Etodolac - Drug Monograph

Introduction

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. It belongs to the pyranocarboxylic acid class and is commonly prescribed for the management of pain and inflammation associated with various musculoskeletal conditions. As a selective cyclooxygenase-2 (COX-2) inhibitor, it offers a favorable gastrointestinal safety profile compared to non-selective NSAIDs while maintaining therapeutic efficacy.

Mechanism of Action

Etodolac exerts its pharmacological effects through reversible inhibition of prostaglandin synthesis by competitively inhibiting both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. It demonstrates approximately 10-fold greater selectivity for COX-2 compared to COX-1. This selective inhibition reduces the formation of prostaglandin precursors, which are mediators of pain, inflammation, and fever. The drug's anti-inflammatory effects are mediated through reduced prostaglandin production in inflamed tissues, while its analgesic action occurs both peripherally and centrally.

Indications

• FDA-approved indications:

- Acute and chronic management of signs and symptoms of osteoarthritis - Management of rheumatoid arthritis - Management of mild to moderate pain

• Off-label uses:

- Juvenile idiopathic arthritis (limited data) - Ankylosing spondylitis - Acute gouty arthritis - Dysmenorrhea

Dosage and Administration

• Osteoarthritis: 600-1200 mg daily in divided doses (400 mg BID or 300 mg BID-TID)
• Rheumatoid arthritis: 400 mg BID or 300 mg TID-QID
• Analgesia: 200-400 mg every 6-8 hours as needed (max 1200 mg/day)

• Geriatric patients: Start with lowest effective dose
• Renal impairment: Avoid in advanced renal disease (CrCl <30 mL/min)
• Hepatic impairment: Use with caution, consider dose reduction
• Pediatric: Safety and efficacy not established

• Administer with food or milk to minimize gastrointestinal upset
• Immediate-release tablets: May be crushed if necessary
• Extended-release tablets: Swallow whole, do not crush or chew

Pharmacokinetics

• Absorption: Well absorbed from GI tract, bioavailability >80%
• Distribution: Vd: 0.4 L/kg, >99% protein bound (primarily albumin)
• Metabolism: Extensive hepatic metabolism via CYP450 enzymes (primarily CYP3A4 and CYP2C9)
• Elimination: Half-life: 6-7 hours (immediate-release), 8-12 hours (extended-release)
• Excretion: Urine (72% as metabolites, <1% unchanged), feces (16%)

Contraindications

• Hypersensitivity to etodolac or other NSAIDs
• History of aspirin-sensitive asthma
• Peri-operative pain in coronary artery bypass graft (CABG) surgery
• Third trimester of pregnancy
• Active peptic ulcer disease or GI bleeding
• Severe renal impairment (CrCl <30 mL/min)
• Severe hepatic impairment (Child-Pugh Class C)

Warnings and Precautions

• Increased risk of serious cardiovascular thrombotic events, including MI and stroke
• Increased risk of serious gastrointestinal bleeding, ulceration, and perforation

• Hypertension and fluid retention
• Renal toxicity, particularly in elderly and volume-depleted patients
• Hepatotoxicity (monitor LFTs)
• Anaphylactoid reactions
• Hematologic effects (anemia, bleeding)
• Exacerbation of asthma in aspirin-sensitive patients
• Avoid use in heart failure patients

Drug Interactions

• Anticoagulants (warfarin): Increased bleeding risk
• Aspirin: Increased GI toxicity, reduced etodolac efficacy
• ACE inhibitors/ARBs: Reduced antihypertensive effect, renal impairment
• Diuretics: Reduced efficacy, renal impairment
• Lithium: Increased lithium levels
• Methotrexate: Increased methotrexate toxicity
• Cyclosporine: Increased nephrotoxicity
• SSRIs/SNRIs: Increased bleeding risk
• CYP2C9 inhibitors: May increase etodolac levels

Adverse Effects

• Dyspepsia (10-15%)
• Nausea (5-10%)
• Diarrhea (5-8%)
• Abdominal pain (4-6%)
• Headache (5-7%)
• Dizziness (3-5%)

• GI bleeding/perforation
• Cardiovascular thrombotic events
• Acute renal failure
• Hepatotoxicity
• Severe skin reactions (SJS, TEN)
• Anaphylaxis
• Hypertension exacerbation
• Heart failure exacerbation

Monitoring Parameters

• Baseline: CBC, renal function, LFTs, blood pressure
• Ongoing:

- Blood pressure regularly - Renal function (every 3-6 months in chronic use) - LFTs (periodically) - Hemoglobin/hematocrit (if anemia suspected) - GI symptoms assessment - Therapeutic response and pain control - Signs of fluid retention

Patient Education

• Take with food or milk to reduce stomach upset
• Report any signs of GI bleeding (black stools, coffee-ground emesis)
• Monitor for cardiovascular symptoms (chest pain, shortness of breath)
• Avoid concurrent aspirin use unless specifically directed
• Report signs of allergic reactions or skin rash immediately
• Use caution when driving or operating machinery due to potential dizziness
• Avoid alcohol consumption during therapy
• Inform all healthcare providers of etodolac use before procedures
• Do not use during late pregnancy
• Store at room temperature away from moisture

References

1. FDA Prescribing Information: Etodolac (2023) 2. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. 3. American College of Rheumatology Guidelines for NSAID Use (2022) 4. Davies NM, Skjodt NM. Clinical pharmacokinetics of etodolac. Clin Pharmacokinet. 1999;36(5):399-410. 5. Coxib and traditional NSAID Trialists' Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs. Lancet. 2013;382(9894):769-779. 6. Micromedex® DrugDex® Evaluation: Etodolac (2024) 7. UpToDate: Etodolac drug information (2024)