indication

For moderate to severe rheumatoid arthritis including acute flares of chronic disease, ankylosing spondylitis, osteoarthritis, acute painful shoulder (bursitis and/or tendinitis) and acute gouty arthritis.

pharmacology

Indomethacin, a NSAIA, with analgesic and antipyretic properties exerts its pharmacological effects by inhibiting the synthesis of prostaglandins involved in pain, fever, and inflammation. Indomethacin inhibits the catalytic activity of the COX enzymes, the enzymes responsible for catalyzing the rate-limiting step in prostaglandin synthesis via the arachidonic acid pathway. Indomethacin is known to inhibit two well-characterized isoforms of COX, COX-1 and COX-2, with greater selectivity for COX-1. COX-1 is a constitutively expressed enzyme that is involved in gastric mucosal protection, platelet and kidney function. It catalyzes the conversion of arachidonic acid to prostaglandin (PG) G2 and PGG2 to PGH2. COX-1 is involved in the synthesis pathways of PGE2, PGD2, PDF2a, PGI2 (also known as prostacyclin) and thromboxane A2 (TXA2). COX-2 is constitutively expressed and highly inducible by inflammatory stimuli. It is found in the central nervous system, kidneys, uterus and other organs. It also catalyzes the conversion of arachidonic acid to PGG2 and PGG2 to PGH2. In the COX-2-mediated pathway, PGH2 is subsequently converted to PGE2 and PGI2 (also known as prostacyclin). PGE2 is involved in mediating inflammation, pain and fever. Decreasing levels of PGE2 leads to decreased inflammation.

mechanism of action

Indomethacin is a prostaglandin G/H synthase (also known as cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. Indomethacin antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Indomethacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. Indomethacin is more selective for COX-1 than COX-2, which accounts for its increased adverse gastric effects relative to other NSAIDs. COX-1 is required for maintaining the protective gastric mucosal layer. The analgesic, antipyretic and anti-inflammatory effects of indomethacin occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation.

toxicity

The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. There have been reports of paresthesias, numbness, and convulsions. The oral LD₅₀ of indomethacin in mice and rats (based on 14 day mortality response) was 50 and 12 mg/kg, respectively.

biotransformation

Hepatic.

absorption

Bioavailability is approximately 100% following oral administration and 80–90% following rectal administration.

half life

4.5 hours

route of elimination

Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion.

drug interactions

Acebutolol: Risk of inhibition of renal prostaglandins

Acenocoumarol: The NSAID, indomethacin, may increase the anticoagulant effect of acenocoumarol.

Alendronate: Increased risk of gastric toxicity

Anisindione: The NSAID, indomethacin, may increase the anticoagulant effect of anisindione.

Atenolol: Risk of inhibition of renal prostaglandins

Betaxolol: Nonsteroidal Anti-Inflammatory Agents such as indomethacin may diminish the antihypertensive effect of Beta-Blockers such as betaxolol. Monitor for increases in blood pressure if a nonsteroidal anti-inflammatory agent (NSAID) is initiated/dose increased, or decreases in blood pressure if a NSAID is discontinued/dose decreased; this is particularly important if NSAID treatment is for extended periods of time. Ophthalmic beta-blockers are likely of little concern.

Bevantolol: Risk of inhibition of renal prostaglandins

Bisoprolol: Risk of inhibition of renal prostaglandins

Bumetanide: The NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, bumetanide.

Carteolol: Risk of inhibition of renal prostaglandins

Carvedilol: Risk of inhibition of renal prostaglandins

Colesevelam: Bile acid sequestrants may decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Monitor for decreased serum concentrations/therapeutic effects of nonsteroidal anti-inflammatory agents (NSAID) if coadministered with bile acid sequestrants. Separating the administration of doses by 2 or more hours may reduce (but not eliminate) the risk of interaction. The manufacturer of colesevelam recommends that drugs should be administered at least 1 hour before or 4 hours after colesevelam.

Cyclosporine: Monitor for nephrotoxicity

Dicumarol: The NSAID, indomethacin, may increase the anticoagulant effect of dicumarol.

Diflunisal: Concomitant therapy with the two NSAIDs, indomethacin and diflunisal, increases the risk of NSAID-related adverse effects (e.g. GI ulcers, bleeds, increased blood pressure).

Esmolol: Risk of inhibition of renal prostaglandins

Ethacrynic acid: The NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, ethacrynic acid.

Furosemide: The NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, furosemide.

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Labetalol: Risk of inhibition of renal prostaglandins

Lithium: The NSAID, indomethacin, may decrease the renal excretion of lithium. Increased risk of lithium toxicity.

Losartan: Indomethacin decreases the effect of losartan

Methotrexate: The NSAID, indomethacin, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Metoprolol: Risk of inhibition of renal prostaglandins

Nadolol: Risk of inhibition of renal prostaglandins

Oxprenolol: Risk of inhibition of renal prostaglandins

Penbutolol: Risk of inhibition of renal prostaglandins

Pindolol: Risk of inhibition of renal prostaglandins

Practolol: Risk of inhibition of renal prostaglandins

Probenecid: Probenecid increases the effect/toxicity of indomethacin

Propranolol: Risk of inhibition of renal prostaglandins

Sotalol: Risk of inhibition of renal prostaglandins

Tamoxifen: Indomethacin may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Indomethacin is initiated, discontinued or dose changed.

Telmisartan: Concomitant use of Telmisartan and Indomethacin may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Timolol: Risk of inhibition of renal prostaglandins

Tolbutamide: Indomethacin, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Indomethacin is initiated, discontinued or dose changed.

Torasemide: The NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, torasemide.

Trandolapril: The NSAID, Indomethacin, may reduce the antihypertensive effect of Trandolapril. Consider alternate therapy or monitor for changes in Trandolapril efficacy if Indomethacin is initiated, discontinued or dose changed.

Treprostinil: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Indomethacin. Monitor for increased bleeding during concomitant thearpy.

Triamterene: Risk of acute renal impairment with this combination

Trimethoprim: The strong CYP2C9 inhibitor, Indomethacine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Indomethacine is initiated, discontinued or dose changed.

Voriconazole: Indomethacin, a strong CYP2C9 inhibitor, may increase the serum concentration of voriconazole by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of voriconazole if indomethacin is initiated, discontinued or dose changed.

Warfarin: Indomethacin, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. The antiplatelet effect of indomethacin may also increase the bleed risk associated with warfarin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of warfarin if indomethacin is initiated, discontinued or dose changed.