Zontivity™ - vorapaxar Manufacturer: Merck FDA Approval Date: May 8, 2014 Stephanie Roach, PharmD Candidate

Zontivity™ - vorapaxar Clinical Application Indications: Reduction of thrombotic CV events in patients with a history of MI or with PAD, in combination with aspirin and/or clopidogrel Place in therapy: Secondary prevention in patients with high risk of thrombosis, low risk of bleeding

Zontivity™ - vorapaxar Clinical Application Black Box Warnings: Do not use in patients with a history of stroke, TIA or ICH, or active pathological bleeding Antiplatelet agents increase the risk of bleeding, including ICH and fatal bleeding Contraindications: History of stroke, TIA, ICH Active Pathologic Bleeding

Zontivity™ - vorapaxar Clinical Application Warnings & Precautions: General risk of bleeding Withholding ZONTIVITY for a brief period will not be useful in managing an acute bleeding event because of its long half-life. There is no known treatment to reverse the antiplatelet effect of ZONTIVITY. Avoid concomitant use with strong CYP3A inhibitors or inducers

Zontivity™ - vorapaxar Clinical Application Pregnancy: Category B Lactation: It is unknown whether vorapaxar or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions, discontinue nursing or discontinue vorapaxar.

Zontivity™ - vorapaxar Drug Facts Pharmacology: Reversible antagonist of protease-activated receptor-1 (PAR-1) Long t1/2 makes it effective irreversible Inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-Induced platelet aggregation

Zontivity™ - vorapaxar Drug Facts Pharmacokinetics: A Bioavailability ~100%, Cmax 1-2 hours D Vd 424L, ≥99% albumin bound M Hepatic, via CYP3A4 and CYP2J2 E Primarily through feces (58%); urine (25%); Effective t1/2: 3-4 days

Zontivity™ - vorapaxar Drug Facts Pharmacodynamics: Onset: At least 80% inhibition of TRAP-induced platelet aggregation w/in 1 week. Duration: Dose & concentration dependent Inhibition of TRAP-induced platelet aggregation at a level of 50% can be expected 4 weeks after discontinuation.

Zontivity™ - vorapaxar Drug Interactions Drug Interactions – Object Drugs:  antiplatelet effect of other antiplatelet agents  bleeding risk with anticoagulants

Zontivity™ - vorapaxar Drug Interactions Drug Interactions – Precipitant Drugs: Strong CYP3A inhibitors  vorapaxar Ex: ketoconazole, clarithromycin, ritonavir Strong CYP3A inducers  vorapaxar Ex: rifampin, carbamazepine, St. John’s Wort and phenytoin

Zontivity™ - vorapaxar Adverse Effects   Vorapaxar Placebo Severe Bleeding 1% Moderate/Severe Bleeding 3% 2.4% Any Bleeding 25% 19.8% Fatal Bleeding 0.2% GI Bleeding 4% 3.5% Depression 2.1% Rash 2.2% 2%

Zontivity™ - vorapaxar Monitoring Parameters Efficacy Monitoring: N/A Toxicity Monitoring: Hgb/HCT S/Sx of bleeding

Zontivity™ - vorapaxar Prescription Information Dosing: Take one 2.08 mg tablet* by mouth once daily, with or without food Cost: 2.08 mg (30), $320.76 Per LexiComp via Uptodate, 09/29/14 2.08 mg tablet equivalent to 2.5 mg vorapaxar sulfate

Zontivity™ - vorapaxar Literature Review Purpose: To evaluate the efficacy and safety of vorapaxar during long-term treatment of patients with established atherosclerotic disease receiving standard therapy Design: phase III, randomized, double- blind, placebo-controlled, international Morrow DA, et al., N Engl J Med. 2012;366:1404-13.

Zontivity™ - vorapaxar Literature Review Inclusion Criteria Exclusion Criteria History of atherosclerosis Spontaneous MI or ischemic stroke* in previous 2 weeks – 12 months PAD with intermittent claudication Age ≥ 18 years Planned revascularization History of bleeding diathesis Recent active bleeding Ongoing treatment with warfarin Active hepatobiliary disease Morrow DA, et al., N Engl J Med. 2012;366:1404-13.

Zontivity™ - vorapaxar Literature Review Baseline Characteristics: Vorapaxar (N=13,225) Placebo (N=13,224) Median Age 61 Female 1514 (11.4%) 1506 (111.4%) White 11562 (87.5%) 11524 (87.2%) Type of Atherosclerosis: MI Stroke PAD 8898 (67.3%) 2435 (18.4%) 1892 (14.3%) 8881 (67.2%) 2448 (18.5%) 1895 (14.3%) Diabetes 3368 (25.5%) 3356 (25.4%) Hypertension 9047 (68.4%) 9127 (69%) Lipid-Lowering Agent 12032 (91%) 12131 (91.7%) Morrow DA, et al., N Engl J Med. 2012;366:1404-13.

Zontivity™ - vorapaxar Literature Review Treatment: 2.08 mg vorapaxar daily vs matching placebo Standard therapy: 94% treated with aspirin 66.5% treated with thienopyridine Morrow DA, et al., N Engl J Med. 2012;366:1404-13.

Zontivity™ - vorapaxar Literature Review Primary Endpoint: Composite of CV death, MI or stroke Secondary Endpoint: CV death, MI, stroke or urgent revascularization Major Safety Endpoint: moderate or severe bleeding (GUSTO criteria) GUSTO: Global use of strategies to open occluded coronary arteries Morrow DA, et al., N Engl J Med. 2012;366:1404-13.

Zontivity™ - vorapaxar Literature Review Results: Vorapaxar (N=13225) Placebo (N=13224) RRR ARR P-value NNT CV Death, MI, Stroke 1028 (9.3%) 1176 (10.5%) 12.6% 1.2% <0.001 82 CV Death, MI, Stroke, Urgent Revascularization 1259 (11.2%) 1417 (12.4%) 16.6% 1.8% 0.001 53 0.095 0.1139 Morrow DA, et al., N Engl J Med. 2012;366:1404-13.

Zontivity™ - vorapaxar Literature Review Safety Endpoints: Vorapaxar (N=13225) Placebo (N=13224) ARI P-value NNH Moderate/Severe Bleeding (GUSTO) 438 (4.2%) 267 (2.5%) 1.29% <0.001 77.5 Fatal Bleeding 29 (0.3%) 20 (0.2%) 0.07% 0.19 ICH 102 (1.0%) 53 (0.5%) 0.37% 270 *do I calculate NNH if it isn’t significant?? Morrow DA, et al., N Engl J Med. 2012;366:1404-13.

Zontivity™ - vorapaxar Literature Review Conclusions: Vorapaxar (in addition to standard therapy) reduced the risk of CV death, MI, or stroke in pts with a history of atherothrombosis, at the cost of increased bleeding Benefit was particularly evident in patients whose qualifying diagnosis was MI *do I calculate NNH if it isn’t significant?? Morrow DA, et al., N Engl J Med. 2012;366:1404-13.

Zontivity™ - vorapaxar Summary Vorapaxar may added to standard therapy to prevent recurrent thrombotic events in patients with a history of atherosclerosis Vorapaxar should be reserved for patients with a HIGH risk of thrombosis and LOW risk of bleeding Vorapaxar is associated with a significant risk of bleeding

Zontivity™ - vorapaxar References Zontivity Package Insert. Merck. May 2014. Include ALL article references in standard format. Morrow DA, et al., N Engl J Med. 2012;366:1404-13. http://www.zontivity.com