Indomethacin

Earn CME/CE in your profession:


Continuing Education Activity

Indomethacin is a non-steroidal anti-inflammatory (NSAID) drug with broad applications. This activity reviews the indications, action, and contraindications of indomethacin as a valuable agent. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional healthcare team.

Objectives:

  • Identify the approved and off-label indications for indomethacin.
  • Describe the mechanism of action of the therapeutic effects of indomethacin.
  • Review the adverse event profile and contraindications to therapy with indomethacin.
  • Outline some interprofessional team strategies for improving care coordination and communication to advance indomethacin therapy and 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[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 in the treatment of 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 important 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[4][5]

Aphthous Stomatitis

Aphthous stomatitis is a pathology that is 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.

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 are also involved in maintaining renal function, GI mucosa, and platelet activity. Inhibition of COX enzymes by NSAIDs may explain some of these drugs' side effects.

COX-1 has involvement 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 appears to be responsible for the maintenance of GI mucosa, while COX-2 seems to be upregulated in inflamed tissues and responsible for producing prostaglandins accountable for inflammation, fever, and pain. Although COX-2 selective NSAIDs may have fewer GI-associated side effects, indomethacin is a non-selective COX inhibitor.[6][7]

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.[8][9] No data supports its anti-viral activity against COVID-19 at present.[10]

Administration

Indomethacin is available for oral administration as immediate-release (25 mg, 50 mg) and extended-release (75 mg) capsule formulation. 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).[11][12] Indomethacin should be administered at the lowest effective dose for the shortest duration to avoid potential side effects.

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 immediate-release formulation. The dose can be increased weekly up to 25 to 50 mg until the maximum dose of 200 mg per day. This dose can be administered at bedtime up to 100 mg 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 immediate-release formulation within one to two days of flare onset.

Specific Population

Renal Impairment: There is no dose adjustment information available for patients with renal impairment. However, indomethacin is not recommended for patients with advanced stages of renal impairment. 

Hepatic Impairment: Indomethacin should be used with caution for patients with hepatic impairment.

Pregnant Women: It is FDA pregnancy category C medicine and use should be avoided.

Breastfeeding Women: Indomethacin is found in low levels in breastmilk 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.[13]

Adverse Effects

As a commonly used drug, researchers have conducted numerous studies on the side 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. 

  • Hypersensitivity reactions have been noted to occur because of indomethacin which includes anaphylaxis, urticaria, and angioedema.
  • As previously mentioned, indomethacin is a non-selective COX inhibitor, and COX-1 is responsible for producing prostaglandins involved in maintaining 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.
  • Indomethacin can also impact the neurologic system resulting in tinnitus, vertigo, depression, dizziness, and headaches. More severe side effects 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.  The elderly population and patients with dehydration, hypovolemia,  renal dysfunction, heart failure, impaired liver function, 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 can impact 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 COX enzymes; inhibition of COX enzymes results in 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.[14]
  • Using higher doses of indomethacin has been linked with higher incidents of cardiovascular adverse reactions of myocardial infarction or stroke, worsening congestive heart failure.[15]
  • 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.

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)
  • 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 incidence of stroke and myocardial infarction. Hence NSAIDs are contraindicated in the patients following CABG.[16]
  • Indomethacin use can cause premature closure of the fetal ductus arteriosus, so it is contraindicated in pregnant women starting the third trimester of pregnancy (on and after 30 weeks gestation).

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, and "flu-like" symptoms, eosinophilia, rash), then monitor for liver function test, AST, and ALT.[17]
  • 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.
  • If a patient treated with indomethacin develops signs and symptoms of anemia, monitor hemoglobin or hematocrit. 
  • 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.[18][19]
  • 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.

Toxicity

Indomethacin toxicity is rare; there are only a few cases reported in the literature. Cases in the literature have demonstrated headache, tinnitus, dizziness, lethargy, drowsiness, confusion, disorientation and restlessness, acute kidney injury (AKI) secondary to indomethacin toxicity.[20][21]

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 a history of gastric or other 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. Open communication of all team members, including clinicians, PAs, NPs, nurses, and pharmacists, regarding the therapeutic goal and potential adverse reactions on the indomethacin regimen, can achieve optimal patient outcomes. [Level 5]


Article Details

Article Author

Akul Munjal

Article Editor:

Abdallah E. Allam

Updated:

12/4/2021 3:36:50 PM

PubMed Link:

Indomethacin

References

[1]

Pacifici GM, Clinical pharmacology of indomethacin in preterm infants: implications in patent ductus arteriosus closure. Paediatric drugs. 2013 Oct;     [PubMed PMID: 23754139]

[2]

Helleberg L, Clinical Pharmacokinetics of indomethacin. Clinical pharmacokinetics. 1981 Jul-Aug;     [PubMed PMID: 7249487]

[3]

Yoshimoto S,Sakai H,Ueda M,Yoshikata M,Mizobuchi M,Nakao H, Prophylactic indomethacin in extremely premature infants between 23 and 24 weeks gestation. Pediatrics international : official journal of the Japan Pediatric Society. 2010 Jun;     [PubMed PMID: 19843236]

[4]

Zhou Y,Wang S,Ying X,Wang Y,Geng P,Deng A,Yu Z, Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer. International journal of nanomedicine. 2017;     [PubMed PMID: 28883726]

[5]

Geng C,Li X,Li Y,Song S,Wang C, Nonsteroidal anti-inflammatory drugs alleviate severity of post-ERCP pancreatitis by inhibiting inflammation and reducing apoptosis. Journal of gastroenterology and hepatology. 2020 Feb 16;     [PubMed PMID: 32064683]

[6]

Lucas S, The Pharmacology of Indomethacin. Headache. 2016 Feb;     [PubMed PMID: 26865183]

[7]

Draper MP,Martell RL,Levy SB, Indomethacin-mediated reversal of multidrug resistance and drug efflux in human and murine cell lines overexpressing MRP, but not P-glycoprotein. British journal of cancer. 1997;     [PubMed PMID: 9062400]

[8]

Amici C,La Frazia S,Brunelli C,Balsamo M,Angelini M,Santoro MG, Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: role of eIF2╬▒ kinase PKR. Cellular microbiology. 2015 Sep     [PubMed PMID: 25856684]

[9]

Kapicio─člu S,Sari M,Kaynar K,Baki A,Ozoran Y, The effect of indomethacin on hepatitis B virus replication in chronic healthy carriers. Scandinavian journal of gastroenterology. 2000 Sep     [PubMed PMID: 11063156]

[10]

Amici C,Di Caro A,Ciucci A,Chiappa L,Castilletti C,Martella V,Decaro N,Buonavoglia C,Capobianchi MR,Santoro MG, Indomethacin has a potent antiviral activity against SARS coronavirus. Antiviral therapy. 2006     [PubMed PMID: 17302372]

[11]

El-Mashad AE,El-Mahdy H,El Amrousy D,Elgendy M, Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. European journal of pediatrics. 2017 Feb;     [PubMed PMID: 28004188]

[12]

Lindo Ricce M,Rodríguez López-Salazar T,Mendoza Jiménez-Ridruejo J,Moreno Monteagudo JA,Santander Vaquero C, Effectiveness of rectal indomethacin in the prevention of acute pancreatitis after endoscopic retrograde cholangiopancreatography in unselected patients. Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva. 2020 Feb 5;     [PubMed PMID: 32022572]

[13]

Indomethacin Drugs and Lactation Database (LactMed). 2006     [PubMed PMID: 30000048]

[14]

Hoppmann RA,Peden JG,Ober SK, Central nervous system side effects of nonsteroidal anti-inflammatory drugs. Aseptic meningitis, psychosis, and cognitive dysfunction. Archives of internal medicine. 1991 Jul;     [PubMed PMID: 2064481]

[15]

Risser A,Donovan D,Heintzman J,Page T, NSAID prescribing precautions. American family physician. 2009 Dec 15     [PubMed PMID: 20000300]

[16]

Kulik A,Bykov K,Choudhry NK,Bateman BT, Non-steroidal anti-inflammatory drug administration after coronary artery bypass surgery: utilization persists despite the boxed warning. Pharmacoepidemiology and drug safety. 2015 Jun     [PubMed PMID: 25907164]

[17]

Indomethacin LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012;     [PubMed PMID: 31643333]

[18]

Chan TY,Lui SF,Chung SY,Luk S,Critchley JA, Adverse interaction between warfarin and indomethacin. Drug safety. 1994 Mar;     [PubMed PMID: 7880236]

[19]

Coster S,Visser MH,Touw DJ,Wirtz PW, Serotonin syndrome with sertraline and indomethacin. Journal of clinical psychopharmacology. 2010 Aug     [PubMed PMID: 20631569]

[20]

González F,López-Herce J,Moraleda C, A child presenting with acute renal failure secondary to a high dose of indomethacin: a case report. Journal of medical case reports. 2009 Feb 3     [PubMed PMID: 19192282]

[21]

Sheehan TM,Boldy DA,Vale JA, Indomethacin poisoning. Journal of toxicology. Clinical toxicology. 1986     [PubMed PMID: 3712524]