Acemetacin

• Approved Indications
• Osteoarthritis: For the symptomatic treatment of osteoarthritis, particularly joint pain and stiffness.
• Rheumatoid Arthritis: To reduce inflammation, swelling, and pain associated with RA.
• Ankylosing Spondylitis: Used for spinal stiffness and inflammation.
• Acute Gouty Arthritis: For short-term treatment of acute gout attacks.
• Postoperative and Post-traumatic Inflammation: Indicated for musculoskeletal pain due to injury or surgery.
• Clinically Accepted Off-label Uses
• Tendinitis, Bursitis, and Non-specific Musculoskeletal Pain: Sometimes used for localized inflammation when NSAID therapy is appropriate.
• Dysmenorrhea (painful menstruation): Off-label in some countries for short-term relief.

• Adults
• Usual dose: 60 to 90 mg daily, given in divided doses or as a single sustained-release dose (e.g., 90 mg once daily).
• Acute conditions (e.g., gout): May require higher short-term dosing, such as 60 mg twice daily for 3–5 days.
• Elderly
• Start at the lowest effective dose due to higher risk of gastrointestinal and renal side effects. Monitor renal function and GI symptoms regularly.
• Renal Impairment
• Contraindicated in severe renal impairment. Use cautiously and with dose adjustment in mild to moderate impairment.
• Hepatic Impairment
• Use with caution; monitor liver function tests regularly.
• Pediatric Use
• Not recommended. Safety and efficacy not established in individuals under 18 years.
• Administration Notes
• Take with food or after meals to reduce gastrointestinal irritation.
• Swallow capsules whole; do not crush or chew.
• Ensure adequate hydration during long-term therapy.

Acemetacin is a prodrug that is rapidly converted in the body to indometacin, its active metabolite. Indometacin non-selectively inhibits cyclooxygenase (COX-1 and COX-2) enzymes, thereby decreasing the synthesis of prostaglandins involved in inflammation, pain, fever, and swelling. The inhibition of prostaglandin production results in reduced vascular permeability, leukocyte migration, and pain sensitization at sites of inflammation.

• Absorption: Rapidly absorbed from the gastrointestinal tract; peak plasma concentrations of acemetacin occur within 1–2 hours.
• Bioactivation: Undergoes first-pass metabolism to active metabolite indometacin, which is responsible for the pharmacological effects.
• Distribution: Widely distributed; highly protein-bound (>90%).
• Metabolism: Hepatic metabolism to indometacin and other inactive metabolites.
• Excretion: Excreted via urine (60%) and feces (40%) as metabolites.
• Half-life: Elimination half-life of indometacin is approximately 4–5 hours, but therapeutic effects may last longer due to accumulation in inflamed tissues.

• Pregnancy:
• FDA Category C (first and second trimester); Category D (third trimester) due to risk of premature closure of the ductus arteriosus and fetal renal toxicity. Avoid use, especially in the third trimester.
• Lactation:
• Indometacin (active metabolite) is excreted in breast milk in small amounts. Potential for adverse effects (e.g., renal, GI, or cardiovascular issues) in the nursing infant exists. Use only if clearly needed.
• General advice: Avoid in late pregnancy; use with caution during lactation or consider alternative NSAIDs with more established safety data.

• Primary Class: Nonsteroidal Anti-inflammatory Drug (NSAID).
• Subclass: Indoleacetic acid derivative; prodrug of indometacin.

• Hypersensitivity to acemetacin, indometacin, or any NSAID.
• History of NSAID-induced bronchospasm, urticaria, or allergic-type reactions.
• Active or history of gastrointestinal bleeding or peptic ulcer disease.
• Severe renal or hepatic impairment.
• Heart failure (uncontrolled), recent coronary bypass surgery (CABG).
• Third trimester of pregnancy.

• Cardiovascular risk: May increase the risk of serious cardiovascular thrombotic events, including MI and stroke, especially with prolonged use or in patients with cardiovascular disease.
• Gastrointestinal risk: Increases risk of GI ulceration, bleeding, and perforation, which can occur at any time without warning.
• Renal risk: May cause renal toxicity including interstitial nephritis, nephrotic syndrome, and renal papillary necrosis. Monitor renal function, especially in elderly and volume-depleted patients.
• Hepatic risk: Hepatic injury including hepatitis and jaundice has occurred; monitor LFTs during therapy.
• Use in asthma: May precipitate bronchospasm in aspirin-sensitive asthmatics.
• Monitor for signs: Unexplained weight gain, edema, chest pain, dark stools, jaundice, or severe GI symptoms should prompt discontinuation.

• Common
• Gastrointestinal: Nausea, dyspepsia, abdominal pain, diarrhea, flatulence.
• CNS: Headache, dizziness, somnolence.
• Musculoskeletal: Joint stiffness or edema.
• Less Common but Serious
• Gastrointestinal bleeding or perforation.
• Hepatotoxicity (elevated liver enzymes, hepatitis).
• Nephrotoxicity (decreased renal function, acute kidney injury).
• Cardiovascular events (hypertension, myocardial infarction).
• Hypersensitivity reactions (rash, angioedema, anaphylaxis).
• Dose-related: GI and renal side effects are more common at higher doses or with chronic use.

• Anticoagulants (e.g., warfarin): Increased risk of bleeding due to platelet dysfunction and GI mucosal damage.
• Antihypertensives (e.g., ACE inhibitors, ARBs, beta-blockers): May reduce antihypertensive effect.
• Diuretics: May decrease diuretic efficacy and increase risk of nephrotoxicity.
• Methotrexate: NSAIDs may reduce renal clearance of methotrexate, increasing toxicity risk.
• Lithium: Reduced excretion may lead to lithium toxicity.
• Cytochrome P450 interaction: Primarily metabolized hepatically but not a strong CYP450 inducer/inhibitor.
• Alcohol: Increases risk of GI irritation and bleeding.

• EMA and WHO Essential Medicines List (EML): Acemetacin is not included in the WHO EML; however, it is approved in many European and Asian countries.
• Regulatory changes: No recent FDA approvals (not approved in the U.S.); recent EMA guidance emphasizes cardiovascular and gastrointestinal safety in NSAID use.
• Recent trends: Prescribers are advised to consider GI protective agents (e.g., PPIs) for long-term users, especially elderly patients.

• Temperature: Store below 25°C (77°F).
• Humidity and light: Protect from excessive moisture and direct light.
• Handling precautions: Keep in tightly closed original container.
• Reconstitution/Refrigeration: Not applicable (oral capsule formulation).
• Shelf-life: Refer to manufacturer labeling; generally 2–3 years if unopened.