zontivity ™ - vorapaxar manufacturer: merck fda approval date: may 8, 2014 stephanie roach, pharmd...

Zontivity™ - vorapaxar

Manufacturer: Merck

FDA Approval Date: May 8, 2014

Stephanie Roach, PharmD Candidate


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



• 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



• 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



• 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.


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


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


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.


Drug Interactions

• Drug Interactions – Object Drugs: antiplatelet effect of other antiplatelet

agents bleeding risk with anticoagulants


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


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%


Monitoring Parameters

• Efficacy Monitoring:• N/A

• Toxicity Monitoring:• Hgb/HCT

• S/Sx of bleeding


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


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.


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


Literature Review

• Baseline Characteristics:


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%)


Literature Review

• Treatment: 2.08 mg vorapaxar daily vs matching placebo

• Standard therapy: • 94% treated with aspirin

• 66.5% treated with thienopyridine



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)



Literature Review


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:


Literature Review


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:


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


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


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

zontivity ™ - vorapaxar manufacturer: merck fda approval date: may 8, 2014 stephanie roach, pharmd...

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