PDL NEW DRUG REVIEW Proprietary Name: Zontivity® Common Name: vorapaxar PDL Category: Platelet Aggregation Inhibitors

Comparable Products Preferred Drug List Status Brilinta Non‐Preferred Clopidogrel Preferred Effient Non‐Preferred

Summary

Indications and Usage: For the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). It has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR). This is a pregnancy category B medication. The safety and efficacy of use in children have not been established.

Drug Interactions: The concomitant use of Zontivity® with strong CYP3A inhibitors (e.g. ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, and conivaptan) or with strong CYP3A inducers (e.g. rifampin, carbamazepine, St. John’s Wort, and phenytoin) should be avoided.

Dosage Forms: Tablets: 2.08mg vorapaxar, equivalent to 2.5mg vorapaxar sulfate

Recommended Dosage: Take one tablet by mouth once daily, with or without food. Use of Zontivity® as monotherapy, being the only administered antiplatelet agent, has not been studied. Rather, it has only been studied as an add‐on to aspirin and/or clopidogrel. Therefore, use Zontivity® with aspirin and/or clopidogrel per their indications or standard of care.

Dose adjustments are not required in those with mild or moderate hepatic impairment or in those with renal impairment; however, use is not recommended in those with severe hepatic impairment.

Common Adverse Drug Reactions: Listed % incidence for adverse drug reactions= reported % incidence for drug (Zontivity®) minus reported % incidence for placebo. Please note that an incidence of 0% means the incidence was the same or that the active drug was less than placebo. The most commonly reported adverse events other than bleeding included anemia (1%), depression (0.3%), and rashes/eruptions/exanthemas (0.2%).

The following table is adapted from the prescribing information of Zontivity®. It contains data on the Non‐CABG‐ Related Bleeds in post‐MI or PAD patients without a history of stroke or TIA in a clinical study (TRA 2°P Study). Clinically significant bleeding included any bleeding requiring medical attention including intracranial hemorrhage (ICH), or clinically significant overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥3g/ml (or, when Hgb is not available, an absolute drop in hematocrit (Hct) of ≥15% or a fall in Hct of 9 to <15%). Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) severe bleeding was

1 defined as fatal, intracranial, or bleeding with hemodynamic compromise requiring intervention. GUSTO moderate bleeding was defined as bleeding requiring transfusion of whole blood or packed red blood cells without hemodynamic compromise.

Non‐CAGB‐Related Bleeds in Post‐MI or PAD patients without a history of stroke or TIA in the TRA 2°P study

Placebo Zontivity® Hazard Ratio (N=10,049) (N=10,059) Endpoints‐ GUSTO Bleeding Categories

Severe 0.8% (N=82) 1% (N=100) 1.24

Moderate or Severe 2% (N=199) 3% (N=303) 1.55

Any GUSTO Bleeding (Severe/Moderate/Mild) 17.6% (N=1769) 25% (N=2518) 1.52

Fatal Bleeding 0.1% (N=14) 0.2% (N=16) 1.15

Intracranial Hemorrhage (ICH) 0.3% (N=31) 0.4% (N=45) 1.46

Clinically significant bleeding 9.5% (N=950) 13.4% (N=1349) 1.47

Gastrointestinal bleeding 3% (N=297) 4% (N=400) 1.37

Zontivity® carries a box warning regarding the increased risk of bleeding. It should not be used in patients with a history of stroke, transient ischemic attack (TIA), or ICH; or with active pathological bleeding. Antiplatelet agents, including Zontivity®, increase the risk of bleeding, including ICH and fatal bleeding.

There is also a warning regarding the general risk of bleeding that indicates Zontivity® increases the risk of bleeding in proportion to the patients underlying bleeding risk. Due to the long half‐life of Zontivity®, withholding treatment for a brief period will not be helpful. Furthermore, there is not a known treatment to reverse the antiplatelet effect of Zontivity®; significant inhibition of platelet aggregation will continue to occur 4 weeks after treatment has been discontinued.

Contraindications: History of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH); Active pathological bleeding such as ICH or peptic ulcer

Manufacturer: Merck Sharp & Dohme Corp

Analysis: Vorapaxar sulfate, the active ingredient of Zontivity®, is a tricyclic himbacine‐derived selective inhibitor of platelet aggregation. It is a reversible antagonist of the protease‐activated receptor‐1 (PAR‐1) that is expressed on platelets; however, its long half‐life makes it effectively irreversible. With in vitro studies, vorapaxar inhibits thrombin‐induced and thrombin receptor agonist peptide (TRAP)‐induced platelet aggregation.

The safety and efficacy of Zontivity® was established in a multicenter, randomized, double‐blind, placebo‐ controlled study (TRA 2°P‐TIMI 50) that included adults who had evidence or a history of atherosclerosis involving the coronary (MI), cerebral (ischemic stroke), or peripheral vascular (peripheral arterial disease [PAD]) systems. In addition to standard of care, adults were randomized to either Zontivity® or placebo, with the primary endpoint being a composite of cardiovascular (CV) death, MI, stroke, and UCR. The composite of CV death, MI, and stroke was a key secondary outcome. There was a median follow‐up of 2.5 years.

Results suggested that the 3‐year event rate was statistically significantly lower in the Zontivity® group vs placebo (11.2% vs 12.4%; hazard ratio 0.88; p=0.001). (IME Comments: This calculates to an NNT of 84). The 3‐year event rate for the key secondary outcome was significantly lower with Zontivity® vs placebo (9.3% vs 10.5%, HR 0.787; p<0.001). (IME Comments: This calculates to an NNT of 84).

2 In a subgroup analysis of this same study that included those post‐MI or PAD patients without a history of stroke or TIA, the 3‐year event rate for the primary endpoint was significantly lower in the Zontivity® group vs placebo (10.1% vs 11.8%, HR 0.83; p<0.001). (IME Comments: This calculates to an NNT of 59). The 3‐year event rate for the secondary outcome in this subgroup was significantly lower with Zontivity® vs placebo (7.9% vs 9.5%, HR 0.80; p<0.001). (IME Comments: This calculates to an NNT of 63).

There is no evidence at this time to support that Zontivity® is more clinically efficacious or safer than the currently available, more cost effective medications. Therefore, it is recommended that Zontivity® remain non‐preferred and be available to the few who are unable to tolerate or who have failed preferred medications.

PDL Placement:  Preferred  Non‐Preferred  Preferred with Conditions

References 1 Zontivity [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp, a subsidiary of Merck & CO; 2014.

Prepared By: IME Date: 10/01/2014 Property of IME and may not be reproduced without permission 3