Clopigel Plus

Approved Indications (Dual Therapy):

• Acute Coronary Syndrome (ACS): Adjunctive use in unstable angina and non‑ST‑elevation myocardial infarction (NSTEMI), and ST‑elevation MI (STEMI) when managed conservatively or with percutaneous coronary intervention (PCI).
• Percutaneous Coronary Intervention (PCI): Post‑PCI with stent placement (drug‑eluting or bare‑metal stents) to prevent stent thrombosis.
• Secondary Prevention of Atherothrombotic Events: In patients with recent MI (within 12 months) or ischemic stroke, and in peripheral arterial disease.

Clinically Accepted Off‑Label Uses (Dual Therapy):

• High‑risk transient ischemic attack (TIA) or minor stroke: Short‑term (e.g., 21 days) dual therapy beginning within 24 hours of event.
• Acute coronary angioplasty without stent: In selected high‑risk patients.
• Peripheral arterial revascularization procedures.

Adults:

• Loading:
• Aspirin: 75–325 mg loading dose (commonly 300 mg) on first day
• Clopidogrel: loading dose 300–600 mg once (600 mg preferred in PCI)
• Maintenance (Dual Therapy):
• Aspirin: 75–100 mg once daily (low dose)
• Clopidogrel: 75 mg once daily
• Duration: typically 12 months post‑STEMI/PCI; shorter (e.g., 6–12 months) or longer based on bleeding/ischemic risk.

Pediatrics: Not recommended.

Elderly (≥75 years):

• Same maintenance dose; consider lower aspirin dose (75 mg) to reduce bleeding risk. Monitor closely.

Renal Impairment:

• No adjustment needed; cautious monitoring in severe impairment.

Hepatic Impairment:

• Clopidogrel may have reduced activation; use with caution. Aspirin tolerated at low dose.

Administration Notes:

• Take with food to minimize gastrointestinal upset.
• Swallow clopidogrel whole; do not crush.
• Discontinue aspirin temporarily before invasive procedures as needed.

Clopidogrel, a thienopyridine prodrug, is metabolized by hepatic CYP2C19 to an active thiol metabolite that irreversibly inhibits the P2Y₁₂ ADP receptor on platelet surfaces, preventing activation of the GPIIb/IIIa complex and inhibiting platelet aggregation.
Aspirin irreversibly inhibits cyclooxygenase‑1 (COX‑1) in platelets, thereby blocking thromboxane A₂ synthesis, reducing platelet activation and aggregation.
Together, they produce dual and synergistic antiplatelet effects, reducing thrombus formation more effectively than either agent alone.

Clopidogrel:

• Absorption: ~50% absorbed orally
• Bioavailability: ~50%; first‑pass hepatic metabolism
• Metabolism: via CYP2C19 to active metabolite; inactive metabolites also formed
• Half‑life: active metabolite t₁/₂ ≈ 6 hours; parent drug ~8 hours
• Elimination: renal (~50% inactive metabolites), fecal elimination

Aspirin (low‑dose):

• Absorption: well absorbed in upper GI tract
• Bioavailability: high, though first‑pass deacetylation
• Metabolism: rapidly deacetylated to salicylate (active metabolite) by plasma esterases
• Half‑life: aspirin ~15–20 minutes; salicylate half‑life 2–3 hours
• Elimination: chiefly renal

Onset: Aspirin onset of platelet inhibition ~1 hour; clopidogrel ~2 hours (full effect by ~5 days with maintenance dose).

Pregnancy:

• Classified as FDA Category C – limited human data; low‑dose aspirin may increase risk of bleeding; clopidogrel risks unknown but rarely used in pregnancy except when benefit outweighs risk (e.g., stent protection).
• Use only if clearly needed and after maternal‑fetal risk–benefit assessment.

Lactation:

• Clopidogrel: excreted in breast milk in minimal amounts; no documented adverse effects; caution advised.
• Low‑dose aspirin: excreted in breast milk; small quantities can increase infant bleeding risk. Avoid high doses; monitor nursing infants.

• Primary Class: Antiplatelet Agents
• Subclass:
• Clopidogrel: P2Y₁₂ receptor antagonist (thienopyridine)
• Aspirin: COX‑1 inhibitor (irreversible platelet aggregation inhibitor)

• Known hypersensitivity to aspirin, NSAIDs, clopidogrel, or excipients
• Active clinically significant bleeding (e.g., peptic ulcer, intracranial hemorrhage)
• History of hemorrhagic stroke
• Severe hepatic impairment with bleeding risk
• Thrombocytopenia or bleeding diathesis
• Concomitant use of proton pump inhibitors known to strongly inhibit CYP2C19 (e.g., omeprazole) that reduce clopidogrel activation is relatively contraindicated

• Bleeding Risk: Elevated risk of gastrointestinal, intracranial, and surgical bleeds. Monitor complete blood counts and hemoglobin.
• Gastrointestinal Toxicity: Risk of ulceration, dyspepsia; consider gastroprotection in high‑risk patients.
• Thrombotic Thrombocytopenic Purpura (TTP): Rarely associated with clopidogrel; monitor for thrombocytopenia and hemolysis.
• Poor Metabolizers (CYP2C19): Reduced clopidogrel efficacy; alternative agents may be considered in known poor metabolizers.
• Hypersensitivity: Aspirin may trigger bronchospasm in aspirin‑sensitive asthmatics.
• Premature Discontinuation: May lead to stent thrombosis and MI.

Common:

• Gastrointestinal discomfort or dyspepsia (aspirin)
• Easy bruising

Less common:

• Headache
• Dizziness
• Mild bleeding such as epistaxis or minor wounds

Serious/Rare:

• Gastrointestinal ulceration or bleeding (aspirin)
• Intracranial hemorrhage
• TTP with clopidogrel
• Severe allergic reactions (e.g., angioedema or anaphylaxis)
• Hypersensitivity respiratory reactions

Side effect severity often dose‑dependent; bleeding risk peaks in first months.

• CYP2C19 inhibitors (e.g., omeprazole, esomeprazole): reduce clopidogrel activation → reduced efficacy
• Other anticoagulants or antiplatelets (e.g., warfarin, heparin, NSAIDs): additive bleeding risk
• Selective COX‑2 inhibitors: may reduce aspirin’s antiplatelet effect if taken concomitantly
• SSRIs/SNRIs: increased risk of bleeding
• Alcohol: potentiates GI irritation and bleeding risk
• NSAIDs (non‑aspirin): additive ulcerogenic and bleeding risk

• Clinical Guidelines (ESC, AHA/ACC 2023): Recommend dual therapy for minimum 6–12 months post‑PCI, tailored duration based on ischemic vs bleeding risk (e.g., PRECISE‑DAPT, ARC‑HBR algorithms).
• FDA Updates: Updated boxed warnings on effectiveness in poor metabolizers; caution with concomitant strong CYP2C19 inhibitors.
• WHO Essential Medicines: Dual antiplatelet combination is standard in secondary prevention post-MI but subject to bleeding risk evaluation.
• New Alerts: Emphasized early dual therapy after minor stroke/TIA (within 24 hrs for 21 days) improves outcomes.

• Temperature: Store tablets at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C and 30 °C.
• Humidity & Light: Protect from moisture and light. Keep tightly closed in original container.
• Handling Precautions: Keep out of reach of children. Do not crush delayed‑release clopidogrel tablets.
• Reconstitution: Not applicable.