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

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:

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