Continuing Education Activity

Indomethacin is a non-steroidal anti-inflammatory (NSAID) drug with broad applications. It inhibits the synthesis of prostaglandins produced primarily by cyclooxygenase enzymes which are critical mediators of inflammation, fever, and pain. Indomethacin is FDA-approved to manage acute pain, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, bursitis, gouty arthritis, and patent ductus arteriosus. This activity reviews the indications, action, and contraindications of indomethacin as a valuable agent. In addition, this activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions) pertinent to members of the interprofessional healthcare team.

Objectives:

• Identify the FDA-approved and off-label indications for indomethacin.
• Describe the mechanism of action of the therapeutic effects of indomethacin.
• Review the adverse event profile of indomethacin.
• Outline some interprofessional team strategies for improving care coordination and communication to advance indomethacin therapy, improve outcomes, and minimize adverse events.

Indications

Indomethacin is a potent nonsteroidal anti-inflammatory drug (NSAID). It is used as an antipyretic, anti-inflammatory, and analgesic agent to treat various conditions.

FDA-Approved Indications

The FDA-approved indications are listed below.[1][2][3]

Pain (Acute)

Indomethacin is indicated for mild to moderate acute pain in adults.

Rheumatoid Arthritis

Clinicians can use indomethacin in the treatment of rheumatoid arthritis (RA); however, more effective disease-modifying anti-rheumatic agents (DMARDs) have demonstrated greater effectiveness in halting the progression of RA; thus, indomethacin is rarely used as monotherapy, but instead often in combination with agents such as adalimumab, etanercept, infliximab, methotrexate.

Ankylosing Spondylitis

Ankylosing spondylitis is a form of inflammatory arthritis primarily impacting the axial skeleton: one of the primary manifestations involves spinal fusion and rigidity. The disease primarily affects males, and more than 90% of patients with the condition test positive for the HLA-B27 haplotype. Clinicians often use indomethacin in conjunction with DMARDs and physical therapy to treat ankylosing spondylitis.

Osteoarthritis

Osteoarthritis (OA), a noninflammatory type of arthritis characterized by joint stress from "wear and tear," can often be effectively treated with indomethacin. However, it is essential to note that while indomethacin and other NSAIDs can be very effective in treating OA, first-line treatment involves acetaminophen.

Bursitis

Bursae are synovial fluid-filled sacs that lubricate joints- bursitis involves bursa inflammation. As a result, bursitis can present with erythematous, 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 the hallux and may also respond to indomethacin therapy.

Patent Ductus Arteriosus 

Patent ductus arteriosus (PDA) is a non-cyanotic heart defect that results in left-to-right shunting. The clinical severity of the condition depends on several factors; however, often, it needs to be closed, and indomethacin can help accomplish this.

Off-labeled Indications

In addition to the FDA-approved indications, there are also off-label uses for indomethacin.[4][5]

Aphthous Stomatitis

Aphthous stomatitis is a pathology defined by frequent and recurrent oral ulcerations. Often these ulcers can be painful, and the cause of the ulcers is unknown. Therefore, treatment for his condition is symptomatic, and indomethacin is a therapeutic option. An ERCP is a procedure involving the insertion of an endoscope into the duodenum to visualize various portions of the GI tract. It can be useful in removing gallstones from the common bile duct; however, it correlates with a risk of post-procedural pancreatitis; indomethacin can mitigate this risk.

Plantar Fasciitis

Plantar fasciitis is an orthopedic pathology that involves pain on the foot's plantar (heel) surface. Walking and bending may aggravate the condition, but indomethacin can help minimize the symptoms of this pathology. Indomethacin can also alleviate back pain. Indomethacin has also been shown to have possible anti-tumor effects and may potentiate the effects of various neoplastic agents.

Preterm-labor

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

Headache Disorders

Indomethacin-responsive headache disorders include paroxysmal hemicrania, primary cough headache, exercise headache, hypnic headache, headache associated with sexual activity, and stabbing headache. Gastroprotection should be offered with PPI or H2 blockers.[8] According to a recent study, indomethacin may be helpful in refractory post-COVID headaches.[9] Preliminary evidence suggests the efficacy of indomethacin for human colorectal cancer; further research is required.[10]

Mechanism of Action

Indomethacin functions like most other NSAIDs. The effects of indomethacin occur because it inhibits the synthesis of prostaglandins. Prostaglandins are produced primarily by cyclooxygenase (COX) enzymes, and prostaglandins are critical mediators of inflammation, fever, and pain. They also maintain renal function, GI mucosa, and platelet activity. Inhibition of COX enzymes by NSAIDs may explain some of these drugs' 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 GI mucosa, while COX-2 is upregulated in inflamed tissues and produces prostaglandins accountable for inflammation, fever, and pain. Consequently, COX-2 selective NSAIDs may have fewer GI-associated side effects; indomethacin is a non-selective COX inhibitor.[11][12]

Indomethacin has anti-viral activity; it down-regulates viral replication, and literature showed its anti-viral activity against rhabdovirus vesicular stomatitis virus, hepatitis B virus, and coronavirus.[13][14] No data supports its anti-viral activity against COVID-19 at present.[15]

Prostaglandin E2 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(PDA) as the concentration of prostaglandin E2 is relatively high. Uncorrected PDA can result in differential cyanosis. Indomethacin, by inhibiting PGE2 synthesis, is useful in the closure of PDA.[1][16]

Pharmacokinetics

Absorption: Indomethacin is well absorbed and attains peak plasma concentrations at 2 hours. Bioavailability is approximately 100%.

Distribution: The high lipid solubility allows indomethacin to cross the blood-brain barrier easily. Indomethacin also achieves high concentration in synovial fluid. 

Metabolism: Indomethacin undergoes enterohepatic circulation. Indomethacin is metabolized via demethylation and deacylation. The major metabolites are O-desmethyl-indomethacin, O-deschlorobenzoyl-indomethacin, and their conjugates with glucuronides.[10]

Excretion: Approximately 60% of the administered indomethacin is excreted in urine by renal tubular secretion, while the remainder is excreted in feces after biliary secretion. The elimination half-life of indomethacin is approximately 7 hours but is highly irregular (1.5 to 16 hours) because of enterohepatic circulation.[17]

Administration

Indomethacin is available for oral administration as immediate-release (25 mg, 50 mg) and extended-release (75 mg) capsule formulations. An oral suspension formulation (25 mg/5 mL) is also available. Indomethacin administration can also be done via an IV injection (1 mg base per vial ) or rectal suppository (50 mg).[18][19] Indomethacin should be administered at the lowest effective dose for the shortest duration to avoid potential side effects. To minimize gastrointestinal adverse effects, administer indomethacin with food.

Pain (Acute)

20 mg three times a day or 40 mg two to three times a day orally.

Rheumatoid Arthritis, Ankylosing Spondylitis, and Osteoarthritis

25 mg two to three times a day orally or via rectal administration as an immediate-release formulation. The dose can be increased weekly to 25 to 50 mg until the maximum dose of 200 mg daily. This dose can be administered up to 100 mg at bedtime for patients with arthritis or night/morning stiffness. Alternatively, 75 mg extended-release capsules can be administered. The maximum recommended daily dose for extended-release capsules is 150 mg.

Bursitis

75 to 150 mg immediate-release formulation can be administered orally or rectally in three to four divided doses. Alternatively, 75 to 150 mg extended-release formulation can be administered orally in one to two divided doses

Gouty Arthritis

Administer 50 mg three times a day orally or rectally as an immediate-release formulation within one to two days of flare onset. American college of rheumatology also recommends prophylactic therapy with NSAIDs when initiating urate-lowering therapy.[20]

Patent Ductus Arteriosus

The initial dose of indomethacin is IV 0.2 mg/kg/dose. No additional doses are required if the ductus arteriosus closes or significantly decreases within 48 hours. If the ductus arteriosus re-opens, a second/third dose may be required at 12 to 24 hours intervals as described. If the infant's age at the time of the first dose is <48 hours, administer 0.1 mg/kg IV. If the age at the time of the first dose is 2 to 7 days, administer 0.2mg/kg IV. If age at the time of the first dose >7 days, administer 0.25 mg/kg IV. If the neonate is nonresponsive to indomethacin, surgery may be necessary to close the ductus arteriosus. Echocardiographically directed indomethacin treatment can help in PDA closure, and dose minimization is possible.[21]

Use in Specific Patient Population

Renal Impairment: No dose adjustment information is available for renal impairment in the manufacturer's labeling. According to KDIGO guidelines, NSAIDs, including indomethacin, should be avoided if GFR <30 ml/min 1.73m^2. Chronic treatment with NSAIDs is not advised in patients with GFR<60 ml/min/1.73 m^2.[22]

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

Pregnancy Considerations: It is former FDA pregnancy category C medicine, and its use should be avoided. FDA suggests limiting NSAIDs use after 30 weeks of pregnancy. If treatment with NSAID is essential, physicians should reduce the dose and duration of therapy. If treatment is extended beyond 48 hours, consider ultrasound monitoring of amniotic fluid and discontinue the NSAID if oligohydramnios is found.[23] Indomethacin may cause premature closure of the ductus arteriosus; its use should be avoided after 30 weeks.[1]

Breastfeeding Considerations: Indomethacin is found in low levels in breast milk, so it is acceptable to be used by lactating women. However, other drugs with established safer profiles during lactation may be preferred, especially when nursing a newborn or preterm infant.[24]

Potentially Inappropriate Medication in Older Adults: Indomethacin is identified as potentially inappropriate medicine for use in older adults according to the American Geriatric Society Beers Criteria. Increased risk of gastrointestinal bleeding/peptic ulcer disease and acute kidney injury in older adults. Indomethacin is more likely than other NSAIDs to have adverse central nervous system reactions.[25] In addition, the American Geriatric Society (AGS) recommends that all NSAIDs should be avoided in patients with stage IV and V CKD.[26]

Adverse Effects

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

• The most common adverse reactions are headache, dizziness, dyspepsia, and nausea. It is essential to recognize that indomethacin is used for various headache disorders, and one of the most common adverse reactions is a headache.[27]
• Hypersensitivity reactions have been noted to occur because of indomethacin, including anaphylaxis, urticaria, and angioedema.[28]
• As previously mentioned, indomethacin is a non-selective COX inhibitor, and COX-1 produces prostaglandins to maintain the gastric mucosa. Inhibition of this process can result in dyspepsia (indigestion), nausea, constipation, and diarrhea. However, the most severe gastric side effect of indomethacin involves the formation of peptic ulcers. Peptic ulcers can present as mid-epigastric pain that is either relieved or exacerbated by eating, depending on their location- the pain with gastric ulcers is exacerbated by eating. In contrast, the pain associated with duodenal ulcers is relieved by eating. Ulcers can rupture and result in an acute surgical abdomen.
• Indomethacin can also affect the liver resulting in elevated liver enzymes and jaundice.[29]
• Indomethacin can also impact the neurologic system resulting in tinnitus, vertigo, depression, dizziness, and headaches. Severe adverse reactions have also been demonstrated, including aseptic meningitis, psychosis, and cognitive dysfunction.
• 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, the elderly population and patients with dehydration, hypovolemia, renal dysfunction, heart failure, impaired liver function, and those taking diuretics, ACE inhibitors, or ARBs are at higher risk of developing adverse events.
• Indomethacin can have several effects on the hematologic system, including agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, thrombocytopenia, and thrombocytopenic purpura. Indomethacin-induced leukocytoclastic vasculitis has been reported.[30]
• Indomethacin can impact the cardiopulmonary system and result in acute respiratory distress, pulmonary edema, and congestive heart failure.[31][32]
• Arachidonic acid is the precursor to prostaglandin synthesis via the COX enzymes; inhibition of COX enzymes results in the shunting of arachidonic acid to the leukotriene synthesis pathway, resulting in the formation of nasal polyps from indomethacin. This condition can also result in respiratory difficulties. Indomethacin can also result in generalized fatigue and somnolence.[33]

Boxed Warning

• NSAIDs, including indomethacin, are associated with an increased risk of cardiovascular thrombotic events, including myocardial infarction and stroke.[34]
• Indomethacin can increase the risk of serious GI bleeding, ulcers, and perforation[35][36]

Drug-Drug Interactions

• The use of indomethacin may decrease the therapeutic effects of several medicines used to treat cardiovascular conditions (e.g., ACE inhibitors, ARB inhibitors, or diuretics).In addition, fluid retention and edema have been reported in patients taking NSAIDs.
• NSAIDs can increase lithium levels; concurrent use of indomethacin with lithium should be avoided.[37][38]
• NSAIDs, including indomethacin with oral apixaban, are associated with an increased risk of bleeding. Avoid concurrent administration combination.[39]
• Concomitant use of indomethacin and methotrexate can increase methotrexate plasma levels. Monitor for signs of methotrexate toxicity.[40]
• Indomethacin can decrease the natriuretic effect of furosemide and thiazide and reduce efficacy. There is an increased risk of acute kidney injury when NSAIDs are combined with diuretics.[41]

Contraindications

NSAIDs have relatively few contraindications; however, according to the package insert, they are as follows: 

• A history of NSAID or salicylate-induced hypersensitivity and atopic reactions after taking NSAIDs (examples include urticaria, asthma, exfoliative dermatitis, toxic epidermal necrolysis, or Stevens-Johnson Syndrome)[42]
• A previous history of coronary artery bypass graft (CABG) surgery is a contraindication for using indomethacin. Two large clinical trials of NSAID use in the first 14 days following CABG surgery reported an increased stroke and myocardial infarction incidence. Hence NSAIDs are contraindicated in the patients following CABG.[43]
• Indomethacin use can cause premature closure of the fetal ductus arteriosus; consequently, use is contraindicated in pregnant women starting the third trimester of pregnancy (on and after 30 weeks gestation).[16]

Monitoring

Indomethacin is not a benign substance- as noted above, there are many potential side effects of the medication; according to the product labeling in specific scenarios, its use needs patient monitoring. 

• If indomethacin is used in patients with a recent myocardial infarction, monitor patients for signs of cardiac ischemia (tachycardia, shortness of breath, sweating, fatigue, pain in neck/jaw/arm/shoulder).
• If the patient reports clinician signs of hepatotoxicity (nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, "flu-like" symptoms, eosinophilia, rash), obtain liver function tests. The enzyme elevation pattern is hepatocellular, but cholestatic and mixed patterns have also been noted.[29]
• Monitor patients for changes in the signs/symptoms of asthma when used in patients with asthma and without known sensitivity to aspirin.
• Watch for signs and symptoms of bleeding and GI ulceration during indomethacin therapy.[36]
• Monitor hemoglobin or hematocrit if a patient treated with indomethacin develops signs and symptoms of anemia.
• Serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms/signs. Therefore, consider monitoring the patient's CBC and a chemistry profile periodically if indomethacin is used long-term.
• Patients with coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin-norepinephrine reuptake inhibitors (SNRIs),  and serotonin reuptake inhibitors (SSRIs) are at increased risk of bleeding. Monitor these patients for signs of bleeding.[44][45]
• Concurrent use of indomethacin with digoxin can increase digoxin's half-life and serum concentration. Monitor serum digoxin levels.[26]

Toxicity

Indomethacin toxicity is rare; only a few cases are reported in the literature. Cases in the literature have demonstrated headache, tinnitus, dizziness, lethargy, drowsiness, confusion, disorientation and restlessness, and acute kidney injury (AKI) secondary to indomethacin toxicity.[46][47]

Management: Provide patients with supportive and symptomatic care following indomethacin overdosage. There is no specific antidote to indomethacin toxicity. For adult patients, consider emesis or giving 60 to 100 gm of activated charcoal to decrease the absorption of NSAIDs from the upper GI tract. Osmotic cathartics can be used in symptomatic patients seen within four hours of overdose or in patients who ingested 5 to 10 times the recommended dosage of indomethacin. Call the local poison control center for detailed information on the treatment protocol.

Enhancing Healthcare Team Outcomes

All healthcare personnel should operate as an interprofessional team and understand the risk associated with indomethacin treatment. Prescribers should tailor the regimen adequately at the lowest effective dose for the shortest duration possible. Clinicians should avoid NSAIDs in patients with peptic ulcers, CABG, and the third trimester of pregnancy. Nurses need to be careful before administering medicines to patients and counsel patients on points to identify therapeutic success or adverse reactions. The prescriber should periodically monitor patients with a history of cardiovascular accidents, serious GI bleeding, hepatotoxicity, and severe renal impairment to prevent potential adverse events. The pharmacist 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 the patient in indomethacin overdose and consult a medical toxicologist if necessary.[48] Open communication of all team members, including clinicians (MD, DO, NP, PA), specialists, nurses, and pharmacists, regarding the therapeutic goal and potential adverse reactions to the indomethacin regimen, can achieve optimal patient outcomes. [Level 5]