Indomethacin

Indomethacin is a potent indole acetic acid NSAID used for acute gout, inflammatory spondyloarthropathies, indomethacin-responsive headache syndromes and closure of patent ductus arteriosus. It has the highest rate of central nervous system and gastrointestinal adverse effects of the common NSAIDs, which limits use in older adults.

Class. Nonselective NSAID (indole derivative).

Mechanism. Potent inhibition of COX-1 and COX-2. It also reduces leucocyte migration and may reduce phospholipase activity.

Pharmacokinetics. Oral bioavailability near 100%, peak at 1 to 2 hours (delayed with food). Protein binding about 99%. Half-life about 4.5 hours in adults, much longer in neonates. Enterohepatic recirculation. Hepatic metabolism (demethylation, glucuronidation) with renal and biliary excretion. It crosses the blood-brain barrier readily.

Acute gout. 50 mg orally three times daily until the attack settles (usually within a few days), then taper quickly. Maximum 200 mg daily.

Inflammatory arthritis and ankylosing spondylitis. 25 mg two to three times daily, increased by 25 to 50 mg daily at weekly intervals to a maximum of 150 to 200 mg daily. Modified-release 75 mg once or twice daily is an alternative. Rectal 100 mg at night, with an oral dose by day if needed. Maximum 200 mg in 24 hours from all routes.

Paroxysmal hemicrania and hemicrania continua (specialist). Begin 25 mg three times daily and increase by 25 mg every few days to 75 mg three times daily (higher doses are used by headache specialists). Response is usually evident within days. Add a proton pump inhibitor.

Patent ductus arteriosus in preterm infants (neonatal unit only). Three intravenous doses at 12 to 24 hour intervals. The first dose is 0.2 mg/kg. The second and third doses are 0.1 mg/kg each if the infant was under 48 hours old at the first dose, 0.2 mg/kg each if 2 to 7 days old, and 0.25 mg/kg each if over 7 days old. Urine output and creatinine decide whether to hold a dose.

Other. Tocolysis is specialist-only, short course, and limited by foetal ductal constriction and oligohydramnios. Use in children is confined to specialist indications.

Contraindications. Active or previous gastrointestinal ulcer, bleeding or perforation; severe heart failure; severe renal or hepatic impairment; third trimester; aspirin-exacerbated respiratory disease; around coronary artery bypass surgery; suspected dengue. In neonates: untreated infection, active bleeding, thrombocytopenia, necrotising enterocolitis, significant renal impairment.

Boxed-warning-level risks. Arterial thrombotic events; gastrointestinal bleeding, ulceration and perforation.

Adverse effects. Common: frontal headache, dizziness, light-headedness, nausea, dyspepsia. Serious: confusion, psychosis and depression (especially in older adults), gastrointestinal haemorrhage, acute kidney injury, hyperkalaemia, bronchospasm, hepatitis, cytopenias and severe skin reactions. In neonates: oliguria, hyponatraemia, intestinal perforation and intraventricular haemorrhage.

Interactions. Probenecid raises indomethacin levels. Raised levels of lithium, methotrexate and digoxin. Reduced efficacy of antihypertensives and loop diuretics. Additive bleeding risk with anticoagulants, antiplatelets, corticosteroids and SSRIs. Kidney injury with ACE inhibitors, angiotensin receptor blockers and diuretics. Triamterene with indomethacin can cause acute kidney injury.

Common prescribing errors. Using in older adults as a routine gout agent; omitting gastroprotection; giving the neonatal ductus course without checking urine output and platelets; exceeding 200 mg daily by combining oral and rectal doses.

Special groups

• Pregnancy: avoid; risk of premature ductal closure and oligohydramnios from 20 weeks.
• Breastfeeding: avoid if possible (rare infant seizures reported); prefer ibuprofen.
• Older adults: generally avoided because of confusion and bleeding risk.
• Kidney impairment: avoid if creatinine clearance is under 30 mL/min.
• Liver impairment: avoid in severe disease.
• Regional: avoid in dehydration and suspected dengue.

Formulations. Capsules 25 and 50 mg, modified-release capsules 75 mg, suppositories 100 mg, and intravenous powder (neonatal).

Administration. Oral doses with food, milk or an antacid. Swallow modified-release capsules whole. Reconstitute the neonatal intravenous powder with preservative-free sterile water or 0.9% sodium chloride and give by slow infusion over 20 to 30 minutes.

Baseline. Blood pressure, creatinine, ulcer history, cardiovascular risk, mental state in older adults. For neonates: urine output, creatinine, platelet count and echocardiogram.

Monitoring. Blood pressure and creatinine in the first 1 to 2 weeks of any prolonged course. Mental state and gastrointestinal symptoms. For neonates, urine output before each dose and serum creatinine, sodium, potassium and platelet count.

Therapeutic drug monitoring. Not used.

Stopping thresholds. Stop for gastrointestinal bleeding, confusion, creatinine rise of 30% or more, new heart failure, severe rash or bronchospasm. Withhold a neonatal dose if urine output is under 0.6 mL/kg/hour or creatinine is over 160 micromol/L.

Referral and escalation. Persistent headache syndromes need neurology review. Gout needing repeated courses calls for urate-lowering therapy. Neonatal ductus treatment is directed by a neonatologist.