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

2. 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

3. 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

4. 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

5. 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.

6. 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

7. 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

8. 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.

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

10. 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

11. 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%

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

13. 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

14. 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:

15. 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:

16. 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:

17. 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:

18. 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:

19. 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
Morrow DA, et al., N Engl J Med. 2012;366:

20. 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:

21. 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:

22. 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

23. Zontivity™ - vorapaxar References
Zontivity Package Insert. Merck. May Include ALL article references in standard format.
Morrow DA, et al., N Engl J Med. 2012;366: