Introduction
Indomethacin is a potent nonsteroidal anti-inflammatory drug (NSAID) belonging to the acetic acid derivative class. First approved by the FDA in 1965, it remains a valuable therapeutic agent for various inflammatory conditions. As a nonselective cyclooxygenase inhibitor, indomethacin provides potent anti-inflammatory, analgesic, and antipyretic effects, though its use requires careful consideration due to its significant adverse effect profile.
Mechanism of Action
Indomethacin exerts its therapeutic effects through nonselective inhibition of cyclooxygenase (COX) enzymes, primarily COX-1 and COX-2. This inhibition prevents the conversion of arachidonic acid to prostaglandin precursors (prostaglandin G2 and prostaglandin H2), thereby reducing the synthesis of prostaglandins, thromboxanes, and prostacyclins. These lipid mediators play crucial roles in pain perception, inflammation, fever generation, and platelet aggregation. The drug's potent anti-inflammatory effects make it particularly useful for conditions where prostaglandin-mediated inflammation is a primary component.
Indications
FDA-Approved Indications:- Moderate to severe rheumatoid arthritis, including acute flares
- Osteoarthritis
- Ankylosing spondylitis
- Acute gouty arthritis
- Acute painful shoulder (bursitis/tendinitis)
- Closure of patent ductus arteriosus in premature infants (IV formulation)
- Prevention of heterotopic ossification
- Treatment of pericarditis
- Management of migraine headaches
- Reduction of biliary pain
Dosage and Administration
Adults:- Rheumatoid arthritis/Osteoarthritis: 25-50 mg 2-3 times daily
- Acute gout: 50 mg three times daily until pain tolerable, then reduce
- Bursitis/Tendinitis: 75-150 mg daily in divided doses for 7-14 days
- Maximum daily dose: 200 mg
- Start with lowest effective dose (25 mg once or twice daily)
- Monitor closely for adverse effects
- Avoid in advanced renal disease (CrCl <30 mL/min)
- Use caution in mild to moderate impairment
- Reduce dosage and monitor closely
- Avoid in severe hepatic impairment
- Take with food or antacids to minimize GI upset
- Immediate-release capsules: with meals
- Sustained-release formulations: may be taken without regard to meals
- Do not crush or chew sustained-release capsules
Pharmacokinetics
Absorption: Well absorbed from GI tract; bioavailability >90% Distribution: Widely distributed throughout body tissues; crosses placenta and blood-brain barrier; 99% protein-bound Metabolism: Extensive hepatic metabolism via O-demethylation, N-deacylation, and glucuronidation Elimination: Primarily renal excretion (60%) with some fecal elimination; half-life 4.5 hours (range 2-11 hours) Onset of Action: 1-2 hours for analgesic effect; 1-4 weeks for full anti-inflammatory effectContraindications
- Hypersensitivity to indomethacin, other NSAIDs, or aspirin
- History of asthma, urticaria, or allergic reactions after taking NSAIDs
- Perioperative pain in coronary artery bypass graft (CABG) surgery
- Third trimester of pregnancy
- Significant renal impairment
- Active peptic ulcer disease or GI bleeding
- Inflammatory bowel disease
Warnings and Precautions
Cardiovascular Risk: Increased risk of serious cardiovascular thrombotic events, MI, and stroke GI Risk: Significant risk of GI bleeding, ulceration, and perforation Hepatotoxicity: May cause severe hepatic reactions; monitor LFTs Renal Effects: May cause renal papillary necrosis and other renal injury Hypertension: Can worsen or cause new-onset hypertension Heart Failure: Increased risk of fluid retention and heart failure Hematologic Effects: May inhibit platelet aggregation and cause anemia Ophthalmic Effects: Corneal deposits and retinal disturbances reportedDrug Interactions
Anticoagulants: Increased risk of bleeding with warfarin, heparin, direct oral anticoagulants Antihypertensives: Reduced effectiveness of ACE inhibitors, ARBs, beta-blockers, diuretics Lithium: Increased lithium levels and toxicity risk Methotrexate: Increased methotrexate toxicity Other NSAIDs: Avoid concomitant use due to additive toxicity Cyclosporine: Increased nephrotoxicity risk SSRIs/SNRIs: Increased risk of GI bleeding Corticosteroids: Increased GI ulcer risk Pemetrexed: Increased pemetrexed concentrations and toxicityAdverse Effects
Common (>10%):- Headache (12%)
- Dizziness (3-9%)
- Dyspepsia, nausea, abdominal pain (3-10%)
- Diarrhea (3-9%)
- GI bleeding and perforation
- Acute renal failure
- Hepatotoxicity
- Stevens-Johnson syndrome
- Aseptic meningitis
- Anaphylactoid reactions
- Cardiovascular thrombotic events
- Severe skin reactions
- Tinnitus
- Edema
- Hypertension
- Depression
- Confusion (especially in elderly)
Monitoring Parameters
Baseline:- Complete blood count
- Renal function tests (BUN, creatinine)
- Liver function tests
- Blood pressure
- GI history and symptoms
- CBC every 6-12 months
- Renal function every 3-6 months
- LFTs periodically
- Blood pressure at each visit
- GI symptoms at each encounter
- Efficacy assessment (pain scales, functional status)
- Signs of fluid retention
- Elderly patients: more frequent monitoring
- Patients with cardiovascular risk factors: regular cardiovascular assessment
- Long-term users: annual comprehensive evaluation
Patient Education
- Take with food or milk to reduce stomach upset
- Report any signs of GI bleeding (black stools, abdominal pain, vomiting blood)
- Watch for signs of cardiovascular events (chest pain, shortness of breath, weakness)
- Monitor for edema and weight gain
- Avoid alcohol consumption during therapy
- Do not take other NSAIDs or aspirin-containing products
- Report vision changes or eye pain immediately
- Use caution when driving or operating machinery due to possible dizziness
- Inform all healthcare providers of indomethacin use
- Seek immediate medical attention for signs of allergic reaction
- Do not use during third trimester of pregnancy
- Store at room temperature away from moisture
References
1. Drugs.com. Indomethacin Professional Monograph. 2023 2. American College of Rheumatology. Guidelines for NSAID Use. Arthritis Care Res. 2020 3. FDA Prescribing Information: Indomethacin Capsules. 2022 4. UpToDate. Indomethacin: Drug Information. Wolters Kluwer, 2023 5. BMJ Best Practice. NSAID Prescribing and Monitoring. 2023 6. Micromedex Solutions. Indomethacin Detailed monograph. Truven Health Analytics, 2023 7. Clinical Pharmacology [Internet]. Indomethacin. Elsevier, 2023 8. American Gastroenterological Association. Management of NSAID-Related Ulcer Complications. Gastroenterology. 2021 9. European League Against Rheumatism. Recommendations for NSAID Use. Ann Rheum Dis. 2022 10. National Institutes of Health. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2023
Note: This monograph provides general information and should not replace professional medical advice. Always consult with a healthcare provider for specific medical guidance.