Indomethacin is a nonsteroidal anti-inflammatory agent (NSAIA) that also exhibits analgesic and antipyretic activity.301
Indomethacin is used orally or rectally for anti-inflammatory and analgesic effects in the symptomatic treatment of moderate to severe rheumatoid arthritis (including acute flares of chronic disease), osteoarthritis, and ankylosing spondylitis.301, 2, 3, 341 Indomethacin is also used orally or rectally for symptomatic treatment of acute painful shoulder (bursitis and/or tendinitis).301, 2, 3, 341 Indomethacin immediate-release capsules, oral suspension, and rectal suppositories are used for the symptomatic treatment of acute gouty arthritis.301, 2, 3
Indomethacin has been used rectally for the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP)† .1213, 1214, 1215, 1216, 1217, 1218
465 Indomethacin has been used in combination with colchicine for the treatment of recurrent pericarditis†.1209, 1210 Indomethacin has also been used for the prevention of heterotopic ossification following total hip arthroplasty† and to inhibit uterine contractions during preterm labor† (tocolysis).466, 467, 468, 469, 470, 1211, 1212, 1219
Indomethacin sodium injection is used IV in the treatment of patent ductus arteriosus (PDA) in premature neonates.301 Indomethacin sodium has also been used prophylactically in select premature neonates at risk for hemodynamically significant PDA† .1233
The potential benefits and risks of indomethacin therapy as well as alternative therapies should be considered prior to initiating therapy.301, 2, 3, 341 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.301, 2, 3, 341
Indomethacin is used orally or rectally for anti-inflammatory and analgesic effects in the symptomatic treatment of moderate to severe rheumatoid arthritis (including acute flares of chronic disease), osteoarthritis, and ankylosing spondylitis.301, 2, 3, 341 Indomethacin is also used orally or rectally for symptomatic treatment of acute painful shoulder (bursitis and/or tendinitis).301, 2, 3, 341 Indomethacin immediate-release capsules, oral suspension, and rectal suppositories are used for the symptomatic treatment of acute gouty arthritis.301, 2, 3
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.301, 2, 3, 341
Clinical evaluations of indomethacin in the management of rheumatoid arthritis have generally shown that the anti-inflammatory and analgesic effects of indomethacin are about equal to those of salicylates, ibuprofen, naproxen, ketoprofen, flurbiprofen, tolmetin, meclofenamate sodium, and diclofenac, but may be slightly less than those of piroxicam.519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532
Clinical evaluations of indomethacin in the management of osteoarthritis have found the efficacy of indomethacin to be comparable to that of naproxen, ketoprofen, and nabumetone.522, 533, 534, 535
Clinical evaluations of indomethacin in the management of ankylosing spondylitis have found the efficacy of indomethacin to be comparable to that of meclofenamate sodium and diclofenac, but potentially reduced compared to that of piroxicam.536, 537, 538 Clinical evaluations of indomethacin in the management of acute gouty arthritis have found the efficacy of indomethacin to be comparable to that of ketoprofen, oral prednisolone, and high-dose celecoxib (loading dose of 800 mg followed by 400 mg twice daily).539, 540, 541
Indomethacin has also been used for the management of Reiter syndrome (now referred to as reactive arthritis)† and the symptomatic treatment of athletic injuries† and juvenile arthritis† .542, 543, 544
The American College of Rheumatology (ACR) guideline on the treatment of rheumatoid arthritis recommends initiation of a disease-modifying antirheumatic drug (DMARD) in DMARD-naïve patients; methotrexate is recommended over other DMARDs for the initial treatment of patients with moderate-to-high disease activity, while hydroxychloroquine is recommended initially for patients with low disease activity.2001 Addition of a biologic or target-specific DMARD is recommended for patients who do not attain treatment goals on methotrexate monotherapy (“treat-to-target” approach).2001 The role of NSAIAs is not discussed in the current ACR guideline on rheumatoid arthritis.2001
Medical management of osteoarthritis of the hip, knee, and/or hand includes both pharmacologic therapy and nonpharmacologic (e.g., educational, behavioral, psychosocial, physical) interventions to reduce pain, maintain and/or improve joint mobility, limit functional impairment, and enhance overall well-being.2002 The ACR strongly recommends exercise, weight loss when necessary in patients with osteoarthritis of the knee and/or hip, self-efficacy and self-management programs, tai chi, cane use, hand orthoses, knee bracing, topical NSAIAs for osteoarthritis of the knee, oral NSAIAs, and intra-articular glucocorticoid injections for osteoarthritis of the knee or hip.2002 Other pharmacologic or nonpharmacologic interventions may be recommended conditionally.2002 Interventions and the order of their selection are patient specific.2002 Factors to consider when making decisions regarding therapy for osteoarthritis include patients' values and preferences, the presence of risk factors for serious adverse GI effects, existing comorbidities (e.g., hypertension, heart failure, other cardiovascular disease, chronic kidney disease), injuries, disease severity, surgical history, and access to and availability of the interventions.2002 Pharmacologic therapy should be initiated with treatments resulting in the least systemic exposure or toxicity.2002 For some patients with limited disease, topical NSAIAs may be an appropriate initial choice for pharmacologic therapy; for other patients, particularly those with osteoarthritis of the hip or with polyarticular involvement, oral NSAIAs may be more appropriate.2002
The ACR, the Spondylitis Association of America, and the Spondyloarthritis Research and Treatment Network issued a joint guideline for the treatment of ankylosing spondylitis in 2019.2008 Treatments for ankylosing spondylitis include NSAIAs, conventional DMARDs (e.g., methotrexate, sulfasalazine), biologic DMARDs (e.g., tumor necrosis factor [TNF] blocking agents, secukinumab, ixekizumab), and/or targeted synthetic DMARDs (e.g., tofacitinib).2008 Specific agents for ankylosing spondylitis treatment are selected according to current disease activity, prior therapies, and the presence of comorbidities.2008 Goals of therapy in ankylosing spondylitis are to alleviate symptoms, improve functioning, maintain the ability to work, decrease complications, and prevent or slow skeletal damage.2008
Continuous NSAIA treatment is typically considered first-line for active ankylosing spondylitis, with other agents used in the treatment of NSAIA-refractory disease.2008 On-demand NSAIAs are recommended for stable ankylosing spondylitis.2008 No preference is given to one NSAIA over another.2008
The ACR issued a guideline for the management of gout in 2020.2006 Treatment with urate-lowering therapy (e.g., allopurinol) is strongly recommended for patients with gout and any of the following: ≥1 subcutaneous tophi, evidence of radiographic damage attributable to gout, or frequent gout flares (≥2 flares annually).2006 It is also conditionally recommended for patients who have previously experienced >1 flare but have infrequent flares (<2 flares annually), and patients experiencing a first flare with moderate-to-severe chronic kidney disease (stage ≥3), serum urate concentration >9 mg/dL, or urolithiasis.2006 Concomitant anti-inflammatory prophylaxis with colchicine, NSAIAs, or prednisone/prednisolone is strongly recommended for 3-6 months after initiation of urate-lowering therapy.2006 First-line therapies for gout flares include colchicine, NSAIAs, and glucocorticoids (oral, intra-articular, or intramuscular); treatment selection should be based on patient-specific factors (e.g., comorbidities, ease of access) and patient preferences.2006
Indomethacin sodium is used IV to promote closure of a hemodynamically significant PDA in premature neonates weighing 500-1750 g when 48 hours of usual medical management (e.g., fluid restriction, diuretics, cardiac glycosides, respiratory support) is ineffective.301 Evidence of a hemodynamically significant PDA may include respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly, or pulmonary plethora on chest x-ray.301 Indomethacin sodium has also been used prophylactically in select premature neonates at risk for hemodynamically significant PDA† .1233
Indomethacin sodium is used IV in the treatment of PDA in premature neonates.301, 302, 303, 306, 309, 310, 312, 316, 319, 322, 1228 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%.301, 302, 303, 306, 309, 310, 312 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 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).306 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.306 Neonates who did not respond to indomethacin therapy required surgical ligation.306 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.306 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.306 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.306 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.306 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.303 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.302, 303
Cochrane reviews have found similar efficacy with respect to PDA closure for indomethacin and ibuprofen (IV or oral); however, ibuprofen is associated with reduced risks of necrotizing enterocolitis and transient renal insufficiency compared with indomethacin.1230, 1231
IV indomethacin sodium has also been used prophylactically in select premature neonates at risk for hemodynamically significant PDA † during the first day of life.316, 400, 509, 1232, 1233 In clinical studies, prophylactic IV administration of indomethacin initiated soon after delivery in low-birthweight (500-1500 g) premature neonates has been shown to decrease the incidence of hemodynamically significant PDA (e.g., large ductal shunts) and the need for subsequent surgical ductal closure in such neonates.316, 400, 405, 472, 509 In addition, 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,402, 403, 405, 509 particularly grade 3 or 4 intraventricular hemorrhage.472 However, despite these beneficial effects, results of one large randomized clinical study indicate that 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.472
In most term infants, the ductus arteriosus closes within 1 to 3 days after birth; when this closure fails to occur, it is referred to as PDA.1232, 1233 Preterm infants frequently present with persistent PDA.1232, 1233 Although spontaneous closure of PDA is common, patients with prolonged hemodynamically important PDA may experience end-organ injury, including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, acute pulmonary hemorrhage, renal failure, or death.1232 The decision to initiate pharmacologic treatment for PDA will depend on patient-specific factors such as gestational age, chronological age, the size of the PDA, and the presence of symptoms (e.g., requirement for greater than minimal respiratory support).1232, 1233
Select infants at high risk of persistent PDA (e.g., gestational age <26 weeks, weight <750 g) are candidates for targeted early prophylactic treatment with indomethacin within 6-24 hours after birth.1232, 1233 If prophylactic treatment is not indicated or not effective, early targeted pharmacologic treatment with ibuprofen or indomethacin is recommended <6 days after birth for infants <28 weeks' gestational age with a moderate-to-large hemodynamically important shunt requiring greater than minimal respiratory support.1233 All infants with very low birth weight ≥6 days of age who require greater than minimal respiratory support should be screened for PDA via echocardiogram; in the presence of a moderate-to-large hemodynamically important PDA and additional risk factors (e.g., failure to wean from the ventilator, fraction of inspired oxygen >0.25), treatment with ibuprofen should be considered.1233 If treatment with ibuprofen is ineffective, rescue treatment with acetaminophen or catheter-based closure/surgical intervention may be considered.1233
Indomethacin has been used in combination with colchicine for the treatment of recurrent pericarditis †.1209, 1210 Some experts recommend colchicine plus aspirin or an NSAIA (typically ibuprofen) first-line for the treatment of acute or recurrent pericarditis.1210
Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis
Indomethacin has been used rectally for the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP)†.1213, 1214, 1215, 1216, 1217, 1218 Most randomized controlled trials examining rectal indomethacin for the prevention of post-ERCP pancreatitis have demonstrated benefit with this agent;1213, 1214 however, one study that primarily enrolled patients at average risk for post-ERCP pancreatitis did not find a substantial difference in the incidence of post-ERCP pancreatitis between rectal indomethacin and placebo.1215 A systematic review and meta-analysis performed by the American Society for Gastrointestinal Endoscopy (ASGE) found that rectal NSAIAs reduced the risk of post-ERCP pancreatitis by approximately 50% in an unselected patient population (i.e., patients with and without risk factors for post-ERCP pancreatitis).1217 As a result, ASGE strongly recommends preprocedural rectal NSAIAs (usually indomethacin) for the prevention of post-ERCP pancreatitis in all patients undergoing ERCP.1217 The American College of Gastroenterology recommends rectal indomethacin to prevent post-ERCP pancreatitis in individuals at high risk of post-ERCP pancreatitis.1218
Indomethacin has been used to inhibit uterine contractions during preterm labor† (tocolysis) and thus prolong gestation.465, 466, 467, 468, 469, 470, 1211, 1212 While indomethacin has demonstrated some benefit in terms of postponement of birth over placebo and betamimetic agents, evidence is limited to data from smaller, low-quality trials.1211 The American College of Obstetricians and Gynecologists (ACOG) states that indomethacin is a potential first-line option for short-term prolongation of pregnancy (up to 48 hours); however, as with any other tocolytic agent, the risks and benefits of indomethacin treatment must be carefully weighed.1212 Adverse effects (e.g., in utero constriction of ductus arteriosus, oligohydramnios, necrotizing enterocolitis in preterm newborns, PDA in newborn) may occur, particularly if indomethacin is used for longer than 48 hours.1212
Indomethacin has been used for the prevention of heterotopic ossification following total hip arthroplasty † .1219
Dispensing and Administration Precautions
The potential benefits and risks of indomethacin therapy as well as alternative therapies should be considered prior to initiating indomethacin therapy.301, 2, 3, 341
Indomethacin is administered orally or rectally.301, 2, 3, 341 Indomethacin sodium is administered by IV injection for the treatment of patent ductus arteriosus (PDA).301
Commercially available indomethacin oral suspension is supplied as a 25 mg/5 mL (5 mg/mL) concentration.2
Oral and Rectal Administration
Indomethacin conventional capsules, oral suspension, and rectal suppositories are administered in 2-4 divided doses daily.301, 2, 3, 341 The extended-release capsules are administered once or twice daily.341 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.301, 2, 3, 341 Extended-release capsules of indomethacin are not recommended for use in the symptomatic treatment of acute gouty arthritis.341 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.341
To ensure complete absorption of the drug, indomethacin suppositories should be retained in the rectum for at least 1 hour.3
Store conventional and extended-release indomethacin capsules at 20-25°C. Conventional capsules should be protected from light.301 Extended-release capsules should be protected from moisture; excursions permitted for extended-release capsules from 15-30°C.341 Store oral suspension at <30°C; avoid temperatures >50°C and do not freeze.2 Store suppositories at 2-8°C.3
Store indomethacin for injection vials at 25°C protected from light; excursions permitted from 15-30°C.301
For IV administration, indomethacin sodium sterile powder for injection 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.301 Preserved diluents (i.e., bacteriostatic water for injection or bacteriostatic sodium chloride injection) containing benzyl alcohol should not be used to reconstitute the drug because benzyl alcohol as a preservative has been associated with toxicity in neonates.301 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.301 Reconstituted indomethacin sodium solutions should not be further diluted in IV infusion solutions.301 Solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.301
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.301
Care should be taken to avoid extravasation of the drug since it may be irritating to extravascular tissues.301
The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.301, 2, 3, 341 Dosage of indomethacin must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.301, 2, 3, 341 Indomethacin 50-mg suppositories can be substituted for indomethacin capsules; however, there will be significant differences between the two dosage regimens in indomethacin blood levels.3
Dosage of indomethacin sodium injection, is expressed in terms of anhydrous indomethacin; the IV injection is labeled for use only in premature infants with PDA.301
Dosage of indomethacin must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.301, 2, 3, 341 Total dosages greater 150-200 mg daily generally do not increase the effectiveness of the drug.301, 2, 3, 341
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.301, 2, 3 If serious adverse effects occur, indomethacin therapy should be discontinued.301, 2, 3
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.301, 2, 3
Ankylosing Spondylitis:For the symptomatic treatment of moderate to severe ankylosing spondylitis, the usual initial adult dosage of indomethacin is 25 mg 2 or 3 times daily.301, 2, 3 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.301, 2, 3
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.301, 2, 3
The usual initial adult dosage of extended-release capsules of indomethacin for the symptomatic treatment of ankylosing spondylitis 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.341
Osteoarthritis: For the symptomatic treatment of moderate to severe osteoarthritis, the usual initial adult dosage of indomethacin is 25 mg 2 or 3 times daily.301, 2, 3 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.301, 2, 3
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.301, 2, 3
The usual initial adult dosage of extended-release capsules of indomethacin for the symptomatic treatment of osteoarthritis 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.341
Rheumatoid Arthritis: For the symptomatic treatment of moderate to severe rheumatoid arthritis, the usual initial adult dosage of indomethacin is 25 mg 2 or 3 times daily.301, 2, 3 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.301, 2, 3
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.301, 2, 3
The usual initial adult dosage of extended-release capsules of indomethacin for the symptomatic treatment of rheumatoid arthritis 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.341
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 dosage reaches 150-200 mg.301, 2, 3
For the symptomatic treatment of acute gouty arthritis, the manufacturers recommend 50 mg of indomethacin 3 times daily until the pain can be tolerated.301, 2, 3 When symptoms subside, dosage should be reduced rapidly until the drug is withdrawn.301, 2, 3 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.301, 2, 3
Administration of extended-release capsules of indomethacin for acute gouty arthritis is not recommended.341
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.301, 2, 3 After signs and symptoms of inflammation have been controlled for several days, indomethacin should be discontinued.301, 2, 3, 341 The usual duration of treatment is 7-14 days.301, 2, 3, 341
When indomethacin has been used in combination with colchicine for the treatment of recurrent pericarditis†1209, 1210 , adults have received initial indomethacin dosages of 75-150 mg daily in 3 divided doses, which is decreased by 25 mg every 1-2 weeks.1210
Juvenile Rheumatoid Arthritis†
If the benefits are thought to outweigh the risks, 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.301, 2, 341 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.301, 2, 341 As symptoms subside, dosage should be reduced to the lowest effective level or, if possible, until the drug is discontinued.301, 2, 341
For the treatment of patent ductus arteriosus (PDA) in premature neonates weighing 500-1750 g after 48 hours of usual medical management (e.g., fluid restriction, diuretics, cardiac glycosides, respiratory support) is ineffective, indomethacin sodium is administered by IV injection.301 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.301 The manufacturer indicates that all 3 doses should be administered in the first course of therapy.301
The first IV dose of each course of indomethacin sodium is 0.2 mg/kg of indomethacin, regardless of the neonate's age.301 Subsequent doses depend on the age of the neonate at the time of administration of the first dose in the first course.301 If anuria or oliguria (i.e., urine output <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.301 For neonates <48 hours of age at the time of the first dose, second and third doses of 0.1 mg/kg each are used.301 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 >7 days of age at the time of the first dose should receive second and third doses of 0.25 mg/kg each.301 If severe adverse effects occur during a course of therapy, the drug should be discontinued.301
Subsequent doses are not necessary if the ductus arteriosus closes or is substantially constricted ≥48 hours after completion of the first course of indomethacin sodium therapy.301 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).301 Surgical ligation of the ductus may be necessary if the ductus arteriosus is unresponsive to indomethacin therapy after 2 courses.301
When indomethacin sodium for injection has been used prophylactically in select premature neonates at risk for hemodynamically significant PDA† within the first day of life (and ≥6 hours after birth), three IV doses of 0.1 mg/kg have been given at 12-hour intervals (single-dose prophylaxis may be considered), although the final dose of indomethacin may be omitted if echocardiography suggests closing of the PDA.1233
The manufacturers make no specific dosage recommendations in patients with hepatic impairment.301, 2, 3, 341
The manufacturers make no specific dosage recommendations in patients with renal impairment.301, 2, 3, 341 Indomethacin should be avoided in patients with advanced renal disease unless the anticipated benefits are expected to outweigh the potential risks of therapy.301, 2, 3, 341 If indomethacin is used in patients with advanced renal disease, monitor for signs of worsening renal function.301, 2, 3, 341
Correct fluid status in dehydrated or hypovolemic patients prior to and monitor renal function during indomethacin therapy in patients with preexisting renal or hepatic impairment, heart failure, dehydration, or hypovolemia.301, 2, 3, 341
When urine volume is significantly reduced after a dose of indomethacin sodium in neonates, subsequent doses should be withheld until urine output returns to normal.301 Monitor renal function and serum electrolytes in neonates who receive indomethacin sodium for PDA closure.301 Indomethacin sodium for injection is contraindicated in neonates with substantially impaired renal function.301
Indomethacin should be used with caution in geriatric individuals ≥65 years of age since increasing age may be associated with increased serious risk of cardiovascular, gastrointestinal and/or renal adverse reactions.301, 2, 3, 341 If the anticipated benefits of the drug outweigh the potential risks, indomethacin should be initiated at the lower end of the dosage range and patients should be monitored for adverse reactions.301, 2, 3, 341
Indomethacin is eliminated mainly by the kidneys and individuals with renal impairment may be at increased risk for toxic reactions to the drug.301, 2, 3, 341 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.301, 2, 3, 341
Cardiovascular Thrombotic Events
A boxed warning concerning the increased risk of cardiovascular thrombotic events is included in the prescribing information for indomethacin.301, 2, 3, 341 Clinical trials of NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, of up to 3 years' duration have shown an increased 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.301, 2, 3, 341 Based on available evidence, it is unclear if the risk of cardiovascular thrombotic events is similar for selective COX-2 inhibitors and prototypical NSAIAs.301, 2, 3, 341 Available data suggest that the increase in risk may occur early (within the first few weeks) following initiation of therapy and may increase with higher dosages.301, 2, 3, 341 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.301, 2, 3, 341 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.301, 2, 3, 341 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).301, 2, 3, 341 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.301, 2, 3, 341 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.301, 2, 3, 341 In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following CABG surgery, the incidence of myocardial infarction and stroke was increased.301, 2, 3, 341 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.301, 2, 3, 341 To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed.301, 2, 3, 341 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.301, 2, 3, 341 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.301, 2, 3, 341 There is no consistent evidence that concomitant use of low-dose aspirin reduces the risk of serious cardiovascular events associated with NSAIAs.301, 2, 3, 341 Concomitant use of aspirin and an NSAIA increases the risk for serious gastrointestinal (GI) events.301, 2, 3, 341
GI Bleeding, Ulceration, and Perforation
A boxed warning concerning the increased risk of serious adverse GI events is included in the prescribing information for indomethacin.301, 2, 3, 341 Serious, sometimes fatal, adverse GI effects (e.g., bleeding, ulceration, or perforation of the esophagus, stomach, or small or large intestine) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.301, 2, 3, 341 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.301, 2, 3, 341 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy.301, 2, 3, 341 Patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis should be monitored even more closely for evidence of GI bleeding.301, 2, 3, 341 In patients receiving NSAIAs in clinical studies, 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.301, 2, 3, 341 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.301, 2, 3, 341 However, short-term therapy is not without risk.301, 2, 3, 341 Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than 10-fold increased risk of developing GI bleeding than patients without these risk factors.301, 2, 3, 341 In addition to a history of ulcer disease, other factors may increase the risk for GI bleeding, including concomitant use of oral corticosteroids, anticoagulants, aspirin, or selective serotonin-reuptake inhibitors (SSRIs); longer duration of NSAIA therapy; smoking; alcohol use; older a and poor general health status.301, 2, 3, 341 The risk of GI bleeding is also increased in patients with advanced liver disease and/or coagulopathy.301, 2, 3, 341 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.301, 2, 3, 341 To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed, and use of ≥1 NSAIA at a time should be avoided.301, 2, 3, 341 In addition, use of NSAIAs should be avoided in patients at higher risk unless the benefits of therapy are expected to outweigh the increased risk of bleeding; for patients who are at high risk, as well as for those with active GI bleeding, alternative therapy other than an NSAIA should be considered.301, 2, 3, 341 If signs and symptoms of a serious GI event occur, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.301, 2, 3, 341 In the clinical trial of indomethacin sodium for PDA closure in preterm neonates, major GI bleeding occurred no more frequently in neonates who received indomethacin versus placebo therapy, although minor GI bleeding (i.e., chemical detection of blood in stool) was observed more frequently in neonates who received indomethacin.301, 2, 3, 341 Indomethacin should not be used in premature neonates with active GI bleeding or known or suspected necrotizing enterocolitis.301
Serum ALT or AST elevations (3 or more times the upper limit of normal [ULN]) have occurred in <1% of patients receiving NSAIAs in controlled clinical studies; elevations less than 3 times the ULN have occurred in up to 15% of patients treated with NSAIAs.301, 2, 3, 341
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 a more severe hepatic reaction.301, 2, 3, 341 Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIAs.301, 2, 3, 341 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).301, 2, 3, 341
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.301, 2, 3, 341 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), or angiotensin-converting enzyme (ACE) inhibitors.301, 2, 3, 341 NSAIAs, including indomethacin, should be used with caution in patients with hypertension.301, 2, 3, 341 Blood pressure should be monitored closely during initiation of indomethacin therapy and throughout therapy.301, 2, 3, 341
Results from a Danish National Registry study indicate that the use of NSAIAs in patients with chronic heart failure was associated with an increase in the risk of death and hospitalization for myocardial infarction or heart failure.301, 2, 3, 341 In addition, findings from a meta-analysis of randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate 2-fold increase in the risk of hospitalization for heart failure.301, 2, 3, 341 Fluid retention and edema have also been observed in some patients receiving NSAIAs.301, 2, 3, 341
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).301, 2, 3, 341
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, they should be monitored for worsening heart failure.301, 2, 3, 341
Renal Toxicity and Hyperkalemia
Long-therapy administration of NSAIAs has resulted in renal papillary necrosis and other renal injuries.301, 2, 3, 341
Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.301, 2, 3, 341 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.301, 2, 3, 341 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.301, 2, 3, 341 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.301, 2, 3, 341 Recovery of renal function to pretreatment levels usually occurs following the discontinuation of NSAIA therapy.301, 2, 3, 341
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.301, 2, 3, 341 If indomethacin is used in patients with advanced renal disease, close monitoring of renal function is recommended.301, 2, 3, 341
Fluid depletion should be corrected prior to initiation of indomethacin therapy, and renal function should be monitored during indomethacin therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.301, 2, 3, 341
Increased serum potassium concentrations have occurred in patients receiving indomethacin, and such increases, including hyperkalemia, have occurred in some patients without renal impairment.301, 2, 3, 341 In patients with normal renal function, increases in serum potassium concentration during indomethacin therapy have been attributed to hyporeninemic hypoaldosteronism induced by the drug.301, 2, 3, 341 Both indomethacin and potassium-sparing diuretics may increase serum potassium levels; the potential effects of concomitant use of these agents on potassium levels and renal function should be considered before administering.301, 2, 3, 341
Indomethacin sodium for injection 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).301 When urine volume is significantly reduced after a dose of indomethacin sodium, subsequent doses should be withheld until urine output returns to normal.301 Indomethacin sodium in premature neonates may also suppress water excretion to a greater extent than sodium, which can cause a significant reduction in serum sodium values and result in hyponatremia.301 Renal function and serum electrolytes should be monitored in neonates receiving the drug.301 The drug is contraindicated in neonates with substantially impaired renal function.301
Anaphylactic reactions have been reported in patients receiving indomethacin; reactions have occurred in those with or without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma.301, 2, 3, 341 Patients receiving indomethacin should be informed of the signs and symptoms of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if such a reaction develops.301, 2, 3, 341
Exacerbation of Asthma Related to Aspirin Sensitivity
Some patients with asthma may have aspirin-sensitivity asthma301, 2, 3, 341 In patients with asthma, aspirin sensitivity can manifest as severe, potentially fatal bronchospasm, chronic rhinosinusitis complicated by nasal polyps, and/or an intolerance to aspirin or other NSAIAs.301, 2, 3, 341 Because cross-reactivity between aspirin and other NSAIAs has been reported in aspirin-sensitive patients, indomethacin is contraindicated in patients with aspirin-sensitive asthma.301, 2, 3, 341 When indomethacin is used in patients with pre-existing asthma (without known aspirin sensitivity), monitor for changes in signs and symptoms of asthma.301, 2, 3, 341
Serious, potentially fatal skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving indomethacin.301, 2, 3, 341, 341 NSAIAs can also cause fixed drug eruption; a more severe, life-threatening presentation is known as generalized bullous fixed drug eruption.301 These serious skin reactions may occur without warning.301, 2, 3, 341 Patients should be advised on the signs and symptoms of serious skin reactions. 301, 2, 3, 341 Indomethacin should be discontinued at the first appearance of rash or any other sign of hypersensitivity.301, 2, 3, 341 Indomethacin is contraindicated in patients with previous serious skin reactions to NSAIAs.301, 2, 3, 341
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
DRESS, a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.301, 2, 341 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.301, 2, 341 Symptoms may resemble those of an acute viral infection.301, 2, 341 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.301, 2, 341 If such signs or symptoms develop, indomethacin should be discontinued and the patient evaluated immediately.301, 2, 341
Fetal/Neonatal Morbidity and Mortality
Use of NSAIAs during pregnancy at about 30 weeks' gestation or later can cause premature closure of the fetal ductus arteriosus.301 Use at about 20 weeks' gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.301, 2, 341
Fetal renal dysfunction has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.301, 2, 341 Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.301, 2, 341 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.301, 2, 341 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.301, 2, 341
Use of NSAIAs should be avoided in pregnant women at about 30 weeks' gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks' gestation, the lowest effective dosage and shortest possible duration of treatment should be used.301, 2, 341 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.301, 2, 341
Anemia has been reported in patients receiving NSAIAs.301, 2, 3, 341 Anemia may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.301, 2, 3, 341 If signs and/or symptoms of anemia occur during therapy with ibuprofen, hemoglobin concentration and hematocrit should be determined.301, 2, 3, 341
NSAIAs, including indomethacin, may increase the risk of bleeding.301, 2, 3, 341 Patients with certain coexisting conditions, such as coagulation disorders and those receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors, may be at increased risk and should be monitored for signs of bleeding.301, 2, 3, 341
Premature neonates receiving indomethacin sodium for injection should be observed closely for bleeding tendencies.301 In one small study in premature infants, platelet aggregation was grossly abnormal after administration of oral indomethacin to close the ductus arteriosus; platelet aggregation returned to normal by the tenth day.301 Indomethacin sodium is contraindicated in neonates with active bleeding, such as those with intracranial hemorrhage or GI bleeding, and in neonates with thrombocytopenia or underlying coagulation defect.301
Masking of Inflammation and Fever
The possibility that the antipyretic and anti-inflammatory effects of indomethacin may mask the usual signs and symptoms of infection should be considered.301, 2, 3, 341 Indomethacin sodium should be used with caution in premature neonates at risk for infection and in those with an existing infection that is adequately controlled.301 Clinicians should be alert to the masking effect of the drug in these neonates.301 The drug is contraindicated in neonates with proven or suspected, untreated infection.301
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning, patients receiving long-term NSAIA therapy should have a CBC and chemistry profile performed periodically.301, 2, 3, 341
Indomethacin should be used with extreme caution in patients with a history of mental depression or other psychiatric disorder, epilepsy, or parkinsonian syndrome as indomethacin may aggravate these conditions.301, 2, 3, 341 If severe adverse nervous system effects occur during indomethacin therapy, the drug should be discontinued.301, 2, 3, 341 The drug should also be discontinued in patients in whom indomethacin-induced headache persists despite a reduction in dosage.301, 2, 3, 341 Indomethacin may cause drowsiness; 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).301, 2, 3, 341
The possibility that indomethacin sodium could potentially increase the risk of intraventricular hemorrhage in premature neonates should be considered since the drug can inhibit platelet aggregation.301 It should be remembered, however, that neonate prematurity itself is associated with an increased risk of intraventricular hemorrhage.301 In the large, multicenter study of indomethacin sodium for PDA the occurrence of intraventricular hemorrhage was not significantly increased in neonates receiving indomethacin sodium versus control.301
Corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients receiving prolonged indomethacin therapy; the drug should be discontinued if these effects occur.301, 2, 3, 341 Patients who experience blurred vision during indomethacin therapy should have an ophthalmologic examination.301, 2, 3, 341 Since these changes can be asymptomatic, periodic ophthalmologic examination is advised during prolonged indomethacin therapy.301, 2, 3, 341
Use of NSAIAs during pregnancy at about 30 weeks' gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks' gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.301, 2, 341 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks' gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks' gestation, the lowest effective dosage and shortest possible duration of treatment should be used.301, 2, 341 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.301, 2, 341 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks' gestation.301, 2, 341
Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.301, 2, 341 Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.301, 2, 341 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.301, 2, 341 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.301, 2, 341 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.301, 2, 341 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.301, 2, 341 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.301, 2, 341 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.301, 2, 341
Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.301, 2, 341 In animal studies, inhibitors of prostaglandin synthesis, such as indomethacin, were associated with increased pre- and post-implantation losses.301, 2, 341 Prostaglandins also have an important role in fetal kidney development.301, 2, 341 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.301, 2, 341
Reproduction studies in mice and rats at dosages of 0.5-4 mg/kg daily have revealed no increase in fetal malformations other than retarded fetal ossification, which was observed at the highest dosage and was attributed to decreased average fetal weight.301, 2, 3, 341 Administration of indomethacin to mice and rats during the last 3 days of gestation at a dosage of 4 mg/kg daily was associated with an increased incidence of neuronal necrosis in the diencephalon in live-born fetuses; no increase in neuronal necrosis was observed at a dosage of 2 mg/kg daily, and administration of the drug to the offspring during the first 3 days of life at a dosage of 0.5 or 4 mg/kg daily did not result in an increase in neuronal necrosis.301, 2, 3, 341
The effects of indomethacin on labor and delivery are unknown.301, 3, 341 In studies with rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, increased the incidence of dystocia, delayed parturition, and increased the incidence of stillbirth.301, 3, 341
Based on available data, indomethacin may be present in human milk.301, 2, 3, 341 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for indomethacin and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.301, 2, 3, 341
Females and Males of Reproductive Potential
Use of NSAIAs, including indomethacin, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.301, 2, 3, 341 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.301, 2, 3, 341 Therefore, withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.301, 2, 3, 341
Indomethacin had no effect on fertility in rats or mice at dosages up to 0.5 mg/kg daily.301, 2, 3, 341
Safety and efficacy of oral or rectal indomethacin have not been established in children ≤14 years of age.301, 2, 341 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.301, 2, 341 The manufacturers state that experience with indomethacin in these children has been limited to use of conventional capsules of the drug.301, 2, 341 Adverse effects associated with use of conventional capsules of the drug in children ≤14 years of age have been similar to those associated with use of this dosage form in adults.301, 2, 341 Hepatotoxicity (sometimes fatal) has occurred in children receiving the drug for juvenile rheumatoid arthritis.301, 2, 341 If the drug is used in children 2-14 years of age, liver function should be monitored periodically.301, 2, 341
Indomethacin should be used with caution in geriatric individuals ≥65 years of age since increasing age may be associated with increased risk of adverse reactions.301, 2, 3, 341 Geriatric individuals appear to be at a greater risk for fatal adverse GI effects (See Cautions: GI Effects).301, 2, 3, 341 Indomethacin may cause confusion or, rarely, psychosis; clinicians should remain alert to the possibility of such adverse reactions in geriatric individuals.301, 2, 3, 341
Indomethacin is eliminated mainly by the kidneys and individuals with renal impairment may be at increased risk for toxic reactions to the drug.301, 2, 3, 341 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.301, 2, 3, 341
Pharmacokinetics of indomethacin have not been evaluated in hepatic impairment.301, 2, 3, 341
Pharmacokinetics of indomethacin have not been evaluated in renal impairment.301, 2, 3, 341 Indomethacin should be avoided in patients with advanced renal disease unless the anticipated benefits are expected to outweigh the potential risks of therapy.301, 2, 3, 341 If indomethacin is used in patients with advanced renal disease, monitor for signs of worsening renal function.301, 2, 3, 341
Adverse effects reported in ≥3% of patients receiving indomethacin in clinical trials include headache, dizziness, dyspepsia, and nausea.301, 2, 3, 341
The most common adverse effects reported in neonates receiving indomethacin sodium for injection for PDA include bleeding issues, a greater incidence of transient oliguria, and elevations in serum creatinine.301
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.301
The effects of anticoagulants such as warfarin and indomethacin on bleeding are synergistic.301, 2, 3, 341 Concomitant use of indomethacin and anticoagulants is associated with a higher risk of serious bleeding compared with use of either agent alone.301, 2, 3, 341 Serotonin release by platelets also plays an important part in hemostasis.301, 2, 3, 341 Available data indicate that concomitant use of drugs that interfere with serotonin uptake (e.g., selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs]) and an NSAIA may increase the risk of bleeding versus an NSAIA alone.301, 2, 3, 341
Monitor patients for signs of bleeding when indomethacin is used concomitantly with anticoagulants (e.g., warfarin), antiplatelets (e.g., aspirin), SSRIs, or SNRIs.301, 2, 3, 341
In premature neonates with patent ductus arteriosus (PDA), closely monitor the prothrombin time when indomethacin sodium for injection is used concomitantly with an anticoagulant.301 Postmarketing reports indicate that bleeding has been reported in some neonates with concomitant use of indomethacin sodium and anticoagulants.301 Indomethacin sodium does not usually influence the hypoprothrombinemia effects of anticoagulation.301
When used concomitantly, NSAIA's can diminish the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, and beta-blockers (e.g., propranolol).301, 2, 3, 341 Additionally, in geriatric or volume-depleted patients (including those receiving diuretics), concomitant use of NSAIAs with ACE inhibitors or angiotensin receptor antagonists may cause a typically reversible deterioration in renal function and possible acute renal failure.301, 2, 3, 341
During concomitant administration of indomethacin with ACE inhibitors, angiotensin receptor antagonists, or beta-blockers, monitor blood pressure; in geriatric, renally impaired, or volume-depleted patients, also monitor for worsening renal function.301, 2, 3, 341 When indomethacin is used concomitantly with ACE inhibitors, angiotensin receptor antagonists, or beta-blockers, patients should be adequately hydrated, and renal function should be assessed at the start of treatment and periodically thereafter.301, 2, 3, 341
Concomitant administration of an NSAIA and cyclosporine may increase the nephrotoxic effects of cyclosporine.301, 2, 3, 341 If NSAIAs and cyclosporine are used concomitantly, renal function should be monitored.301, 2, 3, 341
Therapy in premature neonates with PDA and associated heart failure often includes digoxin.301 Administration of indomethacin in premature neonates receiving digoxin may further prolong the half-life of digoxin.301 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.301
In adults, serum digoxin concentrations also may be increased and elimination half-life prolonged by concomitant indomethacin administration.301, 2, 3, 341 The manufacturers state that serum digoxin concentrations should be monitored closely when indomethacin is used concomitantly.301, 2, 3, 341
Clinical studies and postmarketing reports indicate that NSAIAs reduce the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients.301, 2, 3, 341 This effect has been attributed to indomethacin-induced inhibition of renal prostaglandin synthesis.301, 2, 3, 341 When indomethacin is given with diuretics, renal function and antihypertensive effects of concomitant therapy should be assessed.301, 2, 3, 341
The addition of triamterene to a maintenance regimen with indomethacin resulted in reversible acute renal failure in 2 out of 4 healthy individuals.301, 2, 3, 341 The manufacturers recommend that the combination of indomethacin and triamterene should not be used.301, 2, 3, 341 Because indomethacin and potassium-sparing diuretics each may increase serum potassium levels, the potential additive effects of concomitant use of such agents on serum potassium levels and renal function should be considered.301, 2, 3, 341
Concomitant furosemide therapy may have a beneficial effect on renal function in premature neonates with PDA who are receiving indomethacin.301 In one study in premature neonates with PDA who received injectable indomethacin sodium or combined therapy with indomethacin and furosemide, neonates who received combined therapy had higher urine output, higher urinary excretion of sodium and chloride, and higher glomerular filtration rate than those who received indomethacin alone.301
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.301 In neonates receiving IV indomethacin sodium, consider adjusting the dosage for drugs that rely on adequate renal function for excretion.301
During concomitant use of indomethacin and lithium, a decrease in lithium renal clearance by 20% and an increase in mean lithium concentrations by 15% have been observed.301, 2, 3, 341 The mechanism involved in the reduction of lithium clearance by indomethacin has been attributed to inhibition of renal prostaglandin synthesis.301, 2, 3, 341 If indomethacin and lithium are administered concomitantly, the patient should be monitored for signs of lithium toxicity.301, 2, 3, 341
The risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) is increased when methotrexate is used concomitantly with a NSAIA (e.g., indomethacin, ketoprofen).301, 2, 3, 341 If methotrexate and a NSAIA are administered concomitantly, monitor for methotrexate toxicity.301, 2, 3, 341
Nonsteroidal Anti-inflammatory Agents and Salicylates
Concomitant use of indomethacin and another NSAIA or a salicylate (e.g., diflunisal, salsalate) is not recommended because such use may increase the possibility of adverse GI effects with little or no increase in efficacy.301, 2, 3, 341
Chronic administration of 3.6 grams of aspirin daily with indomethacin decreases plasma indomethacin concentrations by 20%.301, 2, 3, 341 In a clinical study, concomitant use of aspirin and an NSAIA significantly increased the risk for adverse GI events compared to the NSAIA alone.301, 2, 3, 341 Concomitant use of NSAIAs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone.301, 2, 3, 341 Because of the potential for increased bleeding, patients receiving indomethacin should be advised not to take aspirin.301, 2, 3, 341 There is no consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.301, 2, 3, 341
In healthy individuals, concomitant use of indomethacin and diflunisal resulted in decreased renal clearance and significantly increased plasma concentrations of indomethacin.301, 2, 3, 341 In some patients, concomitant use of indomethacin and diflunisal has been associated with fatal GI hemorrhage.301, 2, 3, 341 Concomitant use of indomethacin with diflunisal is not recommended.301, 2, 3, 341
Concomitant use of indomethacin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.301, 2, 3, 341 Administration of NSAIAs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.301, 2, 3, 341 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.301, 2, 3, 341 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant indomethacin and pemetrexed therapy.301, 2, 3, 341
When probenecid is administered concomitantly with indomethacin, plasma concentrations of indomethacin are likely to increase.301, 2, 3, 341 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.301, 2, 3, 341
False-negative results have been reported with the dexamethasone suppression test in patients receiving indomethacin, therefore, these test results should be interpreted with caution.301, 2, 3, 341 Indomethacin reduces basal plasma renin activity (PRA) and elevations in PRA caused by furosemide administration and/or sodium or volume depletion.301, 2, 3, 341 This effect must be considered when evaluating PRA in hypertensive patients.301, 2, 3, 341
Indomethacin has pharmacologic actions similar to those of other prototypical nonsteroidal anti-inflammatory agents (NSAIAs).301, 2, 3, 341 The drug exhibits anti-inflammatory, analgesic, and antipyretic activity.301, 2, 3, 341 The exact mechanisms have not been clearly established, but many actions appear to be associated principally with inhibition of prostaglandin synthesis.301, 2, 3, 341 Indomethacin inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase-1 (COX-1) and -2 (COX-2).301, 2, 3, 341 Prostaglandins are inflammatory mediators and in animal models have been shown to sensitize afferent nerves and potentiate the activity of bradykinin in inducing pain.301, 2, 3, 341
In newborn infants with certain congenital heart defects, prostaglandin E1 dilates the ductus arteriosus, and E-type prostaglandins have been shown to maintain the patency of the ductus.301 Following IV administration of indomethacin in premature neonates with patent ductus arteriosus, a transient decrease in cerebral blood flow velocity and in cerebral blood flow were observed; similar decreases in mesenteric blood flow and velocity have been observed.301 The clinical importance of these effects has not been established.301
Following oral administration of indomethacin conventional capsules, bioavailability is virtually 100%, with 90% of a single dose being absorbed within 4 hours.301 When administered orally with food, a single 50-mg dose of the oral suspension is reportedly bioequivalent to a single 50-mg conventional capsule.2 At a typical therapeutic regimen of 25-50 mg three times daily, steady-state plasma concentrations increase to 1.4 times that following the initial dose.301 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.341
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.3 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.3
Plasma concentrations of indomethacin fluctuate less and are more sustained following oral administration of a single 75-mg extended-release capsule than following oral administration of 3 doses of 25-mg conventional capsules at 4- to 6-hour intervals.341 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 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.341
The disposition of indomethacin sodium following IV administration in premature neonates with patent ductus arteriosus (PDA) has not been extensively studied.301
At therapeutic concentrations in adults, indomethacin is highly bound to plasma proteins (about 99%).301, 2, 3, 341 Plasma protein binding has not been studied in neonates, although the incidence of bilirubin encephalopathy (kernicterus) was not increased, which indicates a lack of bilirubin displacement.301 Indomethacin crosses the blood-brain barrier and the placenta.301, 2, 3, 341 The drug is distributed into breast milk.301, 2, 3, 341
In premature neonates, the serum or plasma elimination half-life of indomethacin following IV injection is inversely related to postnatal age.301 In a limited number of neonates, the mean plasma half-life of indomethacin has been reported to be about 20 hours in those receiving the drug during the first week of life, compared to about 12 hours in those receiving the drug after the first week.301 The elimination half-life in neonates may also be inversely related to body weight.301 In one study, the plasma indomethacin half-life showed considerable interindividual variation but averaged 21 hours in neonates weighing <1 kg and 15 hours in those weighing >1 kg.301
Indomethacin is metabolized in the liver to its glucuronide conjugate and to desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites and their glucuronides.301, 2, 3, 341
About 60% of an oral dose of indomethacin is excreted in urine (26% as indomethacin and its glucuronide) and 33% is excreted in feces (1.5% as indomethacin).301, 2, 3, 341 Indomethacin undergoes appreciable enterohepatic circulation.301, 341 The elimination half-life of indomethacin is approximately 4.5 hours.301, 2, 3, 341
Race does not affect the pharmacokinetics of indomethacin.301, 2, 3, 341
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 25 mg* | ||
50 mg* | Indomethacin Capsules | |||
Capsules, extended-release | 75 mg* | |||
Suspension | 25 mg/5 mL* | Zyla | ||
Indomethacin Oral Suspension | ||||
Rectal | Suppositories | 50 mg* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV use only | 1 mg (of anhydrous indomethacin) | Indomethacin Sodium for Injection |
1. Glenmark Pharmaceuticals, Inc. Indomethacin capsules prescribing information. Mahwah, NJ; 2024 Aug.
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