Ticaflow

1. Indications

Approved Indications:

• Acute Coronary Syndromes (ACS):
• Unstable angina
• Non-ST-elevation myocardial infarction (NSTEMI)
• ST-elevation myocardial infarction (STEMI)
• In patients managed medically or with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)
• Prevention of Atherothrombotic Events:
• Secondary prevention in patients with a history of myocardial infarction (within the previous 1 year)
• Primary Prevention of Cardiovascular Events in high-risk patients with coronary artery disease (CAD) but without prior MI or stroke (in combination with aspirin)
• Prevention of Stroke in Minor Ischemic Stroke or High-Risk Transient Ischemic Attack (TIA) (off-label, guideline-supported)

Adults:

• Initial Dose (ACS):
  180 mg orally as a single loading dose, followed by
  Maintenance Dose: 90 mg orally twice daily with low-dose aspirin (75–100 mg/day)
• Extended Secondary Prevention (post-MI >12 months):
  60 mg orally twice daily (with low-dose aspirin)

Administration:

• Oral route; with or without food
• Crushed tablets may be given via nasogastric tube or mixed with water if necessary

Elderly (≥75 years):

• No dosage adjustment required; monitor for bleeding

Renal Impairment:

• No dose adjustment needed, but caution in severe impairment (CrCl <30 mL/min)

Hepatic Impairment:

• Mild to moderate: No adjustment
• Severe impairment: Contraindicated

Pediatrics:

• Safety and efficacy not established

Duration:

• Typically 12 months post-ACS; may be extended for long-term secondary prevention per physician discretion

Ticagrelor is a direct-acting, reversibly binding oral antagonist of the P2Y₁₂ subtype of adenosine diphosphate (ADP) receptors on platelets. Unlike clopidogrel or prasugrel, it does not require metabolic activation. By blocking the P2Y₁₂ receptor, ticagrelor inhibits ADP-mediated activation of the GPIIb/IIIa receptor complex, thereby reducing platelet aggregation. This prevents thrombus formation in atherothrombotic conditions like ACS. Additionally, it increases endogenous adenosine concentration by inhibiting ENT-1 (equilibrative nucleoside transporter), which may contribute to vasodilation and cardioprotection.

• Absorption: Rapid and well absorbed; peak plasma concentrations (Tmax) in ~1.5 hours
• Bioavailability: ~36%
• Distribution: High plasma protein binding (~99%); large volume of distribution (~87 L)
• Metabolism: Extensively metabolized in the liver via CYP3A4 to active metabolite AR-C124910XX
• Half-life:
• Parent drug: ~7 hours
• Active metabolite: ~9 hours
• Elimination:
• ~58% feces (primarily as metabolites)
• ~27% urine (minor fraction)

• Pregnancy:
• FDA Pregnancy Category: Not assigned under newer labeling; animal studies show fetal toxicity at high doses.
• Use only if clearly needed and benefits outweigh potential risks.
• Lactation:
• Unknown if excreted in human milk. Animal studies show excretion into milk.
• Caution advised; either discontinue drug or breastfeeding based on clinical importance.

• Primary Class: Antiplatelet agent
• Subclass: P2Y₁₂ receptor antagonist
• Generation: Third-generation (non-thienopyridine, reversible inhibitor)

• Known hypersensitivity to ticagrelor or any excipients
• Active pathological bleeding (e.g., GI bleeding, intracranial hemorrhage)
• History of intracranial hemorrhage
• Severe hepatic impairment
• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin)
• Ongoing need for oral anticoagulants (due to increased bleeding risk)

• Bleeding Risk: Major bleeding (e.g., GI, intracranial) possible; monitor for signs
• Dyspnea: Common and generally mild but may require discontinuation
• Bradyarrhythmias: Risk of ventricular pauses, particularly in the first week of treatment
• Renal Dysfunction: Monitor serum creatinine especially in the elderly and patients with pre-existing kidney disease
• Hepatic Impairment: Avoid in severe hepatic dysfunction
• Hyperuricemia: May increase serum uric acid; monitor in gout-prone individuals
• Avoid Abrupt Discontinuation: May increase risk of thrombotic events

Common (≥1%):

• Cardiovascular: Bradycardia, hypertension
• Respiratory: Dyspnea
• Gastrointestinal: Nausea, diarrhea, GI bleeding
• Neurological: Dizziness, headache

Less Common/Rare:

• Epistaxis
• Increased creatinine or uric acid
• Ventricular pauses (esp. in first week)
• Rash, pruritus

Serious (Rare but Important):

• Intracranial hemorrhage
• Severe gastrointestinal bleeding
• Anaphylaxis (very rare)
• Torsades de pointes (very rare)

• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): ↑ Ticagrelor levels → Avoid
• CYP3A4 Inducers (e.g., rifampicin, carbamazepine): ↓ Ticagrelor efficacy → Avoid
• Strong P-gp inhibitors (e.g., cyclosporine): May ↑ exposure → Use caution
• Simvastatin/Lovastatin (>40 mg): ↑ risk of statin toxicity → Use ≤40 mg/day
• Aspirin (>100 mg/day): Reduced efficacy of ticagrelor → Limit to low-dose (75–100 mg/day)
• Anticoagulants (e.g., warfarin, DOACs): ↑ bleeding risk → Use with caution

• ESC 2023: Recommends ticagrelor (± aspirin) as a preferred agent in ACS with lower bleeding risk
• FDA Label Update (2021): Confirmed long-term benefit of 60 mg twice daily post-MI beyond 12 months
• WHO Guidelines (latest edition): Included in antiplatelet regimens for ACS where clopidogrel resistance or recurrence is an issue
• TICO & TWILIGHT Trials: Support early aspirin discontinuation (Ticagrelor monotherapy) in select PCI populations to reduce bleeding

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C
• Humidity: Store in a dry place; protect from excessive moisture
• Light Protection: Store in original container; protect from light
• Handling: No refrigeration or reconstitution required; keep tablets in blister packs until use