Continuing Education Activity

Indomethacin is a potent nonsteroidal anti-inflammatory drug with broad applications. The drug inhibits prostaglandin synthesis produced by cyclooxygenase enzymes, which are critical mediators of inflammation, fever, and pain. Indomethacin is approved by the US Food and Drug Administration (FDA) to manage acute pain, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, bursitis, gouty arthritis, and patent ductus arteriosus. Clinicians often use indomethacin as a supportive treatment within a medication regimen.

This activity focuses on the indications, contraindications, and administration methods of indomethacin as a valuable therapeutic agent, as well as its key factors, such as off-label uses, dosing, pharmacokinetics, monitoring, and relevant interactions. This activity underscores the crucial role of interprofessional healthcare teams in monitoring indomethacin therapy by tailoring treatment plans to individual patient needs depending on pain acuity, making informed decisions, and optimizing dosage regimens while minimizing adverse reactions. This evidence-based approach improves patient outcomes in inflammatory conditions treated with indomethacin.

Objectives:

• Identify the specific indications for indomethacin therapy in different inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, and patent ductus arteriosus.

• Implement appropriate dosing regimens of indomethacin based on the patient's condition, considering factors such as pain severity, renal function, and age.

• Apply evidence-based guidelines and clinical recommendations for using indomethacin in specific patient populations, including pediatric, geriatric, and pregnant individuals.

• Collaborate with other healthcare providers to optimize indomethacin therapy and coordinate comprehensive patient care.

Indications

Indomethacin is a potent nonsteroidal anti-inflammatory drug (NSAID) with broad applications. This medication has antipyretic, anti-inflammatory, and analgesic properties that treat various conditions.

FDA-Approved Indications

Indomethacin is approved by the US Food and Drug Administration (FDA) to manage acute pain, rheumatoid and gouty arthritis, ankylosing spondylitis, osteoarthritis, bursitis, gouty arthritis, and patent ductus arteriosus.[1][2][3]

Pain: Indomethacin is indicated for the treatment of mild-to-moderate acute pain in adults.

Rheumatoid arthritis: Indomethacin can be utilized to manage rheumatoid arthritis; however, more effective disease-modifying anti-rheumatic drugs (DMARDs) have shown superior efficacy in inhibiting rheumatoid arthritis progression. Consequently, indomethacin is infrequently used as monotherapy and is often administered with agents such as adalimumab, etanercept, infliximab, and methotrexate.

Ankylosing spondylitis: Ankylosing spondylitis is an inflammatory arthritis that primarily affects the axial skeleton, often leading to spinal fusion and rigidity. The condition predominantly affects men, with over 90% of patients testing positive for the HLA-B27 haplotype. Treatment typically involves the use of indomethacin alongside DMARDs and physical therapy.

Osteoarthritis: Osteoarthritis, a noninflammatory arthritis characterized by joint stress from "wear and tear," can often be effectively treated with indomethacin. However, while indomethacin and other NSAIDs can be very effective in treating osteoarthritis, first-line treatment usually involves acetaminophen.

Bursitis: Bursitis is characterized by inflammation of the bursae, which are synovial fluid-filled sacs that lubricate joints. Bursitis can result in erythematous and painful joints. This pathology is also treatable with indomethacin.

Gouty arthritis: Gouty arthritis involves the deposition of urate crystals in joints. This presents with an acute erythematous joint, often affecting the hallux, and may also respond to indomethacin therapy.

Patent ductus arteriosus—Intravenous formulation only: Patent ductus arteriosus is a non-cyanotic heart defect that results in left-to-right shunting. A systematic review reveals that prophylactic indomethacin reduces the incidence of severe intraventricular hemorrhage but does not appear to affect mortality or neurodevelopmental disability.[4]

Off-Label Uses

Post-endoscopic retrograde cholangiopancreatography pancreatitis: The American Society for Gastrointestinal Endoscopy suggests that rectal indomethacin may reduce the risk and severity of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.[5][6][7] 

ERCP involves inserting an endoscope into the duodenum to visualize various portions of the gastrointestinal tract. This procedure is often used to remove gallstones from the common bile duct. However, this procedure carries a risk of post-procedural pancreatitis, which can be mitigated by administering indomethacin. According to the 2024 American Gastroenterological Association guidelines, rectal indomethacin is recommended to prevent post-ERCP pancreatitis in high-risk individuals (American College of Gastroenterology [ACG], ERCP Guidelines).

Pericarditis: According to the American College of Cardiology, NSAIDs are recommended for acute pericarditis. NSAIDs such as ibuprofen and indomethacin should be considered.[8]

Aphthous stomatitis: Aphthous stomatitis is a pathology characterized by frequent and recurrent oral ulcerations, which can be painful. The cause of these ulcers is unknown, and treatment is symptomatic. Indomethacin is a therapeutic option for managing this condition.

Plantar fasciitis: Plantar fasciitis is an orthopedic pathology involving pain on the plantar (heel) surface of the foot. Walking and bending may aggravate the condition, but indomethacin can help minimize the symptoms. Indomethacin can also alleviate back pain, has possible antitumor effects, and may potentiate the effects of various neoplastic agents.

Preterm labor: Preterm labor is parturition that occurs between 20 0/7 weeks and 36 6/7 weeks of gestation. Indomethacin is commonly used as a tocolytic NSAID in preterm labor. A systematic review indicates that using indomethacin leads to a reduction in preterm births.[9][10]

Headache disorders: Indomethacin-responsive headache disorders include paroxysmal hemicrania and hemicrania continua. An essential diagnostic criterion for these conditions is the response to a therapeutic dosage of indomethacin.[11] This criterion is also effective for primary cough headache, exercise headache, hypnic headache, headache associated with sexual activity, and stabbing headache.[12] Gastroprotection should be offered with proton pump inhibitors or H2 blockers.[13] According to a recent study, indomethacin may be helpful in refractory post-COVID headaches.[14] Preliminary evidence also suggests the efficacy of indomethacin for human colorectal cancer, though further research is required.[15]

Mechanism of Action

Indomethacin functions like most other NSAIDs by inhibiting the synthesis of prostaglandins. Prostaglandins are primarily produced by cyclooxygenase (COX) enzymes and are critical mediators of inflammation, fever, and pain. They also maintain renal function, gastrointestinal mucosa, and platelet activity. The inhibition of COX enzymes by NSAIDs can lead to some adverse effects.

COX-1 is involved in the production of thromboxane A2—a critical mediator of platelet aggregation. Thus, inhibition of this enzyme is likely responsible for the anti-platelet effects of NSAIDs. COX-1 is responsible for maintaining gastrointestinal mucosa, whereas COX-2 is upregulated in inflamed tissues and produces prostaglandins accountable for inflammation, fever, and pain. Consequently, COX-2-selective NSAIDs may have fewer gastrointestinal-associated adverse effects. Indomethacin, however, is a nonselective COX inhibitor.[16][17]

Indomethacin exhibits anti-viral activity by down-regulating viral replication. Literature has demonstrated its efficacy against various viruses, including rhabdovirus vesicular stomatitis virus, hepatitis B virus, and coronavirus.[18][19] Although preliminary data suggest the antiviral activity of indomethacin against COVID-19, further extensive research is necessary to confirm this.[20][21]

Prostaglandin E2 (PGE2) relaxes smooth muscle and inhibits the closure of the ductus arteriosus. In preterm infants with respiratory distress syndrome, the ductus arteriosus fails to close, resulting in patent ductus arteriosus due to the relatively high concentration of PGE2. Uncorrected patent ductus arteriosus can lead to differential cyanosis. Indomethacin aids in closing a patent ductus arteriosus by inhibiting the synthesis of PGE2.[1][22]

Pharmacokinetics

Absorption: Indomethacin is well absorbed and reaches peak plasma concentrations within 2 hours. The bioavailability of the drug is approximately 100%.

Distribution: Indomethacin's high lipid solubility facilitates easy crossing of the blood-brain barrier. Additionally, it achieves high concentrations in synovial fluid. 

Metabolism: Indomethacin enters enterohepatic circulation and is metabolized via demethylation and deacylation pathways. The major metabolites include O-desmethyl-indomethacin, O-deschloro-benzoyl-indomethacin, and their glucuronide conjugates.

Excretion: Approximately 60% of administered indomethacin is excreted in urine via renal tubular secretion, with the remainder excreted in feces following biliary secretion. The elimination half-life of indomethacin is approximately 7 hours but is highly irregular (1.5-16 hours) due to enterohepatic circulation.[12][15]

Administration

Available Dosage Forms and Strengths

Indomethacin is available for oral administration in immediate-release (25 mg and 50 mg) and extended-release (75 mg) capsule formulations. In addition, an oral suspension formulation (25 mg/5 mL) is available. Indomethacin can be administered via intravenous (IV) injection (1 mg base per vial) or rectal suppository (50 mg). Indomethacin should be administered at the lowest effective dose for the shortest duration possible to minimize potential adverse effects.[23][24] 

Adult Dosage

Pain: In pain management, healthcare providers often prescribe indomethacin at a dosage of 20 mg (3 times daily) or 40 mg (2-3 times daily). Clinicians recommend that indomethacin be administered with food to reduce the risk of adverse gastrointestinal effects.

Rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis: Healthcare providers typically prescribe 25 mg of indomethacin (2-3 times a day) orally or via rectal administration as an immediate-release formulation. The dosage may be gradually increased on a weekly basis, reaching 25 to 50 mg until a maximum daily dose of 200 mg is reached. For patients experiencing arthritis-related symptoms or morning stiffness, doses up to 100 mg can be administered at bedtime. Alternatively, extended-release capsules of 75 mg may be used, with a maximum recommended daily dose of 150 mg.

Bursitis: Healthcare providers may prescribe an immediate-release formulation of 75 to 150 mg to patients with bursitis. This formulation can be administered orally or rectally in 3 to 4 doses throughout the day. Alternatively, an extended-release formulation of 75 to 150 mg can be taken orally in 1 to 2 doses.

Gouty arthritis: For gouty arthritis, healthcare providers typically recommend administering 50 mg of indomethacin orally or rectally as an immediate-release formulation, 3 times daily, within 1 to 2 days of the onset of a flare. Additionally, the American College of Rheumatology recommends prophylactic therapy with NSAIDs when initiating urate-lowering treatment.

Patent ductus arteriosus: The initial dosage of indomethacin for patent ductus arteriosus is administered IV at 0.2 mg/kg per dose. No additional doses are required if the ductus arteriosus closes or significantly decreases within 48 hours. However, if the ductus arteriosus re-opens, a second or third dose may be needed at 12- to 24-hour intervals as prescribed. For infants aged 48 hours or younger at the time of the first dose, 0.1 mg/kg of indomethacin should be administered IV. For newborns aged 2 to 7 days, 0.2 mg/kg of indomethacin should be administered IV. In addition, for newborns aged 7 days or older, 0.25 mg/kg of indomethacin should be administered IV.

In cases where the neonate is unresponsive to indomethacin, surgical intervention may be necessary to close the ductus arteriosus. Echocardiographically directed indomethacin treatment can aid in patent ductus arteriosus closure, with the possibility of minimizing the dosage.[25][26]

Specific Patient Populations

Renal impairment: The manufacturer's labeling does not provide specific dosage adjustment information for renal impairment. According to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, NSAIDs, including indomethacin, should be avoided if the glomerular filtration rate (GFR) is less than 30 mL/min/1.73 m². Chronic treatment with NSAIDs is not advised in patients with GFR less than 60 mL/min/1.73 m².[27]

Hepatic impairment: Clinicians should use indomethacin cautiously in patients with hepatic impairment.

Pregnancy considerations: Indomethacin is a former FDA pregnancy category C medicine and should generally be avoided during pregnancy. The FDA recommends limiting NSAID use after 30 weeks of pregnancy. If treatment with NSAID is essential, clinicians should minimize the dosage and duration of therapy. If treatment extends beyond 48 hours, ultrasound monitoring of amniotic fluid should be considered, and the NSAID should be discontinued if oligohydramnios is detected. Indomethacin may cause premature closure of the ductus arteriosus; therefore, its use should be avoided after 30 weeks.[1][28]

Breastfeeding considerations: Indomethacin is present in low levels in breast milk, allowing lactating women to use the medication. However, other drugs with established safer profiles during lactation may be preferred, especially when nursing a newborn or preterm infant.[29]

Pediatric patients: IV indomethacin has FDA approval for treating hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1750 g. Administering indomethacin early, within the first 1 to 2 days of birth, to close a patent ductus arteriosus, compared to delaying treatment for 3 to 4 days after diagnosis, reduces the risks of pulmonary hemorrhage, intraventricular hemorrhage, and the need for ligation.

Older patients taking potentially inappropriate medications: Indomethacin is identified as potentially inappropriate medicine for use in older adults according to the American Geriatrics Society (AGS) Beers Criteria. The AGS Beers Criteria mentions an increased risk of acute kidney injury, gastrointestinal bleeding, and peptic ulcer disease existing in older adults. Indomethacin is more likely than other NSAIDs to have adverse central nervous system reactions. In addition, the AGS recommends avoiding all NSAIDs in patients with stages IV and V chronic kidney disease.[30][31]

Indomethacin use is associated with increased lung water clearance and improved lung compliance. Multiple births and intrauterine infection have been identified as potential risk factors for a lack of response to indomethacin treatment in preterm infants with patent ductus arteriosus. For children with oligoarticular juvenile idiopathic arthritis, the American College of Rheumatology recommends a trial of NSAIDs such as indomethacin as part of initial therapy.[32][33][34]

Adverse Effects

As a commonly used drug, researchers have conducted numerous studies on the adverse effects. Adverse reactions from the product label are mentioned. Indomethacin (and most other NSAIDs) can impact most body organ systems, including the gastrointestinal, neurological, renal, hematological, and cardiopulmonary systems. 

• The most common adverse reactions to indomethacin include headache, dizziness, dyspepsia, and nausea. Despite its use in treating various headache disorders, one of the most frequently reported adverse reactions is a headache.

• Hypersensitivity reactions to indomethacin can occur and include anaphylaxis, urticaria, and angioedema.

• As previously mentioned, indomethacin is a nonselective COX inhibitor, and COX-1 produces prostaglandins crucial for maintaining the gastric mucosa. Inhibition of this process can lead to dyspepsia (indigestion), nausea, constipation, and diarrhea. However, the most severe gastric adverse reaction to indomethacin involves the formation of peptic ulcers, which can manifest as mid-epigastric pain either relieved or exacerbated by eating. Gastric ulcers typically worsen with eating, while the pain associated with duodenal ulcers is alleviated by food intake. Ulcers have the potential to rupture, leading to an acute surgical abdomen.

• Indomethacin can also affect the liver, resulting in elevated liver enzymes and jaundice.

• Indomethacin can also affect the neurological system, potentially resulting in tinnitus, vertigo, depression, dizziness, and headaches. Severe adverse reactions, including aseptic meningitis, psychosis, and cognitive dysfunction, have also been reported.

• COX enzymes are responsible for the synthesis of prostaglandins involved in renal function. Inhibition of this process can result in renal insufficiency. Indomethacin can also result in hyperkalemia and acute interstitial nephritis. Therefore, older individuals and patients with conditions such as dehydration, hypovolemia, renal dysfunction, heart failure, impaired liver function, and those taking diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARBs) are at higher risk of experiencing adverse events.

• Indomethacin can have several effects on the hematologic system, including agranulocytosis, aplastic and hemolytic anemia, leukopenia, thrombocytopenia, and thrombocytopenic purpura. In addition, cases of indomethacin-induced leukocytoclastic vasculitis have been reported.

• Indomethacin can affect the cardiopulmonary system and result in acute respiratory distress, pulmonary edema, and congestive heart failure.

• Arachidonic acid is the precursor to prostaglandin synthesis via the action of COX enzymes. Inhibition of COX enzymes can divert arachidonic acid to the leukotriene synthesis pathway, potentially leading to the formation of nasal polyps in response to indomethacin. This condition may also manifest as respiratory difficulties. Additionally, indomethacin use can result in generalized fatigue and somnolence.[35][36][37][38][39][40][41]

Drug-Drug Interactions

• Indomethacin may reduce the efficacy of various medications used to manage cardiovascular conditions (eg, ACE inhibitors, ARB inhibitors, or diuretics). Moreover, patients taking NSAIDs, including indomethacin, have reported fluid retention and edema.

• NSAIDs can increase lithium levels; thus, concurrent use of indomethacin with lithium should be avoided.

• The concurrent use of NSAIDs, including indomethacin, with oral apixaban is associated with an elevated risk of bleeding. Therefore, it is advisable to avoid combining these medications.

• Concomitant use of indomethacin and methotrexate can increase methotrexate plasma levels. Therefore, monitoring for signs of methotrexate toxicity is recommended.

• Indomethacin can decrease the natriuretic effect of furosemide and thiazide, reducing their efficacy. Combining NSAIDs with diuretics increases the risk of acute kidney injury.[42][43][44][45][46]

Contraindications

Warnings and Precautions 

• Patients with a history of NSAID or salicylate-induced hypersensitivity and atopic reactions, such as urticaria, asthma, exfoliative dermatitis, toxic epidermal necrolysis, or Stevens-Johnson syndrome, should avoid indomethacin.

• Patients with a history of coronary artery bypass graft (CABG) surgery should not use indomethacin. An increased incidence of stroke and myocardial infarction is reported when 2 large clinical trials of NSAIDs were used within the first 14 days following CABG surgery. Hence, NSAIDs are contraindicated in the patients following CABG.

• Indomethacin use can cause premature closure of the fetal ductus arteriosus; consequently, it is contraindicated in pregnant women starting in the third trimester (on and after 30 weeks of gestation).

• The IV formulation of indomethacin is not recommended for patients suspected of having necrotizing enterocolitis. It is also contraindicated in cases of active intracranial hemorrhage or gastrointestinal bleeding.

• The IV administration of indomethacin is not recommended for individuals with congenital heart disease who require the patent ductus arteriosus to maintain adequate systemic or pulmonary blood flow.[22][47][48]

Box Warnings

• NSAIDs, including indomethacin, are associated with an increased risk of cardiovascular thrombotic events, including myocardial infarction and stroke.

• Indomethacin can increase the risk of serious gastrointestinal bleeding, ulcers, and perforation [49][50][51]

Monitoring

Indomethacin is not a benign substance; as noted above, many potential adverse effects of the medication are apparent according to the product labeling in specific scenarios, and its use requires patient monitoring. 

• If indomethacin is used in patients with a recent myocardial infarction, patients should be monitored for signs of cardiac ischemia (tachycardia, shortness of breath, sweating, and fatigue, as well as pain in the neck, jaw, arm, or shoulder).

• Liver function tests should be obtained if the patient reports signs of hepatotoxicity (nausea, fatigue, diarrhea, pruritus, jaundice, right upper quadrant tenderness, flu-like symptoms, eosinophilia, and rash). The enzyme elevation pattern is hepatocellular, but cholestatic and mixed patterns have also been noted.

• Patients should be monitored for changes in the signs or symptoms of asthma when used in patients with asthma and without known sensitivity to aspirin.

• The signs and symptoms of bleeding and gastrointestinal ulceration should be observed during indomethacin therapy.

• Patients should be monitored for changes in signs or symptoms of asthma when indomethacin is used in individuals with asthma and without known sensitivity to aspirin.

• Severe gastrointestinal bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs. Therefore, patients should have their complete blood count and chemistry profile periodically monitored if indomethacin is used long-term.

• Patients with coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (eg, aspirin), serotonin-norepinephrine reuptake inhibitors, and serotonin reuptake inhibitors are at an increased risk of bleeding. These patients should be monitored for signs of bleeding.

• Concurrent use of indomethacin with digoxin can increase the half-life and serum concentration. Serum digoxin levels should be monitored.[31][37][51][52][53]

Toxicity

Signs and Symptoms of Overdose

Indomethacin toxicity is rare, with only a few cases reported in the literature. Documented cases have demonstrated symptoms such as headache, tinnitus, dizziness, lethargy, drowsiness, confusion, disorientation, restlessness, and acute kidney injury secondary to indomethacin toxicity.[54][55]

Management of Overdose

Healthcare providers should offer patients supportive and symptomatic care following indomethacin dosage. A specific antidote for indomethacin toxicity is not available. For adult patients, administering 60 to 100 g of activated charcoal should be considered to decrease the absorption of NSAIDs from the upper gastrointestinal tract. Osmotic cathartics may be used in symptomatic patients observed within 4 hours of overdose or in patients who ingested 5 to 10 times the recommended dosage of indomethacin. The local poison control center should be contacted for detailed information on the treatment protocol.

Enhancing Healthcare Team Outcomes

All healthcare personnel should operate as an interprofessional team and understand the risks of indomethacin treatment. Prescribers should tailor the regimen to the lowest effective dose for the shortest duration possible. Clinicians should avoid NSAIDs in patients with peptic ulcers, those who have undergone CABG, and those in the third trimester of pregnancy. Nurses must exercise caution before administering medications and counseling patients on identifying therapeutic success or adverse reactions. Prescribers should periodically monitor patients with a history of cardiovascular events, hepatotoxicity, and severe gastrointestinal bleeding and renal impairment to prevent potential adverse events. Pharmacists should verify the dose, perform medication reconciliation, check for drug interactions, educate patients, and report any concerns to the clinician.

The critical care team should rapidly stabilize patients experiencing an indomethacin overdose and consult a medical toxicologist if necessary. An interprofessional team approach, with open communication between clinicians, specialists, nurses, and pharmacists regarding the therapeutic goals and potential adverse reactions to the indomethacin regimen, can lead to optimal patient outcomes.[56][57]