Brand name: Indocin
Drug class: Reversible COX-1/COX-2 Inhibitors

Medically reviewed by Drugs.com on May 10, 2025. Written by ASHP.

Introduction

NSAIA; also exhibits analgesic and antipyretic activity.¹

Uses for Indomethacin

Consider potential benefits and risks of indomethacin therapy as well as alternative therapies before initiating therapy with the drug.^{1 2 3 341} Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.^{1 2 3 341}

Inflammatory Diseases

Oral and rectal formulations used for symptomatic treatment of osteoarthritis, moderate to severe rheumatoid arthritis (including acute flares of chronic disease), ankylosing spondylitis, and acute painful shoulder (i.e., bursitis and/or tendinitis)^{1 2 3 341 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538}

Immediate-release oral and rectal formulations used for symptomatic relief of acute gouty arthritis.^{1 2 3 539 540 541}

Guidelines on the treatment of rheumatoid arthritis from the American College of Rheumatology (ACR) recommend initiation of a disease-modifying antirheumatic drug (DMARD) for most patients; role of NSAIAs not discussed.²⁰⁰¹

ACR recommends topical/oral NSAIAs for treatment of osteoarthritis, among other interventions.²⁰⁰² Therapy selection is patient-specific; factors to consider include patients' values and preferences, risk factors for serious adverse GI effects, existing comorbidities (e.g., hypertension, heart failure, other cardiovascular disease, chronic kidney disease), injuries, disease severity, surgical history, and access to and availability of the interventions.²⁰⁰²

Continuous NSAIA treatment is considered first-line for active ankylosing spondylitis in current guidelines.²⁰⁰⁸ On-demand NSAIAs are recommended for stable ankylosing spondylitis.²⁰⁰⁸ No preference is given to one NSAIA over another.²⁰⁰⁸

First-line therapies for gout flares include colchicine, NSAIAs, and glucocorticoids (oral, intra-articular, or intramuscular); treatment selection should be based on patient-specific factors (e.g., comorbidities, ease of access) and patient preferences.²⁰⁰⁶

Patent Ductus Arteriosus (PDA)

Used IV to promote closure of a hemodynamically significant PDA in premature neonates weighing 500–1750 g when 48 hours of usual medical management (e.g., fluid restriction, diuretics, cardiac glycosides, respiratory support) is ineffective.^{301 302 303 306 309 310 312 316 319 322 1228 1230 1231}

Has also been used prophylactically in select premature neonates at risk for hemodynamically significant PDA^{† [off-label]} during first day of life.^{316 400 402 403 472 509 1232 1233}

Decision to initiate pharmacologic treatment for PDA will depend on patient-specific factors such as gestational age, chronological age, size of PDA, and presence of symptoms (e.g., requirement for greater than minimal respiratory support).^{1232 1233} Select infants at high risk of persistent PDA (e.g., gestational age <26 weeks, weight <750 g) are candidates for targeted early prophylactic treatment with indomethacin within 6–24 hours after birth.^{1232 1233} If prophylactic treatment is not indicated or not effective, early targeted pharmacologic treatment with ibuprofen or indomethacin recommended <6 days after birth for infants <28 weeks’ gestational age with a moderate-to-large hemodynamically important shunt requiring greater than minimal respiratory support.¹²³³

Pericarditis

Has been used in combination with colchicine for treatment of recurrent pericarditis^{† [off-label]} .^{1209 1210}

Some experts recommend colchicine plus aspirin or an NSAIA (typically ibuprofen) first-line for treatment of acute or recurrent pericarditis.¹²¹⁰

Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) Pancreatitis

Has been used rectally for prevention of post-ERCP pancreatitis^{† [off-label]}.^{1213 1214 1215 1216 1217 1218} American Society for Gastrointestinal Endoscopy strongly recommends preprocedural rectal NSAIAs (usually indomethacin) for prevention of post-ERCP pancreatitis in all patients undergoing ERCP.¹²¹⁷ American College of Gastroenterology recommends rectal indomethacin to prevent post-ERCP pancreatitis in high-risk patients.¹²¹⁸

Preterm Labor

Has been used to inhibit uterine contractions during preterm labor (tocolysis)^{† [off-label]} .^{465 466 467 468 469 470 1211 1212}

Other Uses

Has been used for prevention of heterotopic ossification following total hip arthroplasty^{† [off-label]} .¹²¹⁹

Indomethacin Dosage and Administration

General

Patient Monitoring

• Blood pressure should be monitored closely when initiating indomethacin and throughout therapy.^{1 2 3 341}

• Patients receiving long-term NSAIA therapy should have a CBC and chemistry profile performed periodically.^{1 2 3 341}

• Renal function should be monitored during indomethacin therapy in patients with preexisting renal or hepatic impairment, heart failure, dehydration, or hypovolemia.^{1 2 3 341}

• If oral or rectal indomethacin is used in children 2–14 years of age, liver function should be monitored periodically.^{1 2 3 341}

• Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.^{1 2 3 341}

• Patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis should be monitored more closely for evidence of GI bleeding.^{1 2 3 341}

• Patients with certain coexisting conditions such as coagulation disorders and those receiving concomitant therapy with anticoagulants, antiplatelet agents, or selective serotonin-reuptake inhibitors (SSRIs) may be at increased risk of bleeding and should be monitored for signs of bleeding.^{1 2 3 341}

• Neonates receiving indomethacin sodium for injection for PDA closure should be monitored for blood in stool and for intraventricular hemorrhage.³⁰¹

• Renal function and serum electrolytes should be monitored in neonates receiving indomethacin sodium for injection for PDA closure; subsequent doses of indomethacin sodium should be withheld if urine volume is significantly reduced after administration.³⁰¹

Premedication and Prophylaxis

• Dehydration and hypovolemia should be corrected before initiating indomethacin therapy.^{1 2 3 341}

Other General Considerations

• Indomethacin should be used with caution in patients with asthma, and patients should be monitored for changes in asthma.^{1 2 3 341}

• Use of >1 NSAIA at a time should be avoided.^{1 2 3 341}

• Use of NSAIAs should be avoided in patients at higher risk of bleeding unless the benefits of therapy are expected to outweigh the increased risk of bleeding.^{1 2 3 341} Higher risk patients include those with a history of ulcer disease or other factors that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids, anticoagulants, aspirin, or SSRIs; longer duration of NSAIA therapy; smoking; alcohol use; older age, poor general health status, advanced liver disease and/or coagulopathy.^{1 2 3 341}

• Indomethacin should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if indomethacin is used in such patients, the patient should be monitored for cardiac ischemia.^{1 2 3 341}

• Indomethacin should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if indomethacin is used in such patients, the patient should be monitored for worsening heart failure.^{1 2 3 341}

• Indomethacin should be used with caution in premature neonates with an existing infection that is adequately controlled, and clinicians should be alert to the masking effect of the drug in these neonates.³⁰¹

Dispensing and Administration Precautions

• The 2023 American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults includes indomethacin on the list of PIMs that are best avoided by older adults in most circumstances or under specific situations, such as certain diseases, conditions, or care settings.⁹⁹⁹ The criteria are intended to apply to adults 65 years of age and older in all ambulatory, acute, and institutional settings of care, except hospice and end-of-life care settings.⁹⁹⁹ For non-COX-2-selective oral NSAIAs such as indomethacin, the Beers Criteria Expert Panel specifically recommends that chronic use be avoided unless other alternatives are not effective and the patient can take a gastroprotective agent (proton-pump inhibitor or misoprostol).⁹⁹⁹ Additionally, short-term scheduled use should be avoided in combination with oral or parenteral corticosteroids, anticoagulants, or antiplatelet agents unless other alternatives are not effective and the patient can take a gastroprotective agent.⁹⁹⁹

Administration

Administer orally or rectally (for inflammatory diseases or pericarditis)^{1 2 3 341} or by IV infusion (for PDA).³⁰¹

Oral Administration

In patients who have persistent night pain and/or morning stiffness, a large portion (maximum 100 mg) of the total daily dose may be given at bedtime.^{1 2}

Conventional Capsules and Oral Suspension

Administer conventional capsules and oral suspension in 2–4 divided doses daily.^{1 2}

Extended-release Capsules

Administer extended-release capsules once or twice daily.³⁴¹

Extended-release capsules can be used as an alternative to conventional capsules: 75 mg once daily (extended-release) as an alternative to 25 mg 3 times daily (conventional); 75 mg twice daily (extended-release) as an alternative to 50 mg 3 times daily (conventional).³⁴¹

Swallow extended-release capsules intact.³⁴¹

Extended-release capsules are not recommended for treatment of acute gouty arthritis.³⁴¹

Rectal Administration

Administer in 2–4 divided doses daily.³

Retain suppositories in rectum for ≥1 hour to ensure complete absorption.³

In patients who have persistent night pain and/or morning stiffness, a large portion (maximum 100 mg) of the total daily dose may be given at bedtime.³

IV Administration

Administer by IV infusion.³⁰¹

Avoid extravasation (irritating to extravascular tissues).³⁰¹

Reconstitution

Reconstitute vial containing 1 mg of indomethacin with 1 or 2 mL of preservative-free 0.9% sodium chloride injection or sterile water for injection to provide a solution containing 1 mg/mL or 0.5 mg/mL, respectively.³⁰¹ Further dilution is not recommended.³⁰¹

Use of bacteriostatic water for injection containing benzyl alcohol is not recommended because of potential risk of benzyl alcohol exposure if administered to a neonate.³⁰¹

Prepare solutions immediately before use; discard any unused solution.³⁰¹

Rate of Administration

Optimum rate not established; may administer dose over 20–30 minutes.³⁰¹

Dosage

Available as indomethacin and indomethacin sodium; dosage expressed in terms of indomethacin.^{1 2 3 341}

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.^{1 2 3 341} Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.^{1 2 3}

May substitute indomethacin 50-mg suppositories for indomethacin capsules; however, there will be significant differences between the two dosage regimens in indomethacin blood levels.³

Indomethacin injection is labeled for use only in premature infants with PDA.³⁰¹

Pediatric Patients

Inflammatory Diseases

Juvenile Rheumatoid Arthritis†

Oral

Children ≥2 years of age: Initially, 1–2 mg/kg daily in divided doses.^{1 2 341} Increase dosage until a satisfactory response is achieved, up to maximum dosage of 3 mg/kg daily or 150–200 mg daily (whichever is less) in divided doses; limited data support the use of a maximum dosage of 4 mg/kg daily or 150–200 mg daily (whichever is less) in divided doses.^{1 2 341} As symptoms subside, reduce dosage to the lowest effective level or discontinue the drug.^{1 2 341}

Patent Ductus Arteriosus (PDA)

IV

Each course of therapy consists of up to 3 doses administered at 12- to 24-hour intervals.³⁰¹

Base dosage on neonate’s age at the time therapy is initiated.³⁰¹

If anuria or oliguria (urine output <0.6 mL/kg per hour) is present at the time of a second or third dose, withhold the dose until laboratory determinations indicate that renal function has returned to normal.³⁰¹

If ductus arteriosus closes or is substantially constricted 48 hours or longer after completion of the first course, no further doses are necessary.³⁰¹

If ductus reopens, a second course of 1–3 doses may be administered.³⁰¹ Surgical ligation may be necessary if ductus is unresponsive to 2 courses of therapy.³⁰¹

Prophylaxis in Select Premature Neonates at Risk for Hemodynamically Significant PDA†

IV

6-24 hours after birth: Three doses of 0.1 mg/kg administered at 12-hour intervals (single-dose prophylaxis may be considered); may omit final dose if echocardiography suggests closing of PDA.¹²³³

Adults

Inflammatory Diseases

Ankylosing Spondylitis

Oral

Conventional capsules or oral suspension: Initially, 25 mg 2 or 3 times daily.^{1 2} If needed, increase dosage by 25 or 50 mg daily at weekly intervals until a satisfactory response is obtained up to a maximum dosage of 150–200 mg daily.^{1 2}

Extended-release capsules: Initially, 75 mg once daily.³⁴¹ May increase dosage to 75 mg twice daily.³⁴¹

Rectal

25 mg 2 or 3 times daily.³ If needed, increase dosage by 25 or 50 mg daily at weekly intervals until a satisfactory response is obtained up to a maximum dosage of 150–200 mg daily.³

Osteoarthritis

Oral

Conventional capsules or oral suspension: Initially, 25 mg 2 or 3 times daily.^{1 2} If needed, increase dosage by 25 or 50 mg daily at weekly intervals until a satisfactory response is obtained up to a maximum dosage of 150–200 mg daily.^{1 2}

Extended-release capsules: Initially, 75 mg once daily.³⁴¹ May increase dosage to 75 mg twice daily.³⁴¹

Rectal

25 mg 2 or 3 times daily.³ If needed, increase dosage by 25 or 50 mg daily at weekly intervals until a satisfactory response is obtained up to a maximum dosage of 150–200 mg daily.³

Rheumatoid Arthritis

After an acute exacerbation, attempt to reduce to smallest effective dosage.^{1 2 3}

Oral

Conventional capsules or oral suspension: Initially, 25 mg 2 or 3 times daily.^{1 2} If needed, increase dosage by 25 or 50 mg daily at weekly intervals until a satisfactory response is obtained up to a maximum dosage of 150–200 mg daily.^{1 2}

Extended-release capsules: Initially, 75 mg once daily.³⁴¹ May increase dosage to 75 mg twice daily.³⁴¹

Rectal

25 mg 2 or 3 times daily.³ If needed, increase dosage by 25 or 50 mg daily at weekly intervals until a satisfactory response is obtained up to a maximum dosage of 150–200 mg daily.³

Gout

Oral

Conventional capsules: 50 mg 3 times daily until pain is tolerable; then reduce dosage rapidly and discontinue.¹

Painful Shoulder

Oral

Conventional capsules or oral suspension: 75–150 mg daily in 3 or 4 divided doses.^{1 2} Discontinue once symptoms have been controlled for several days; usual course of therapy is 7–14 days.^{1 2}

Extended-release capsules: 75 mg once or twice daily.³⁴¹ Discontinue once symptoms have been controlled for several days; usual course of therapy is 7–14 days.³⁴¹

Rectal

75–150 mg daily in 3 or 4 divided doses.³ Discontinue once symptoms have been controlled for several days; usual course of therapy is 7–14 days.³

Recurrent Pericarditis†

Oral

In combination with colchicine: 75–150 mg daily in 3 divided doses.¹²¹⁰ Decrease by 25 mg every 1–2 weeks.¹²¹⁰

Special Populations

Hepatic Impairment

No specific dosage recommendations.^{1 2 3 341}

Renal Impairment

No specific dosage recommendations.^{1 2 3 341}

Avoid use in patients with advanced renal disease unless anticipated benefits are expected to outweigh potential risks; monitor for worsening renal function if used in advanced renal disease.^{1 2 3 341}

Monitor renal function and serum electrolytes in neonates who receive indomethacin sodium for injection for PDA closure; withhold subsequent doses of indomethacin sodium if urine volume is significantly reduced after administering.³⁰¹ Indomethacin sodium is contraindicated in neonates with substantially impaired renal function.³⁰¹

Geriatric Patients

Careful dosage selection recommended due to possible age-related decreases in renal function.^{1 2 3 341}

Cautions for Indomethacin

Contraindications

• Indomethacin is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.^{1 2 3 341}

• Nonsteroidal anti-inflammatory agents (NSAIAs), including indomethacin, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, potentially fatal, anaphylactic reactions may occur in such patients.^{1 2 3 341}

• Indomethacin is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.^{1 2 3 341}

• Indomethacin sodium for injection is contraindicated in neonates with congenital heart disease when patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (e.g., neonates with pulmonary atresia, severe tetralogy of Fallot, or severe coarctation of the aorta).³⁰¹

• Indomethacin sodium for injection is contraindicated in neonates with proven or suspected, untreated infection.³⁰¹

• Indomethacin sodium for injection is contraindicated in neonates with active bleeding, such as those with intraventricular hemorrhage or GI bleeding, and in neonates with thrombocytopenia or underlying coagulation defect.³⁰¹

• Indomethacin sodium for injection is contraindicated in neonates with substantially impaired renal function.³⁰¹

• Indomethacin sodium for injection is contraindicated in neonates with known or suspected necrotizing enterocolitis.³⁰¹

• Indomethacin suppositories are contraindicated in patients with a history of proctitis or recent rectal bleeding.³

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.^{1 2 3 341}

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.^{1 2 3 341}

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.^{1 2 3 341}

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.^{1 2 3 341}

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.^{1 2 3 341}

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.^{1 2 3 341}

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;^{1 2 3 341} absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.^{1 2 3 341}

Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia.^{1 2 3 341} Contraindicated in the setting of CABG surgery.^{1 2 3 341}

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs; such concomitant use increases risk for serious adverse GI events.^{1 2 3 341}

Bleeding, Ulceration, and Perforation

Serious GI toxicity (e.g., bleeding, ulceration, perforation of the esophagus, stomach, or small or large intestine) can occur with or without warning symptoms; risk factors include history of GI bleeding or ulceration; longer duration of NSAIA therapy; concomitant use of oral corticosteroids, anticoagulants, aspirin, or selective serotonin-reuptake inhibitors (SSRIs); older age; smoking; alcohol use; poor general health; and advanced liver disease and/or coagulopathy.^{1 2 3 341} Even short-term therapy is not without risk.^{1 2 3 341}

Incidence of major GI bleeding reported in neonates receiving IV indomethacin in clinical studies similar to that in neonates receiving placebo; minor GI bleeding occurred more frequently in indomethacin-treated neonates.³⁰¹

To minimize the risk of adverse GI effects, use the lowest effective dosage for the shortest possible duration and avoid use of >1 NSAIA at a time.^{1 2 3 341} Avoid NSAIA therapy in patients at higher risk unless benefits of therapy outweigh the increased bleeding risk.^{1 2 3 341} Use alternative therapy in higher risk patients or in those with active bleeding.^{1 2 3 341} If signs or symptoms of a serious GI event occur, initiate prompt evaluation and treatment.^{1 2 3 341} Discontinue the NSAIA until serious GI event has been ruled out.^{1 2 3 341}

Other Warnings/Precautions

Hepatotoxicity

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.^{1 2 3 341}

Elevations of serum ALT or AST reported.^{1 2 3 341} Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur or if liver function test abnormalities persist or worsen.^{1 2 3 341}

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.^{1 2 3 341} Use with caution in patients with hypertension; monitor BP closely during initiation and throughout therapy.^{1 2 3 341}

Impaired response to ACE inhibitors and diuretics may occur.^{1 2 3 341}

Heart Failure and Edema

Fluid retention and edema reported.^{1 2 3 341}

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase risk of death and hospitalization in patients with heart failure.^{1 2 3 341}

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.^{1 2 3 341}

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.^{1 2 3 341}

Renal Toxicity and Hyperkalemia

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.^{1 2 3 341}

Renal toxicity observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion; in such patients, NSAIAs may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.^{1 2 3 341} Increased risk of renal toxicity in adults with renal or hepatic impairment or heart failure, dehydration, hypovolemia, in geriatric patients, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.^{1 2 3 341}

Correct volume depletion in dehydrated or hypovolemic patients prior to initiating; monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.^{1 2 3 341}

May precipitate renal insufficiency in neonates, including acute renal failure; increased risk in those with extracellular volume depletion, CHF, sepsis, or hepatic dysfunction or those receiving concomitant therapy with a nephrotoxic drug.³⁰¹ If a substantial reduction in urine output occurs, withhold additional doses until output returns to normal.³⁰¹

Hyponatremia reported in neonates.³⁰¹ Monitor renal function and serum electrolytes.³⁰¹

Increases in serum potassium, including hyperkalemia, reported in adults.^{1 2 3 341}

Anaphylactic Reactions

Anaphylactic reactions (e.g., anaphylaxis, angioedema) reported.^{1 2 3 341} Immediate medical intervention and discontinuance for anaphylaxis.^{1 2 3 341}

Exacerbation of Asthma Related to Aspirin Sensitivity

Caution in patients with asthma because some patients may have aspirin-sensitive asthma; monitor for changes in asthma.^{1 2 3 341}

Contraindicated in patients with aspirin-sensitive asthma; aspirin sensitivity asthma can manifest as severe, potentially fatal bronchospasm with chronic rhinosinusitis and nasal polyps and/or an intolerance to aspirin or other NSAIAs.^{1 2 3 341}

Serious Skin Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed drug eruptions, including bullous fixed drug eruption) reported; can occur without warning.^{1 2 3 341} Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).^{1 2 3 341}

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

DRESS, a potentially fatal or life-threatening syndrome of multi-organ hypersensitivity, reported in patients receiving NSAIAs.^{1 2 341} Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).^{1 2 341} Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.^{1 2 341} If signs or symptoms of DRESS develop, discontinue indomethacin and immediately evaluate the patient.^{1 2 341}

Fetal/Neonatal Morbidity and Mortality

NSAIA use during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus, and use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.^{1 2 341} Avoid NSAIAs at about ≥30 weeks of gestation; if NSAIA therapy necessary between about 20-30 weeks of gestation, use the lowest effective dosage for the shortest possible duration, and consider monitoring of amniotic fluid volume via ultrasound examination if duration of NSAIA treatment exceeds 48 hours.^{1 2 341}

Hematologic Toxicity

Anemia reported.^{1 2 3 341} Determine hemoglobin concentration or hematocrit if signs or symptoms of anemia occur.^{1 2 3 341}

May increase risk of bleeding.^{1 2 3 341} Possible increased risk in patients with coagulation defects and in those receiving concomitant anticoagulants, antiplatelets, or serotonin reuptake inhibitors; monitor for signs of bleeding.^{1 2 3 341}

Potential for spontaneous intraventricular hemorrhage in neonates.³⁰¹ Observe premature infants for signs of bleeding.³⁰¹

Contraindicated in neonates who are bleeding and in those with thrombocytopenia or coagulation defects.³⁰¹

Masking of Inflammation and Fever

May mask certain signs of infection.^{1 2 3 341}

Laboratory Monitoring

Obtain CBC and chemistry profile periodically during long-term use.^{1 2 3 341}

CNS Effects

May aggravate depression or other psychiatric disturbances, epilepsy, or parkinsonism; use with caution in patients with these conditions.^{1 2 3 341}

May cause drowsiness; may impair ability to perform activities requiring mental alertness.^{1 2 3 341}

May cause headache.^{1 2 3 341} Discontinue the drug in patients in whom indomethacin-induced headache persists despite a reduction in dosage.^{1 2 3 341}

Ocular Effects

Corneal deposits and retinal disturbances reported in patients receiving long-term therapy.^{1 2 3 341} Ophthalmic examination recommended in patients with blurred vision; periodic ophthalmic examinations recommended in patients receiving long-term therapy.^{1 2 3 341}

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.^{1 2 341}

Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.^{1 2 341}

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice.^{1 2 341}

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs.^{1 2 341} Oligohydramnios is often, but not always, reversible following NSAIA discontinuance.^{1 2 341} Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.^{1 2 341} In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.^{1 2 341} Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).^{1 2 341} Deaths associated with neonatal renal failure also reported.^{1 2 341} Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.^{1 2 341} Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.^{1 2 341}

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.^{1 2 341} In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.^{1 2 341}

Adverse effects reported in animal reproduction studies with indomethacin (e.g., increased fetal resorptions, retarded fetal ossification, increased incidence of neuronal necrosis).^{1 2 3 341}

Effects of indomethacin on labor and delivery not known.^{1 3 341} In animal studies, NSAIAs increased incidence of dystocia, delayed parturition, and increased incidence of stillbirth.^{1 3 341}

Lactation

Distributed into human milk.^{1 2 3 341}

Females and Males of Reproductive Potential

NSAIAs may be associated with reversible infertility in some women.^{1 2 3 341} Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.^{1 2 3 341}

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.^{1 2 3 341}

Pediatric Use

Safety and efficacy established in neonates receiving the drug for PDA.³⁰¹

Safety and efficacy of oral or rectal indomethacin not established in children ≤14 years of age.^{1 2 341} Indomethacin should not be used in children 2–14 years of age unless toxicity or lack of efficacy with other drugs justifies the risk; monitor closely if used.^{1 2 3 341}

Adverse effects reported in children receiving indomethacin capsules generally comparable to those reported in adults.^{1 2 3 341} Hepatotoxicity, sometimes fatal, has been reported in pediatric patients with juvenile rheumatoid arthritis.^{1 2 3 341} Periodic assessment of liver function recommended.^{1 2 3 341}

Geriatric Use

Caution advised.^{1 2 3 341} Geriatric patients appear to tolerate NSAIA-induced adverse effects less well than younger individuals.^{1 2 3 341} Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.^{1 2 3 341}

Possible confusion or, rarely, psychosis in geriatric patients.^{1 2 3 341}

Substantially eliminated by the kidney; select dosage carefully and assess renal function periodically since geriatric patients more likely to have decreased renal function.^{1 2 3 341}

Hepatic Impairment

Pharmacokinetics not evaluated in hepatic impairment.^{1 2 3 341}

Renal Impairment

Pharmacokinetics not evaluated in renal impairment.^{1 2 3 341} Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.^{1 2 341}

Common Adverse Effects

Adverse effects reported in ≥3% of patients include headache, dizziness, dyspepsia, and nausea.

Common adverse effects reported in neonates include bleeding issues, a greater incidence of transient oliguria, and elevations in serum creatinine.³⁰¹

Drug Interactions

Drugs Excreted by the Kidney

Indomethacin may reduce renal function; possible pharmacokinetic interaction with drugs that rely on adequate renal function for excretion.³⁰¹ In neonates receiving IV indomethacin, consider dosage adjustment for drugs that rely on adequate renal function for excretion.³⁰¹

Specific Drugs and Laboratory Tests

Indomethacin Pharmacokinetics

Absorption

Bioavailability

Almost completely absorbed (90%) following oral administration as conventional capsules;¹ bioavailability following rectal administration is 80–90% of that of the conventional capsule.³

Indomethacin extended-release capsules release 25 mg of drug initially and the remaining 50 mg over 12 hours; 90% absorbed within 12 hours.³⁴¹

When administered with food, the commercially available conventional capsules and oral suspension are bioequivalent.²

Distribution

Extent

Crosses the placenta and blood-brain barrier.^{1 2 3 341}

Distributed into human milk.^{1 2 3 341}

Plasma Protein Binding

99% (in adults).^{1 2 3 341} Protein binding in neonates not studied; however, incidence of kernicterus not increased, indicating lack of bilirubin displacement.³⁰¹

Elimination

Metabolism

Metabolized in the liver to glucuronide conjugate and to desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites and their glucuronides.^{1 2 3 341}

Elimination Route

Undergoes appreciable enterohepatic circulation.^{301 341} Following oral administration, excreted in the urine (60%) and feces (33%) as unchanged drug and metabolites.³⁴¹

Half-life

Adults: 4.5 hours.^{1 2 3 341}

Neonates <7 days of age: 20 hours.³⁰¹

Neonates >7 days of age: 12 hours.³⁰¹

Neonates weighing <1 kg: 21 hours.³⁰¹

Neonates weighing >1 kg: 15 hours.³⁰¹

Stability

Storage

Oral

Conventional or Extended-release Capsules

20–25°C.^{1 341}

Conventional capsules: protect from light. ¹

Extended-release capsules: protect from moisture; excursions permitted from 15–30°C.³⁴¹

Suspension

<30°C; avoid temperatures >50°C.² Protect from freezing.²

Rectal

Suppositories

2-8ºC.³

Parenteral

Powder for Injection

25°C protected from light; excursions permitted from 15-30°C.³⁰¹

Does not contain preservatives; prepare just prior to administration and discard any unused portion.³⁰¹ .

Actions

• Inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase-1 (COX-1) and COX-2.^{1 2 3 301 341}

• Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.^{1 2 3 301 341}

• Permits closure of the ductus arteriosus in premature neonates by inhibiting prostaglandin synthesis.³⁰¹

Advice to Patients

• Advise patients to read the medication guide for nonsteroidal anti-inflammatory agents (NSAIAs) that is provided each time the drug is dispensed.^{1 2 3 341}

• Advise patients to be alert for symptoms of cardiovascular thrombotic events (e.g., chest pain, shortness of breath, weakness, slurring of speech), and to immediately report any of these symptoms to their healthcare provider.^{1 2 3 341}

• Advise patients to report symptoms of ulceration and bleeding (e.g., epigastric pain, dyspepsia, melena, hematemesis) to their healthcare provider. ^{1 2 3 341} In patients receiving concomitant low-dose aspirin for cardiac prophylaxis with indomethacin, inform patients of the increased risk for and signs and symptoms of GI bleeding.^{1 2 3 341}

• Inform patients of the signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, “flu-like” symptoms).^{1 2 3 341} If any of these signs or symptoms occur, instruct patients to stop indomethacin and seek immediate medical attention.^{1 2 3 341}

• Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.^{1 2 3 341}

• Inform patients of the signs of an anaphylactic reaction, which include difficulty breathing and face or throat swelling.^{1 2 3 341} Instruct patients to receive immediate medical help if these occur.^{1 2 3 341}

• Advise patients to immediately stop indomethacin if they develop any type of rash during therapy and to immediately contact their healthcare provider.^{1 2 3 341}

• Inform females of reproductive potential who desire to become pregnant that NSAIAs may be associated with a reversible delay in ovulation.^{1 2 3 341}

• Inform patients that concomitant use of indomethacin with other NSAIAs or salicylates (e.g., diflunisal, salsalate) is not recommended because of the increased risk of GI toxicity and little or no increase in efficacy.^{1 2 3 341} Alert patients that NSAIAs may be present in some OTC medications used for colds, fever, or insomnia.^{1 2 3 341}

• Instruct patients to not use low-dose aspirin concomitantly with indomethacin until speaking with their healthcare provider.^{1 2 3 341}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^{1 2 3 341}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 2 3 341} Inform pregnant women that indomethacin and other NSAIAs should be avoided starting at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus.^{1 2 3 341}

• Importance of informing patients of other important precautionary information.^{1 2 3 341}

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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