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 proteaseactivated 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 TRAPinduced 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%
1%
Moderate/Severe
Bleeding
3%
2.4%
Any Bleeding
25%
19.8%
Fatal Bleeding
0.2%
0.2%
GI Bleeding
4%
3.5%
Depression
2.4%
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
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
• History of atherosclerosis
• Spontaneous MI or
ischemic stroke* in
previous 2 weeks – 12
months
• PAD with intermittent
claudication
Exclusion Criteria
• Planned revascularization
• History of bleeding diathesis
• Recent active bleeding
• Ongoing treatment with
warfarin
• Active hepatobiliary disease
• Age ≥ 18 years
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)
61
61
Female
1514 (11.4%)
1506 (111.4%)
White
11562 (87.5%)
11524 (87.2%)
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%)
Median Age
Type of Atherosclerosis:
• MI
• Stroke
• PAD
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)
Morrow DA, et al., N Engl J Med. 2012;366:1404-13.
Zontivity™ - vorapaxar
Literature Review
• Results:
Vorapaxar Placebo
(N=13225) (N=13224)
RRR
ARR
Pvalue
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%
53
0.001
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
Pvalue
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%
<0.001
270
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
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
1.
Zontivity Package Insert. Merck. May 2014. Include
ALL article references in standard format.
2.
Morrow DA, et al., N Engl J Med. 2012;366:1404-13.
3.
http://www.zontivity.com