Indomethacin

Indomethacin is a prescription medication most commonly used to relieve moderate to severe pain, tenderness, and swelling caused by a variety of conditions.

Indomethacin belongs to a group of drugs called non-steroidal anti-inflammatory drugs (NSAIDs). These work by stopping the body’s production of a substance that causes pain, fever, and inflammation.

This medication comes in oral suspension, capsule, extended release capsule, and rectal suppository forms and is taken two or three times a day, with food.

Do not chew, divide, or break extended release indomethacin capsules. Swallow these capsules whole.

This medication is also available in an injectable form to be given directly into vein by a healthcare professional for the treatment of a patent ductus arteriosus in newborn infants.

Common side effects of indomethacin include headache, dizziness, vomiting, diarrhea, and constipation.

Indomethacin can also cause dizziness, drowsiness, and blurred vision. Do not drive or operate heavy machinery until you know how indomethacin affects you.

Oral:

Serious side effects have been reported with oral indomethacin including the following:

• unexplained weight gain
• fever
• blisters
• rash
• itching
• hives
• swelling of the eyes, face, tongue, lips, throat, hands, feet, ankles, or lower legs
• difficulty breathing or swallowing
• hoarseness
• pale skin
• fast heartbeat
• excessive tiredness
• unusual bleeding or bruising
• lack of energy
• nausea
• loss of appetite
• pain in the upper right part of the stomach
• flu-like symptoms
• yellowing of the skin or eyes
• cloudy, discolored, or bloody urine
• back pain
• difficult or painful urination
• blurred vision or other problems with sight

Topical:

Serious side effects have been reported with indomethacin suppositories including the following:

• unexplained weight gain
• fever
• blisters
• rash
• itching
• hives
• swelling of the eyes, face, tongue, lips, throat, hands, feet, ankles, or lower legs
• difficulty breathing or swallowing
• hoarseness
• pale skin
• fast heartbeat
• excessive tiredness
• unusual bleeding or bruising
• lack of energy
• nausea
• loss of appetite
• pain in the upper right part of the stomach
• flu-like symptoms
• yellowing of the skin or eyes
• cloudy, discolored, or bloody urine
• back pain
• difficult or painful urination
• blurred vision or other problems with sight

Injectable:

• Serious side effects have been reported with indomethacin injection including the following:
• Perforations in the stomach or intestine
• Decreased blood sugar
• Fluid retention
• Pulmonary hypertension

Indomethacin can cause dizziness, drowsiness, and blurred vision. Do not drive or operate heavy machinery until you know how indomethacin affects you.

Do not take indomethacin if you:

• are allergic to indomethacin or to any of its ingredients
• are allergic to aspirin or other NSAIDs

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Indomethacin falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

If indomethacin is taken during the third trimester of pregnancy, it can cause cardiovascular problems, bleeding problems, renal failure, and a risk of necrotizing enterocolitis in the fetus.

• Ankylosing Spondylitis
• Bursitis
• Gout (Gouty Arthritis)
• NSAIDs (Nonsteroidal Antiinflammatory Drugs)
• Pain Management Medication Types
• Psoriatic Arthritis
• Rheumatoid Arthritis (RA)

Usual Adult Dose for Acute Gout:

50 mg orally or rectally 3 times a day
Duration of therapy: Until gout attack has resolved

Comments:
-Relief of pain has been observed within 2 to 4 hours; tenderness and heat usually subside within 24 to 36 hours; swelling gradually disappears in 3 to 5 days.
-Extended release capsules are not recommended for the treatment of acute gouty arthritis.

Use: For the treatment of acute gouty arthritis.

Usual Adult Dose for Bursitis:

Immediate-release capsules and suspension:
75 to 150 mg orally per day in 3 or 4 divided doses

Suppository:
50 mg rectally up to 3 times a day

Extended Release:
75 mg orally once or twice a day

Comments:
-The lowest effective dose for the shortest duration possible should be used based on individual patient treatment goals.
-Therapy should continue until signs/symptoms of inflammation have been controlled for several days; usually 7 to 14 days

Use: For the treatment of acute painful shoulder (e.g. bursitis, tendonitis).

Usual Adult Dose for Tendonitis:

Immediate-release capsules and suspension:
75 to 150 mg orally per day in 3 or 4 divided doses

Suppository:
50 mg rectally up to 3 times a day

Extended Release:
75 mg orally once or twice a day

Comments:
-The lowest effective dose for the shortest duration possible should be used based on individual patient treatment goals.
-Therapy should continue until signs/symptoms of inflammation have been controlled for several days; usually 7 to 14 days

Use: For the treatment of acute painful shoulder (e.g. bursitis, tendonitis).

Usual Adult Dose for Pain:

20 mg orally 3 times a day or 40 mg orally 2 to 3 times a day

Comment:
-The lowest effective dose for the shortest duration possible should be used based on individual patient treatment goals.

Use: For the treatment of mild to moderate acute pain

Usual Adult Dose for Rheumatoid Arthritis:

Immediate-release capsules and suspension:
-Initial dose: 25 mg orally 2 or 3 times a day
-Maintenance dose: Adjust dose as needed and tolerated in increments of 25 mg or 50 mg weekly until satisfactory response or maximum dose is achieved
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg

Suppository:
-Initial dose: 50 mg rectally once a day
-Maintenance dose: 50 to 200 mg rectally per day in divided doses
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg per day

Comment: For patients who have persistent night pain or morning stiffness, a larger portion of the total daily dose (up to 100 mg) orally or rectally at bedtime may be helpful.

Extended-release:
-Initial dose: 75 mg orally once a day
For patients currently receiving immediate-release at 150 mg per day:
-Initial dose: 75 mg orally twice a day

Comments:
-Once response to therapy is determined, dose and frequency should be adjusted to the lowest effective dose for the shortest duration possible to suit the individual patient's treatment goals.
-During acute flares, it may be necessary to increase the dose by 25 mg or 50 mg daily.
-Doses above 150 mg to 200 mg once a day generally do not increase the effectiveness of this drug.

Use: For the treatment of active stages of moderate to severe rheumatoid arthritis, including acute flares of chronic disease.

Usual Adult Dose for Ankylosing Spondylitis:

Immediate-release capsules and suspension:
-Initial dose: 25 mg orally 2 or 3 times a day
-Maintenance dose: Adjust dose as needed and tolerated in increments of 25 mg or 50 mg weekly until satisfactory response or maximum dose is achieved
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg

Suppository:
-Initial dose: 50 mg rectally once a day
-Maintenance dose: 50 to 200 mg rectally per day in divided doses
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg per day

Comment: For patients who have persistent night pain or morning stiffness, a larger portion of the total daily dose (up to 100 mg) orally or rectally at bedtime may be helpful.

Extended-release:
-Initial dose: 75 mg orally once a day
For patients currently receiving immediate-release at 150 mg per day:
-Initial dose: 75 mg orally twice a day

Comments:
-Once response to therapy is determined, dose and frequency should be adjusted to the lowest effective dose for the shortest duration possible to suit the individual patient's treatment goals.
-During acute flares, it may be necessary to increase the dose by 25 mg or 50 mg daily.
-Doses above 150 mg to 200 mg once a day generally do not increase the effectiveness of this drug.

Use: For the treatment of active stages of moderate to severe ankylosing spondylitis.

Usual Adult Dose for Osteoarthritis:

Immediate-release capsules and suspension:
-Initial dose: 25 mg orally 2 or 3 times a day
-Maintenance dose: Adjust dose as needed and tolerated in increments of 25 mg or 50 mg weekly until satisfactory response or maximum dose is achieved
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg

Suppository:
-Initial dose: 50 mg rectally once a day
-Maintenance dose: 50 to 200 mg rectally per day in divided doses
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg per day

Comment: For patients who have persistent night pain or morning stiffness, a larger portion of the total daily dose (up to 100 mg) orally or rectally at bedtime may be helpful.

Extended-release:
-Initial dose: 75 mg orally once a day
For patients currently receiving immediate-release at 150 mg per day:
-Initial dose: 75 mg orally twice a day

Comments:
-Once response to therapy is determined, dose and frequency should be adjusted to the lowest effective dose for the shortest duration possible to suit the individual patient's treatment goals.
-During acute flares, it may be necessary to increase the dose by 25 mg or 50 mg daily.
-Doses above 150 mg to 200 mg once a day generally do not increase the effectiveness of this drug.

Use: For the treatment of active stages of moderate to severe osteoarthritis.

Usual Pediatric Dose for Patent Ductus Arteriosus:

Dosing depends on age of neonate at time of therapy; A course of therapy is defined as 3 IV doses given at 12 to 24 hour intervals.

Age at first dose: Less than 48 hours:
-First dose: 0.2 mg/kg IV
-Second dose: 0.1 mg/kg IV
-Third dose: 0.1 mg/kg IV

Age at first dose: 2 to 7 days:
-First dose: 0.2 mg/kg IV
-Second dose: 0.2 mg/kg IV
-Third dose: 0.2 mg/kg IV

Age at first dose: Over 7 days:
-First dose: 0.2 mg/kg IV
-Second dose: 0.25 mg/kg IV
-Third dose: 0.25 mg/kg IV

Comments:
-Monitor urinary output; if anuria or marked oliguria (urinary output less than 0.6 mL/kg/hr) is evident at time of the second or third dose, hold drug until laboratory studies indicate renal function has returned to normal.
-If ductus arteriosus closes or has significantly reduced in size 48 hours or more after completion of the first course, no further doses are needed.
-If ductus arteriosus re-opens, a second course of 1 to 3 doses may be given.
-If neonate is unresponsive after 2 courses of therapy, surgery may be necessary.

Use: For the closure of a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1750 g when 48 hours of usual medical management is ineffective; clear-cut clinical evidence of hemodynamically significant patent ductus arteriosus should be present (e.g., respiratory distress, continuous murmur, hyperactive precordium, cardiomegaly and pulmonary plethora on chest x-ray).

Usual Pediatric Dose for Rheumatoid Arthritis:

2 to 14 years:
-Initial dose: 1 to 2 mg/kg/day orally in divided doses
-Maximum dose: 3 mg/kg/day or 150 to 200 mg/day, whichever is less; limited data supports a maximum of 4 mg/kg/day

Comments:
-Safety and efficacy have not been established in patients 14 years and younger; use should be limited to patients for whom toxicity or lack of efficacy with other drugs warrants the risk.
-As symptoms subside, the dose should be reduced or discontinued.
-Use in pediatric patients have been confined to the use of capsules.

Over 14 years:
Immediate-release capsules and suspension:
-Initial dose: 25 mg orally 2 or 3 times a day
-Maintenance dose: Adjust dose as needed and tolerated in increment of 25 mg or 50 mg weekly until satisfactory response or maximum dose is achieved
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg

Suppository:
-Initial dose: 50 mg rectally once a day
-Maintenance dose: 50 to 200 mg rectally per day in divided doses
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg per day

Comment:
-For patients who have persistent night pain or morning stiffness a larger portion of the total daily dose (up to 100 mg) orally or rectally at bedtime may be helpful.

Extended-release:
-Initial dose: 75 mg orally once a day
For patients currently receiving immediate-release at 150 mg per day:
-Initial dose: 75 mg orally twice a day

Comments:
-Once response to therapy is determined, dose and frequency should be adjusted to the lowest effective dose for the shortest duration possible to suit the individual patient's treatment goals.
-During acute flares, it may be necessary to increase the dose by 25 mg or 50 mg daily.
-Doses above 150 mg to 200 mg once a day generally do not increase the effectiveness of this drug.

Use: For the treatment of active stages of moderate to severe rheumatoid arthritis, including acute flares of chronic disease.

Usual Pediatric Dose for Ankylosing Spondylitis:

Over 14 years:
Immediate-release capsules and suspension:
-Initial dose: 25 mg orally 2 or 3 times a day
-Maintenance dose: Adjust dose as needed and tolerated in increment of 25 mg or 50 mg weekly until satisfactory response or maximum dose is achieved
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg

Suppository:
-Initial dose: 50 mg rectally once a day
-Maintenance dose: 50 to 200 mg rectally per day in divided doses
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg per day

Comment:
-For patients who have persistent night pain or morning stiffness a larger portion of the total daily dose (up to 100 mg) orally or rectally at bedtime may be helpful.

Extended-release:
-Initial dose: 75 mg orally once a day
For patients currently receiving immediate-release at 150 mg per day:
-Initial dose: 75 mg orally twice a day

Comments:
-Once response to therapy is determined, dose and frequency should be adjusted to the lowest effective dose for the shortest duration possible to suit the individual patient's treatment goals.
-During acute flares, it may be necessary to increase the dose by 25 mg or 50 mg daily.
-Doses above 150 mg to 200 mg once a day generally do not increase the effectiveness of this drug.

Use: For the treatment of active stages of moderate to severe rheumatoid arthritis.

Usual Pediatric Dose for Osteoarthritis:

Over 14 years:
Immediate-release capsules and suspension:
-Initial dose: 25 mg orally 2 or 3 times a day
-Maintenance dose: Adjust dose as needed and tolerated in increment of 25 mg or 50 mg weekly until satisfactory response or maximum dose is achieved
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg

Suppository:
-Initial dose: 50 mg rectally once a day
-Maintenance dose: 50 to 200 mg rectally per day in divided doses
-Maximum single dose: 100 mg
-Maximum daily dose: 200 mg per day

Comment:
-For patients who have persistent night pain or morning stiffness a larger portion of the total daily dose (up to 100 mg) orally or rectally at bedtime may be helpful.

Extended-release:
-Initial dose: 75 mg orally once a day
For patients currently receiving immediate-release at 150 mg per day:
-Initial dose: 75 mg orally twice a day

Comments:
-Once response to therapy is determined, dose and frequency should be adjusted to the lowest effective dose for the shortest duration possible to suit the individual patient's treatment goals.
-During acute flares, it may be necessary to increase the dose by 25 mg or 50 mg daily.
-Doses above 150 mg to 200 mg once a day generally do not increase the effectiveness of this drug.

Use: For the treatment of active stages of moderate to severe rheumatoid arthritis.

Usual Pediatric Dose for Bursitis:

Over 14 years:
Immediate-release capsules and suspension:
75 to 150 mg orally per day in 3 or 4 divided doses

Suppository:
50 mg rectally up to 3 times a day

Extended Release:
75 mg orally once or twice a day

Comments:
-The lowest effective dose for the shortest duration possible should be used based on individual patient treatment goals.
-Therapy should continue until signs/symptoms of inflammation have been controlled for several days; usually 7 to 14 days

Use: For the treatment of acute painful shoulder (e.g. bursitis, tendonitis).

Usual Pediatric Dose for Tendonitis:

Over 14 years:
Immediate-release capsules and suspension:
75 to 150 mg orally per day in 3 or 4 divided doses

Suppository:
50 mg rectally up to 3 times a day

Extended Release:
75 mg orally once or twice a day

Comments:
-The lowest effective dose for the shortest duration possible should be used based on individual patient treatment goals.
-Therapy should continue until signs/symptoms of inflammation have been controlled for several days; usually 7 to 14 days

Use: For the treatment of acute painful shoulder (e.g. bursitis, tendonitis).

Ask your doctor before using indomethacin if you take an antidepressant such as citalopram, escitalopram, fluoxetine (Prozac), fluvoxamine, paroxetine, sertraline (Zoloft), trazodone, or vilazodone. Taking any of these medicines with an NSAID may cause you to bruise or bleed easily.

Ask a doctor or pharmacist if it is safe for you to use indomethacin if you are also using any of the following drugs:

• cyclosporine;

• lithium;

• methotrexate;

• probenecid;

• a blood thinner (warfarin, Coumadin, Jantoven);

• heart or blood pressure medication, including a diuretic or "water pill"; or

• steroid medicine (such as prednisone).

This list is not complete. Other drugs may interact with indomethacin, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Prototypical NSAIA; indoleacetic acetic acid derivative.301 341 420

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.301 341 420 455 456 457 458 461 462 463

• Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.301 341 420

• Permits closure of the ductus arteriosus in premature neonates by inhibiting prostaglandin synthesis.301

Indomethacin capsules are contraindicated in the following patients:

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to Indomethacin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]

• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]

• In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].  

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.  

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

Mechanism of Action

Indomethacin has analgesic, anti-inflammatory, and antipyretic properties.  

The mechanism of action of Indomethacin capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).  

Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because Indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Pharmacokinetics

Absorption

Following single oral doses of Indomethacin capsules 25 mg or 50 mg, Indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered Indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of Indomethacin oral suspension was found to be bioequivalent to a 50 mg Indomethacin capsule when each was administered with food. With a typical therapeutic regimen of 25 or 50 mg three times a day, the steady-state plasma concentrations of Indomethacin are an average 1.4 times those following the first dose.  

Distribution

Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk.  

Elimination

Metabolism 

Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of Indomethacin are formed.  

Excretion

Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as Indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as Indomethacin). The mean half-life of Indomethacin is estimated to be about 4.5 hours.  

Specific Populations

Pediatric 

The pharmacokinetics of Indomethacin capsules have not been investigated in pediatric patients.  

Race  

Pharmacokinetic differences due to race have not been identified.  

Hepatic Impairment  

The pharmacokinetics of Indomethacin capsules have not been investigated in patients with hepatic impairment.  

Renal Impairment  

The pharmacokinetics of Indomethacin capsules have not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)].  

Drug Interaction Studies 

Aspirin   

In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases Indomethacin blood levels approximately 20% [see Drug Interactions (7)].  

When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)].  

Diflunisal   

In normal volunteers receiving Indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of Indomethacin [see Drug Interactions (7)].  

• Indocin
• Tivorbex

Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties

Other proposed mechanisms not fully elucidated (and possibly contributing to the anti-inflammatory effect to varying degrees), include inhibiting chemotaxis, altering lymphocyte activity, inhibiting neutrophil aggregation/activation, and decreasing proinflammatory cytokine levels.

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; Neonates: PDA: 0.36 L/kg; Post-PDA closure: 0.26 L/kg; Adults: 0.34-1.57 L/kg

Metabolism

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

Excretion

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

Clearance: Preterm neonates: ~19 mL/hour/kg (range: 4.7-45.5 mL/hour/kg) (Al Za'abi 2007)

IV: Reconstitute with 1 mL of preservative-free NS or SWFI to a concentration of 0.1 mg per 0.1 mL, or with 2 mL diluent to a concentration of 0.05 mg per 0.1 mL. Reconstitute solution just prior to each administration; further dilution after reconstitution is not recommended. Discard any unused portion. Do not use preservative-containing diluents for reconstitution.

False-negative dexamethasone suppression test; may lead to false-positive aldosterone/renin ratio (ARR) (Funder 2016)