INDOMETHACIN
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Non-selective cyclooxygenase (COX-1 and COX-2) inhibitor, reducing prostaglandin synthesis.
| Metabolism | Primarily hepatic via O-demethylation, N-deacylation, and glucuronidation. Enzymes: CYP2C9 (minor), UGTs. |
| Excretion | Renal excretion of unchanged drug and metabolites (approximately 60% as parent drug and glucuronide conjugate; 23% as O-desmethyl metabolite; 13% as glucuronide of O-desmethyl metabolite); biliary/fecal elimination accounts for 30-40%, primarily as glucuronide conjugates. |
| Half-life | Terminal elimination half-life is approximately 4.5 hours (range 2.6-11.2 hours) in adults; prolonged in neonates (up to 17 hours) and in patients with renal impairment or cholestasis; clinical context: dosing interval adjustments needed in hepatic or renal disease. |
| Protein binding | 99% bound, primarily to albumin. |
| Volume of Distribution | 0.34-1.57 L/kg; large Vd indicates extensive tissue distribution; crosses blood-brain barrier and placenta. |
| Bioavailability | Oral: near 100% (almost complete absorption); Rectal: approximately 80% of oral; IV: 100%. |
| Onset of Action | Oral: 30 minutes (antipyretic, analgesic); Rectal: 30-60 minutes; Intravenous: rapid, within minutes for closure of ductus arteriosus. |
| Duration of Action | Oral: 4-6 hours (analgesic, antipyretic); Rectal: 4-6 hours; IV: effects on ductus closure persist for 24-48 hours after infusion; clinical note: anti-inflammatory effect may require 1-2 weeks of continuous therapy. |
| Action Class | NSAID's- Non-Selective COX 1&2 Inhibitors (acetic acid) |
25-50 mg orally 2-3 times daily; maximum 200 mg/day. Also available as 75 mg sustained-release capsule orally once daily, or 50 mg rectally 3-4 times daily.
| Dosage form | CAPSULE |
| Renal impairment | GFR 10-50 mL/min: reduce dose by 25%; GFR <10 mL/min: avoid use or reduce dose by 50%. |
| Liver impairment | Child-Pugh Class B: reduce dose by 50%; Child-Pugh Class C: avoid use. |
| Pediatric use | For patent ductus arteriosus: 0.2 mg/kg IV initially, then 0.1 mg/kg at 12-24 hour intervals, up to 3 doses. For other indications: 1-2 mg/kg/day orally in 2-4 divided doses, maximum 4 mg/kg/day. |
| Geriatric use | Initiate at lowest effective dose (e.g., 25 mg twice daily) due to increased risk of GI, renal, and CNS adverse effects. Monitor renal function and adjust accordingly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
ACE inhibitors and ARBs may have diminished antihypertensive effect Increases risk of serious cardiovascular thrombotic events and GI bleeding.
| Breastfeeding | Small amounts excreted in breast milk; M/P ratio approximately 0.4. Use with caution due to potential for adverse effects in infant (e.g., seizures, apnea); American Academy of Pediatrics considers compatible but alternatives preferred. |
| Teratogenic Risk | First trimester: Risk of cardiac defects (odds ratio 1.86) and oral clefts; second/third trimester: Premature closure of ductus arteriosus, oligohydramnios, necrotizing enterocolitis, intracranial hemorrhage; avoid after 30 weeks gestation. |
■ FDA Black Box Warning
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. Risk may be increased in patients with existing cardiovascular disease or risk factors. Indomethacin is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
| Serious Effects |
Hypersensitivity to indomethacin or other NSAIDs; History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs; Peri-operative pain in CABG surgery; Active gastrointestinal bleeding or ulcer disease; Severe uncontrolled heart failure; Advanced renal disease; Pregnancy (particularly third trimester); Lactation (use with caution).
| Precautions | Cardiovascular risk (thrombotic events, hypertension, fluid retention); Gastrointestinal risk (ulceration, bleeding, perforation); Renal risk (acute renal injury, nephrotoxicity); Hematologic (inhibition of platelet aggregation, prolonged bleeding time); Central nervous system (CNS) effects (headache, dizziness, depression, psychosis); Hepatic toxicity; Use in pregnancy (third trimester may cause premature closure of ductus arteriosus). |
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| Fetal Monitoring |
| Fetal echocardiography for ductal patency and amniotic fluid index via ultrasound; maternal renal function, platelet count, and blood pressure monitoring; avoid if significant oligohydramnios or ductal constriction. |
| Fertility Effects | Reversible inhibition of ovulation due to prostaglandin synthesis inhibition; may delay conception; no evidence of permanent infertility. |