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CAMBER PHARMACE
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indomethacin er 75 mg capsule

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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.

Inflammatory Diseases

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.)

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.)

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.

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 and Cautions: Precautions and Contraindications.)

Indomethacin has been used successfully in the treatment of idiopathic pericarditis and postpericardiotomy pericarditis in children (11-15 years of age).

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.

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.

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.

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.

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.

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.)

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.

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.

Dosage and Administration

Reconstitution and Administration

The potential benefits and risks of indomethacin therapy as well as alternative therapies should be considered prior to initiating indomethacin therapy.

Indomethacin is administered orally or rectally. Indomethacin sodium is administered by IV injection for the treatment of patent ductus arteriosus (PDA).

Oral and Rectal Administration

Indomethacin conventional capsules, oral suspension, and rectal suppositories are administered in 2-4 divided doses daily. The extended-release capsules are administered once or twice daily. To reduce adverse GI effects of the drug, the conventional or extended-release capsules or oral suspension should be administered orally immediately after meals or with food or antacids. Extended-release capsules of indomethacin must be administered and swallowed intact. Extended-release capsules of indomethacin are not recommended for use in the symptomatic treatment of acute gouty arthritis. Once-daily administration of 75-mg extended-release capsules of indomethacin can be used as an alternative dosage form for thrice-daily administration of 25-mg conventional indomethacin capsules; twice-daily administration of 75-mg extended-release capsules of indomethacin can be substituted for thrice-daily administration of 50-mg conventional indomethacin capsules.

To ensure complete absorption of the drug, indomethacin suppositories should be retained in the rectum for at least 1 hour.

IV Administration

For IV administration, indomethacin sodium trihydrate sterile powder should be reconstituted by adding 1 or 2 mL of sterile water for injection or 0.9% sodium chloride injection to the vial labeled as containing 1 mg of indomethacin to provide solutions containing approximately 1 or 0.5 mg/mL, respectively.Preserved diluents (i.e., bacteriostatic water for injection or bacteriostatic sodium chloride injection) should not be used to reconstitute the drug. Because reconstituted solutions of the drug contain no preservatives, solutions should be prepared just prior to administration of each dose and any unused portion should be discarded. Reconstituted indomethacin sodium solutions should not be further diluted in IV infusion solutions.(See Chemistry and Stability: Stability.) Solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The manufacturer currently states that the optimal rate of injection has not been established, but some studies indicate that indomethacin sodium solutions may be injected IV over 20-30 minutes. Previously, indomethacin sodium was administered IV over 5-10 seconds. Limited data indicate that the slower administration rate (e.g., over 20-30 minutes) may produce some amelioration, albeit inconsistently, in the indomethacin-associated reduction in cerebral blood flow and cerebral blood-flow velocity in premature neonates with patent ductus arteriosus (PDA), effects that may result in cerebral ischemia in such neonates. Limited data indicate that fast (i.e., over 20 seconds or less) IV administration of indomethacin also may be associated with substantial decreases in mesenteric artery blood flow velocity in neonates with PDA, which presumably may contribute to the development of necrotizing enterocolitis. Indomethacin sodium also has been given by continuous infusion over 36 hours in a very limited number of premature neonates with PDA; cerebral blood flow or cerebral blood-flow velocity was not decreased in these neonates. Additional studies are needed to determine the optimum rate of IV administration of indomethacin in premature neonates with PDA, taking into consideration the drug's effects on cerebral ischemia or intraventricular hemorrhage.

Care should be taken to avoid extravasation of the drug since it may be irritating to extravascular tissues.

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed. Dosage of indomethacin must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.

Dosage of indomethacin sodium, which is available as the trihydrate, is expressed in terms of anhydrous indomethacin.

Inflammatory Diseases

Dosage of indomethacin must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. Total dosages greater than 200 mg daily generally do not increase the effectiveness of the drug. If extended-release capsules of the drug are used for initiating or titrating dosage, the patient should be observed for possible signs and symptoms of intolerance to adverse effects.

Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis

For the symptomatic treatment of moderate to severe rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis, the usual initial adult dosage of indomethacin is 25 mg 2 or 3 times daily. If this dosage is well tolerated, dosage may be increased by 25 or 50 mg daily at weekly intervals until a satisfactory response is obtained or a dosage of 150-200 mg daily is reached.

The usual initial adult dosage of extended-release capsules of indomethacin for the symptomatic treatment of these conditions is one 75-mg capsule daily, administered in the morning or at bedtime; if this dosage is well tolerated, dosage may be increased to 75 mg twice daily.

Symptomatic improvement may occur after 4-6 days of indomethacin therapy; some patients may require up to 1 month of therapy before benefit is apparent. In patients who have persistent night pain and/or morning stiffness, administration of a large portion (a maximum of 100 mg) of the total daily dose orally or rectally at bedtime may be helpful.

Acute Exacerbations of Chronic Rheumatoid Arthritis

For the symptomatic treatment of acute exacerbations of chronic rheumatoid arthritis, the usual initial dosage of indomethacin may be increased by 25 or 50 mg daily until a satisfactory response is obtained or until the total daily dose reaches 150-200 mg.

If minor adverse effects develop as indomethacin dosage is increased, the dosage should be rapidly reduced to a tolerated level while observing the patient closely. If serious adverse effects occur, indomethacin therapy should be discontinued.

After the acute phase of the disease is controlled, repeated attempts should be made to reduce the indomethacin dosage until the patient is receiving the smallest effective dosage or the drug has been discontinued.

Gout

Various dosages have been used in the symptomatic treatment of acute gouty arthritis. The manufacturers recommend 50 mg of indomethacin 3 times daily until the pain can be tolerated. When symptoms subside, dosage should be reduced rapidly until the drug is withdrawn. Relief of pain has been reported in 2-4 hours, tenderness and heat usually subside in 24-36 hours, and swelling gradually disappears in 3-5 days. Administration of extended-release capsules of indomethacin for acute gouty arthritis is not recommended.

Acute Painful Shoulder

For the symptomatic treatment of acute painful shoulder (bursitis and/or tendinitis), the usual initial adult dosage of indomethacin is 75-150 mg daily in 3 or 4 divided doses. After signs and symptoms of inflammation have been controlled for several days, indomethacin should be discontinued. The usual duration of treatment is 7-14 days.

Juvenile Arthritis

If the benefits are thought to outweigh the risks (see Cautions: Pediatric Precautions), children 2-14 years of age may receive an initial oral indomethacin dosage of 1-2 mg/kg daily in divided doses for the management of juvenile rheumatoid arthritis. Dosage may be increased until a satisfactory response is achieved or a maximum dosage of 3 mg/kg daily or 150-200 mg daily (whichever is less) in divided doses is reached; limited data support the use of a maximum dosage of 4 mg/kg daily or 150-200 mg daily (whichever is less) in divided doses. As symptoms subside, dosage should be reduced to the lowest effective level or, if possible, until the drug is discontinued.

Pericarditis

In children with idiopathic pericarditis or postpericardiotomy pericarditis, 50-100 mg of indomethacin daily in 2-4 divided doses has been administered.

Patent Ductus Arteriosus

For the treatment of patent ductus arteriosus (PDA) in premature neonates, indomethacin sodium is administered by IV injection. Extemporaneously prepared oral or rectal suspensions or solutions of indomethacin have occasionally been used for the treatment of PDA, but administration of such preparations may present problems in drug delivery and absorption in premature neonates. (See Pharmacokinetics: Absorption.)

For the treatment of PDA in premature neonates, each course of therapy consists of up to 3 doses of indomethacin sodium administered at 12- to 24-hour intervals. The manufacturer indicates that all 3 doses should be administered in the first course of therapy, but some clinicians state that subsequent doses occasionally may be omitted if there is evidence of complete closure (e.g., resolution of murmur and lack of need for respiratory support) after the first or second dose in the course.

The first IV dose of each course of indomethacin sodium trihydrate is 0.2 mg/kg of indomethacin, regardless of the neonate's age. Subsequent doses depend on the age of the neonate at the time of administration of the first dose in the first course. If anuria or oliguria (i.e., urine output less than 0.6 mL/kg per hour) is present at the time of a second or third dose, the dose should be withheld until laboratory determinations indicate that renal function has returned to normal. (See Cautions: Renal and Electrolyte Effects.) For neonates younger than 48 hours of age at the time of the first dose, second and third doses of 0.1 mg/kg each are used. Neonates 2-7 days of age at the time of the first dose should receive second and third doses of 0.2 mg/kg each, and those older than 7 days of age at the time of the first dose should receive second and third doses of 0.25 mg/kg each. If severe adverse effects occur during a course of therapy, the drug should be discontinued.

Subsequent doses are not necessary if the ductus arteriosus closes or is substantially constricted 48 hours or longer after completion of the first course of indomethacin sodium therapy. If the ductus reopens (i.e., evidence of recurrence of significant PDA), a second course of 1-3 doses, given at 12- to 24-hour intervals, may be administered; doses in the second course are the same as those used in the first course (i.e., determined by the age of the neonate at the time of the first dose in the first, not second, course). Surgical ligation of the ductus may be necessary if the ductus arteriosus is unresponsive to indomethacin therapy after 2 courses.

Indomethacin sodium trihydrate has also been administered prophylactically to premature neonates (less than age 7 days) with subclinical PDA in an initial IV indomethacin dose of 0.2 mg/kg followed by two IV doses of 0.1 mg/kg at 12-hour intervals.

When indomethacin is administered shortly after birth, a long duration of action may be expected after a single dose; the risk of accumulation of the drug should be considered when more than one dose is required. (See Pharmacokinetics: Elimination.)

Genitourinary and Renal Diseases

Although other NSAIAs are preferred in the management of primary dysmenorrhea, 25 or 50 mg of indomethacin has been given 3 or 4 times daily in the management of severe primary dysmenorrhea until symptoms were relieved. Indomethacin has been reported to be most effective if therapy is initiated several days prior to menstruation.

When used in the management of Bartter's syndrome, indomethacin has been administered to children in dosages of 0.5-2 mg/kg daily in divided doses; adults have received dosages of 150 mg daily in divided doses.

Cautions

Adverse effects have been estimated to occur in 30-60% of patients treated with indomethacin, and serious reactions requiring discontinuance of the drug occur in about 10% of patients. Most adverse reactions appear to be dose-related and mainly involve the CNS and GI tract. In controlled clinical studies, the frequency of indomethacin-induced adverse effects was similar in patients receiving equivalent daily dosages of extended-release or conventional capsules. Adverse reactions reported with conventional indomethacin capsules may also occur with rectal suppositories or the oral suspension of the drug. Although the relevance to premature neonates receiving indomethacin IV for the treatment of patent ductus arteriosus (PDA) is not known, the possibility that adverse reactions reported in adults receiving the drug orally may also occur in neonates receiving the drug IV should be considered.

Unless otherwise specified, the frequencies of adverse effects associated with indomethacin use for the treatment of PDA in premature neonates are derived from experience from clinical studies and anecdotal reports in which the drug was administered IV, rectally, or orally. Adverse reactions (especially psychotic episodes and GI effects) may be particularly likely to occur in geriatric patients. Careful instructions to, and observation of, patients taking indomethacin are essential to prevent serious and irreversible, possibly fatal, adverse reactions.

Cardiovascular Effects

Adverse cardiovascular effects, including congestive heart failure, tachycardia, chest pain, arrhythmia, and palpitations, occur in less than 1% of patients receiving indomethacin. Indomethacin also may cause hypertension, pulmonary hypertension, and edema; reduce the actions of some hypotensive agents; and may enhance the hypertensive effect of sympathomimetic agents. (See Hypotensive Agents and Diuretics and also see Other Drugs, in Drug Interactions.) Hypotension has also occurred. Although a causal relationship has not been established, thrombophlebitis and bradycardia have been reported in patients receiving the drug. Intraventricular bleeding (see Cautions: Nervous System Effects) has been reported in 3-9% and bradycardia and pulmonary hypertension in 1-3% of premature neonates receiving the drug for PDA.

Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease. Use of NSAIAs also is associated with an increased risk of heart failure.

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study. Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied. Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use. Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment. Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years). Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased. Therefore, NSAIAs are contraindicated in the setting of CABG surgery.

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs. However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another. Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality. Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure. In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure. Fluid retention and edema also have been observed in some patients receiving NSAIAs.

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

GI Effects

GI disturbances most frequently reported with indomethacin therapy include nausea, with or without vomiting, and dyspepsia (including indigestion, heartburn, and epigastric pain), which occur in 3-9% of patients. Diarrhea, abdominal distress or pain, or constipation occur in 1-3% of patients receiving the drug. Other adverse GI effects, occurring in less than 1% of patients, include anorexia, bloating (including distention), flatulence, gastroenteritis, rectal bleeding, proctitis, ulcerative stomatitis, intestinal strictures (diaphragms), and gingival ulcers.

Indomethacin may reactivate latent peptic or intestinal lesions. Single or multiple ulcerations of the esophagus, stomach, duodenum, or small and/or large intestine, occasionally resulting in death, have been reported in less than 1% of patients receiving indomethacin and may occur in patients with no previous history of ulcers; hemorrhage and perforation of such lesions have occurred. Rarely, ulceration has been associated with stenosis and obstruction. GI bleeding without obvious ulcer formation may occur. In one study, occult GI bleeding was reported to be less with indomethacin (200 mg daily) than with aspirin (3.9 g daily) and about the same as that occurring with tolmetin (1.2 g daily). In a study in healthy adults, gastroscopic evidence of mucosal abnormalities was greater in individuals receiving conventional oral capsules of the drug than in those receiving placebo or rectal suppositories. However, in a controlled clinical study in patients with rheumatoid arthritis, the incidence of adverse upper GI effects was similar in patients receiving rectal suppositories or conventional oral capsules, but the incidence of adverse lower GI effects was greater in patients receiving suppositories; gastroscopic findings also were similar following rectal suppositories or conventional oral capsules in a crossover study in patients with rheumatic diseases. Perforation of preexisting sigmoid lesions such as diverticula and carcinoma has been reported. Increased abdominal pain in patients with ulcerative colitis has been reported to occur rarely. The development of ulcerative colitis and regional ileitis also has occurred rarely.

GI bleeding has occurred in 3-9% of premature neonates receiving indomethacin for PDA. In a large, multicenter study, the frequency of major GI bleeding was similar for indomethacin-treated neonates and those not receiving the drug; however, minor GI bleeding, as evidenced by occult blood in feces, occurred more frequently in indomethacin-treated neonates. Vomiting, abdominal distention, and transient ileus have occurred in 1-3% of neonates. Necrotizing enterocolitis has occurred in premature neonates receiving the drug for PDA, but the frequency of this effect has been similar to that observed in premature neonates not receiving indomethacin and a causal relationship to the drug has not been established. Focal GI (gastric, jejunal, ileal, rectal) perforation has occurred in premature neonates who received the drug IV, orally via nasogastric tube, or rectally. Pathologic examination of resected specimens in several of these neonates revealed well-defined perforation that was surrounded by well-circumscribed, superficial, mucosal ulceration; histologic findings included moderate to marked mucosal hemorrhagic necrosis with some submucosal hemorrhage but without substantial inflammatory infiltration.

Although a causal relationship has not been directly determined, one case-control analysis suggests that NSAIAs may contribute to the formation of esophageal stricture in patients with gastroesophageal reflux.

Adverse GI effects of orally administered indomethacin may be minimized by administering the drug immediately after meals, with food, or with antacids. Because of the potential severity of adverse GI effects, clinicians must be alert to signs and symptoms of GI reactions in patients receiving indomethacin. Stools should be examined periodically for occult blood in patients receiving long-term indomethacin therapy. Therapy should be discontinued if GI bleeding occurs. If GI symptoms occur, the benefits of continued therapy with indomethacin should be weighed against the possible risks.

Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic. Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up. In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur. If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects. In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year. Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event. However, short-term therapy is not without risk. High dosages of any NSAIA probably are associated with increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs. Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors. In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status. Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis. In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy. Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy. In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest. In addition, efficacy of usual dosages of H2-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established. Therefore, most clinicians do not recommend use of H2-receptor antagonists for the prevention of NSAIA-associated ulcers. Another approach in high-risk patients who would benefit from NSAIA therapy is use of a NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of GI bleeding than are prototypical NSAIAs. However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori-negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk. Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.

Nervous System Effects

Headache, which appears to be dose related, is the most frequent adverse effect, occurring in at least 10% (although some estimates range from 25-50%) of patients treated with indomethacin. Headache is more common and most severe in the morning and may be accompanied by frontal throbbing, apparent swelling of the temporal vessels, vomiting, tinnitus, ataxia, tremor, dizziness, insomnia, or vertigo. If headache persists despite reduction of dosage, indomethacin should be discontinued. In one study, adverse CNS effects (e.g., frontal headache and lightheadedness) appeared to increase when plasma indomethacin concentrations exceeded 6 mcg/mL. Dizziness also is common in patients receiving indomethacin, occurring in 3-9% of patients. Vertigo, somnolence, depression, and fatigue (including malaise and listlessness) occur in 1-3% of patients.

Less frequently reported adverse nervous system effects, occurring in less than 1% of patients receiving indomethacin, include lightheadedness, drowsiness, confusion, psychic disturbances (including psychotic episodes), hallucinations, nightmares, depersonalization, feelings of floating or unreality, insomnia, muzziness, anxiety (including nervousness), muscle weakness, involuntary muscle movements, ataxia, dysarthria, syncope, paresthesia, aggravation of epilepsy and parkinsonian syndrome, seizures, peripheral neuropathy, and coma.

Intraventricular (intracranial) hemorrhage has been reported in 3-9% of premature neonates receiving indomethacin for PDA; however, it appears that the frequency of this effect is similar for indomethacin-treated neonates and those not receiving the drug. Extension of intraventricular hemorrhage has also been reported in neonates receiving indomethacin for PDA, but this effect did not appear to be drug related. Although the risk, if any, remains to be clearly delineated, the possibility that indomethacin could potentially increase the risk of intraventricular hemorrhage in premature neonates should be considered since the drug can inhibit platelet aggregation and prolong bleeding time.(See Pharmacology: Hematologic Effects.) It should be remembered, however, that prematurity itself is associated with an increased risk of intraventricular hemorrhage. There is preliminary evidence that indomethacin may decrease cerebral blood flow in neonates and that prophylactic administration of the drug may have a beneficial effect in preventing the development of intraventricular hemorrhage, possibly by inhibiting prostaglandin-mediated cerebral blood flow and preventing germinal matrix capillary damage; however, in one study, a protective effect was not evident, and additional study is necessary to elucidate the effects of indomethacin on cerebral blood flow and whether such a protective effect occurs.

Pseudotumor cerebri occurred in one adult treated with indomethacin for Bartter's syndrome and was attributed to sodium and water retention induced by the drug. One suicide, possibly related to indomethacin-induced depression, has been reported.

If severe nervous system reactions occur, indomethacin should be discontinued.

Hematologic Effects

Adverse hematologic effects of indomethacin occur in less than 1% of patients and include anemia secondary to GI bleeding, hemolytic anemia (including hemolytic anemia with positive antiglobulin [Coombs'] test results), bone marrow depression, aplastic anemia (sometimes fatal), agranulocytosis, leukopenia, thrombocytopenia, and thrombocytopenic purpura. Thrombocytopenia has also occurred in premature neonates receiving the drug for PDA. Iron deficiency anemia may develop secondary to GI bleeding in patients receiving indomethacin. There have been several reports of leukemia in patients who had received indomethacin, but a causal relationship to the drug has not been established. Disseminated intravascular coagulation also has been reported.

Indomethacin inhibits platelet aggregation, but this effect usually disappears within 24 hours after discontinuing the drug. Indomethacin may prolong bleeding time (but within the normal range) in healthy individuals; however, this effect may be exaggerated in patients with underlying hemostatic defects. Indomethacin therapy has been associated with platelet dysfunction and bleeding tendencies in premature neonates with PDA. In one study in premature neonates with PDA, a single oral dose of indomethacin (0.2-0.3 mg/kg by nasogastric tube) resulted in severe platelet dysfunction, with normal function returning only 9-10 days later. In another study in premature neonates with PDA who received indomethacin IV (0.2 mg/kg initially, followed by 0.1 mg/kg 12 and 24 hours later), bleeding time increased from a pretreatment mean of 3.6 minutes to means of 8.7 minutes 2 hours after the first dose and 8.9 and 5.3 minutes 2 and 48 hours, respectively, after the third dose; thrombocytopenia also occurred, but clinical signs of bleeding were minor. Intraventricular (intracranial) hemorrhage and GI bleeding have occurred in premature neonates receiving the drug for PDA. (See Cautions: Nervous System Effects and also GI Effects.) In a large, multicenter study in premature neonates with PDA, bleeding tendencies (e.g., gross macroscopic GI bleeding, oozing at the site of injection, pulmonary hemorrhage, disseminated intravascular coagulation), other than intraventricular hemorrhage, occurred more frequently in neonates receiving indomethacin than in those receiving usual medical management alone; however, life-threatening hemorrhage, other than intraventricular, did not occur.

Patients who may be adversely affected by a prolongation of bleeding time should be carefully observed during indomethacin therapy. Neonates should be carefully observed for bleeding.

Ocular and Otic Effects

Corneal deposits and retinal disturbances, including those of the macula, have been reported in less than 1% of patients receiving prolonged indomethacin therapy; the drug should be discontinued if these effects occur. Other reported ocular effects occurring in less than 1% of patients include blurred vision, conjunctival pain, photophobia, diplopia, toxic amblyopia, nightblindness, mydriasis, and loss of vision. Patients who experience visual disturbances during indomethacin therapy should have an ophthalmologic examination.

The retinopathy of prematurity (retrolental fibroplasia) has developed in 3-9% of premature neonates who were treated with indomethacin for PDA; however, the frequency of this effect appears to be similar in indomethacin-treated neonates and in those not receiving the drug. In a large, multicenter study in premature neonates with PDA, indomethacin appeared to have a beneficial effect in reducing the development of severe (grade III-V), but not less severe, retinopathy; however, this possible beneficial effect was less evident after 1 year of follow-up and additional study is necessary to determine whether such an effect occurs. After 1 year of follow-up in this study, the frequency of strabismus was similar in indomethacin-treated neonates and in those not receiving the drug. After 3.5 years of follow-up in another study, the frequency of retinopathy, amblyopia, optic nerve atrophy, myopia, or hyperopia was similar in children who had received indomethacin for PDA as neonates and in those who had undergone surgical ligation of the ductus arteriosus.

Tinnitus occurs in 1-3% of patients receiving indomethacin. Hearing disturbances and deafness occur in less than 1% of patients. After 3.5 years of follow-up in one study, the frequency and severity of audiologic abnormalities were similar in children who had received indomethacin for PDA as neonates and in those who had undergone surgical ligation of the ductus arteriosus.

Renal and Electrolyte Effects

Acute interstitial nephritis with hematuria, proteinuria, and, occasionally, nephrotic syndrome has occurred in less than 1% of patients receiving indomethacin. Reversible worsening of renal function, including renal failure, has been reported following indomethacin administration in patients with moderate to severe renal impairment or with sodium retention associated with hepatic disease or congestive heart failure. Abnormal laboratory findings may include increases in BUN and serum creatinine concentrations, proteinuria, hematuria, and albuminuria. Hematuria occurs in less than 1% of patients receiving indomethacin; transient occult hematuria has been reported in neonates receiving the drug. Acute renal failure has occurred in at least one patient who was not known to have prior renal dysfunction. As with other NSAIAs, long-term administration of indomethacin in animals has resulted in renal papillary necrosis and other pathologic renal abnormalities. Renal papillary necrosis occurred in 2 young adults who had received prolonged therapy with low dosages of indomethacin (37.5-100 mg daily for 12-17 years) in the treatment of juvenile rheumatoid arthritis. In addition, an association between prolonged (e.g., daily for 1 year or longer) NSAIA use, including indomethacin, and chronic renal failure also has been described in certain high-risk patients, but current evidence suggests that the overall potential risk, if any, is low in patients receiving the drug, and additional study and experience are necessary to confirm and elucidate these findings.

Increased serum potassium concentrations have occurred in 3-9% of premature neonates with PDA receiving indomethacin, and such increases, including hyperkalemia, have occurred in less than 1% of other patients receiving the drug, including some patients without renal impairment. Several patients with preexisting renal disease and at least one patient with no apparent renal disease developed severe hyperkalemia following indomethacin therapy. In one study in patients with baseline serum potassium concentrations of about 4-5 mEq/L who were receiving indomethacin for musculoskeletal pain, pericarditis, or fever, serum potassium concentrations increased in most patients during therapy with the drug. In some of these patients, serum potassium increased by more than 1 mEq/L and exceeded 5 mEq/L in most patients within 2-6 days of therapy. Patients most likely to experience increases in serum potassium during indomethacin therapy included those with preexisting mild to moderate renal dysfunction and geriatric patients. In patients with normal renal function, increases in serum potassium concentration during indomethacin therapy have been attributed to hyporeninemic hypoaldosteronism induced by the drug. Serum potassium concentrations have increased by about 0.5-0.8 mEq/L within 12-36 hours after administration of indomethacin in several studies in premature neonates but subsequently returned toward baseline (e.g., within 72 hours) following discontinuance of the drug.

Mild, transient renal insufficiency, usually manifested as a reversible decrease in urine output, occurs in about 40% of premature neonates during indomethacin therapy for PDA. Urine output usually decreases during the first 12 hours after indomethacin is administered and usually returns to pretreatment levels within 48 hours after the last dose of the drug (sometimes within 24 hours). Transient increases in serum potassium, BUN, and serum creatinine concentrations; transient decreases in urinary excretion of sodium, chloride, and potassium and in urinary osmolarity, free water clearance, and glomerular filtration rate; and transient and asymptomatic decreases in serum sodium concentrations have also occurred in these neonates. In a large, multicenter study, the frequency of transient oliguria and increased serum creatinine concentrations (1.8 mg/dL or greater) was higher in indomethacin-treated neonates than in those not receiving the drug. Weight gain secondary to fluid retention has occurred in 1-3% of premature neonates receiving the drug. Changes in acid-base balance, including acidosis and alkalosis, have also occurred in 1-3% of neonates; however, a causal relationship to the drug has not been established. Decreased urinary excretion of kallikrein and prostaglandins F, E-M, and 6-keto-F, and decreased plasma renin activity have also been reported in these neonates. There was no evidence of major delayed renal toxicity after 1 year of follow-up in one study in infants who had received indomethacin as neonates for PDA.

Fatal glomerulonephritis with nonthrombocytopenic purpura and urinary frequency has been reported but not definitely attributed to indomethacin.

Some clinicians recommend that renal function tests be performed every 3 months in patients receiving long-term indomethacin therapy. Renal function, including measurement of urine output and serum electrolytes, should be closely monitored in neonates receiving the drug. If a substantial reduction in urine output (i.e., less than 0.6 mL/kg per hour) occurs during indomethacin therapy in neonates, additional doses of the drug should be withheld until output returns toward normal.

Dermatologic and Sensitivity Reactions

Adverse dermatologic effects of indomethacin occur in less than 1% of patients and include pruritus, urticaria, rash, macular and morbilliform eruptions, erythema nodosum, petechiae or ecchymosis, exfoliative dermatitis, loss of hair, Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis.

Acute anaphylaxis, asthma, angioedema, acute respiratory distress, dyspnea, purpura, angiitis, pulmonary edema, fever, and a rapid fall in blood pressure resembling shock have been reported as hypersensitivity reactions to indomethacin and occur in less than 1% of patients receiving the drug. The drug may precipitate asthma in aspirin-sensitive individuals who have had no previous exposure to indomethacin; it has been suggested that of the currently available NSAIAs, indomethacin may be most likely to induce signs and symptoms of a sensitivity reaction in individuals with aspirin-induced bronchospasm. Sensitivity reactions to the structurally different NSAIAs appear to be related mainly to inhibition of prostaglandin synthesis in patients with bronchospastic reactions; however, other mechanisms may be involved. For a further discussion of cross-sensitivity of NSAIAs, see .

Hepatic Effects

Jaundice and toxic hepatitis, possibly fatal, may occur rarely in patients receiving indomethacin. Increases in serum ALT (SGPT), AST (SGOT), alkaline phosphatase, and bilirubin concentrations and in cephalin flocculation and thymol turbidity values occurred in one case of fatal hepatitis. Green urine was reported in one patient with indomethacin-induced hepatitis with biliverdinemia. Histologic analysis of liver tissues from this patient revealed centrilobular degeneration, swelling, some fatty changes of parenchymal cells, regeneration of hepatic cells, and infiltration of both parenchyma and portal zone by neutrophils and mononuclear cells. The manufacturer of parenteral indomethacin sodium trihydrate states that displacement of bilirubin from albumin by indomethacin, as evidenced by an increased frequency of kernicterus, has not been observed in controlled studies in premature neonates receiving the drug for PDA. In vitro evidence suggests that indomethacin-induced displacement of bilirubin is unlikely at dosages used in these neonates.

Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with NSAIAs; meaningful (3 times the upper limit of normal) elevations of serum ALT (SGPT) or AST (SGOT) concentration have occurred in less than 1% of patients receiving NSAIAs in controlled clinical studies. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Patients, including neonates, who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving indomethacin should be evaluated for evidence of the development of a more severe hepatic reaction. Although such reactions are rare, indomethacin should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).

Respiratory Effects

Apnea and exacerbation of pulmonary infection have occurred in 1-3% of premature neonates receiving indomethacin for PDA. Bronchopulmonary dysplasia, hyaline membrane disease, and pulmonary insufficiency also have occurred in these neonates; however, the frequency of these effects in indomethacin-treated neonates appears to be similar to or less than that in neonates not receiving the drug. In addition, indomethacin-induced closure of the ductus arteriosus has been associated with a decreased need for ventilatory support in some studies. The frequency of pneumothorax in indomethacin-treated neonates has been similar to that in neonates not receiving the drug but less than that in neonates undergoing surgical ligation of the ductus.

Other Adverse Effects

Fulminant necrotizing fasciitis, which may be fatal and usually is associated with group A β-hemolytic streptococcal infection, has been reported rarely in patients receiving nonsteroidal anti-inflammatory agents, including indomethacin. Vaginal bleeding, weight gain, flushing or sweating, epistaxis, and breast changes (including enlargement and tenderness) have occurred in less than 1% of patients receiving indomethacin. Acute pancreatitis with increased serum amylase concentration and urinary frequency have been reported, but a causal relationship to indomethacin has not been established.

Decreased plasma glucose concentrations, occasionally resulting in hypoglycemia, have been observed in 1-3% of premature neonates receiving indomethacin for PDA. Plasma glucose concentrations decreased from a pretreatment mean of about 95 mg/dL to means of about 70 mg/dL 24-72 hours after administration of the drug in one study in these neonates. Hyperglycemia and glucosuria have been reported in less than 1% of other patients receiving the drug.

Precautions and Contraindications

Patients should be advised that indomethacin, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur. Patients also should be informed that, while some NSAIAs may be commonly employed for conditions that are less serious, NSAIA therapy often is considered essential for the management of some diseases. Clinicians may wish to discuss with their patients the potential risks and likely benefits of NSAIA therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without a NSAIA may represent an acceptable alternative to both the patient and clinician.

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.(See Cautions: Cardiovascular Effects.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed. Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease. Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy. Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs. Indomethacin should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if indomethacin is used in such patients, the patient should be monitored for cardiac ischemia.

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs. Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving indomethacin should be advised not to take aspirin.

Use of NSAIAs, including indomethacin, can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events. Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents. NSAIAs, including indomethacin, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation of indomethacin therapy and throughout therapy.

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that indomethacin should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if indomethacin is used in such patients, the patient should be monitored for worsening heart failure. In patients with severe congestive heart failure, particularly those with hyponatremia, inhibition of prostaglandin synthesis induced by the drug may cause clinical deterioration of cardiovascular status by interfering with prostaglandin-mediated, circulatory homeostatic mechanisms.(See Pharmacology: Cardiovascular Effects.) Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure. Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema. Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).(See Drug Interactions.)

Indomethacin is contraindicated in neonates with congenital heart disease when patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (e.g., neonates with pulmonary atresia, severe tetralogy of Fallot, or severe coarctation of the aorta).

The risk of potentially serious adverse GI effects should be considered in patients receiving indomethacin, particularly in patients receiving chronic therapy with the drug. Indomethacin should be used with caution and under close supervision in patients with a history of GI disease. Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.

Indomethacin should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulcer disease, and such patients should receive an appropriate ulcer preventive regimen. All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely for signs of ulcer perforation or GI bleeding.To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed. For patients who are at high risk, therapy other than an NSAIA should be considered.

Indomethacin suppositories are contraindicated in patients with a history of proctitis or recent rectal bleeding. The possibility that adverse GI effects reported with oral or rectal administration of indomethacin in older children and adults also may occur with parenteral administration of the drug in premature neonates should be considered.

Indomethacin should not be used in premature neonates with active GI bleeding or known or suspected necrotizing enterocolitis. For additional information on adverse GI effects of indomethacin and associated precautions, see Cautions: GI Effects.

NSAIAs, including indomethacin, may mask the usual signs and symptoms of infection; the drug should be used with extreme caution in patients with an existing infection since fulminant necrotizing fasciitis, which may be fatal and usually is associated with group A β-hemolytic streptococcal infection, has been reported rarely in patients receiving nonsteroidal anti-inflammatory agents including indomethacin. In addition, deaths attributed to overwhelming sepsis have been reported very rarely in children with severe rheumatoid arthritis who received the drug; a direct causal relationship to indomethacin has not been established. Activation of latent infections including tuberculosis has been attributed to indomethacin. A severe reaction to a smallpox vaccination in one patient has also been attributed to indomethacin, although a causal relationship has not been established.

Indomethacin should be used with caution in premature neonates with an existing infection that is adequately controlled, and clinicians should be alert to the masking effect of the drug in these neonates. The drug is contraindicated in neonates with proven or suspected, untreated infection.

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion. Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation. Patients at greatest risk of this reaction include those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II antagonist; and geriatric patients. Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs. Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.

Indomethacin has not been evaluated in patients with advanced renal disease, and the manufacturer states that use of indomethacin is not recommended in such patients. If indomethacin is used in patients with advanced renal disease, close monitoring of renal function is recommended.

Indomethacin also may precipitate renal insufficiency, including acute renal failure, in premature neonates with PDA, especially those with other conditions that might adversely affect renal function (e.g., those with extracellular fluid depletion, congestive heart failure, sepsis, or hepatic dysfunction and those receiving a nephrotoxic drug concomitantly). Renal function and serum electrolytes should be monitored closely in neonates receiving the drug.(See Caution: Renal and Electrolyte Effects.) The drug is contraindicated in neonates with substantially impaired renal function.

The risk of increased serum potassium concentration, including hyperkalemia, should be considered in any patient receiving indomethacin therapy, including those with normal renal function.

Indomethacin also should be used with extreme caution in patients with a history of mental depression or other psychiatric disorder, epilepsy, or parkinsonian syndrome because the drug may aggravate these conditions. If severe adverse nervous system effects occur during indomethacin therapy, the drug should be discontinued. The drug should also be discontinued in patients in whom indomethacin-induced headache persists despite a reduction in dosage. Patients should be warned that indomethacin may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving indomethacin should be evaluated for evidence of the development of a more severe hepatic reaction. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIAs. Indomethacin should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).

Indomethacin can inhibit platelet aggregation and may prolong bleeding time. (See Cautions: Hematologic Effects.) The drug should be used with caution in patients who may be adversely affected by a prolongation of bleeding time (e.g., patients receiving anticoagulant therapy). If signs and/or symptoms of anemia occur during therapy with indomethacin, hemoglobin concentration and hematocrit should be determined. Premature neonates receiving the drug should be observed closely for bleeding tendencies. Indomethacin is contraindicated in neonates with active bleeding, such as those with intraventricular hemorrhage or GI bleeding, and in neonates with thrombocytopenia or underlying coagulation defect.

Because ocular changes may be asymptomatic, patients receiving prolonged indomethacin therapy should be given periodic ophthalmologic examinations at least once a year; a thorough examination is also indicated whenever blurred vision occurs. (See Cautions: Ocular and Otic Effects.)

Indomethacin is not a substitute for corticosteroid therapy. Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration, and the drugs should be used concomitantly with caution. If corticosteroid dosage is decreased during indomethacin therapy, it should be done gradually and patients should be observed for adverse effects, including adrenocortical insufficiency or symptomatic exacerbation of the inflammatory condition being treated.

Anaphylactoid reactions have been reported in patients receiving indomethacin. Patients receiving indomethacin should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving indomethacin. These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur. Indomethacin should be discontinued at the first appearance of rash or any other sign of hypersensitivity.

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.

Indomethacin is contraindicated in patients with known hypersensitivity to the drug. In addition, NSAIAs, including indomethacin, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients. Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, indomethacin should be used with caution in patients with asthma. In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad. For a further discussion of cross-sensitivity of NSAIAs,

Indomethacin is contraindicated in the setting of CABG surgery.

Pediatric Precautions

Safety and efficacy of oral indomethacin have not been established in children 14 years of age and younger. Therefore, the drug should not be administered to children 2-14 years of age except under circumstances when inefficacy or toxicity associated with other drugs warrants the risk; such children should be monitored closely. The manufacturers state that experience with indomethacin in these children has been limited to use of conventional capsules of the drug. Adverse effects associated with use of conventional capsules of the drug in children 14 years of age and younger have been similar to those associated with use of this dosage form in adults. Hepatotoxicity (sometimes fatal) has occurred in children receiving the drug for juvenile rheumatoid arthritis. If the drug is used in children 2-14 years of age, liver function should be monitored periodically.

Indomethacin therapy has been associated with GI bleeding, necrotizing enterocolitis, intraventricular hemorrhage, and renal insufficiency in premature neonates receiving the drug for PDA. These effects have also been observed in neonates with PDA who did not receive the drug. (See Cautions: GI Effects, Nervous System Effects, and Renal and Electrolyte Effects.) The drug is generally contraindicated in neonates with substantially impaired renal function, thrombocytopenia, coagulation disorders, active bleeding from any cause, recent intracranial hemorrhage, known or suspected necrotizing enterocolitis, or proven or suspected, untreated infection. The drug also is contraindicated in neonates with congenital heart disease when patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (e.g., neonates with pulmonary atresia, severe tetralogy of Fallot, or severe coarctation of the aorta). For additional information on precautions associated with indomethacin use in neonates, see Cautions: Precautions and Contraindications and other sections in Cautions.

Geriatric Precautions

Indomethacin should be used with caution in geriatric individuals 65 years of age or older since increasing age may be associated with increased risk of adverse reactions. Geriatric individuals appear to tolerate GI ulceration or bleeding less well than other individuals, and many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.(See Cautions: GI Effects.) Indomethacin may cause confusion or, rarely, psychosis; clinicians should remain alert to the possibility of such adverse reactions in geriatric individuals.

Indomethacin is eliminated mainly by the kidneys and individuals with renal impairment may be at increased risk for toxic reactions to the drug. Because geriatric patients frequently have decreased renal function, particular attention should be paid to indomethacin dosage and it may be useful to monitor renal function in these patients.

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, indomethacin has been shown to have various adverse effects in animals during reproduction studies. Dosages of 5-15 mg/kg daily have resulted in maternal toxicity and death, increased fetal resorptions, and fetal malformations in mice. Indomethacin inhibits prostaglandin synthesis which may result in prolongation of gestation and interference with labor if the drug is given late in pregnancy. When indomethacin was administered during the 27th-34th weeks of gestation to control premature uterine contractions in humans, adverse fetal reactions including constriction of the fetal ductus arteriosus, neonatal primary pulmonary hypertension, and fetal deaths have occurred. Other adverse effects associated with such use have included oligohydramnios (in the absence of premature rupture of the amniotic membrane) and neonatal edema (including hydrops), bleeding disorders, transient oliguric renal failure, and focal ileal perforation. Reduced number and excessive muscularity of pulmonary blood vessels have occurred in offspring of rats given 2-4 mg/kg daily during the last trimester of gestation; these findings are similar to those associated with the syndrome of persistent pulmonary hypertension of the newborn. Phocomelia and agenesis of the penis in one human neonate have tentatively been attributed to fetal exposure to indomethacin. Use of indomethacin during pregnancy is not recommended by the manufacturers, since safety of the drug in pregnant women has not been established and because of the drug's potential adverse effects on the fetus, including effects on the cardiovascular system (e.g., closure of the ductus arteriosus, degenerative myocardial changes), platelets (e.g., bleeding), renal function (e.g., renal failure with oligohydramnios), and GI system (e.g., bleeding, perforation) during the last trimester.

Fertility

Indomethacin had no effect on fertility in rats or mice at dosages up to 0.5 mg/kg daily.

Lactation

Indomethacin is distributed into milk. Seizures occurred in one breast-fed neonate (6 days of age) after the mother had taken approximately 200 mg of indomethacin daily for about 3 days. Indomethacin should not be used in nursing women.

Drug Interactions

Protein-bound Drugs

Because indomethacin is highly protein bound, it theoretically could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Patients receiving indomethacin with any of these drugs should be observed for adverse effects.

Anticoagulants and Thrombolytic Agents

The effects of warfarin and NSAIAs on GI bleeding are synergistic. Concomitant use of indomethacin and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.

It appears that indomethacin has little, if any, direct influence on the hypoprothrombinemic effect of warfarin or other oral anticoagulants when these drugs are administered concurrently. Because indomethacin may cause GI bleeding and may inhibit platelet aggregation, the drug should be used with caution in patients receiving any anticoagulant or thrombolytic agent (e.g., streptokinase).

Alcohol

In one study in healthy adults, concomitant ingestion of a single dose of indomethacin (25 mg) and alcohol (50 g) resulted in a prompt prolongation of bleeding time compared with control values, although neither drug alone had any effect on bleeding time. The mechanism of this interaction was not determined.

Nonsteroidal Anti-inflammatory Agents

Concomitant use of indomethacin and another NSAIA is not recommended because such use may increase the possibility of adverse GI effects with little or no increase in efficacy.

Administration of aspirin with indomethacin may decrease plasma indomethacin concentrations and diminish urinary excretion of indomethacin. Although the mechanism and clinical importance of this interaction have not been determined, it has been suggested that the efficiency of GI absorption of indomethacin is diminished and biliary clearance of the drug is increased during combined therapy. Fatal aplastic anemia has been reported in patients receiving indomethacin and aspirin, although indomethacin alone may produce this effect. Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving indomethacin should be advised not to take aspirin. There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

In healthy individuals, concomitant use of indomethacin and diflunisal resulted in decreased renal clearance and increased plasma concentrations of indomethacin. In addition, this combination has been associated with fatal GI hemorrhage in some patients. Indomethacin and diflunisal should therefore not be used concomitantly.

Hypotensive Agents and Diuretics

Indomethacin may reduce the hypotensive effects of hydralazine, furosemide, β-adrenergic blocking agents (e.g., atenolol, propranolol), or thiazide diuretics. In at least one patient with severe congestive heart failure, administration of indomethacin appeared to antagonize the diuretic effects of furosemide and spironolactone, resulting in exacerbation of the clinical signs of cardiac failure. The mechanism(s) of these interactions is uncertain but has been attributed to indomethacin-induced inhibition of prostaglandin synthesis which may result in fluid retention and/or changes in vascular resistance. The clinical importance of these reactions has not been established; however, when indomethacin is added to the regimen of a patient receiving hydralazine, furosemide, thiazides, or a β-adrenergic blocking agent, or when one of these agents is added to a regimen of a patient receiving indomethacin, the patient should be closely observed to determine if the desired antihypertensive effect is obtained. When evaluating plasma renin activity in hypertensive patients, it should be kept in mind that indomethacin blocks the furosemide-induced increase in plasma renin activity.

It appears that concomitant furosemide therapy may have a beneficial effect on renal function in premature neonates with PDA who are receiving indomethacin. In one study in premature neonates with PDA who received indomethacin or combined therapy with indomethacin and furosemide, neonates who received combined therapy had higher urine output, urinary excretion of sodium and chloride, and glomerular filtration rate than those who received indomethacin alone.

Concomitant use of indomethacin and triamterene has adversely affected renal function. In one study, concomitant administration of indomethacin and triamterene to 4 healthy adults resulted in a 60-70% decrease in creatinine clearance in 2 individuals; renal function returned to normal within 2 weeks after both drugs were discontinued. When the drugs were given separately, triamterene caused no consistent change in renal function; indomethacin induced an average 10% decrease in creatinine clearance. Acute anuric renal failure occurred within 2 days after concomitant use of indomethacin and triamterene in a 79-year-old woman with compensated congestive heart failure. BUN and serum creatinine concentrations increased to 102 and 10.2 mg/dL, respectively, within several days of concomitant therapy in this woman, and subsequently returned toward normal over 2 months; anuria persisted for 11 days after discontinuance of the drugs. Although the mechanism of this interaction was not determined, it has been postulated that indomethacin may inhibit triamterene-stimulated synthesis of renal prostaglandins that mediate an adaptive mechanism for renal blood flow preservation in response to triamterene-mediated renal vasoconstriction. The manufacturers recommend that the combination of indomethacin and triamterene not be used.

There is some evidence that concomitant administration of drugs that inhibit prostaglandin synthesis, including indomethacin, may reduce the blood pressure response to angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) or angiotensin II receptor antagonists (e.g., losartan). Limited data indicate that concomitant administration of NSAIAs with ACE inhibitors or angiotensin II receptor antagonists occasionally may result in acute reduction of renal function; however, the possibility cannot be ruled out that one drug alone may cause such an effect. Blood pressure should be monitored carefully when an NSAIA is initiated in patients receiving an ACE inhibitor or angiotensin II receptor antagonist, and clinicians should be alert for evidence of impaired renal function.

In healthy adults, indomethacin does not appear to influence the pharmacokinetics of hydrochlorothiazide.

Digoxin

Therapy in premature neonates with PDA and associated heart failure often includes digoxin. Administration of indomethacin in premature neonates receiving digoxin may further prolong the half-life of digoxin in these neonates, as a result of an indomethacin-induced reduction in renal function. In one study in premature neonates with PDA receiving digoxin, initiation of indomethacin therapy (mean total dose of 0.32 mg/kg) resulted in a mean digoxin half-life of 97 hours and an increase in mean serum digoxin concentrations from 2.2 to 3.2 ng/mL; increased serum digoxin concentrations were correlated with decreased urine output in these neonates. When indomethacin and digoxin are used concomitantly in premature neonates, the neonate should be observed closely for signs of digoxin toxicity; frequent ECG monitoring and determinations of serum digoxin concentrations may be necessary to prevent or detect impending cardiac glycoside toxicity. Dosage reduction of digoxin should be considered when the glycoside is used concomitantly with indomethacin in neonates. Some clinicians have suggested that digoxin dosage be initially reduced by about 50% when indomethacin is initiated in these neonates, and that subsequent dosage be adjusted according to urine output and serum digoxin concentrations.

In adults, serum digoxin concentrations also may be increased and elimination half-life prolonged by concomitant indomethacin administration, but data are conflicting. In a study in healthy adults, indomethacin (150 mg orally daily) did not appear to alter substantially elimination half-life, systemic clearance, or distribution of digoxin. However, in a study in adults with congestive heart failure and normal renal and hepatic function who were maintained on digoxin, steady-state serum digoxin concentrations (obtained 12 hours after a dose) increased by a mean of about 40% (range: 0-100%) during concomitant administration of indomethacin (150 mg orally daily) and returned to pretreatment values following discontinuance of the NSAIA. In this study, concomitant administration of ibuprofen (1.8 g orally daily) had no apparent effect on serum digoxin concentrations. While the clinical importance and mechanism of this potential interaction require further elucidation, the manufacturers state that serum digoxin concentrations should be monitored closely when indomethacin is used concomitantly.

Drugs Increasing Serum Potassium Concentrations

Because indomethacin may increase serum potassium concentrations, the drug should be used cautiously with other drugs that may increase serum potassium (e.g., potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, potassium supplements). Patients most likely to experience indomethacin-induced increases in serum potassium concentration include those with preexisting mild to moderate renal dysfunction, geriatric patients, and premature neonates. The potential effects of indomethacin and other drugs that may increase serum potassium on renal function and potassium kinetics should be considered when the drugs are used concomitantly, and serum potassium concentrations should be monitored before and periodically during concomitant therapy.

Lithium

In one study in psychiatric and healthy individuals with steady-state plasma lithium concentrations, indomethacin (150 mg daily) increased plasma lithium concentration by 30-60% and reduced renal lithium clearance. The mechanism involved in the reduction of lithium clearance by indomethacin is not known but has been attributed to inhibition of prostaglandin synthesis, possibly in the distal tubule. If indomethacin and lithium are administered concurrently, the patient should be closely observed for signs of lithium toxicity, and plasma lithium concentrations should be carefully monitored during the initial stages of combined therapy. In addition, appropriate adjustment in lithium dosage may be required when therapy with indomethacin is discontinued.

Methotrexate

Severe, sometimes fatal, toxicity has occurred following administration of a NSAIA (e.g., indomethacin, ketoprofen) concomitantly with methotrexate (principally high-dose therapy) in patients with various malignant neoplasms or rheumatoid arthritis. The toxicity was associated with elevated and prolonged blood concentrations of methotrexate. The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination. Further studies are needed to evaluate the interaction between NSAIAs and methotrexate. Caution is advised if methotrexate and a NSAIA are administered concomitantly.

Cyclosporine

Concomitant administration of a NSAIA and cyclosporine may increase the nephrotoxic effects of cyclosporine; this interaction may be related to inhibition of renal prostaglandin (e.g., prostacyclin) synthesis. NSAIAs and cyclosporine should be used concomitantly with caution and renal function should be closely monitored.

Probenecid

When probenecid is administered concomitantly with indomethacin, plasma concentration, plasma half-life, and therapeutic effects of indomethacin have been reported to increase. The mechanisms of this interaction remain unknown but have been attributed to blockade of renal tubular secretion of indomethacin and to interference with the biliary clearance of indomethacin. Although the clinical importance of the interaction has not been established, the manufacturers suggest that a decreased total daily dose of indomethacin may produce a satisfactory therapeutic response when indomethacin and probenecid are used concurrently and that increases in indomethacin dosage, if necessary, should be made carefully and in small increments. Indomethacin does not interfere with the uricosuric action of probenecid.

Other Drugs

Indomethacin has been reported to increase trough and peak serum aminoglycoside (e.g., amikacin, gentamicin) concentrations in premature neonates who were receiving the drugs concomitantly. Increases in serum aminoglycoside concentrations appeared to be related to indomethacin-induced decreases in urine output. Serum aminoglycoside concentrations and renal function should be closely monitored and aminoglycoside dosage adjusted accordingly when aminoglycosides are used concomitantly with indomethacin in premature neonates.

In one study in patients with rheumatoid arthritis, concomitant administration of indomethacin and prednisolone resulted in increased plasma concentrations of free prednisolone; total plasma prednisolone concentrations were unchanged.

Severe hypertension occurred in at least one patient when indomethacin was taken with phenylpropanolamine.

Indomethacin exacerbated phenylbutazone-related renal failure in one patient.

Acute renal failure was reported in 2 patients who received indomethacin with penicillin or nafcillin; however, a direct causal relationship has not been established.

Because indomethacin therapy may reduce renal function, reduction in dosage of any concurrently administered drug that depends on adequate renal function for elimination should be considered. Indomethacin should be used cautiously, if at all, with other drugs that might potentiate the adverse GI effects.

Pharmacokinetics

Absorption

Indomethacin is rapidly and almost completely absorbed from the GI tract in healthy adults. Following oral administration, bioavailability is virtually 100%, with 90% of a single dose being absorbed within 4 hours. When administered orally with food, a single 50-mg dose of the oral suspension is reportedly bioequivalent to a single 50-mg conventional capsule. The extended-release capsules of indomethacin (designed to release 25 mg of the drug initially and the remaining 50 mg over an extended time period) are 90% absorbed within 12 hours. The rate of absorption following rectal administration of suppositories of the drug generally has been reported to be more rapid than that following oral administration of conventional capsules; however, in one study in healthy adults, the rate of absorption was slower following rectal administration of suppositories than following oral administration of conventional capsules. The bioavailability following rectal administration of suppositories of the drug has generally been reported to be comparable to or slightly less than that following oral administration of the drug. The manufacturer states that bioavailability following rectal administration of suppositories of the drug has been reported to be about 80-90% in controlled clinical studies; the decreased bioavailability compared with oral administration may have resulted from incomplete retention of the suppository (i.e., less than 1 hour) within the rectum. In one study following oral administration of a single 75-mg dose (as 25-mg conventional capsules) or rectal administration of a single 100-mg suppository in adults with normal renal, hepatic, and GI function, however, the dose-adjusted AUC was substantially smaller following rectal administration than following oral administration. Indomethacin is absorbed into the aqueous humor following topical application to the eye, but does not appear to achieve appreciable systemic concentrations.(See Pharmacokinetics: Distribution.)

In premature neonates, absorption of oral indomethacin appears to be poor and incomplete; bioavailability is reportedly only about 20%. It has been suggested that poor oral absorption of the drug in premature neonates may result from abnormal pH-dependent diffusion and gastric motility and from lower gastric acid secretion. In neonates, gastric emptying time and motility are increased and peristalsis is irregular and unpredictable. In addition, the lack of solubility of the capsule form of indomethacin in aqueous media (See Chemistry and Stability: Chemistry.) may present problems in drug delivery and absorption from extemporaneous preparations.

In one study in healthy fasting adults, peak plasma concentrations of indomethacin occurred in 0.5-2 hours and were about 0.8-2.5 mcg/mL following a 25-mg oral dose, and 2.5-4 mcg/mL following a 50-mg oral dose. When indomethacin was administered orally to healthy fasting individuals in 25-mg doses 3 times daily, mean steady-state plasma drug concentrations ranged from 0.39-0.63 mcg/mL.

When indomethacin is taken with food or an aluminum and magnesium hydroxides antacid, peak plasma concentrations of the drug may be slightly decreased or delayed; however, the clinical significance of this effect has not been established. Plasma concentrations of indomethacin fluctuate less and are more sustained following oral administration of a single 75-mg extended-release capsule (Indocin SR) than following oral administration of 3 doses of 25-mg conventional capsules at 4- to 6-hour intervals.

In multiple-dose studies, the mean steady-state plasma concentration of indomethacin attained with daily administration of a 75-mg extended-release capsule was comparable to that following administration of conventional indomethacin capsules in a dosage of 25 mg 3 times daily (given at 6-hour intervals); however, there were differences in the plasma indomethacin concentrations achieved with the 2 regimens, especially after 12 hours. In one multiple-dose study, mean plasma indomethacin concentrations 11 and 16 hours after rectal administration of single daily doses as 100-mg suppositories or oral administration of single daily doses as four 25-mg conventional capsules were comparable. Although the relationship between plasma indomethacin concentrations and anti-inflammatory effect has not been precisely determined, a therapeutic range of 0.5-3 mcg/mL has been suggested.

The results of one study in healthy adults suggest that plasma concentrations following oral administration of indomethacin appear to be related to circadian rhythms; evening ingestion resulted in the smallest peak plasma drug concentration and longest time to peak. Further studies are necessary before recommendations based on this finding can be made.

In premature neonates, serum or plasma indomethacin concentrations appear to depend on postnatal age. In one study, neonates who received their first IV dose of indomethacin of 0.2 mg/kg at 48 hours of age or younger had mean serum indomethacin concentrations of approximately 0.6 mcg/mL at 12 hours after administration and those who received their first dose beyond 7 days of age had mean serum indomethacin concentrations of approximately 0.37 mcg/mL. In the same study, following multiple IV doses (0.2 mg/kg at 12-hour intervals), mean serum indomethacin concentrations 12 hours after the third dose were approximately 2.3 mcg/mL in the younger neonates and 0.75 mcg/mL in the older neonates. Limited pharmacokinetic data are available in premature neonates following oral administration of the drug. In one study, plasma indomethacin concentrations of 0.027-0.31 mcg/mL were attained 3-4 hours after oral doses of 0.1-0.3 mg/kg to premature neonates with gestational ages of 28-36 weeks and birthweights of 0.8-1.96 kg.

Distribution

At therapeutic concentrations, indomethacin is approximately 99% bound to plasma proteins.

In healthy adults, the volume of distribution of indomethacin has been reported to range from 0.34-1.57 L/kg. In one study in premature neonates, the volume of distribution of indomethacin (calculated on the basis of birthweight) was about 0.287 L in neonates weighing greater than 1 kg and about 0.216 L in neonates weighing less than 1 kg.

Peak indomethacin concentrations in synovial fluid have been reported to occur 1.5 hours after peak serum drug concentrations and were approximately 20% of those in serum.

Following topical application of a 1% aqueous or oil suspension of indomethacin to the eye for 18-24 hours prior to cataract surgery, mean aqueous humor concentrations at the time of surgery were 198 or 429 ng/mL in patients receiving the aqueous or oil suspension, respectively. Indomethacin was not detected (lower limits of detection: 50 ng/mL) in aqueous humor at the time of surgery in patients who received 100 mg of the drug orally in divided doses during the 24-hour period prior to surgery (last dose was administered 2 hours prior to surgery); mean simultaneous plasma concentration of the drug in patients receiving oral indomethacin was 642 ng/mL.

Indomethacin crosses the blood-brain barrier in small amounts and appears to freely cross the placenta. The drug is distributed into milk; one breast-fed neonate (6 days of age) received an estimated 0.5-2 mg of indomethacin daily during maternal ingestion of 200 mg of the drug daily for 3 days. (See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination

In studies in healthy adults or patients with rheumatoid arthritis, the disappearance of indomethacin from plasma appears to be biphasic with a half-life of approximately 1 hour during the initial phase and 2.6-11.2 hours during the second phase; variations in terminal plasma half-life may be due to individual differences in enterohepatic circulation of the drug. There appears to be no difference between plasma half-life in healthy adults and in rheumatoid arthritis patients.

In premature neonates, the serum or plasma elimination half-life of indomethacin is inversely related to postnatal age. In a limited number of neonates, the mean plasma half-life of indomethacin has been reported to be about 20-28 hours in those receiving the drug during the first week of life, compared to about 12-19 hours in those receiving the drug after the first week. The elimination half-life in neonates may also be inversely related to body weight. In one study, the plasma indomethacin half-life showed considerable interindividual variation but averaged 21 hours in neonates weighing less than 1 kg and 15 hours in those weighing more than 1 kg. Total body clearance of indomethacin increases with increasing postnatal age. It was suggested that extensive enterohepatic circulation may commonly occur in premature neonates and may contribute to the relatively long half-life of elimination. Age-dependent IV dosage schedules have been proposed. (See Dosage and Administration: Patent Ductus Arteriosus.)

Geriatric patients have reportedly shown greater serum concentrations and longer plasma half-lives of indomethacin than younger adults; however, these findings need further documentation.

In one study in healthy adults and patients with arthritis, the half-life for disappearance of indomethacin from synovial fluid was 9 hours.

Indomethacin is metabolized in the liver to its glucuronide conjugate and to desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites and their glucuronides. These metabolites do not appear to possess anti-inflammatory activity. A portion of the drug is also N-deacylated by a nonmicrosomal system.

Approximately 33% or more of a 25-mg oral dose of indomethacin is excreted in feces principally as demethylated metabolites in their unconjugated forms; 1.5% of fecal drug excretion occurs as indomethacin. Indomethacin and its conjugates undergo enterohepatic circulation.

About 60% of a 25-mg oral dose of indomethacin is excreted in urine in 48 hours; renal tubular secretion of indomethacin and/or its glucuronide derivative appears to occur. About 30% of urinary drug excretion occurs as indomethacin and its glucuronide, with the balance consisting of the metabolites and their glucuronides.

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