zontivity ™ - vorapaxar manufacturer: merck fda approval date: may 8, 2014 stephanie roach, pharmd...
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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
EPrimarily 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% 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
Morrow DA, et al., N Engl J Med. 2012;366:1404-13.
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
Zontivity™ - vorapaxar
Literature Review
• Baseline Characteristics:
Morrow DA, et al., N Engl J Med. 2012;366:1404-13.
Vorapaxar (N=13,225) Placebo (N=13,224)
Median Age 61 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%)
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
Morrow DA, et al., N Engl J Med. 2012;366:1404-13.
Vorapaxar (N=13225)
Placebo (N=13224)
RRR ARR P-value
NNT
CV Death, MI, Stroke1028 (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
• Results:
Zontivity™ - vorapaxar
Literature Review
Morrow DA, et al., N Engl J Med. 2012;366:1404-13.
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% <0.001 270
• Safety Endpoints:
Zontivity™ - vorapaxar
Literature Review
Morrow DA, et al., N Engl J Med. 2012;366:1404-13.
• 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
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