Transcript zontivity
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