Uses
Indomethacin is used orally or rectally for anti-inflammatory and analgesic effects in the symptomatic treatment of active stages of moderate to severe rheumatoid arthritis (including acute flares of chronic disease), osteoarthritis, and ankylosing spondylitis. Indomethacin is also used orally or rectally for symptomatic treatment of acute gouty arthritis and acute painful shoulder (bursitis and/or tendinitis). Extended-release capsules of indomethacin are not recommended for use in the treatment of acute gouty arthritis.
Indomethacin sodium is used IV in the treatment of patent ductus arteriosus in premature neonates.
The potential benefits and risks of indomethacin therapy as well as alternative therapies should be considered prior to initiating indomethacin therapy. The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.
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Inflammatory Diseases
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Rheumatoid Arthritis and Osteoarthritis
When used in the treatment of rheumatoid arthritis, indomethacin has relieved pain and stiffness; reduced swelling, fever, tenderness, and the number of joints involved; and improved mobility and grip strength. In the treatment of osteoarthritis, indomethacin has relieved pain and stiffness and improved mobility. In patients with rheumatoid arthritis or osteoarthritis, other NSAIAs (e.g., naproxen, fenoprofen) usually have been considered before indomethacin because of indomethacin's potential for adverse reactions, particularly at high dosages. However, because clinical experience indicates that indomethacin does not appear to be associated with a substantially greater risk of toxicity than most other NSAIAs, the drug may be considered for initial therapy. Indomethacin appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process.
Most clinical evaluations of indomethacin in the management of rheumatoid arthritis or osteoarthritis have shown that the anti-inflammatory and analgesic effects of usual dosages of indomethacin are greater than those of placebo and about equal to those of usual dosages of salicylates, phenylbutazone (no longer commercially available in the US), ibuprofen, and naproxen. Patient response to NSAIAs is variable; patients who do not respond to or cannot tolerate one drug might be successfully treated with a different agent. However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs.
(See Cautions: Dermatologic and Sensitivity Reactions.) In a controlled clinical study in patients with osteoarthritis, single daily doses of 75-mg extended-release capsules of indomethacin were as effective in relieving pain and stiffness and improving mobility as multiple daily doses of conventional 25-mg capsules of the drug administered 3 times daily.
In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction. Disease modifying antirheumatic drugs (DMARDs) (e.g., azathioprine, cyclosporine, etanercept, oral or injectable gold compounds, hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, penicillamine, sulfasalazine) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy. DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs. NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.
Indomethacin has been used in conjunction with corticosteroids in patients with rheumatoid arthritis; results of one study indicated that when indomethacin was used concomitantly with prednisolone in the treatment of rheumatoid arthritis, plasma concentrations of free prednisolone were increased
(see Drug Interactions: Other Drugs) .Use of indomethacin with aspirin is not recommended. There is no proof that the combination is more efficacious than either drug alone, the potential for adverse reactions is increased, and there is some evidence that aspirin decreases plasma concentrations of indomethacin.
(See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)
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Gout
Indomethacin is among the drugs of choice for relieving the pain, fever, redness, swelling, and tenderness of acute gouty arthritis. The drug does not correct hyperuricemia, but is used for its anti-inflammatory, antipyretic, and analgesic effects. Indomethacin is at least as effective as usual dosages of colchicine or phenylbutazone (no longer commercially available in the US) in relieving attacks of acute gouty arthritis and, for short-term use, indomethacin is better tolerated than usual dosages of colchicine. Extended-release capsules of indomethacin are not recommended for use in these patients.
For long-term prophylactic treatment of gouty arthritis, colchicine in usual dosages appears to be better tolerated and more effective than indomethacin. If probenecid is administered concurrently with indomethacin, a reduction in indomethacin dosage may be necessary.
(See Drug Interactions: Probenecid.)
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Ankylosing Spondylitis
Many clinicians consider indomethacin a drug of choice in the management of ankylosing spondylitis. In one study, the anti-inflammatory and analgesic effects of indomethacin in the management of ankylosing spondylitis were greater than those of usual dosages of aspirin and about equal to those of usual dosages of phenylbutazone.
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Pericarditis
Indomethacin is used to reduce the pain, fever, and inflammation of pericarditis, including that occurring during maintenance hemodialysis. However, in the treatment of post-myocardial infarction pericarditis, NSAIAs are potentially harmful and aspirin is considered the treatment of choice. (
See Cautions: Cardiovascular Effects andCautions: Precautions and Contraindications .)Indomethacin has been used successfully in the treatment of idiopathic pericarditis and postpericardiotomy pericarditis in children (11-15 years of age).
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Other Inflammatory Conditions
In the management of Reiter's syndrome, many clinicians consider indomethacin a drug of choice.
When used in the symptomatic treatment of acute painful shoulder (bursitis and/or tendinitis), the anti-inflammatory and analgesic effects of indomethacin are greater than those of placebo and about equal to those of naproxen sodium. Indomethacin has also been used for symptomatic treatment of traumatic synovitis, tennis elbow, athletic injuries, psoriatic arthritis, juvenile arthritis, Paget's disease, mild uveitis, and acute pseudogout.
Indomethacin also has been used to reduce the pain, fever, and inflammation of pleurisy and pleuritic chest pain of diverse origins.
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Patent Ductus Arteriosus
Indomethacin sodium is used IV in the treatment of patent ductus arteriosus (PDA) in premature neonates. The drug is believed to inhibit the synthesis of prostaglandins that maintain ductal patency.
(See Pharmacology: Cardiovascular Effects.) The drug is used IV to promote closure of a hemodynamically significant PDA (i.e., a left-to-right shunt large enough to compromise cardiorespiratory status) in premature neonates weighing 500-1750 g when 36-48 hours of usual medical management (e.g., fluid restriction, diuretics, cardiac glycosides, respiratory support) is ineffective. Evidence of hemodynamically significant PDA includes the presence of a continuous murmur over the anterior thorax or a systolic murmur or, in the absence of a murmur, respiratory distress requiring prolonged ventilatory support (e.g., intermittent mandatory ventilation for 48 hours or longer or escalating need for respiratory support). In addition, other criteria for hemodynamically significant PDA may include one or more of the following: hyperactive precordium, increased pulse pressure or bounding pulses, tachycardia, tachypnea, hepatomegaly, the need for varying levels of respiratory support, echocardiographic abnormalities, and/or cardiomegaly with radiographic evidence of pulmonary plethora.Although the reported rates for successful closure of the ductus have varied, experience with IV administration of the drug has shown that indomethacin is substantially more effective than usual medical management alone (placebo group) and that the rate of successful indomethacin-induced closure is 75-90%. In the National Collaborative Study on Patent Ductus Arteriosus (a large, multicenter, placebo-controlled study) in premature neonates with hemodynamically significant PDA who weighed 500-1750 g, IV indomethacin sodium trihydrate combined with usual medical management produced successful ductal closure within 48 hours in 79% of neonates versus a 28% 48-hour closure rate in neonates receiving only usual medical management (placebo group). Subsequent reopening of the ductus arteriosus occurred in 26 and 12% of the indomethacin-treated and placebo groups, respectively, but the ductus reclosed in 69 and 42% of these, respectively; final closure rates were 79% in indomethacin-treated neonates and 35% in the placebo group. Neonates who did not respond to indomethacin therapy required surgical ligation. In neonates who did not initially respond to usual medical management but were randomly selected to subsequently receive indomethacin, the final closure rate was 70% (54% within 48 hours after initiating indomethacin); the remainder required surgical ligation. In this study, closure rates were not significantly related to birthweight, gestational age, gender, race, or plasma indomethacin concentration, although the rates were lowest in neonates weighing less than 1 kg, in those with a gestational age less than 30 weeks, and in those younger than 5 days of age when therapy was initiated. Neonates weighing less than 1 kg who received indomethacin or only usual medical management prior to 5 days of age had a final closure rate of 54 or 26%, respectively. However, the ratio of the rate of indomethacin-induced ductal closure to that of only usual medical management was greatest among smaller neonates (less than 1 kg), those with a gestational age less than 29 weeks, and those initially treated after the fifth day of life. Following IV indomethacin therapy in another study in premature neonates with hemodynamically significant PDA, no correlations were found between the number of doses required for ductal closure (1-6 doses of 0.2 mg/kg) and birthweight, gestational age, or age at the time of the first dose. In this and another study, 50-60% of the responders achieved ductal closure within 48 hours of a single dose and about 90% of responders required 3 doses or fewer.
The relationship between plasma or serum indomethacin concentrations and successful closure of the ductus remains unclear. While substantial constriction of the ductus appears to be correlated with indomethacin concentrations 24 hours after a dose, generally appearing to be associated with concentrations exceeding 0.25 mcg/mL, current evidence indicates that exceeding this concentration may not be predictive of either successful initial or permanent closure of the ductus. In one study, however, the time of subsequent reopening of the ductus was related to the plasma concentration of the drug. Because serum indomethacin concentrations appear to be inversely related to postnatal age
(see Pharmacokinetics: Elimination) , age-dependent IV dosage schedules have been proposed.(See Dosage and Administration: Patent Ductus Arteriosus.) IV indomethacin sodium trihydrate has been used prophylactically in premature neonates with subclinical PDA and as routine prophylaxis during the first day of life in low-birthweight premature neonates. In clinical studies, prophylactic IV administration of indomethacin in premature neonates less than 7 days of age and weighing less than 1 kg with subclinical PDA and routine prophylactic IV administration of indomethacin initiated soon after delivery in low-birthweight (500-1500 g) premature neonates have been shown to decrease the incidence of hemodynamically significant PDA (e.g., large ductal shunts) and the need for subsequent medical and surgical ductal closure in such neonates. In addition, routine prophylactic IV administration of indomethacin initiated soon after delivery in selected low-birthweight (500-1500 g) premature neonates substantially decreased the development of intraventricular or periventricular hemorrhage, particularly grade 3 or 4 intraventricular hemorrhage. However, despite these beneficial effects, results of one large randomized clinical study indicate that routine prophylactic IV administration of indomethacin (0.1 mg/kg once daily for 3 days) does not improve the rate of survival without neurosensory impairment (e.g., cerebral palsy, cognitive delay, deafness, blindness) at 18 months of age.
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Genitourinary and Renal Diseases
Indomethacin has been used occasionally to relieve severe primary dysmenorrhea. Indomethacin in dosages of 25 mg 3 times daily is reported to be more effective than placebo or aspirin (500 mg 3 times daily) in relieving painful menstruation; however, because of potentially serious adverse effects of indomethacin, other NSAIAs (e.g., ibuprofen, mefenamic acid, naproxen sodium) have been studied more extensively and are preferred for treatment of primary dysmenorrhea.
Indomethacin has been used to inhibit uterine contractions during preterm labor (tocolysis) and thus prolong gestation. However, safety and efficacy of indomethacin for tocolysis have not been established and such use is controversial since there have been reports of serious adverse fetal effects, including constriction of the fetal ductus arteriosus, neonatal primary pulmonary hypertension, and fetal deaths.
(See Cautions: Pregnancy, Fertility, and Lactation.) Indomethacin has been used for symptomatic treatment of Bartter's syndrome.
(See Pharmacology: Genitourinary and Renal Effects.) However, because of potentially serious adverse effects of indomethacin, the drug may not be suitable for the long-term therapy necessary to control the disease; use of other NSAIAs such as ibuprofen is being evaluated.
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Fever
Indomethacin has been used for its antipyretic effect in the management of fever associated with infection in children and with neoplasms (e.g., Hodgkin's disease, hepatic metastases of solid tumors). The drug appears to be more effective in reducing fever associated with neoplasms than fever caused by infections. In adults with fever associated with various neoplasms, indomethacin has effectively controlled fever that had not responded to other antipyretics (e.g., aspirin, acetaminophen), antineoplastic agents, and/or anti-infective agents. Indomethacin has been reported to have a greater antipyretic effect than aspirin in children with infection. However, indomethacin should not be used routinely as an antipyretic because of potentially serious adverse effects.
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Orthostatic Hypotension
Indomethacin has been recommended by some clinicians to treat orthostatic hypotension associated with multiple system atrophy characterized by predominantly autonomic failure (formerly known as Shy-Drager syndrome). It has been suggested, however, that at least some autonomic activity must be present for indomethacin therapy to be successful in this condition.
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Pulmonary Hypertension
Although indomethacin has been used in the treatment of primary pulmonary hypertension, it appears that the drug provides little hemodynamic benefit in these patients and may adversely affect their hemodynamic status.
(See Pharmacology: Cardiovascular Effects.)
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Cystoid Macular Edema
A 1% indomethacin suspension has been applied topically to the eye for the prevention of postoperative cystoid macular edema in patients undergoing cataract surgery or retinal surgery, but a commercially available ophthalmic preparation currently is not available in the US.
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Other Uses
Indomethacin has also been used for symptomatic treatment of postoperative pain, biliary pain, chronic erythema nodosum, and certain types of headache (e.g., cluster headache, exertional headache).
Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease among patients who received a NSAIA for 2 years or longer. Similar findings have been reported from some other, but not all, observational studies.