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Indomethacin

Pronunciation

Pronunciation

(in doe METH a sin)

Index Terms

  • Indomethacin
  • Indomethacin Sodium Trihydrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Tivorbex: 20 mg, 40 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #2 (indigotine), fd&c red #40]

Generic: 25 mg, 50 mg

Capsule Extended Release, Oral:

Generic: 75 mg

Solution Reconstituted, Intravenous:

Indocin: 1 mg (1 ea)

Generic: 1 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 1 mg (1 ea)

Suppository, Rectal:

Indocin: 50 mg (30 ea)

Suspension, Oral:

Indocin: 25 mg/5 mL (237 mL) [contains alcohol, usp; pineapple-coconut-mint flavor]

Brand Names: U.S.

  • Indocin
  • Tivorbex

Pharmacologic Category

  • Nonsteroidal Anti-inflammatory Drug (NSAID), Oral
  • Nonsteroidal Anti-inflammatory Drug (NSAID), Parenteral

Pharmacology

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

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

Absorption

Oral: Immediate release: Neonates: Formulation specific; Adults: Prompt and extensive; Extended release: Adults: 90% over 12 hours (Note: 75 mg product is designed to initially release 25 mg and then 50 mg over an extended period of time)

Distribution

Crosses blood-brain barrier; Neonates: PDA: 0.36 L/kg; Post-PDA closure: 0.26 L/kg; Adults: 0.34-1.57 L/kg

Metabolism

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

Excretion

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

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

Onset of Action

~30 minutes

Time to Peak

Oral: Immediate release: 2 hours; Tivorbex capsules: 1.67 hours

Duration of Action

4 to 6 hours

Half-Life Elimination

Neonates: Postnatal age (PNA) <2 weeks: ~20 hours; PNA >2 weeks: ~11 hours

Adults: 2.6-11.2 hours; 7.6 hours (Tivorbex)

Protein Binding

99%

Use: Labeled Indications

Acute pain, mild to moderate (Tivorbex only): Treatment of mild to moderate acute pain in adults

Arthritis (excluding Tivorbex): Treatment of moderate to severe rheumatoid arthritis (RA), including acute flares of chronic disease; moderate to severe osteoarthritis (OA); acute gouty arthritis (except extended-release [ER] capsules)

Inflammatory conditions (excluding Tivorbex): Treatment of moderate to severe ankylosing spondylitis; acute painful bursitis and/or tendinitis of the shoulder (excluding Canadian products)

Patent ductus arteriosus (IV only): To close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g when 48 hours usual medical management (eg, fluid restriction, diuretics, digitalis, respiratory support) is ineffective.

Use: Unlabeled

Management of preterm labor; prevention of pancreatitis post-endoscopic retrograde cholangiopancreatography (ERCP)

Contraindications

Hypersensitivity (eg, anaphylactic reactions, serious skin reactions) to indomethacin, aspirin, other NSAIDs, or any component of the formulation; perioperative pain in the setting of coronary artery bypass graft (CABG) surgery; history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAID agents (severe, even fatal, anaphylactic-like reactions have been reported); patients with a history of proctitis or recent rectal bleeding (suppositories)

Neonates (IV only): Necrotizing enterocolitis (proven or suspected); significant renal impairment; active bleeding (including intracranial hemorrhage and gastrointestinal bleeding), thrombocytopenia, coagulation defects; untreated infection (proven or suspected); congenital heart disease where patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (eg, pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta)

Canadian labeling: Additional contraindications (not in US labeling): Severe uncontrolled heart failure; known hyperkalemia; active gastric/duodenal/peptic ulcer; active GI bleed; history of recurrent GI ulceration; active GI inflammatory disease; cerebrovascular bleeding or other bleeding disorders; severe hepatic impairment or active liver disease; severe renal impairment (CrCl <30 mL/minute) or deteriorating renal function; concurrent use with other NSAIDs; complete or partial syndrome of nasal polyps; children and adolescents <14 years of age; breast-feeding; pregnancy (third trimester)

Dosage

Patent ductus arteriosus:

Neonates weighing between 500 to 1,750 g: IV: Initial: 0.2 mg/kg, followed by 2 doses depending on postnatal age (PNA):

PNA at time of first dose <48 hours: 0.1 mg/kg at 12- to 24-hour intervals

PNA at time of first dose 2 to 7 days: 0.2 mg/kg at 12- to 24-hour intervals

PNA at time of first dose >7 days: 0.25 mg/kg at 12- to 24-hour intervals

Note: In general, may use 12-hour dosing interval if urine output >1 mL/kg/hour after prior dose; use 24-hour dosing interval if urine output is <1 mL/kg/hour but >0.6 mL/kg/hour. Doses should be withheld if patient has oliguria (urine output <0.6 mL/kg/hour) or anuria at the scheduled time of the second or third dose; do not give additional doses until renal function has returned to normal. If the ductus arteriosus closes or is significantly reduced in size after 48 hours or more from completion of first course, no further doses are necessary. If the ductus arteriosus reopens, a second course of 1 to 3 doses may be given; if unresponsive after 2 doses, surgery may be necessary.

Inflammatory/rheumatoid disorders: Note: Use lowest effective dose for the shortest duration possible. Canadian labeling contraindicates use in children and adolescents <14 years.

Children ≥2 years (limited data available):

Oral (excluding extended-release capsules and Tivorbex): Initial: 1 to 2 mg/kg/day in 2 to 4 divided doses; maximum daily dose: 4 mg/kg/day or 200 mg/day, whichever is less

Adolescents >14 years and Adults:

Oral (immediate-release [excluding Tivorbex]), rectal: 25 mg 2 to 3 times daily; if well tolerated, increase daily dosage by 25 or 50 mg at weekly intervals until satisfactory response or a total daily dose of 150 to 200 mg/day (maximum dose: 200 mg/day) is reached. In patients with arthritis and persistent night pain and/or morning stiffness may give the larger portion (up to maximum of 100 mg) of the total daily dose at bedtime.

Oral (extended-release capsule): Initial: 75 mg once daily, may increase to 75 mg twice daily (maximum dose: 150 mg/day).

Bursitis/tendonitis of the shoulder: Oral (excluding Tivorbex and Canadian products), rectal (excluding Canadian products): Adults: Initial dose: 75 to 150 mg/day in 3 to 4 divided doses or 1 to 2 divided doses for extended release; usual treatment is 7 to 14 days; discontinue after signs/symptoms of inflammation have been controlled for several days.

Acute gouty arthritis: Oral (excluding extended-release capsules and Tivorbex), rectal: Adults: 50 mg 3 times daily until pain is tolerable then rapidly reduce dose to complete cessation of drug; usual treatment <3 to 5 days

Acute pain (mild to moderate): Adults: Oral (Tivorbex only): 20 mg 3 times daily or 40 mg 2 or 3 times daily

Prevention of pancreatitis post-endoscopic retrograde cholangiopancreatography (ERCP) (off-label use): Rectal: Adults: 100 mg immediately after ERCP (Elmunzer, 2012)

Elderly: Refer to adult dosing. Use lowest recommended dose and frequency in elderly to initiate therapy for indications listed in adult dosing.

Dosage adjustment in renal impairment:

US labeling:

Oral/rectal: There are no dosage adjustments provided in the manufacturer’s labeling; not recommended in patients with advanced renal disease.

Injection: If anuria or marked oliguria (urinary output <0.6 mL/kg/hour) evident at the scheduled time of the second or third dose, hold dose until renal function returns to normal. Use is contraindicated in neonates with significant renal impairment.

Canadian labeling:

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and consider lower doses.

Severe impairment (CrCl <30 mL/minute) or deteriorating renal function: Use is contraindicated.

Dosage adjustment in hepatic impairment:

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling. Use is contraindicated in severe liver impairment or active liver disease.

Reconstitution

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

Administration

Oral: Administer with food, immediately after meals, or with milk or antacids to decrease GI adverse effects. Extended-release capsules must be swallowed whole; do not crush.

IV: Administer over 20 to 30 minutes. Reconstitute IV formulation just prior to administration; discard any unused portion; avoid IV bolus administration or infusion via an umbilical catheter into vessels near the superior mesenteric artery as these may cause vasoconstriction and can compromise blood flow to the intestines. Do not administer intra-arterially. Avoid extravascular injection or leakage; solution may be irritating to tissue.

Dietary Considerations

May cause GI upset; take with food or milk to minimize

Compatibility

Stable in NS.

Y-site administration: Incompatible with amino acid injection, calcium gluconate, cimetidine, dobutamine, dopamine, gentamicin, levofloxacin, pantoprazole, tobramycin.

Compatibility in syringe: Incompatible with pantoprazole.

Storage

Capsules: Store at 20°C to 25°C (68°F to 77°F). Protect ER capsules from moisture.

Tivorbex: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in the original container; protect from moisture and light.

IV: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Store vials in original carton until contents used.

Suppositories: Store refrigerated at 2°C to 8°C (36°F to 46°F).

Canadian labeling: Store below 30°C (86°F). Protect from light; elevated humidity; and excessive heat.

Suspension: Store below 30°C (86°F). Avoid temperatures above 50°C (122°F). Protect from freezing.

Drug Interactions

5-ASA Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-ASA Derivatives. Monitor therapy

ACE Inhibitors: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of GI bleeding may be increased with this combination. Monitor therapy

Aliskiren: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Aliskiren. Management: Monitor renal function periodically in patients receiving aliskiren and any nonsteroidal anti-inflammatory agent. Patients at elevated risk of renal dysfunction include those who are elderly, are volume depleted, or have pre-existing renal dysfunction. Monitor therapy

Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants. Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Anticoagulants: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antidepressants (Tricyclic, Tertiary Amine): May enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

Apixaban: NSAID (Nonselective) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of apixaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Consider therapy modification

Bisphosphonate Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of NSAID (Nonselective). Monitor therapy

CycloSPORINE (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Specifically, elevated diclofenac concentrations have been reported. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (e.g., hypertension) during concomitant therapy with NSAIDs. Consider therapy modification

Dabigatran Etexilate: NSAID (Nonselective) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of dabigatran and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Deferasirox: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Diclofenac (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Seek alternatives to the combined use of diclofenac with other nonsteroidal anti-inflammatory agents (NSAIDs). Avoid the use of diclofenac/misoprostol with other NSAIDs. Consider therapy modification

Digoxin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Digoxin. Monitor therapy

Drospirenone: Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

Edoxaban: NSAID (Nonselective) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of edoxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Eplerenone: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Eplerenone. Monitor therapy

Floctafenine: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Glucagon: Indomethacin may diminish the therapeutic effect of Glucagon. Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Haloperidol: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Haloperidol. Specifically including drowsiness and confusion. Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Management: Concomitant treatment with these agents should generally be avoided. If used concomitantly, increased diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds) must be employed. Consider therapy modification

HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of HydrALAZINE. Monitor therapy

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Ketorolac (Nasal): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Ketorolac (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Lithium: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. Consider therapy modification

Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Consider therapy modification

Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Methotrexate. Management: Alternative anti-inflammatory therapy should be considered whenever possible, especially if the patient is receiving higher, antineoplastic doses of methotrexate. Consider therapy modification

Morniflumate: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of other Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

NSAID (COX-2 Inhibitor): Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of NSAID (COX-2 Inhibitor). Avoid combination

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of nonsteroidal antiinflammatory drugs (NSAIDs) with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

PEMEtrexed: NSAID (Nonselective) may increase the serum concentration of PEMEtrexed. Management: Patients with mild-to-moderate renal insufficiency (estimated creatinine clearance 45-79 mL/min) should avoid NSAIDs for 2-5 days prior to, the day of, and 2 days after pemetrexed. Consider therapy modification

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Potassium-Sparing Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

PRALAtrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum levels and/or toxicity if used concomitantly with an NSAID. Monitor for decreased pralatrexate serum levels with NSAID discontinuation. Monitor therapy

Probenecid: May increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Prostaglandins (Ophthalmic): Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Monitor therapy

Quinolone Antibiotics: Nonsteroidal Anti-Inflammatory Agents may enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolone Antibiotics. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolone Antibiotics. Monitor therapy

Rivaroxaban: NSAID (Nonselective) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of rivaroxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Salicylates: NSAID (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. NSAID (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of NSAID (Nonselective). Exceptions: Choline Magnesium Trisalicylate. Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of NSAID (Nonselective). NSAID (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider using alternative analgesics, when appropriate, and/or addition of a gastroprotective agent. Monitor patients closely for signs/symptoms of bleeding, and for evidence of diminished SSRI effectiveness with concurrent use. Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

Sodium Phosphates: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with NSAIDs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tacrolimus (Systemic). Monitor therapy

Talniflumate: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Tenofovir Products: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Thiazide Diuretics: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide Diuretics. Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tiludronate: Indomethacin may increase the serum concentration of Tiludronate. Management: Separate doses of tiludronate at least two hours before or two hours after indomethacin. Consider therapy modification

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Treprostinil: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Monitor therapy

Triamterene: Indomethacin may enhance the nephrotoxic effect of Triamterene. Management: Consider alternatives to concomitant treatment with triamterene and indomethacin. If the combination cannot be avoided, monitor for development of renal failure. Consider therapy modification

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vancomycin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Vancomycin. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin E: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin E (Oral): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): NSAID (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Test Interactions

False-negative dexamethasone suppression test

Adverse Reactions

>10%:

Central nervous system: Headache (12% to 16%)

Gastrointestinal: Vomiting (≤12%)

Hematologic & oncologic: Postoperative hemorrhage (≤11%)

1% to 10%:

Cardiovascular: Presyncope (≤3%), syncope (≤2%)

Central nervous system: Dizziness (3% to 9%), depression (<3%), drowsiness (<3%), fatigue (<3%), malaise (<3%), vertigo (<3%)

Dermatologic: Pruritus (1% to 4%), hyperhidrosis (2%), skin rash (1% to 2%)

Endocrine & metabolic: Hot flash (2%)

Gastrointestinal: Epigastric pain (3% to 9%), heartburn (3% to 9%), nausea (3% to 9%), dyspepsia (2% to 9%), constipation (≤6%), diarrhea (≤3%), abdominal pain (<3%), decreased appetite (≥2%), rectal irritation (suppository), tenesmus (suppository)

Otic: Tinnitus (<3%)

Miscellaneous: Swelling (3%; postprocedural)

<1% (Limited to important or life-threatening): Acute respiratory distress, agranulocytosis, anaphylaxis, anemia, angioedema, aphthous stomatitis, aplastic anemia, aseptic meningitis, asthma, bone marrow depression, cardiac arrhythmia, cardiac failure, cerebrovascular accident, chest pain, cholestatic jaundice, coma, confusion, convulsions, corneal deposits, depersonalization, depression, diplopia, disseminated intravascular coagulation, dysarthria, edema, erythema multiforme, erythema nodosum, exacerbation of epilepsy, exacerbation of Parkinson’s disease, exfoliative dermatitis, fluid retention, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal perforation (rare), gastrointestinal ulcer, glycosuria, gynecomastia, hearing loss, hematuria, hemodynamic deterioration (patients with severe heart failure and hyponatremia), hemolytic anemia, hepatic failure, hepatic necrosis, hepatitis (including fatal cases), hepatotoxicity (idiosyncratic) (Chalasani, 2014), hyperglycemia, hyperkalemia, hypersensitivity reaction, hypertension, hypotension, immune thrombocytopenia, interstitial nephritis, intestinal obstruction, intestinal stenosis, involuntary muscle movements, jaundice, leukopenia, maculopathy, myocardial infarction, necrotizing fasciitis, nephrotic syndrome, oliguria, peripheral neuropathy, proctitis, psychosis, pulmonary edema, purpura, rectal hemorrhage, regional ileitis, renal failure, renal insufficiency, retinal disturbance, shock, significant cardiovascular event, Stevens-Johnson syndrome, stomatitis, syncope, thrombocytopenia, thrombophlebitis, toxic amblyopia, toxic epidermal necrolysis, ulcerative colitis, vaginal hemorrhage

ALERT: U.S. Boxed Warning

Cardiovascular risk:

Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic reactions, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at a greater risk.

Indomethacin is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal risks:

NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse reactions, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These reactions can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious GI reactions.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Do not use in patients who experience bronchospasm, asthma, rhinitis, or urticaria with NSAID or aspirin therapy.

• Cardiovascular events: [US Boxed Warning]: NSAIDs are associated with an increased risk of adverse cardiovascular thrombotic events, including MI and stroke. Risk may be increased with duration of use or pre-existing cardiovascular risk factors or disease. Carefully evaluate individual cardiovascular risk profiles prior to prescribing. Use caution in patients with fluid retention. Avoid use in heart failure (ACCF/AHA [Yancy, 2013]). Concurrent administration of ibuprofen, and potentially other nonselective NSAIDs, may interfere with aspirin’s cardioprotective effect. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.

• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Headache may occur; cessation of therapy required if headache persists after dosage reduction.

• Gastrointestinal events: [US Boxed Warning]: NSAIDs may increase risk of gastrointestinal irritation, inflammation, ulceration, bleeding, and perforation. These events may occur at any time during therapy and without warning. Use caution with a history of GI disease (bleeding or ulcers), concurrent therapy with aspirin, anticoagulants and/or corticosteroids, smoking, use of alcohol, the elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of gastrointestinal complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt, 2008).

• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).

• Hepatic effects: Notable elevations of ALT or AST (eg, >3 x ULN) have been reported. Severe hepatic reactions (eg, jaundice, fulminant hepatitis, liver necrosis, liver failure) have occurred with NSAID use, some with fatal outcomes; discontinue immediately if clinical signs or symptoms of liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash).

• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.

• Ophthalmic effects: Prolonged therapy may cause corneal deposits and retinal disturbances, including those of the macula. Discontinue use with blurred or diminished vision and perform ophthalmologic exam. Periodically evaluate vision in all patients receiving long-term therapy.

• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation. Patients with impaired renal function, dehydration, heart failure, liver dysfunction, those taking diuretics, and ACE inhibitors, and the elderly are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Long-term NSAID use may result in renal papillary necrosis and other renal injury.

• Skin reactions: NSAIDs may cause potentially fatal serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); discontinue use at first sign of skin rash or hypersensitivity.

Disease-related concerns:

• Asthma: Use is contraindicated in patients with aspirin-sensitive asthma; severe bronchospasm may occur, which can be fatal. Use caution in patients with other forms of asthma.

• Coronary artery bypass graft surgery: [US Boxed Warning]: Use is contraindicated for treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery.

• Depression: Use caution with depression; use may aggravate depression or other psychiatric disorders.

• Epilepsy: Use caution with epilepsy; use may aggravate this condition.

• Hepatic impairment: Use with caution in patients with decreased hepatic function. Closely monitor patients with any abnormal LFT. Canadian labeling contraindicates use in severe hepatic impairment or active liver disease.

• Hypertension: Use with caution; may cause new-onset hypertension or worsening of existing hypertension. Monitor blood pressure closely during initiation of treatment and throughout the course of therapy.

• Parkinsonism: Use caution with Parkinson’s disease; use may aggravate this condition.

• Renal impairment: Not recommended for use in patients with advanced renal disease; monitor closely if therapy must be initiated. The injection formulation is contraindicated in neonates with significant renal impairment. Canadian labeling contraindicates use in severe renal impairment (CrCl <30 mL/minute) or deteriorating renal function.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Nonselective oral NSAID use is associated with an increased risk of GI bleeding and peptic ulcer disease in older adults in high risk category (eg, >75 years or age or receiving concomitant oral/parenteral corticosteroids, anticoagulants, or antiplatelet agents). Risk of adverse events may be higher with indomethacin compared to other NSAIDs; avoid use in this age group (Beers Criteria). Indomethacin may cause confusion or, rarely, psychosis; remain alert to the possibility of such adverse reactions in elderly patients.

• Pediatric: Oral: There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. Closely monitor if needed in pediatric patients ≥2 years and periodically assess liver function.

Other warnings/precautions:

• Appropriate use: Tivorbex is not indicated for long-term use.

• Surgical/dental procedures: Withhold for at least 4 to 6 half-lives prior to surgical or dental procedures.

Monitoring Parameters

Monitor response (pain, range of motion, grip strength, mobility, ADL function), inflammation; observe for weight gain, edema; monitor renal function (serum creatinine, BUN); observe for bleeding, bruising; evaluate gastrointestinal effects (abdominal pain, bleeding, dyspepsia); mental confusion, disorientation, CBC, blood pressure, liver function tests (particularly with pediatric use); ophthalmologic exams with prolonged therapy

Pregnancy Risk Factor

C (<30 weeks gestation); C/D (≥30 weeks gestation [manufacturer specific])

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies; studies in pregnant women have demonstrated risk to the fetus if administered at ≥30 weeks gestation. Indomethacin crosses the placenta and can be detected in fetal plasma and amniotic fluid. Indomethacin exposure during the first trimester is not strongly associated with congenital malformations; however, cardiovascular anomalies and cleft palate have been observed following NSAID exposure in some studies. The use of an NSAID close to conception may be associated with an increased risk of miscarriage. Nonteratogenic effects have been observed following NSAID administration during the third trimester, including myocardial degenerative changes, prenatal constriction of the ductus arteriosus, failure of the ductus arteriosus to close postnatally, and fetal tricuspid regurgitation; renal dysfunction or failure, oligohydramnios; gastrointestinal bleeding or perforation, increased risk of necrotizing enterocolitis; intracranial bleeding (including intraventricular hemorrhage), platelet dysfunction with resultant bleeding; and pulmonary hypertension. The risk of fetal ductal constriction following maternal use of indomethacin is increased with gestational age and duration of therapy. Because they may cause premature closure of the ductus arteriosus, use of NSAIDs late in pregnancy should be avoided (use after 31 or 32 weeks gestation is not recommended by some clinicians). Indomethacin has been used for a short duration (eg, ≤48 hours) in the management of preterm labor. Indomethacin should be used with caution in pregnant women with hypertension. The chronic use of NSAIDs in women of reproductive age may be associated with infertility that is reversible upon discontinuation of the medication. Use during pregnancy (third trimester) is contraindicated in the Canadian labeling.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience pyrosis, diarrhea, constipation, flatulence, fatigue, or rectal irritation. Have patient report immediately to prescriber signs of hepatic impairment, signs of hemorrhaging, signs of renal impairment, dyspnea, excessive weight gain, edema of extremities, angina, tachycardia, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, considerable headache, severe dizziness, syncope, significant asthenia, vision changes, tinnitus, mood changes, depression, intolerable nausea, severe dyspepsia, considerable back pain, hematochezia, rectal pain, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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