cardiovascular thromboembolism, including myocardial infarction and stroke, which can be fatal; it is not known whether this risk also applies to pediatric patients who use NSAIDs for the management of chronic conditions. The FDA warns that the risk of myocardial infarction or stroke can occur as early as the first weeks of using a NSAID, and risk may increase with higher doses and longer duration of use. Data demonstrate that adult patients treated with NSAIDs were more likely to die in the first year after a myocardial infarction compared to those not treated with NSAIDs. NSAIDs may increase the risk of a cardiovascular thrombotic event in patients with or without underlying heart disease or risk factors for heart disease. Patients with known heart disease or risk factors appear to have a greater likelihood of an event following NSAID use, likely due to a higher baseline risk. Current evidence is insufficient to determine if the risk of an event is higher or lower for any particular NSAID compared to other NSAIDs. There is an increased risk of heart failure with NSAID use. Avoid the use of indomethacin in patients with a recent/acute myocardial infarction and/or severe heart failure unless the benefits are expected to outweigh the risks. Caution is recommended when administering indomethacin to patients with cardiac disease, cardiomyopathy, cardiac arrhythmias (e.g., tachycardia), significant coronary artery disease (e.g., angina, history of myocardial infarction), peripheral vascular disease, cerebrovascular disease (e.g., stroke, transient ischemic attack), high blood pressure, pre-existing renal disease, fluid retention, or edema. Closely monitor blood pressure during indomethacin receipt. In the context of chronic therapy, use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse cardiovascular event. Inform patients to seek immediate medical attention if they experience any signs or symptoms of a cardiovascular thrombotic event and/or worsening heart failure.

Indomethacin may cause new renal dysfunction and can also worsen existing impairment; monitor patients with renal disease carefully. Intravenous indomethacin is known to have significant adverse renal effects on many neonates receiving the drug for PDA closure; indomethacin is contraindicated in neonates with significant renal impairment (renal failure). The risk of renal failure/oliguria is greater in neonates who receive indomethacin compared to those who receive ibuprofen lysine. Neonates receiving a concurrent loop diuretic (e.g., furosemide) are at higher risk for renal failure than those receiving indomethacin monotherapy. Renal function must be carefully monitored and assessed prior to each dose of indomethacin in neonates. Correct volume status in patients with dehydration and hypovolemia. Patients with renal impairment, hepatic impairment, heart failure, extracellular volume depletion (i.e., hypovolemia or dehydration), sepsis, and those taking diuretics or nephrotoxic drugs are at the highest risk for complications related to suboptimal renal perfusion; monitor renal function closely. Hyperkalemia has been reported with the use of indomethacin, even in some patients without renal impairment.

Monitor serum sodium and glucose concentrations before and during intravenous indomethacin therapy in neonates; correct any electrolyte imbalance prior to initiating indomethacin. In relation to adverse renal effects, intravenous indomethacin may suppress water excretion to a greater extent than sodium excretion, which may result in hyponatremia. In addition, indomethacin is known to cause hypoglycemia in neonates; carefully monitor neonates with a recent history of low glucose or with risk factors for hypoglycemia (e.g., those born to mothers with gestational diabetes mellitus). Some experts suggest that an increase in glucose infusion rate (GIR) by 2 mg/kg/min may prevent hypoglycemic episodes.

Anemia may be exacerbated with the chronic use of indomethacin or other NSAIDs. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythrogenesis. Patients who have initial hemoglobin values of 10 g/dl or less and who are to receive long-term NSAID therapy should have hemoglobin values determined periodically.

Indomethacin inhibits platelet aggregation and may prolong bleeding time. Intramuscular injections should be administered cautiously; IM injections may cause bleeding, bruising, or hematomas.

Indomethacin inhibits platelet aggregation and may prolong bleeding time ; use of indomethacin may cause increased bleeding in patients with dental disease. Patients or caregivers should inform their dentist they are taking chronic indomethacin prior to any dental work due to a potential increased risk of bleeding. Patients should be instructed on proper oral hygiene.

Indomethacin should be used with caution in patients with hepatic disease. There have been reports of fatal hepatotoxicity in children receiving indomethacin. Indomethacin should not be prescribed for infants, children, or adolescents younger than 14 years unless the benefit outweighs potential risks (e.g., as in use in newborns to facilitate closure of patent ductus arteriosus [PDA]). If indomethacin is prescribed for pediatric patients (except for the purpose of PDA closure), they should receive the lowest possible dose for the shortest duration possible and be closely monitored with periodic assessment of liver function. Indomethacin should be discontinued if elevated hepatic enzymes persist or worsen or if signs or symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant pain, flu-like symptoms) develop. Indomethacin is metabolized in the liver; accumulation can occur in patients with significant hepatic disease increasing risk of toxicity.

Indomethacin should be used with caution in patients with a seizure disorder, Parkinson's disease (including rare pediatric forms), major depression, or other psychiatric disturbance. Indomethacin may aggravate these conditions. Indomethacin may cause drowsiness; therefore, patients and caregivers should be cautioned against activities requiring coordination and concentration until they know how the drug affects them.

Indomethacin is contraindicated in the setting of coronary artery bypass graft surgery (CABG). An increased incidence of myocardial infarction and stroke was found through analysis of data regarding the use of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days after CABG surgery. While CABG is not a typical procedure in pediatric patients, the exact risk factor for these adverse events is not clear; possible implications in pediatric patients, particularly those undergoing other types of cardiac surgery, are not known.

Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who have received prolonged indomethacin therapy. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. Patients experiencing visual disturbance should undergo a thorough ophthalmologic examination. It is advisable to discontinue therapy if such changes are observed.

Indomethacin suppositories are contraindicated in patients with a history of proctitis or recent rectal bleeding. Rectally administered indomethacin should be used with caution in patients with hemorrhoids, anal, or rectal inflammation.

Description: Indomethacin is a nonsteroidal antiinflammatory drug (NSAID) that has analgesic and antipyretic effects; however, its most common use in the pediatric population is for patent ductus arteriosus (PDA) closure in premature neonates. It is also used off-label for juvenile arthritis and prevention of intraventricular hemorrhage (IVH). When administering intravenously to neonates, the infusion rate should be over at least 20-30 minutes to minimize the effect on cerebral blood flow. When compared to ibuprofen lysine, the other NSAID used for PDA closure, it appears that indomethacin has more adverse effect on renal function and carries a higher risk of necrotizing enterocolitis ; however, unlike ibuprofen lysine, indomethacin has been shown to lower the incidence and severity of IVH in premature neonates. All NSAIDs, including indomethacin, cause an increased risk of serious gastrointestinal adverse effects including bleeding, ulceration, and perforation; indomethacin is contraindicated in infants with necrotizing enterocolitis. Intravenous indomethacin is FDA-approved for use in neonates; other formulations are not approved for use in pediatric patients.

General dosing information
-For PDA Closure: A meta analysis of 5 trials (combined n = 431) compared prolonged indomethacin regimens to short course (<= 3 doses) and found no statistically significant difference in successful PDA closure, need for ligation, reopening or re-treatment. There was an increased incidence of necrotizing enterocolitis (NEC) and a decreased incidence of renal impairment with the prolonged course; the authors concluded that the benefits of a prolonged course do not outweigh the risks.


For treatment of a hemodynamically significant patent ductus arteriosus (PDA) in premature infants when usual medical management is ineffective:
NOTE: Indomethacin is FDA-approved for use in premature neonates weighing 500 to 1750 g.
Intravenous dosage:
Premature Neonates < 48 hours of age: 0.2 mg/kg IV followed by 2 doses of 0.1 mg/kg IV at 12 to 24-hour intervals with careful attention to urinary output. If oliguria (urine output less than 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 fails to close or reopens, a second course of 1 to 3 doses may be given. Discontinue treatment if severe adverse reactions occur.
Premature Neonates age 2 to 7 days: 0.2 mg/kg/dose IV every 12 to 24 hours for a total of 3 doses; pay careful attention to urinary output. If oliguria (urine output less than 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 fails to close or reopens, a second course of 1 to 3 doses may be given. Discontinue treatment if severe adverse reactions occur.
Premature Neonates age > 7 days: 0.2 mg/kg IV followed by 2 doses of 0.25 mg/kg IV at 12 to 24-hour intervals with careful attention to urinary output. If oliguria (urine output less than 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 fails to close or reopens, a second course of 1 to 3 doses may be given. Discontinue treatment if severe adverse reactions occur.
Oral dosage:
Neonates: 0.2 mg/kg/dose PO every 12 to 24 hours for 3 doses has been used off-label ; however, IV is usually the preferred route of administration. Of note, one study used a water-based indomethacin formulation prepared from capsules and the other used an ethanol-based preparation.

For intraventricular hemorrhage prevention*:
Intravenous dosage:
Premature Neonates weighing less than 1250 g: 0.1 mg/kg/dose IV every 24 hours for 3 doses, beginning 6 to 12 hours after birth.

For treatment of juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA)*:
Oral dosage (regular-release capsules, suspension):
Children > 2 years and Adolescents <= 14 years: 1 to 2 mg/kg/day PO in divided doses (every 8 hours) initially (Max initial adult dose: 25 mg/dose). Dosage may be increased up to a usual maximum dose of 3 mg/kg/day (Max: 150 to 200 mg/day). Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day (Max: 150 to 200 mg/day). As symptoms subside, reduce the total daily dosage to the lowest level required to control symptoms or discontinue indomethacin. Manufacturers note that safety and efficacy have not been established; indomethacin should only be used if possible toxicity/lack of benefit from other drugs justifies potential risk.
Adolescents 15 to 17 years: 25 mg/dose PO 2 to 3 times per day initially. Daily dosage may be increased by 25 to 50 mg/day at weekly intervals as needed up to a maximum of 150 to 200 mg/day.

For the treatment of acute and recurrent pericarditis*:
-for the treatment of acute pericarditis*:
Oral dosage (immediate-release):
Children and Adolescents 2 to 17 years: 1 to 2 mg/kg/day PO divided in 2 to 4 doses for 1 to 4 weeks. Max: 4 mg/kg/day up to 150 to 200 mg/day. Consider tapering dose gradually every 1 to 2 weeks.
-for the treatment of recurrent pericarditis*:
Oral dosage (immediate-release):
Children and Adolescents 2 to 17 years: 1 to 2 mg/kg/day PO divided in 2 to 4 doses for at least 2 to 4 weeks in combination with colchicine. Max: 4 mg/kg/day up to 150 to 200 mg/day. Consider tapering dose gradually every 1 to 2 weeks.

Maximum Dosage Limits:
-Neonates
<= 7 days: 0.2 mg/kg/dose IV; 0.2 mg/kg/dose PO has been used off-label for PDA closure.
> 7 days: 0.25 mg/kg/dose IV; 0.2 mg/kg/dose PO has been used off-label for PDA closure.
-Children
< 2 years: Safety and efficacy have not been established.
>= 2 years: Safety and efficacy have not been established; however, doses up to 4 mg/kg/day (Max: 200 mg/day) PO of the immediate-release capsules or suspension have been used off-label for juvenile idiopathic arthritis.
-Adolescents
13-14 years: Safety and efficacy have not been established; however, doses up to 4 mg/kg/day (Max: 200 mg/day) PO of the immediate-release capsules or suspension have been used off-label for juvenile idiopathic arthritis.
15-17 years: 200 mg/day PO; safety and efficacy of IV have not been established.

Patients with Hepatic Impairment Dosing
Although specific guidelines are not available, dosage reduction may be necessary in patients with hepatic dysfunction.

Patients with Renal Impairment Dosing
Neonates: Delay doses of indomethacin if urine output (UOP) < 0.6 ml/kg/hour; consider using every 24 hour dosing interval if UOP is 0.6-1 ml/kg/hour.
Specific guidelines for dosage adjustments in non-neonatal patients with renal impairment are not available; however, dosage adjustments or discontinuation should be considered to prevent further renal impairment or other toxicity. Oral indomethacin is not recommended for use in patients with advanced renal disease.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Indomethacin competitively inhibits both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, by blocking arachidonate binding resulting in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. The enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step of the synthesis of prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).
-Effects on Patent Ductus Arteriosis: In the treatment of patent ductus arteriosus (PDA) in premature neonates, indomethacin appears to reduce circulating prostaglandins that maintain the duct in a dilated state. A decrease in their production permits the ductus to close. Studies in healthy young animals and in premature infants with PDA indicated that, after the first dose of IV 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.
-Effects for Intraventricular Hemorrhage Prophylaxis: Compared to ibuprofen lysine, indomethacin has a stronger COX-1 inhibition, which results in more vasoconstrictive effects. Indomethacin decreases cerebral blood flow and oxygen consumption more than ibuprofen lysine, which is preventative in the occurrence of intraventricular hemorrhage when given prophylactically.
-Renal Effects: In the kidney, prostaglandins, produced by both COX-1 and COX-2, are important regulators of sodium and water reabsorption through PGE2 and of renal function and hemodynamics via PGI2 in response to vasoconstrictive factors (e.g., endothelin-1, a factor that increases peripheral vascular resistance) and through effects on the renin-angiotensin system. In conditions where renal blood flow is dependent upon prostaglandin synthesis, administration of NSAIDs can result in significant decreases in renal blood flow leading to acute renal failure. In addition, alterations in sodium and water reabsorption may worsen in increased blood pressure, which can be significant in selected individuals.
-GI Effects: Gastrointestinal side effects of indomethacin are primarily contributed to COX-1 inhibition; however, potential role of COX-2 inhibition in the GI tract has not been fully elucidated.
-Anti-inflammatory Activity: The anti-inflammatory mechanism of indomethacin is due to decreased prostaglandin synthesis via inhibition of COX-1 and COX-2. It appears that the anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme. However, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis. Indomethacin is more selective for COX-1 than COX-2.
-Analgesic Activity: Indomethacin is effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, NSAIDs have an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.
-Antipyretic Activity: Indomethacin promotes a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE2, in circumventricular organs in and near the hypothalamus. Although not indicated for the management of fever, indomethacin may mask fever in some patients, especially with high or chronic dosing.
-Platelet Effects: The inhibition of platelet aggregation seen with indomethacin is due to dose-dependent inhibition of COX-1 in platelets leading to decreased concentrations of platelet thromboxane A2 and an increase in bleeding time. The inhibition of platelet aggregation is reversible within 24 hours of discontinuation of indomethacin. This differs from aspirin, which irreversibly binds to COX-1 in platelets inhibiting this enzyme for the life of the cell.

Pharmacokinetics: Indomethacin is administered orally, rectally, or intravenously. In adults, the drug is approximately 99% bound to plasma proteins; however, it has been found to cross the blood-brain barrier. Protein binding in neonates has not been clearly defined. In controlled trials, no evidence of bilirubin displacement has been observed (as evidenced by an increased incidence of kernicterus). Indomethacin is metabolized in the liver and undergoes significant enterohepatic recirculation. Indomethacin undergoes O-demethylation by CYP2C9, which is its major metabolic pathway. Some of the drug is also N-deacylated by a non-microsomal system. Metabolites do not appear to have anti-inflammatory activity. The mean plasma half-life of indomethacin is 4.5 hours in adult patients; however, it is longer in premature neonates. About 60% of an indomethacin dose is recovered in the urine as drug and metabolites (26% as indomethacin and its glucuronide) and 33% is recovered in the feces (1.5% as indomethacin).

Affected cytochrome P450 isoenzymes: CYP2C9
Indomethacin is a substrate of the hepatic cytochrome isoenzyme CYP2C9.


-Route-Specific Pharmacokinetics
Oral Route
In adults, the bioavailability of the oral capsules is virtually 100%, and the suspension and capsules are bioequivalent at a dose of 50 mg when administered with food. The bioavailability of ethanol-based indomethacin syrup is also high in neonates (F = 0.986) ; however, the bioavailability of other oral products in neonates may be lower.


-Special Populations
Pediatrics
Premature Neonates
In 2 neonatal studies including 127 premature neonates, the mean serum half-life of intravenous indomethacin was 17.3 +/- 2.8 to 20.4 +/- 4.9 hours. Serum half-lives of indomethacin were longer in younger neonates < 7 days and decreased after 7 days of postnatal age (21.4 +/- 5.6 hours vs. 12.22 +/- 3.39 hours). Additionally, the half-life was longer in neonates weighing < 1000 g compared to those > 1000 g (20.74 +/- 5.17 hours vs. 15.44 +/- 3.38 hours). The mean clearance was 20.7 +/- 10.8 ml/hour/kg, and the volume of distribution was 0.551 +/- 0.187 L/kg. In addition to slower renal clearance due to immature renal function, it has been suggested that extensive enterohepatic circulation may occur in premature neonates and contribute to the relatively longer half-life.