Indomethacin (Indocin) is available as an oral, IV, and per rectal formulation. It is a non-selective NSAID that has anti-inflammatory, antipyretic, and analgesic properties.

Indomethacin Uses:

• Acute pain, mild to moderate (Tivorbex only):

  • Treatment of mild to moderate pain acute in onset in adults

• Ankylosing spondylitis (excluding Tivorbex):

  • Treatment of moderate to severe ankylosing spondylitis

• Bursitis/tendonitis of the shoulder (excluding Tivorbex):

  • Treatment of acute painful bursitis and/or tendonitis of the shoulder

• Gout, acute flares (excluding Tivorbex and ER capsules):

  • Treatment of acute gout flares

• Osteoarthritis (excluding Tivorbex):

  • Treatment of moderate to severe osteoarthritis

• Patent ductus arteriosus (IV only):

  • To shut down a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g, when 48 hours usual medical management (eg, fluid restriction, diuretics, digitalis, respiratory support) is not effective

• Rheumatoid arthritis (excluding Tivorbex):

  • Treatment of moderate to severe rheumatoid arthritis, including acute flares of chronic disease

• Off Label Use of Indomethacin in Adults:

  • Prevention of pancreatitis post-endoscopic retrograde cholangiopancreatography (ERCP)
  • Management of preterm labor

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Indomethacin dose in the treatment of acute mild to moderate pain:

• Oral (Tivorbex only): 20 mg 3 times a day or 40 mg 2 or 3 times daily

Indomethacin dose in the treatment of Ankylosing spondylosis, osteoarthritis, or rheumatoid arthritis:

Note: Use the lowest effective dose of indomethacin for the shortest duration possible.

• Oral (immediate release [excluding Tivorbex)]), rectal:
  • 25 mg 2 to 3 times a daily;
  • if well tolerated, increase the daily dosage by 25 or 50 mg at weekly intervals until satisfactory response or a daily dose of 150 to 200 mg/day
  • maximum dose: 200 mg/day is reached.
  • In patients with arthritis and persistent night pain and/or morning stiffness may give the larger portion (up to a maximum of 100 mg) of daily dose at bedtime.
• Oral (extended-release capsules):
  • Initial: 75 mg once a day, may increase to 75 mg twice a day.
  • The maximum dose is 150 mg/day).

Indomethacin dose in the treatment of Bursitis/ tendonitis of the shoulder:

• Oral (excluding Tivorbex), rectal:
  • Initial dose: at 75 to 150 mg/day in 3 to 4 divided doses or 1 to 2 divided doses for extended-release;
  • The usual treatment is 7 to 14 days;
  • discontinue after signs/symptoms of inflammation have been controlled for several days.

Indomethacin Dose in the treatment of acute flare of Gout:

• Oral (excluding Tivorbex and ER capsules), rectal:
  • 50 mg 3 times a day;
  • initiate within 24 to 48 hours of flare onset;
  • discontinue 2 to 3 days after clinical signs resolution;
  • usual duration: for 5 to 7 days.

Indomethacin dose in the Prevention of pancreatitis post-endoscopic retrograde cholangiopancreatography (ERCP):

• Rectal: 100 mg immediately after ERCP.

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Indomethacin Dose in the treatment of Inflammatory/ rheumatoid disorders:

Note: Use lowest effective dose:

• Children ≥2 years and Adolescents:

  • Initial: 1 to 2 mg/kg/day orally in 2 to 4 divided doses;
  • The usual initial adult dose range: 25 to 50 mg;
  • The maximum daily dose: 4 mg/kg/day or 200 mg/day, whichever is less.

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Indomethacin Pregnancy Risk Category: C (D in third trimester)

• • • Placenta crosses over to Indomethacin
    • Some studies have shown that birth defects can be caused by in utero NSAID use. However, the data is inconsistent.
    • Following in utero NSAID use, nonteratogenic effects such as prenatal constriction, persistent pulmonary hypertension, oligohydramnios and necrotizing enterocolitis have been seen in the fetus/neonate.
    • Additionally, postnatal nonclosure of ductus arteriosus may occur. This can be difficult to manage medically.
    • Because NSAIDs can cause premature closure of ductus arteriosus, indomethacin product labels specifically state that use should be stopped starting at 30 weeks gestation.
    • Pregnancy may cause an increase in the clearance of indomethacin.
    • Preterm labor can be managed with NSAIDs.
    • Consider the risks and benefits of each agent before you choose one.
    • NSAIDs may be used to treat mild rheumatoid-arthritis flares in pregnant women. However, it should be avoided or minimized early in pregnancy.
    • Women of reproductive age who have been using NSAIDs for a long time may experience infertility. This can be reversed by stopping the medication.
    • Women who have difficulty conceiving or are undergoing fertility treatment should consider quitting.
    • There may be an increased chance of miscarriage if NSAIDs are taken close to conception.

Use of Indomethacin while breastfeeding

• • Breast milk contains Indomethacin.
  • Women who used indomethacin as postpartum pain relief have experienced hypertensive crises and other psychiatric side effect.
  • Postpartum women who want to breastfeed may use NSAIDs. However, it is better to use agents other than indomethacin.
  • Women who breastfeed prematurely or jaundiced babies, as well as infants with platelet dysfunction and thrombocytopenia, should avoid Indomethacin.
  • Indomethacin therapy is not recommended for neonates suffering from severe renal impairment.

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Indomethacin Dose in Kidney Disease:

• Oral/rectal:

  • There are no dosage adjustments provided in the drug manufacturer's labeling; not recommended in patients with advanced renal disease.

• Injection:

  • If anuria or marked oliguria (urinary output <0.6 mL/kg/hour) evident at the scheduled time of the second or third dose, hold dose until renal function returns to normal.
  • Use is contraindicated in neonates with significant renal impairment.

• KDIGO 2012 guidelines provide the following recommendations for NSAIDs:

  • eGFR 30 to <60 mL/minute/1.73 m²:

    • Temporarily discontinue in patients with intercurrent disease that increases the risk of acute kidney injury.

  • eGFR <30 mL/minute/1.73 m²:

    • Avoid use.

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Indomethacin Dose in Liver disease:

• There are no dosage adjustments provided in the drug manufacturer's labeling;
• Use with caution.

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Common Side Effects of Indomethacin:

• Central nervous system:

  • Headache

• Gastrointestinal:

  • Vomiting

• Hematologic & oncologic:

  • Postoperative hemorrhage

Less Common Side Effects of Indomethacin:

• Cardiovascular:

  • Presyncope
  • Syncope

• Central Nervous System:

  • Dizziness
  • Depression
  • Drowsiness
  • Fatigue
  • Malaise
  • Vertigo

• Dermatologic:

  • Pruritus
  • Hyperhidrosis
  • Skin Rash

• Endocrine & Metabolic:

  • Hot Flash

• Gastrointestinal:

  • Epigastric Pain
  • Heartburn
  • Nausea
  • Dyspepsia
  • Constipation
  • Abdominal Distress
  • Abdominal Pain
  • Diarrhea
  • Decreased Appetite

• Otic:

  • Tinnitus

• Miscellaneous:

  • Swelling

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Contraindications to Indomethacin:

• • • Hypersensitivity to indomethacin and any other component of the formulation (eg, anaphylactic reaction, severe skin reactions)
    • Use in conjunction with coronary artery bypass surgery (CABG);
    • History of asthma, urticaria or allergic-type reactions following aspirin or any other NSAID agent;
    • Patients with a history or recent rectal bleeding (suppositories)

Only for neonates (IV):

• • • Evidence of or suspicion of Necrotizing Enterocolitis
    • significant renal impairment;
    • Active bleeding (including intracranial hemorhage or gastrointestinal bleeding)
    • thrombocytopenia,
    • coagulation defects;
    • Untreated Infection (proven or suspected);
    • congenital heart disease in which the ductus Arteriosus must be properly functioning to ensure adequate pulmonary and systemic blood flow.

Canadian labeling:Additional contraindications not listed in the US labeling:

• • • Uncontrolled severe heart failure
    • Hyperkalemia is a known condition.
    • active gastric/duodenal/peptic ulcer;
    • active GI bleed;
    • History of recurrent GI Ulceration
    • Active GI inflammatory Disease
    • cerebrovascular bleeding and other bleeding disorders
    • Grave hepatic impairment, active liver disease
    • Grave renal impairment (CrCl 30 mg/minute) or deteriorating renal function
    • Concurrent use of other NSAIDs
    • Complete or partial syndrome of nasal Polyps
    • Children and adolescents under 14 years old;
    • Breastfeeding
    • Third trimester of pregnancy

Warnings and precautions

• • Anaphylactoid reactions

    • Anaphylactoid reactions can occur even in patients who have never been exposed to anaphylactic substances.
    • Patients with the "aspirin trifecta" (bronchial asthma and aspirin intolerance, rhinitis) could be at higher risk.
    • Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with a nonsteroidal anti-inflammatory drug (NSAID) or aspirin therapy.

  • Cardiovascular events: [US Boxed Warn]

    • The increased risk of severe (and possibly fatal) adverse cardiovascular events due to NSAIDs, such as stroke and MI, can be caused by NSAIDs.
    • This risk can occur during treatment, and it may increase as the duration of treatment is continued.
    • The relative risk seems to be the same in people with and without cardiovascular disease, or risk factors for it. However, the absolute incidence of serious cardiovascular events (which can occur early in treatment) was higher among patients with known cardiovascular disease and those who received higher doses.
    • Exacerbation or new-onset hypertension can occur. NSAIDs could also affect the response to ACE inhibitors, thiazide or loop diuretics; may cause cardiovascular events. Monitor blood pressure.
    • Patients with edema may experience sodium and fluid retention.
    • Avoid using in the event of heart failure.
    • Patients with MI should not be used unless the benefits are greater than the risk to their cardiovascular health.
    • To reduce cardiovascular events, use the lowest effective dose for the most time. Patients at high risk should consider alternate therapies.

  • CNS effects

    • It may cause blurred vision, drowsiness, blurred vision and other neurologic effects that can impair physical or psychological abilities. Patients should be cautious about tasks that require mental alertness, such as operating machinery, driving, or operating machinery.
    • If headaches persist after reducing dosage, it is possible to stop therapy.

  • [US Boxed Warning]: GI events

    • NSAIDs increase the risk of severe GI inflammation, ulceration and bleeding (may be fatal); patients older than 65 years old and those with a history peptic ulcer disease or GI bleeding are more at risk.
    • These events can occur without warning and at any time during therapy.
    • Patients with active GI bleeding should not be used.
    • Avoid non-aspirin NSAIDs in patients who have had a history or experience of severe lower GI bleeding.
    • Be cautious if you have a history of GI problems, and concurrent treatment that increases the risk of GI bleeding (eg aspirin, anticoagulants, corticosteroids, selective Serotonin reuptake inhibits), advanced hepatic diseases, coagulopathy or smoking, elderly patients or those with underlying conditions.
    • To reduce the risk of GI adverse reactions, use the lowest effective dose for the shortest time. Patients at high risk should consider alternate treatments.
    • Concomitant use of aspirin can lead to a significant increase in the risk for GI complications (eg ulcers)
    • It is recommended to take concurrent gastroprotective therapy, such as proton pump inhibitors.

  • Hematologic effects

    • Patients with coagulation disorders and those on anticoagulants need to be closely monitored for platelet adhesion or aggregation.
    • Anemia can occur. Patients on long-term NSAID therapy need to be closely monitored.
    • Rarely, NSAIDs have been linked to severe blood dyscrasias like thrombocytopenia, agranulocytosis, and aplastic anemia.

  • Hepatic effects

    • Reports of transaminase elevations were made.
    • Patients with abnormal liver function tests should be closely monitored.
    • With NSAIDs, rare, sometimes fatal, severe hepatic reactions have been observed (eg, fulminant hepatitis or hepatic necrosis),
    • If you experience any symptoms or signs of liver disease, discontinue use immediately.

  • Hyperkalemia:

    • Hyperkalemia may be increased by NSAIDs, especially in the elderly.
      • elderly patients,
      • Diabetic patients
      • Patients with kidney disease and
      • Concomitant use with other agents that can induce hyperkalemia (eg ACE inhibitors).
    • Monitor potassium closely.

  • Ophthalmic effects

    • Extended therapy can cause corneal deposits or retinal disturbances.
    • If you have blurred or reduced vision, discontinue using the product and consult an ophthalmologist.
    • All patients receiving long-term therapy should be evaluated periodically for vision.

  • Effects on the renal system:

    • NSAIDs can cause impairment of renal function. Dose-dependent decreases may occur in prostaglandin synthesis, which reduces renal blood flow. This may lead to renal decompensation (usually reversible).
    • Patients with impaired renal function, heart disease, hypovolemia, heart attack, hepatic impairment, diuretics and ACE inhibitors, as well as elderly patients, are at higher risk for nephrotoxicity.
    • Before starting treatment, hydrate the patient.
    • Monitor your renal function carefully.
    • Long-term NSAID usage can cause renal papillary necrosis and other injuries.

  • Reactions to skin:

    • NSAIDs can cause severe and potentially fatal skin adverse reactions, including exfoliative dermatitis (SJS), Stevens-Johnson syndromes (SJS) and toxic epidermal necrolysiss (TEN); these may occur without warning.
    • Stop using it immediately if you notice any skin rash or hypersensitivity.

  • Aseptic meningitis

    • Aseptic meningitis may increase in patients with systemic Lupus Erythematosus (SLE), and mixed connective tissue disorders.

  • Asthma

    • Patients with asthma that is aspirin-sensitive should not use this medication. It can cause severe and possibly fatal bronchospasm.
    • Patients with other forms or asthma should be cautious.

  • Bariatric surgery

    • Gastric ulceration
      • After bariatric surgery, avoid the use of non-selective NSAIDs in long-term.
      • development of anastomotic ulcerations/perforations may occur.
      • Short-term use of celecoxib or IV ketorolac is recommended for multimodal pain management strategies for postoperative pain.

  • Coronary bypass surgery for coronary artery bypass: [US Boxed Warn]

    • In the case of coronary bypass graft (CABG), surgery, it is not recommended to use.
    • After CABG surgery, stroke and MI risk may increase.

  • Depression

    • Be careful with depression
    • Use may worsen depression and other psychiatric disorders.

  • Epilepsy:

    • Be careful with epilepsy. It can be aggravated by excessive use.

  • Hepatic impairment

    • Patients with hepatic impairment should be cautious.
    • Patients with advanced hepatic diseases are more at risk for GI bleeding when they use NSAIDs.

  • Parkinsonism

    • Parkinson's disease is a serious condition.
    • This condition may be exacerbated by using.

  • Renal impairment

    • Patients with advanced renal disease should be advised not to use this product.
    • If abnormal renal function tests are persistently or significantly worsening, discontinue use.
    • In neonates with severe renal impairment, the injection formulation is not recommended.

Indomethacin: Drug Interaction

Risk Factor C (Monitor therapy)
5-Aminosalicylic Acid Derivatives	Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-Aminosalicylic Acid Derivatives.
Acalabrutinib	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.)	May enhance the antiplatelet effect of other Agents with Antiplatelet Properties.
Alcohol (Ethyl	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of GI bleeding may be increased with this combination.
Aliskiren	Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Aliskiren. Management: Monitor renal function periodically in patients receiving aliskiren and any nonsteroidal anti-inflammatory agent. Patients at elevated risk of renal dysfunction include those who are elderly, are volume depleted, or have pre-existing renal dysfunction.
Aminoglycosides	Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants.
Aminolevulinic Acid (Topical)	Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).
Angiotensin II Receptor Blockers	May enhance the adverse/toxic effect of Nonsteroidal AntiInflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function.
Angiotensin-Converting Enzyme Inhibitors	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors.
Anticoagulants	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Exceptions: Bemiparin; Enoxaparin; Heparin.
Beta-Blockers	Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol.
Bisphosphonate Derivatives	Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern.
Bremelanotide	May decrease the serum concentration of Indomethacin.
Cephalothin	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased.
Collagenase (Systemic)	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased.
Corticosteroids (Systemic)	May enhance the adverse/toxic effect of Nonsteroidal AntiInflammatory Agents (Nonselective).
Dasatinib	May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Deferasirox	Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.
Deoxycholic Acid	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased.
Desmopressin	Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Desmopressin.
Digoxin	Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Digoxin.
Drospirenone	Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Drospirenone.
Eplerenone	Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Eplerenone.
Fat Emulsion (Fish Oil Based)	May enhance the adverse/toxic effect of Agents with Antiplatelet Properties.
Felbinac	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Glucagon	Indomethacin may diminish the therapeutic effect of Glucagon.
Glucosamine	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Haloperidol	Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Haloperidol. Specifically including drowsiness and confusion.
HydrALAZINE	Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of HydrALAZINE.
Ibritumomab Tiuxetan	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding.
Ibrutinib	May enhance the adverse/toxic effect of Agents with Antiplatelet Properties.
Inotersen	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Limaprost	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
MetFORMIN	Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of MetFORMIN.
Multivitamins/Fluoride (with ADE)	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Multivitamins/Minerals (with ADEK, Folate, Iron)	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Multivitamins/Minerals (with AE, No Iron)	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Naftazone	May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents.
Obinutuzumab	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.
Omega-3 Fatty Acids	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Pentosan Polysulfate Sodium	May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents.
Pentoxifylline	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Porfimer	Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.
Potassium-Sparing Diuretics	Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium-Sparing Diuretics.
PRALAtrexate	Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum levels and/or toxicity if used concomitantly with an NSAID. Monitor for decreased pralatrexate serum levels with NSAID discontinuation.
Probenecid	May increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents.
Prostacyclin Analogues	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Prostaglandins (Ophthalmic)	Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic).
Quinolones	Nonsteroidal Anti-Inflammatory Agents may enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolones.
Salicylates	Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result.
Serotonin/Norepinephrine Reuptake Inhibitors	May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective).
Tacrolimus (Systemic)	Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tacrolimus (Systemic).
Thiazide and Thiazide-Like Diuretics	May enhance the nephrotoxic effect of Nonsteroidal AntiInflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics.
Thrombolytic Agents	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
Tipranavir	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Tolperisone	Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Tolperisone. Specifically, the risk of hypersensitivity reactions may be increased. Tolperisone may enhance the therapeutic effect of Nonsteroidal Anti-Inflammatory Agents.
Tricyclic Antidepressants (Tertiary Amine)	May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective).
Vancomycin	Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Vancomycin.
Verteporfin	Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.
Vitamin E (Systemic)	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Zanubrutinib	May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
Risk Factor D (Consider therapy modification)
Apixaban	Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of apixaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding.
Bemiparin	Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin and nonsteroidal anti-inflammatory agents (NSAIDs) due to the increased risk of bleeding. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding.
Bemiparin	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding.
Bile Acid Sequestrants	May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents.
CycloSPORINE (Systemic)	Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs.
Dabigatran Etexilate	Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of dabigatran and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding.
Diclofenac (Systemic)	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Seek alternatives to the combined use of diclofenac with other nonsteroidal anti-inflammatory agents (NSAIDs). Avoid the use of diclofenac/misoprostol with other NSAIDs.
Edoxaban	Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of edoxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding.
Enoxaparin	Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue nonsteroidal anti-inflammatory agents (NSAIDs) prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding.
Enoxaparin	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding.
Heparin	Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or nonsteroidal anti-inflammatory agents (NSAIDs) if coadministration is required.
Heparin	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required.
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry)	May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Management: Avoid combination when possible. If used, monitor more closely for evidence of bleeding. Discontinue herbal products with anticoagulant or antiplatelet actions 2 weeks prior to surgical, dental, or invasive procedures.
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry)	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Management: Concomitant treatment with these agents should generally be avoided. If used concomitantly, increased diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds) must be employed.
Lithium	Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium.
Loop Diuretics	Nonsteroidal Anti-Inflammatory Agents may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended.
Methotrexate	Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Methotrexate. Management: Alternative anti-inflammatory therapy should be considered whenever possible, especially if the patient is receiving higher, antineoplastic doses of methotrexate.
Rivaroxaban	Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of rivaroxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding.
Salicylates	Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Exceptions: Choline Magnesium Trisalicylate.
Selective Serotonin Reuptake Inhibitors	May enhance the antiplatelet effect of Nonsteroidal AntiInflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider alternatives to NSAIDs. Monitor for evidence of bleeding and diminished antidepressant effects. It is unclear whether COX-2-selective NSAIDs reduce risk.
Sincalide	Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction.
Sodium Phosphates	May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with NSAIDs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely.
Tenofovir Products	Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose.
Tiludronate	Indomethacin may increase the serum concentration of Tiludronate.
Triamterene	Indomethacin may enhance the nephrotoxic effect of Triamterene. Management: Consider alternatives to concomitant treatment with triamterene and indomethacin. If the combination cannot be avoided, monitor for development of renal failure.
Vitamin K Antagonists (eg, warfarin)	Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising.
Risk Factor X (Avoid combination)
Acemetacin	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Aminolevulinic Acid (Systemic)	Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).
Dexibuprofen	Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Dexibuprofen.
Dexketoprofen	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Floctafenine	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Ketorolac (Nasal)	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Ketorolac (Systemic)	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Macimorelin	Nonsteroidal Anti-Inflammatory Agents may diminish the diagnostic effect of Macimorelin.
Mifamurtide	Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Mifamurtide.
Morniflumate	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective)	Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective).
Omacetaxine	Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of nonsteroidal antiinflammatory drugs (NSAIDs) with omacetaxine in patients with a platelet count of less than 50,000/uL.
Pelubiprofen	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Phenylbutazone	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Talniflumate	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Tenoxicam	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.
Urokinase	Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase.
Zaltoprofen	May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.

 

Monitoring parameters:

• Monitor response (pain, range of motion, grip strength, mobility, ADL function), inflammation;
• observe for weight gain, edema;
• monitor renal function (urine output, serum creatinine, BUN);
• observe for bleeding, bruising;
• evaluate gastrointestinal effects (abdominal pain, bleeding, dyspepsia);
• mental confusion, disorientation,
• CBC,
• blood pressure,
• liver function tests (particularly with pediatric use);
• periodic ophthalmologic exams with prolonged therapy

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How to administer Indomethacin?

Oral:

• Administer with food or immediately after meals, and/ or with milk or antacids to decrease GI adverse effects.
• Extended-release capsules must be swallowed whole;
• Do not crush.

Rectal formulations:

• For rectal use only;
• not for oral or intravaginal use.

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Mechanism of action of Indomethacin:

• Reversibly inhibits COX-1 and COX-2 enzymes. This results in lower production of prostaglandin precursors. It has antipyretic and analgesic properties.
• Other proposed mechanisms not fully elucidated (and possibly contributing to the anti-inflammatory effect to varying degrees), but include inhibiting chemotaxis, altering lymphocyte activity, inhibiting neutrophil aggregation/activation, and reducing proinflammatory cytokine levels.
•  

The onset of action:

• ~30 minutes

Duration:

• 4 to 6 hours

Absorption:

• Oral:
  • Immediate release:
  • Neonates: Formulation specific;
  • Adults: Prompt and extensive;
• Extended-release:
  • Adults: 90% over 12 hours
  • (Note: 75 mg product is designed to initially release 25 mg and then 50 mg over an extended period of time)

Distribution:

• Crosses blood-brain barrier

Protein binding:

• 99%

Metabolism:

• Hepatic; significant enterohepatic recirculation;
• active metabolites include desmethyl, desbenzoyl and desmethyl-desbenzoyl (all in unconjugated form)

Bioavailability:

• Neonates, premature:
  • Percent bioavailability reported in the literature is highly variable and may be influenced by formulation components and indomethacin physicochemical properties
  • some have suggested that aqueous formulations are less bioavailable as compared to ethanol-based formulations
  • aqueous suspension (in saline): 13% to 20%
  • ethanol-based (96% v/v) suspension: 98.6%
• Adults:
  • Oral: 100%;
  • rectal: 80% to 90% (than that absorbed from capsule form)

Half-life elimination:

• Neonates: Postnatal age (PNA) <2 weeks: ∼20 hours; PNA >2 weeks: ∼11 hours
• Adults: 2.6-11.2 hours; 7.6 hours (Tivorbex)

Time to peak:

• Oral: Immediate release: 2 hours; Tivorbex capsules: 1.67 hours

Excretion:

• Urine (60%, primarily as glucuronide conjugates);
• feces (33%, primarily as metabolites; 1.5% as unchanged drug)

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International Brand Names of Indomethacin:

• Indocin
• Tivorbex
• APO-Indomethacin
• MINT-Indomethacin
• RATIO-Indomethacin
• SANDOZ Indomethacin
• TEVAIndomethacin
• Adco-Indogel
• Agilex
• Amuno Retard
• Andocit
• Anodyne
• Antalgin
• Argilex
• Arthrexin
• Artrilona S
• Artrinovo
• Bonidon
• Catlep
• Chrono-Indocid
• Confortid
• Docin
• Ekmetacin
• Elmego Spray
• Elmetacin
• Flamaret
• IDC
• Idicin
• Idomethine
• IM-75
• Imet
• Inacid
• Indacin
• Indaflex
• Indalgin
• Indanet
• Indecin
• Indo
• Indobene
• Indocap
• Indocap S.R.
• Indocid
• Indocid-R
• Indocin
• Indocin I.V.
• Indocolir
• Indocollirio
• Indocollyre
• Indoflam Eye
• Indogesic
• Indolag
• Indolgina
• Indomecin
• Indomed F
• Indomee
• Indomel
• Indomen
• Indomet
• Indometa
• Indomin
• Indono
• Indorem
• Indos
• Indosan
• Indosima
• Indosin Gel
• Indosule
• Indovis
• Indoxen
• Indoy
• Indozu
• Indylon
• Inomet
• Insaid
• Lu Qi
• Malival
• Metacen
• Methacin
• Methocid
• Metindol
• Mobilat
• Moviflex
• Omexin
• Paragan
• Recticin-100
• Reumacid
• Reusin
• Rheumacid
• Rindocin
• Rothacin
• Schmerz Spray
• Sigadoc-Spray
• Sportflex
• Stratasin
• Twich
• Uniof
• Vi-Gel
• Xantomicin Forte

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Indomethacin Brand Names in Pakistan:

Indomethacin Injection 200 mcg/ml
Liometacen	Chiesi Pharmaceuticals (Pvt) Ltd.

 

Indomethacin 25 mg Tablets
Methacil	Mediceena Pharma (Pvt) Ltd.

 

Indomethacin 25 mg Capsules
Anglocid	Euro Pharma International
Endocin	Rogen Pharmaceuticals
Epomet	Epoch Pharmaceutical
Eromethacin	Eros Pharmaceuticals
Incin	Marvi Laboratories
Indacin	Karachi Pharmaceutical Laboratory
Indobid	Adamjee Pharmaceuticals (Pvt) Ltd.
Indocap	Hamaz Pharmaceutical (Pvt) Ltd.
Indomethacin	Munawar Pharma (Pvt) Ltd.
Indomethacin	Geofman Pharmaceuticals
Liskocid	Lisko Pakistan (Pvt) Ltd
Matindol	Krka-Pak Pharmaceutical & Chemical Works
Methacid	Unexo Labs (Pvt) Ltd.

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