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					Tentative Review – Pending Approval
New Drug Introduction: BrilintaTM (BriliqueTM)/ Ticagrelor
Pharmacology              Non-thienopyridine, cyclopentyltriazolopyrimidine antiplatelet agent;
                          selectively and reversibly binds to platelet P2Y12 class of ADP receptors,
                          leading to decreased platelet activation and aggregation
Agent – Generic           Cyclopentyltriazolopyrimidine – ticagrelor (BrilintaTM, BriliqueTM)
(Brand)
Manufacturer              AstraZeneca
Approval Date             09/2010 (tentative) – submitted for approval on 11/16/2009
Indications               Reduction of thromboembolic events in patients with acute coronary
                          syndrome, unstable angina, NSTEMI or STEMI to be managed:
                              1. Medically
                              2. Invasively with PCI (with or without stent) and/or CABG
Contraindications         Hypersensitivity to any component of the product
                          Active pathological bleeding
Warnings                  Increased risk of intracranial bleeding and hemorrhagic strokes
                          Increased risk of cardiovascular events if drug is prematurely discontinued
Precautions               Moderate to severe hepatic impairment
                          Elderly patients (> 65 years old)
Pharmacokinetics          A – bioavailability ~ 36%, Tmax ~ 2.6 hrs
                          D – Vd ~ 87.5L, greater than 99% protein-bound
                          M – oxidative metabolism by CYP3A4/5
                          E – urine < 1% (unchanged), t½ ~ 7-9 hrs (parent and active metabolite)
Drug Interactions –       Ticagrelor (parent and active metabolite) is a P-gp substrate and inhibitor
Object Drugs
Digoxin                    Digoxin AUC ~ 28%
Drug Interactions –       Ticagrelor is a moderate inhibitor of CYP2C9, weak inhibitor of CYP3A4,
Precipitant drugs         and a strong inhibitor of CYP3A5
Strong CYP3A inhibitors    Ticagrelor AUC ~ 7-fold
Strong CYP3A inducers      Ticagrelor AUC ~ 86%
Adverse Effects           (Ticagrelor %) [Clopidogrel %]
                                 Dyspnea (13.8) [7.8]                  Dyspepsia (4.8) [2.8]
                             Major bleeding (11.6) [11.2]             Bradycardia (4.4) [4.0]
                                 Headache (9.6) [8.6]                   Dizziness (4.2) [3.1]
                                 Chest pain (7.5) [8.9]                 Diarrhea (3.0) [3.4]
                                   Nausea (6.6) [3.4]                   Syncope (1.1) [0.8]
                                  Insomnia (5.4) [2.8]                    Rash (0.9) [0.6]
Monitoring Efficacy       None
Monitoring Toxicity       CBC, signs of bleeding
Dosing - Initial          Loading dose = 180 mg
Dosing - Usual            Maintenance dose = 90 mg twice daily
Renal Adjustment          No adjustment necessary
Hepatic Adjustment        Mild – no adjustment necessary
                          Moderate to high - unknown
Cost: Source: www.drugstore.com accessed 09/2010
 Brand – Generic               Dose(s)                                            $ (30d)
       TM
Brilinta – ticagrelor                     90 mg                                      n/a
Plavix® – clopidogrel                     75 mg                                     $166
                                           5 mg
Effient® – prasugrel                                                                $190
                                          10 mg

Summary
 Ticagrelor belongs to a new class of antiplatelet agents called cyclopentyltriazolopyrimidines, and is
  the first oral antiplatelet agent that exhibits reversible binding to P2Y12 ADP receptors
 Ticagrelor does not require hepatic activation to form an active metabolite (like prasugrel and
  clopidogrel), and thus has a faster onset of action compared to other antiplatelet agents
 Ticagrelor may be more effective than clopidogrel in preventing thromboembolic events after ACS,
  but it is associated with increased risk of major bleeding and dyspnea


References:
1. Marciniak TA. Memorandum: Department of Health and Human Services. June 29, 2010.
2. Cannon CP, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive
   strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet.
   2010;375(9711):283-93.
3. Teng R, et al. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending
   doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J
   Clin Pharmacol. 2010;66(5):487-96.
4. Cannon CP, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral
   adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-
   segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll
   Cardiol. 2007;50(19):1844-51.
5. Wallentin L, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl
   J Med. 2009;361(11):1045-57.

Date Prepared: 09/15/2010
Editor: Peter G. Koval, Pharm.D., BCPS
Author: Lisa Kim, Pharm.D. Candidate, UNC School of Pharmacy

				
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