Does Indocin (indomethacin) cause side effects?

Indocin (indomethacin) is a nonsteroidal anti-inflammatory drug (NSAID) that reduces fever, pain and inflammation caused by osteoarthritis, rheumatoid arthritis, gouty arthritis or ankylosing spondylitis. Indocin works by reducing the production of prostaglandins. 

Prostaglandins are chemicals that the body produces and which cause the fever and pain that are associated with inflammation. Indomethacin blocks the enzymes that make prostaglandins (cyclooxygenase 1 and 2) and thereby reduces the levels of prostaglandins. As a result, fever, pain and inflammation are reduced. 

Common side effects of Indocin include

Serious side effects of Indocin include

Drug interactions of Indocin include cholestyramine and colestipol, which may decrease absorption of Indocin by binding to Indocin in the intestine and preventing absorption into the body.

  • Indocin and other NSAIDs may decrease the elimination of lithium by the kidneys and, therefore, increase the blood level of lithium, which could lead to lithium toxicity.
  • Indocin may interfere with the blood pressure-lowering effects of drugs that are given to reduce blood pressure.
  • When Indocin is used in combination with methotrexate or aminoglycosides the blood levels of the methotrexate or aminoglycoside may increase, which may lead to more methotrexate or aminoglycoside-related side effects.
  • Indocin should be avoided by patients with a history of asthma attacks, hives or other allergic reactions to aspirin or other NSAIDs.
    • If aspirin is taken with Indocin there may be an increased risk for developing an ulcer.
    • Persons who have more than 3 alcoholic beverages per day may be at increased risk of developing stomach ulcers when taking Indocin or other NSAIDs.
  • Indocin increases the negative effect of cyclosporine on kidney function and reduces the effect of furosemide and thiazide diuretics because of prostaglandin inhibition.
  • Individuals taking oral blood thinners or anticoagulants should avoid Indocin because Indocin also thins the blood, and excessive blood thinning may lead to bleeding. 

Use of Indocin during pregnancy has not been adequately studied. Indocin may have adverse effects on the fetus. 

Indocin is excreted in breast milk and therefore should be avoided by breastfeeding mothers.

What are the important side effects of Indocin (indomethacin)?

Common side effects of indomethacin are:

Other important side effects are:

Some individuals are allergic to NSAIDs and may develop shortness of breath when an NSAID is taken. People with asthma are at a higher risk for experiencing serious allergic reaction to NSAIDs. Individuals with a serious allergy to one NSAID are likely to experience a similar reaction to a different NSAID.

Indomethacin may cause ulceration of the stomach or intestine, and the ulcers may bleed. Sometimes, ulceration may lead to perforation of the intestine and bleeding can occur without abdominal pain, and black tarry stools, weakness, and dizziness upon standing (orthostatic hypotension) may be the only signs of a ulceration.

NSAIDs can reduce the ability of blood to clot thereby increasing bleeding after an injury.

NSAIDs reduce the flow of blood to the kidneys and impair function of the kidneys. The impairment is most likely to occur in patients with preexisting impairment of kidney function or congestive heart failure, and use of NSAIDs in these patients should be done cautiously. Individuals who have nasal polyps or are allergic to aspirin or other NSAIDs should not use indomethacin because there is an increased risk of severe allergic reactions in these individuals.

Indocin (indomethacin) side effects list for healthcare professionals

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Cardiovascular Thrombotic Events
  • GI Bleeding, Ulceration and Perforation
  • Hepatotoxicity
  • Hypertension
  • Heart Failure and Edema
  • Renal Toxicity and Hyperkalemia
  • Anaphylactic Reactions
  • Serious Skin Reactions
  • Hematologic Toxicity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

  • In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving indomethacin capsules than in the group taking Indocin Suppositories or placebo.
  • In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with Indocin Suppositories or indomethacin capsules was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group.
  • The adverse reactions for indomethacin capsules listed in the following table have been arranged into two groups:
    •  (1) incidence greater than 1%; and
    • (2) incidence less than 1%.
    • The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients).
    • The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing.
    • The probability of a causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely.
  • The adverse reactions reported with indomethacin capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the suppositories.

Table 1 Summary of Adverse Reactions for Indomethacin Capsules

Incidence greater than 1%Incidence less than 1%
GASTROINTESTINAL
nausea* with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain)
diarrhea
abdominal distress or pain
constipation
anorexia
bloating (includes distension)
flatulence
peptic ulcer
gastroenteritis
rectal bleeding
proctitis
single or multiple ulcerations,
including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines
intestinal ulceration associated with stenosis and obstruction
gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis
ulcerative stomatitis
toxic hepatitis and jaundice (some fatal cases have been reported)
intestinal strictures (diaphragms)
CENTRAL NERVOUS SYSTEM
headache (11.7%)
dizziness*
vertigo
somnolence
depression and fatigue (including malaise and listlessness)
anxiety (includes nervousness)
muscle weakness
involuntary muscle movements
insomnia
muzziness
psychic disturbances including psychotic episodes
mental confusion
drowsiness
light-headedness
syncope
paresthesia
aggravation of epilepsy and parkinsonism
depersonalization
coma
peripheral neuropathy
convulsion
dysarthria
SPECIAL SENSES
tinnitusocular - corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin capsulesblurred vision
diplopia
hearing disturbances, deafness
CARDIOVASCULAR
Nonehypertension
hypotension
tachycardia
chest pain
congestive heart failure
arrhythmia; palpitations
METABOLIC
Noneedema
weight gain
fluid retention
flushing or sweating
hyperglycemia
glycosuria
hyperkalemia
INTEGUMENTARY
Nonepruritus
rash; urticaria
petechiae or ecchymosis
exfoliative dermatitis
erythema nodosum
loss of hair
Stevens-Johnson syndrome
erythema multiforme
toxic epidermal necrolysis
HEMATOLOGIC
Noneleukopenia
bone marrow depression
anemia secondary to obvious or occult
gastrointestinal bleeding
aplastic anemia
hemolytic anemia
agranulocytosis
thrombocytopenic purpura
disseminated intravascular coagulation
HYPERSENSITIVITY
Noneacute anaphylaxis
acute respiratory distress
rapid fall in blood pressure resembling a
shock-like state
angioedema
dyspnea
asthma
purpura
angiitis
pulmonary edema
fever
GENITOURINARY
Nonehematuria
vaginal bleeding
proteinuria
nephrotic syndrome
interstitial nephritis
BUN elevation
renal insufficiency, including renal failure
MISCELLANEOUS
Noneepistaxis
breast changes, including enlargement and tenderness, or gynecomastia
* Reactions occurring in 3% to 9% of patients treated with indomethacin capsules. (Those reactions occurring in less than 3% of the patients are unmarked.)

Causal Relationship Unknown

Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians:

  • Cardiovascular: Thrombophlebitis
  • Hematologic: Although there have been several reports of leukemia, the supporting information is weak
  • Genitourinary: Urinary frequency
  • A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome

What drugs interact with Indocin (indomethacin)?

See Table 2 for clinically significant drug interactions with indomethacin.

Table 2 Clinically Significant Drug Interactions with Indomethacin

Drugs That Interfere with Hemostasis
Clinical Impact:
  • Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
  • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of Indocin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding.
Aspirin
Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone.
Intervention: Concomitant use of Indocin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding.

Indocin is not a substitute for low dose aspirin for cardiovascular protection.

ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
  • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
  • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:
  • During concomitant use of Indocin and ACE inhibitors, ARBs, or beta blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
  • During concomitant use of Indocin and ACE-inhibitors or ARBs in patients who are elderly, volumedepleted, or have impaired renal function, monitor for signs of worsening renal function.
  • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.

It has been reported that the addition of triamterene to a maintenance schedule of Indocin resulted in reversible acute renal failure in two of four healthy volunteers. Indocin and triamterene should not be administered together. Both Indocin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of Indocin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.

Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of Indocin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels.
Digoxin
Clinical Impact:The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:During concomitant use of Indocin and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:During concomitant use of Indocin and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:During concomitant use of Indocin and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:Concomitant use of Indocin and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:During concomitant use of Indocin and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy.

Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.

Intervention:The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:Concomitant use of Indocin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:During concomitant use of Indocin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:During the concomitant use of Indocin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

Effects On Laboratory Tests

  • Indocin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion.
  • These facts should be considered when evaluating plasma renin activity in hypertensive patients.
  • False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported.
  • Thus, results of the DST should be interpreted with caution in these patients.

Summary

Indocin (indomethacin) is a nonsteroidal anti-inflammatory drug (NSAID) that reduces fever, pain and inflammation by reducing the production of prostaglandins. Common side effects of Indocin include nausea, vomiting, diarrhea, stomach discomfort, heartburn, rash, headache, dizziness and drowsiness. Use of Indocin during pregnancy has not been adequately studied. Indocin may have adverse effects on the fetus. Indocin is excreted in breast milk and therefore should be avoided by breastfeeding mothers.

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Medically Reviewed on 11/12/2020
References
FDA Prescribing Information

Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.