Generic Name

Icosapent

Mechanism

• Selective absorption of eicosapentaenoic acid (EPA) – Icosapent ethyl is a highly purified ester of EPA (≥ 90 % purity) that delivers > 3 g/day of free EPA to plasma.
• Dyslipidemia modulation – EPA reduces hepatic very‑low‑density lipoprotein (VLDL) triglyceride synthesis, increases clearance of triglyceride‑rich lipoproteins, and shifts fatty acid composition of cell membranes toward atheroprotective species.
• Anti‑inflammatory & anti‑thrombotic effects – EPA metabolizes to resolvins and protectins, dampening cytokine release, platelet aggregation, and endothelial dysfunction, thereby reinforcing cardiovascular risk reduction beyond triglyceride lowering alone.

Pharmacokinetics

• Absorption – Rapidly hydrolyzed in the gastrointestinal tract to free EPA; peak plasma concentration (~4–6 h post‑dose).
• Distribution – Widely distributed in plasma lipoprotein fractions; extensive incorporation into phospholipids of endothelial cells.
• Metabolism – Minimal CYP450 involvement; predominantly esterases and phospholipases convert Icosapent ethyl to EPA.
• Elimination – EPA is β‑oxidized; the terminal half‑life of free EPA is ~12 h; Icosapent ethyl’s terminal half‑life ~16 h. No major drug‑drug interactions via CYP pathways.
• Food effect – Moderate; high lipid meals slightly increase bioavailability but clinical benefits are maintained on an empty stomach.

Indications

• Hypertriglyceridemia (serum TG > 200 mg/dL) – Adjunct to statin therapy in adults at high cardiovascular risk.
• Secondary prevention of ASCVD – Adults with established atherosclerotic disease and triglyceride range 200–499 mg/dL.
• High‑risk metabolic syndrome – Used to lower triglycerides when statins alone are insufficient.

Contraindications

• Hypersensitivity to EPA, omega‑3 fatty acids, or any component of the formulation.
• Major bleeding (e.g., active peptic ulcer, recent hemorrhage) – caution due to modest BP‑lowering and platelet inhibition.
• Concurrent anticoagulation (warfarin, DOACs) – monitor INR/anti‑Xa levels; dose adjustments may be required.
• Pregnancy & lactation – safety data limited; generally avoid unless benefits outweigh risks.

Warnings
• Bleeding risk – Rare but documented especially at high doses or in presence of concurrent anticoagulants; monitor for bruising, hematuria, or epistaxis.
• Hepatic monitoring – Although rare, monitor liver enzymes if baseline hepatic dysfunction exists.
• Gastrointestinal tolerance – Mild GI upset (nausea, diarrhea) may occur; consider splitting dose.

Dosing

• Standard regimen – 4 g/day (2 g twice daily) after an overnight fast or at least 1 h before/after meals.
• Initiation – Start at 2 g BID for the first week to improve tolerability, then titrate to 2 g BID.
• Titration – Not routinely required; maximum 4 g/day may be used for severe hypertriglyceridemia if statins are ineffective.
• Duration – Long‑term therapy; adherence is essential for sustained triglyceride reduction and cardiovascular benefit.

Adverse Effects

• Drug interactions – Minimal; avoid high‑dose aspirin, clopidogrel, or warfarin without monitoring.

Monitoring

• Baseline – Fasting lipids (TG, LDL-C), CBC, CMP, liver enzymes, coagulation profile if on anticoagulants.
• Follow‑up – Repeat fasting lipids at 4–12 weeks; thereafter every 6 months or per ASCVD protocol.
• Safety – Monitor for signs of bleeding every visit; screen for GI symptoms or rash.
• Adherence – Reinforce dietary omega‑3 intake, limit alcohol, and coordinate with statin schedules.

Clinical Pearls

• Efficacy > 10% TG reduction – Consistent with REDUCE‑IT trial; achieve greater risk reduction when combined with statin therapy.
• Dose‑splitting improves tolerability – Taking 1 g at breakfast and 1 g at dinner prevents GI upset while maintaining steady EPA levels.
• Rapid triglyceride decline – 50–60 % reduction can be seen by 4 weeks; use short‑term lipid panel if rapid response is needed.
• Omega‑3 synergy – EPA’s benefits are distinct from DHA‑rich fish oil; favoring EPA may provide clearer cardiovascular outcomes.
• Patient counseling – Explain that Icosapent ethyl is not a "natural" supplement but a prescription drug requiring a healthcare prescription and regular monitoring.