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Zontivity vorapaxar 2.08 mg Tablet, Film Coated, 30-count — NDC 66992-208-30 (Billing 66992-0208-30)

by WraSer Pharmaceuticals, LLC · 30 TABLET, FILM COATED in 1 BOTTLE

This is a package of 30 tablets of Zontivity vorapaxar 2.08 mg Tablet, Film Coated from WraSer Pharmaceuticals, LLC, no longer marketed, no longer in the FDA NDC Directory. It is the main listing for this product, which comes in 2 package sizes.

NDC 66992-0208-30
🏷️ FDA NDC (as labeled) 66992-208-30 billing pads the product segment with a zero
This package
Contains30-count Pack sizes2 compare ↓
Main listing for product 66992-208 · Also comes in: 90 tablets 66992-208-90
Rx only Brand Discontinued Non-controlled ⚠ Inactivated by FDA ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Jul 31, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

NDC database record

One package, one record: these facts belong to NDC 66992-208-30 alone.

Record
FDA NDC Directory package listing · Human prescription drug
Code segments
66992 labeler · 208 product · 30 package
Billing quantity
30 EA per package
Barcode (UPC-A, from the NDC)
3 6699220830 6
FDA record last changed
Jul 31, 2026
⚠️
Excluded from the active FDA NDC Directory. FDA inactivated this product’s listing record, so it is excluded from the active NDC Directory. The listing was last certified through Dec 2023. A label may still appear on DailyMed, but the NDC is no longer in the current FDA NDC Directory. Search the FDA NDC Directory ↗

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 66992-208-30
Product NDC 66992-208
11-digit billing NDC 66992020830
NCPDP billing unit EA — each (per item)
Application # NDA204886
SPL Set ID f2abe3ed-ed3d-4215-a489-b18341ce85bc
Mechanism of action Protease-activated Receptor-1 Antagonist [EPC], Protease-activated Receptor-1 Antagonists
DEA schedule Non-controlled
Marketing category NDA
Marketing status Discontinued
FDA listing status Inactivated by FDA (certified through Dec 2023)
Route ORAL
Dosage form TABLET, FILM COATED
Substance VORAPAXAR SULFATE

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GPI-14 85155780300320
GCN Seq No 072336
GCN 36504
HICL code 041137
Ingredient (HICL) Vorapaxar Sulfate
HIC1 code M
Therapeutic class — broad (HIC1) Blood
HIC2 code M9
Therapeutic class — intermediate (HIC2) Drugs Given To Alter Blood Coagulation
HIC3 code M9P
Therapeutic class — specific (HIC3) Platelet Aggregation Inhibitors
AHFS code 20:12.18.00
AHFS class Platelet-Aggregation Inhibitors
FDB label name ZONTIVITY 2.08 MG TABLET
FDB brand name Zontivity
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 072336
  • GCN: 36504
  • GPI-14 (Medi-Span): 85155780300320
  • HICL (First Databank): 041137
  • AHFS class code: 20:12.18.00
Why two NDCs? The FDA registers this code as 66992-208-30 — a 5-3-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the product segment → 66992-0208-30. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

Clinical

Label name ZONTIVITY 2.08 MG TABLET Ingredient Vorapaxar Sulfate
📗 Our plain-language guide HelloPharmacist
  • Zontivity is prescribed to lower your chances of having another heart attack, a stroke, or a procedure to unblock arteries — especially if you've already had a heart attack or have...
  • Why was I prescribed Zontivity? What exactly does it do?
  • Zontivity should not be taken alone. It has only been studied alongside aspirin and/or clopidogrel, and your doctor will prescribe it as part of that combination. The three medicat...
  • Do I have to take other blood thinners with it, or can I take Zontivity on its own?
📖 Read our full Vorapaxar guide →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

Pricing

A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.

Price systemPer eachPer package
Retail pharmacies payNADAC · weekly Not in the retail survey — common for institutional, discontinued, or low-volume packs.
Medicaid paysCMS SDUD · 12 mo No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data.
Medicare drug plans payPart D · quarterly No Part D plan price is available for this NDC in our data.
ℹ️
No price is published for this exact package yet. CMS surveys NADAC per package size, so a different pack of the same drug often has one.
Try another pack size: 90 tablets
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
66992-0208-30 You're viewing this Main listing 30 TABLET, FILM COATED in 1 BOTTLE 2022-09-21 — Inactivated by FDA
66992-0208-90 66992-208-90 90 TABLET, FILM COATED in 1 BOTTLE 2022-09-21 — Inactivated by FDA

You're viewing the smallest of 2 pack sizes for this product.

Pack size FAQ

What quantity is in this package?
This is a 30-count package — 30 tablet, film coated in 1 bottle.
How does this package differ from NDC 66992-0208-90?
Both are Zontivity vorapaxar 2.08 mg Tablet, Film Coated — the drug itself is identical. This page's package is the 30-count one, while NDC 66992-0208-90 is the 90 tablets package.
What NDC number is used to bill for this package of Zontivity vorapaxar 2.08 mg Tablet, Film Coated?
Use the 11-digit billing form listed in the identifiers section of this page. Pharmacy and medical claims use the 11-digit form; the FDA label may print a shorter form of the same code.

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Zontivity 2.08 mgthis 66992-0208-30 WraSer 30 tablets — — Discontinued —
About this product: this is the brand-name version. We did not find an FDA-approved generic match for this exact strength, form and route.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2014
First FDA approval
May 2014
📍
2026
Currently FDA-listed
12 years listed
🛡️
2027
Latest patent/protection listed
not a guaranteed launch date
🔒No FDA-approved generic found

We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.

🛡️ Latest patent/protection date listed: FDA patent/protection data lists protections through Dec 2027. This may affect when a full generic version becomes widely available, but it is not a guaranteed launch date.
📅 FDA approved May 8, 2014 RLD RS ⏳ ~1.2 yr to latest listed protection

Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.

Patents & exclusivity — FDA Orange Book
US 7304078 — drug substance (U-1512)
2014 2016 2018 2020 2022 2024 2026 2028
Today
LOE
Substance patent Formulation patent Method-of-use patent Exclusivity Pediatric +6mo
🏛️FDA exclusivity
FDA-granted marketing protection. It’s separate from patents and may be shorter than patent protection.
🧪Product / substance patents
Patents covering the active ingredient, product, formulation, or related drug features.
🎯Method-of-use patents
Patents covering specific approved uses. These can sometimes be carved out with a “skinny label,” but not always.
🛈 What do these terms mean?
Patent
Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
Substance patent
Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
Formulation (product) patent
Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
Method-of-use patent
A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
Skinny label
A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
Exclusivity
FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
Paragraph IV
A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
RLD / RS
Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
TE / AB rating
FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
LOE (loss of exclusivity)
The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.

Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.

Listed patents (1)
PatentTypeUse codeExpires
US 7304078 ↗ Drug substance U-1512 Dec 23, 2027
Common questions
Is there a generic version of ZONTIVITY 2.08 MG TABLET?
No FDA-approved generic equivalent is currently listed in the FDA Orange Book for ZONTIVITY 2.08 MG TABLET. Based on the patents and exclusivity currently listed, the Orange Book estimate is that full-label generic entry may be delayed until Dec 2027 — an estimate, not a guaranteed launch date.
The FDA approved a generic — why can’t I get it at my pharmacy yet?
FDA approval and pharmacy availability are two different things. The FDA can approve a generic years before it actually reaches pharmacies, because the brand company may still hold patents or have a settlement that delays the launch. A manufacturer also has to choose to make and sell it, and have supply ready. So a drug can be “FDA-approved generic exists” and still be brand-only at the counter today.
Why do different websites show different generic release dates?
Generic availability is not based on one single date. Some sources use the first exclusivity expiration, some use the last product patent, and others use the latest method-of-use patent. Patent challenges, settlements, licenses, and label carve-outs can also change the real-world launch date. This page shows the underlying Orange Book dates so you can see why estimates may differ.
What does “FDA listed” mean?
It means the product appears in the FDA’s official NDC directory. That’s a good sign a product exists and is intended for the U.S. market, but on its own it does not confirm a pharmacy can fill it today. Where we have recent retail pricing data (NADAC) for a product, we label it “Availability likely” instead.
What does a patent or protection date mean here?
It’s the latest date currently listed in the FDA Orange Book for a patent or exclusivity on the brand product. It can affect when a full generic version becomes widely available — but it is not a guaranteed generic launch date. Generics sometimes arrive earlier (through a settlement or patent challenge) or later (a manufacturer still has to make and sell one).
What does “current Orange Book estimate” mean?
It means we are using the latest patent and exclusivity dates currently listed in the FDA Orange Book. It is not a guaranteed launch date.
Can a generic come out before the last patent expires?
Sometimes. A generic company may challenge a patent, settle with the brand manufacturer, receive a license, or obtain approval with a narrower label that avoids a patented use. In other cases, the last listed protection may delay full-label generic competition.
Can a generic come out after the listed dates?
Yes. Even after patents or exclusivity expire, a generic still needs FDA approval and a manufacturer must choose to market it. Supply, litigation, business decisions, or regulatory issues can delay actual availability.
What is the difference between patents and exclusivity?
Patents are legal protections usually issued by the U.S. Patent and Trademark Office. FDA exclusivity is marketing protection granted by the FDA. They are separate, and either one can affect generic timing.
Why are there multiple patent dates?
One drug can have several patents covering different things: the active ingredient, a formulation, a manufacturing process, or a specific approved use. That is why a page may show several expiration dates instead of one simple generic date.
Built from FDA Orange Book patent and exclusivity data. Dates are refreshed from public FDA data when available; the marker is max(latest patent expiry, latest exclusivity expiry). Paragraph-IV settlements and first-filer 180-day exclusivity can shift the real date; a method-of-use patent may allow an earlier skinny-label generic for non-protected indications. Generic launch timing is an estimate, not a guarantee.
Where does this data come from?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

Inactive Ingredients / Excipients

Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.

🧪 Avoiding an ingredient? See Vorapaxar inactive ingredients by manufacturer: every current product's list side by side, so you can ask your pharmacy for the version that does not list it.

Loading inactive ingredients from the official FDA label in the background. No external source is being called by this page request.
Where does this data come from?
Source: official FDA Structured Product Labeling (SPL) via DailyMed and the openFDA label index. Structured IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerWraSer Pharmaceuticals, LLC
Application holderKEY THERAPEUTICS LLC
FDA applicationNDA204886 (NDA)
Labeler code66992
Product typeHuman Prescription Drug
The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🚨 Boxed Warning 🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📦 Storage and Handling 📋 Description 💬 Information for Patients 💬 Medication Guide 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📄 Package Label / Principal Display Panel
🚨 Boxed Warning 109 words ▾

WARNING: BLEEDING RISK Do not use ZONTIVITY in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH); or active pathological bleeding [see CONTRAINDICATIONS (4.1 , 4.2) ] . Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding, including ICH and fatal bleeding [see Warnings and Precautions (5.1) ]. WARNING: BLEEDING RISK See full prescribing information for complete boxed warning.

Do not use ZONTIVITY in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH); or active pathological bleeding. ( 4.1 , 4.2 ) Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding, including ICH and fatal bleeding. ( 5.1 )

🎯 Indications and Usage 120 words ▾

1 INDICATIONS AND USAGE ZONTIVITY is a protease-activated receptor-1 (PAR-1) antagonist indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). ZONTIVITY has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization. ( 1.1 )

1.1Patients with History of Myocardial Infarction (MI) or with Peripheral Arterial Disease (PAD) ZONTIVITY ® is indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). ZONTIVITY has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR).

⏱️ Dosage and Administration 128 words ▾

2 DOSAGE AND ADMINISTRATION One tablet of ZONTIVITY orally once daily. ( 2.1 ) Use with aspirin and/or clopidogrel according to their indications or standard of care. There is limited clinical experience with other antiplatelet drugs and none with ZONTIVITY as the only antiplatelet agent. ( 2.2 )

2.1General Dosing Information Take one tablet of ZONTIVITY 2.08 mg orally once daily, with or without food.

2.2Coadministration with Other Antiplatelet Drugs There is no experience with use of ZONTIVITY alone as the only administered antiplatelet agent. ZONTIVITY has been studied only as an addition to aspirin and/or clopidogrel. Use ZONTIVITY with aspirin and/or clopidogrel according to their indications or standard of care [see Clinical Studies (14) ] . There is limited clinical experience with other antiplatelet drugs.

💊 Dosage Forms and Strengths 27 words ▾

3 DOSAGE FORMS AND STRENGTHS ZONTIVITY tablets, 2.08 mg vorapaxar, are yellow, oval-shaped, film-coated tablets with "351" on one side. Tablets: 2.08 mg vorapaxar. ( 3 )

⛔ Contraindications 109 words ▾

4 CONTRAINDICATIONS History of stroke, TIA, or ICH. ( 4.1 ) Active pathologic bleeding. ( 4.2 )

4.1History of Stroke, Transient Ischemic Attack (TIA), or Intracranial Hemorrhage (ICH) ZONTIVITY is contraindicated in patients with a history of stroke, TIA, or ICH because of an increased risk of ICH in this population [see Adverse Reactions (6) ] . Discontinue ZONTIVITY in patients who experience a stroke, TIA, or ICH [see Adverse Reactions (6.1) and Clinical Studies (14) ] .

4.2Active Pathologic Bleeding ZONTIVITY is contraindicated in patients with active pathological bleeding such as ICH or peptic ulcer [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] .

⚠️ Warnings and Cautions ~1 min read ▾

5 WARNINGS AND PRECAUTIONS Like other antiplatelet agents, ZONTIVITY increases the risk of bleeding. ( 5.1 ) Avoid use with strong CYP3A inhibitors or inducers. ( 5.2 )

5.1General Risk of Bleeding Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding, including ICH and fatal bleeding [see Adverse Reactions (6.1) ] . ZONTIVITY increases the risk of bleeding in proportion to the patient's underlying bleeding risk. Consider the underlying risk of bleeding before initiating ZONTIVITY.

General risk factors for bleeding include older age, low body weight, reduced renal or hepatic function, history of bleeding disorders, and use of certain concomitant medications (e.g., anticoagulants, fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs [NSAIDS], selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors) increases the risk of bleeding [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Avoid concomitant use of warfarin or other anticoagulants.

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), or other surgical procedures. 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.

Significant inhibition of platelet aggregation remains 4 weeks after discontinuation [see Overdosage (10) and Clinical Pharmacology (12.2 , 12.3) ].

5.2Strong CYP3A Inhibitors or Inducers Strong CYP3A inhibitors increase and inducers decrease ZONTIVITY exposure. Avoid concomitant use of ZONTIVITY with strong CYP3A inhibitors or inducers [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

🤒 Adverse Reactions ~3 min read ▾

6 ADVERSE REACTIONS The following serious adverse reaction is also discussed elsewhere in the labeling: Bleeding [see Boxed Warning and Warnings and Precautions (5.1) ] . Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact WraSer Pharmaceuticals at 1-800-988-6115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ZONTIVITY was evaluated for safety in 13,186 patients, including 2,187 patients treated for more than 3 years, in the Phase 3 study TRA 2°P TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events).

The overall study population, patients who had evidence or a history of atherosclerosis involving the coronary (post-MI), cerebral (ischemic stroke), or peripheral vascular (documented history of PAD) systems, was treated once a day with ZONTIVITY (n=13,186) or placebo (n=13,166). Patients randomized to ZONTIVITY received treatment for a median of 2.3 years. The adverse events in the ZONTIVITY-treated (n=10,059) and placebo-treated (n=10,049) post-MI or PAD patients with no history of stroke or TIA are shown below [see Contraindications (4) ] .

Bleeding GUSTO severe bleeding was 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. (GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.) The results for the bleeding endpoints in the post-MI or PAD patients without a history of stroke or TIA are shown in Table 1. ZONTIVITY increased GUSTO moderate or severe bleeding by 55%.

Table 1: Non-CABG-Related Bleeds in Post-MI or PAD Patients without a History of Stroke or TIA (First Dose to Last Dose + 30 Days) in the TRA 2°P Study Placebo (n=10,049) ZONTIVITY (n=10,059) Endpoints Patients with events (%) K-M % K-M estimate at 1,080 days. Patients with events (%) K-M % Hazard Ratio Clinically significant bleeding includes any bleeding requiring medical attention including ICH, or clinically significant overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥3 g/dL (or, when Hgb is not available, an absolute drop in hematocrit (Hct) of ≥9%). , Hazard ratio is ZONTIVITY group vs. placebo group.

(95% CI) GUSTO Bleeding Categories Severe 82 (0.8%) 1.0% 100 (1.0%) 1.3% 1.24 (0.92 - 1.66) Moderate or Severe 199 (2.0%) 2.4% 303 (3.0%) 3.7% 1.55 (1.30 - 1.86) Any GUSTO Bleeding (Severe/Moderate/Mild) 1769 (17.6%) 19.8% 2518 (25.0%) 27.7% 1.52 (1.43 - 1.61) Fatal Bleeding 14 (0.1%) 0.2% 16 (0.2%) 0.2% 1.15 (0.56 - 2.36) Intracranial Hemorrhage (ICH) 31 (0.3%) 0.4% 45 (0.4%) 0.6% 1.46 (0.92-2.31) Clinically Significant Bleeding 950 (9.5%) 10.9% 1349 (13.4%) 15.5% 1.47 (1.35 - 1.60) Gastrointestinal Bleeding 297 (3.0%) 3.5% 400 (4.0%) 4.7% 1.37 (1.18-1.59) The effects of ZONTIVITY on bleeding were examined in a number of subsets based on demographic and other baseline characteristics.

Many of these are shown in Figure 1. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Figure 1: Subgroup Analyses (GUSTO Moderate or Severe Bleeding) in Post-MI or PAD Patients without a History of Stroke or TIA in the TRA 2°P Study (First Dose to Last Dose + 30 Days) In TRA 2°P, 367 post-MI or PAD patients without a history of stroke or TIA underwent CABG surgery.

Study investigators were encouraged not to discontinue treatment with study drug (i.e., ZONTIVITY or placebo) prior to surgery. Approximate… [Excerpted — this section continues on DailyMed.]

🔄 Drug Interactions 92 words ▾

7 DRUG INTERACTIONS

7.1Effects of Other Drugs on ZONTIVITY Vorapaxar is eliminated primarily by metabolism, with contributions from CYP3A4 and CYP2J2. Strong CYP3A Inhibitors Avoid concomitant use of ZONTIVITY with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . Strong CYP3A Inducers Avoid concomitant use of ZONTIVITY with strong inducers of CYP3A (e.g., rifampin, carbamazepine, St.

John's Wort and phenytoin) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ].

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS Pregnancy: When pregnancy is detected, discontinue vorapaxar and initiate appropriate alternative therapy. ( 8.1 ) Lactation: Breastfeeding not recommended. ( 8.2 )

8.1Pregnancy Risk Summary Based on the potential for serious adverse reactions (such as maternal bleeding/hemorrhage) and the long half-life which makes it effectively irreversible, discontinue vorapaxar when pregnancy is detected and initiate alternative therapy with a shorter duration of action [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.1 , 12.2) ] . Available data from postmarketing experience with ZONTIVITY use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, no embryo/fetal toxicities, malformations or maternal toxicities were observed in rats and rabbits exposed during the period of organogenesis at exposures 56 times and 26 times, respectively, the human systemic exposure at the recommended human dose (RHD) (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of vorapaxar at 0, 5, 25, and 75 mg/kg from implantation to closure of the fetal hard palate (6th to 17th day of gestation). Maternal systemic exposures were approximately 0, 7, 56, and 285 times greater than exposures in women treated at the RHD based on AUC.

No embryo/fetal toxicities, malformations, or maternal toxicities were observed in rats receiving exposures up to 56 times the human systemic exposure at the RHD. In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of vorapaxar at 0, 2, 10, or 20 mg/kg from implantation to closure of the fetal hard palate (7th to 19th day of gestation). The NOAEL for maternal and fetal toxicity was equal to or above the highest dose tested.

However, an overall increase in the number of litters with any malformation was observed at the highest dose, where systemic exposures were 89-fold higher than the human exposure at RHD. The effects of vorapaxar on prenatal and postnatal development were assessed in pregnant rats dosed at 0, 5, 25, or 50 mg/kg/day from implantation through the end of lactation. Rat pups had decreased survival and body weight gain from birth to postnatal day 4 and decreased body weight gain for the overall pre-weaning period at exposures 67 times the human exposure at the RHD.

Both male and female pups displayed effects on sensory function (acoustic startle) and neurobehavioral (locomotor assay) development on post-natal day (PND) 20 and 21, but not later (PND 60, 61) in development, whereas decreased memory was observed in female pups on PND 27 at 31 times the human exposure at the RHD. In utero and lactational exposure did not affect fertility or reproductive behavior of offspring at exposures up to 67 times the RHD.

8.2Lactation Risk Summary There are no data on the presence of vorapaxar or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. When vorapaxar was administered to lactating rats, vorapaxar was actively secreted in the milk of rats. When a drug is present in animal milk, it is likely the drug will be present in human milk.

Because of the potential for serious adverse reactions in the breastfed infant, such as bleeding, advise patients that breastfeeding is not recommended during treatment with ZONTIVITY.

8.4Pediatric Use The safety and effectiveness of ZONTIVITY in pediatric patients have not been establishe… [Excerpted — this section continues on DailyMed.]

🤰 Pregnancy ~2 min read ▾

8.1Pregnancy Risk Summary Based on the potential for serious adverse reactions (such as maternal bleeding/hemorrhage) and the long half-life which makes it effectively irreversible, discontinue vorapaxar when pregnancy is detected and initiate alternative therapy with a shorter duration of action [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.1 , 12.2) ] . Available data from postmarketing experience with ZONTIVITY use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, no embryo/fetal toxicities, malformations or maternal toxicities were observed in rats and rabbits exposed during the period of organogenesis at exposures 56 times and 26 times, respectively, the human systemic exposure at the recommended human dose (RHD) (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of vorapaxar at 0, 5, 25, and 75 mg/kg from implantation to closure of the fetal hard palate (6th to 17th day of gestation). Maternal systemic exposures were approximately 0, 7, 56, and 285 times greater than exposures in women treated at the RHD based on AUC.

No embryo/fetal toxicities, malformations, or maternal toxicities were observed in rats receiving exposures up to 56 times the human systemic exposure at the RHD. In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of vorapaxar at 0, 2, 10, or 20 mg/kg from implantation to closure of the fetal hard palate (7th to 19th day of gestation). The NOAEL for maternal and fetal toxicity was equal to or above the highest dose tested.

However, an overall increase in the number of litters with any malformation was observed at the highest dose, where systemic exposures were 89-fold higher than the human exposure at RHD. The effects of vorapaxar on prenatal and postnatal development were assessed in pregnant rats dosed at 0, 5, 25, or 50 mg/kg/day from implantation through the end of lactation. Rat pups had decreased survival and body weight gain from birth to postnatal day 4 and decreased body weight gain for the overall pre-weaning period at exposures 67 times the human exposure at the RHD.

Both male and female pups displayed effects on sensory function (acoustic startle) and neurobehavioral (locomotor assay) development on post-natal day (PND) 20 and 21, but not later (PND 60, 61) in development, whereas decreased memory was observed in female pups on PND 27 at 31 times the human exposure at the RHD. In utero and lactational exposure did not affect fertility or reproductive behavior of offspring at exposures up to 67 times the RHD.

🧒 Pediatric Use 16 words ▾

8.4Pediatric Use The safety and effectiveness of ZONTIVITY in pediatric patients have not been established.

🧓 Geriatric Use 97 words ▾

8.5Geriatric Use In TRA 2°P, in post-MI or PAD patients without a history of stroke or TIA, 33% of patients were ≥65 years of age and 9% were ≥75 years of age. The relative risk of bleeding (ZONTIVITY compared with placebo) was similar across age groups. No overall differences in safety or effectiveness were observed between these patients and younger patients.

ZONTIVITY increases the risk of bleeding in proportion to a patient's underlying risk. Because older patients are generally at a higher risk of bleeding, consider patient age before initiating ZONTIVITY [see Adverse Reactions (6.1) ].

🆘 Overdosage 67 words ▾

10 OVERDOSAGE There is no known treatment to reverse the antiplatelet effect of ZONTIVITY, and neither dialysis nor platelet transfusion can be expected to be beneficial if bleeding occurs after overdose. Inhibition of platelet aggregation can be expected for weeks after discontinuation of normal dosing [see Clinical Pharmacology (12.2) ] . There is no standard test available to assess the risk of bleeding in an overdose situation.

🧬 Clinical Pharmacology ~3 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Vorapaxar is a reversible antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets, but its long half-life makes it effectively irreversible. Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation in in vitro studies. Vorapaxar does not inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen or a thromboxane mimetic and does not affect coagulation parameters ex vivo .

PAR-1 receptors are also expressed in a wide variety of cell types, including endothelial cells, neurons, and smooth muscle cells, but the pharmacodynamic effects of vorapaxar in these cell types have not been assessed.

12.2Pharmacodynamics At the recommended dose, ZONTIVITY achieves ≥80% inhibition of TRAP-induced platelet aggregation within one week of initiation of treatment. The duration of platelet inhibition is dose- and concentration-dependent. Inhibition of TRAP-induced platelet aggregation at a level of 50% can be expected at 4 weeks after discontinuation of daily doses of ZONTIVITY 2.08 mg, consistent with the terminal elimination half-life of vorapaxar [see Clinical Pharmacology (12.3) ] .

In healthy volunteer studies, no changes in platelet P-selectin and soluble CD40 ligand (sCD40L) expression or coagulation test parameters (TT, PT, aPTT, ACT, ECT) occurred after single- or multiple- dose (28 days) administration of vorapaxar. No meaningful changes in P-selectin, sCD40L, or hs-CRP concentrations were observed in patients treated with vorapaxar in the phase 2/3 clinical trials. Evaluation of Vorapaxar on QTc Interval The effect of vorapaxar on the QTc interval was evaluated in a thorough QT study and in other studies.

Vorapaxar had no effect on the QTc interval at single doses up to 48 times the recommended dose.

12.3Pharmacokinetics Vorapaxar exposure increases in an approximately dose-proportional manner following single doses up to 16 times the recommended dose. Vorapaxar pharmacokinetics are similar in healthy subjects and patients. Absorption After oral administration of a single ZONTIVITY 2.08 mg dose under fasted conditions, peak concentrations (C max ) occur at 1 hour post-dose (range: 1 to 2 h).

The mean absolute bioavailability as determined from a microdosing study is approximately 100%. Ingestion of vorapaxar with a high-fat meal resulted in no meaningful change in AUC with a small (21%) decrease in C max and delayed time to peak concentration (45 minutes). ZONTIVITY may be taken with or without food.

Distribution The mean volume of distribution of vorapaxar is approximately 424 liters (95% CI: 351-512). Vorapaxar and the major circulating active metabolite, M20, are extensively bound (≥99%) to human plasma proteins. Vorapaxar is highly bound to human serum albumin and does not preferentially distribute into red blood cells.

Metabolism Vorapaxar is eliminated by metabolism via CYP3A4 and CYP2J2. The major active circulating metabolite is M20 (monohydroxy metabolite) and the predominant metabolite identified in excreta is M19 (amine metabolite). The systemic exposure of M20 is ~20% of the exposure to vorapaxar.

Excretion The primary route of elimination is through the feces. In a 6-week study, 84% of the administered radiolabeled dose was recovered as total radioactivity with 58% collected in feces and 25% in urine. Vorapaxar is eliminated primarily in the form of metabolites, with no unchanged vorapaxar detected in urine.

Vorapaxar exhibits multi-exponential disposition with an effective half-life of 3-4 days and an apparent terminal elimination half-life of 8 days. Steady-state is achieved by 21 days following once-daily dosing with an accumulation of 5- to 6-fold. The apparent terminal elimination half-life for vorapaxar is approximately 8 days (range 5-13 days) and is similar for the active metabolite.

The terminal elimination half-life is important to determine the time to offset the pha… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action 99 words ▾

12.1Mechanism of Action Vorapaxar is a reversible antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets, but its long half-life makes it effectively irreversible. Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation in in vitro studies. Vorapaxar does not inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen or a thromboxane mimetic and does not affect coagulation parameters ex vivo .

PAR-1 receptors are also expressed in a wide variety of cell types, including endothelial cells, neurons, and smooth muscle cells, but the pharmacodynamic effects of vorapaxar in these cell types have not been assessed.

📦 How Supplied / Storage and Handling 101 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING ZONTIVITY tablets, 2.08 mg vorapaxar, are yellow, oval-shaped, film-coated tablets with "351" on one side. They are supplied as follows: NDC 66992-208-30 bottles of 30 tablets NDC 66992-208-90 bottles of 90 tablets Storage of bottles Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). [See USP Controlled Room Temperature.] Store tablets in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.

Storage of blisters Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). [See USP Controlled Room Temperature.] Store in the original package until use.

📦 Storage and Handling 64 words ▾

Storage of bottles Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). [See USP Controlled Room Temperature.] Store tablets in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.

Storage of blisters Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). [See USP Controlled Room Temperature.] Store in the original package until use.

📋 Description 183 words ▾

11 DESCRIPTION ZONTIVITY contains vorapaxar sulfate, a tricyclic himbacine-derived selective inhibitor of platelet aggregation mediated by PAR-1. The chemical name of vorapaxar sulfate is ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(1E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethen-1-yl}-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate sulfate. The empirical formula is C 29 H 33 FN 2 O 4 ∙H 2 SO 4 , and its molecular weight is 590.7.

The structural formula is: Vorapaxar sulfate is a white to off-white solid. Vorapaxar sulfate is freely soluble in methanol and slightly soluble in ethanol, acetone, 2-propanol, and acetonitrile. In aqueous solution, it is slightly soluble in pH 1; its solubility decreases with increasing pH.

ZONTIVITY tablets are formulated with vorapaxar sulfate, but during manufacture and storage, partial conversion from vorapaxar sulfate to vorapaxar free base may occur. ZONTIVITY is available for oral use as tablets containing 2.08 mg of vorapaxar, which is equivalent to 2.5 mg of vorapaxar sulfate. Each film-coated tablet of ZONTIVITY contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, and magnesium stearate.

In addition, the film coating contains the following inactive ingredients: lactose monohydrate, hypromellose, titanium dioxide, triacetin (glycerol triacetate), and iron oxide yellow. Chemical Structure

💬 Information for Patients 167 words ▾

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved Patient Labeling ( Medication Guide ). Benefits and Risks Summarize the benefits and potential side effects of ZONTIVITY. Tell patients to take ZONTIVITY exactly as prescribed.

Inform patients not to discontinue ZONTIVITY without discussing it with the prescribing physician. Tell patients to read the Medication Guide. Bleeding Inform patients that they: May bleed and bruise more easily.

Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine. Invasive Procedures Instruct patients to: Inform physicians and dentists that they are taking ZONTIVITY before any surgery or dental procedure. Tell the doctor performing any surgery or dental procedure to talk to the prescribing physician before stopping ZONTIVITY.

Concomitant Medications Tell patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so that the physician knows about other treatments that may affect bleeding risk. Lactation Advise patients that breastfeeding is not recommended during treatment with Zontivity

💬 Medication Guide ~3 min read ▾

Medication Guide ZONTIVITY ® (zon-TIV-iti) (vorapaxar) Tablets Read this Medication Guide before you start taking ZONTIVITY and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about ZONTIVITY? ZONTIVITY is used to lower your chance of having another serious problem with your heart or blood vessels, but ZONTIVITY (and similar drugs) can cause bleeding that can be serious and lead to death. Call your doctor right away if you have any of these signs or symptoms of bleeding while taking ZONTIVITY: bleeding that is severe or that you cannot control pink, red, or brown urine vomiting blood or your vomit looks like "coffee grounds" red or black stools (looks like tar) coughing up blood or blood clots.

While you take ZONTIVITY and for about 4 weeks after your treatment with ZONTIVITY is stopped: you may bruise and bleed more easily (nose bleeds may be common) it will take longer than usual for any bleeding to stop. Do not take ZONTIVITY if you: have had a stroke or "mini stroke" (also known as transient ischemic attack or TIA) have had bleeding in your brain currently have unusual bleeding, such as bleeding in your head, stomach or intestines (an ulcer). If you have a stroke, TIA, or bleeding in your brain while taking ZONTIVITY your doctor should stop your treatment with ZONTIVITY.

Follow your doctor's instructions about stopping ZONTIVITY. Do not stop taking ZONTIVITY without talking to the doctor who prescribed it for you. What is ZONTIVITY?

ZONTIVITY is a prescription medicine used to treat people who have had a heart attack or reduced blood flow in their legs (peripheral arterial disease). ZONTIVITY is used with aspirin and/or clopidogrel to lower your chance of having another serious problem with your heart or blood vessels, such as heart attack, stroke, or death. It is not known if ZONTIVITY is safe and effective in children.

What should I tell my doctor before taking ZONTIVITY? Before you take ZONTIVITY, tell your doctor if you: have had bleeding problems or history of stomach ulcers have had a stroke or "mini-stroke" (also known as transient ischemic attack or TIA) have had any recent serious injury or surgery plan to have surgery or a dental procedure have kidney problems or severe liver problems are pregnant or plan to become pregnant. It is not known if ZONTIVITY will harm your unborn baby. are breastfeeding or plan to breastfeed.

It is not known if ZONTIVITY passes into your breast milk. You and your doctor should decide if you will take ZONTIVITY or breastfeed. You should not do both.

Tell all of your doctors and dentists that you are taking ZONTIVITY. They should talk to the doctor who prescribed ZONTIVITY for you before you have any surgery or dental procedure. Tell your doctor about all the medicines you take , including prescription and over-the-counter medicines, vitamins, dietary or herbal supplements.

Taking ZONTIVITY with certain other medicines may increase your risk of bleeding and may affect how ZONTIVITY works. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take ZONTIVITY? Take ZONTIVITY exactly as prescribed by your doctor. Take ZONTIVITY 1 time each day.

Take ZONTIVITY with or without food. Take ZONTIVITY with aspirin and/or clopidogrel as prescribed by your doctor. Do not stop taking ZONTIVITY without first talking to the doctor who prescribed it for you.

If you take too much ZONTIVITY, call your doctor, or go to the nearest emergency room right away. What are the possible side effects of ZONTIVITY? See " What is the most important information I should know about ZONTIVITY? " Anemia (low level of red blood cells) Depression Rash These are not all the possible side effects of ZONTIVITY.

Call your doctor for medical advice about side effects. You may rep… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacokinetics ~3 min read ▾

12.3Pharmacokinetics Vorapaxar exposure increases in an approximately dose-proportional manner following single doses up to 16 times the recommended dose. Vorapaxar pharmacokinetics are similar in healthy subjects and patients. Absorption After oral administration of a single ZONTIVITY 2.08 mg dose under fasted conditions, peak concentrations (C max ) occur at 1 hour post-dose (range: 1 to 2 h).

The mean absolute bioavailability as determined from a microdosing study is approximately 100%. Ingestion of vorapaxar with a high-fat meal resulted in no meaningful change in AUC with a small (21%) decrease in C max and delayed time to peak concentration (45 minutes). ZONTIVITY may be taken with or without food.

Distribution The mean volume of distribution of vorapaxar is approximately 424 liters (95% CI: 351-512). Vorapaxar and the major circulating active metabolite, M20, are extensively bound (≥99%) to human plasma proteins. Vorapaxar is highly bound to human serum albumin and does not preferentially distribute into red blood cells.

Metabolism Vorapaxar is eliminated by metabolism via CYP3A4 and CYP2J2. The major active circulating metabolite is M20 (monohydroxy metabolite) and the predominant metabolite identified in excreta is M19 (amine metabolite). The systemic exposure of M20 is ~20% of the exposure to vorapaxar.

Excretion The primary route of elimination is through the feces. In a 6-week study, 84% of the administered radiolabeled dose was recovered as total radioactivity with 58% collected in feces and 25% in urine. Vorapaxar is eliminated primarily in the form of metabolites, with no unchanged vorapaxar detected in urine.

Vorapaxar exhibits multi-exponential disposition with an effective half-life of 3-4 days and an apparent terminal elimination half-life of 8 days. Steady-state is achieved by 21 days following once-daily dosing with an accumulation of 5- to 6-fold. The apparent terminal elimination half-life for vorapaxar is approximately 8 days (range 5-13 days) and is similar for the active metabolite.

The terminal elimination half-life is important to determine the time to offset the pharmacodynamic effect [see Clinical Pharmacology (12.2) ] . Specific Populations The effects of intrinsic factors on the pharmacokinetics of vorapaxar are presented in Figure 2 [see Use in Specific Populations (8.5 , 8.6 , 8.7) ] . In general, effects on the exposure of vorapaxar based on age, race, gender, weight, and moderate renal insufficiency were modest (20-40%; see Figure 2 ).

No dose adjustments are necessary based upon these factors. Because of the inherent bleeding risks in patients with severe hepatic impairment, ZONTIVITY is not recommended in such patients [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7) ] . Figure 2: Effect of Intrinsic Factors on the Pharmacokinetics of Vorapaxar † See Warnings and Precautions.

(5.1) and Use in Specific Populations. (8.7) Figure 2 Drug Interactions [see also Drug Interactions (7) ] Anticoagulants and Antiplatelet Agents An interaction study with vorapaxar and warfarin in healthy subjects did not demonstrate a clinically significant pharmacokinetic or pharmacodynamic interaction [see Warnings and Precautions (5.1) and Figure 4 ] . Vorapaxar did not affect prasugrel pharmacokinetics and prasugrel did not affect vorapaxar pharmacokinetics following multiple-dose administration at steady-state [see Warnings and Precautions (5.1) and Figures 3 and 4 ] .

The pharmacokinetic interaction between vorapaxar and clopidogrel has not been evaluated. However, the use of vorapaxar on a background of clopidogrel is supported by the clinical data from TRA 2°P and TRA•CER [see Adverse Reactions (6.1) and Clinical Studies (14) ] . Effects of Other Drugs on Vorapaxar The effects of other drugs on the pharmacokinetics of vorapaxar are presented in Figure 3 as change relative to vorapaxar administered alone (test/reference).

Phase 3 data suggest that coadministration of a weak or moderat… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacodynamics 169 words ▾

12.2Pharmacodynamics At the recommended dose, ZONTIVITY achieves ≥80% inhibition of TRAP-induced platelet aggregation within one week of initiation of treatment. The duration of platelet inhibition is dose- and concentration-dependent. Inhibition of TRAP-induced platelet aggregation at a level of 50% can be expected at 4 weeks after discontinuation of daily doses of ZONTIVITY 2.08 mg, consistent with the terminal elimination half-life of vorapaxar [see Clinical Pharmacology (12.3) ] .

In healthy volunteer studies, no changes in platelet P-selectin and soluble CD40 ligand (sCD40L) expression or coagulation test parameters (TT, PT, aPTT, ACT, ECT) occurred after single- or multiple- dose (28 days) administration of vorapaxar. No meaningful changes in P-selectin, sCD40L, or hs-CRP concentrations were observed in patients treated with vorapaxar in the phase 2/3 clinical trials. Evaluation of Vorapaxar on QTc Interval The effect of vorapaxar on the QTc interval was evaluated in a thorough QT study and in other studies.

Vorapaxar had no effect on the QTc interval at single doses up to 48 times the recommended dose.

🔬 Clinical Studies ~3 min read ▾

14 CLINICAL STUDIES The clinical evidence for the effectiveness of ZONTIVITY is supported by TRA 2°P - TIMI 50. TRA 2°P was a multicenter, randomized, double-blind, placebo-controlled study conducted in patients who had evidence or a history of atherosclerosis involving the coronary (spontaneous MI ≥2 weeks but ≤12 months prior), cerebral (ischemic stroke), or peripheral vascular (documented peripheral arterial disease [PAD]) systems. Patients were randomized to receive daily treatment with ZONTIVITY (n=13,225) or placebo (n=13,224) in addition to standard of care.

The study's primary endpoint was the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR). The composite of cardiovascular death, MI, and stroke was assessed as key secondary endpoint. The median follow-up was 2.5 years (up to 4 years).

The findings in all randomized patients for the primary efficacy composite endpoint show a 3-year K-M event rate of 11.2% in the ZONTIVITY group compared to 12.4% in the placebo group (hazard ratio [HR]: 0.88; 95% confidence interval [CI], 0.82 to 0.95; p=0.001). The findings for the key secondary efficacy endpoint show a 3-year Kaplan-Meier (K-M) event rate of 9.3% in the ZONTIVITY group compared to 10.5% in placebo group (HR 0.87; 95% CI, 0.80 to 0.94; p<0.001). Although TRA 2°P was not designed to evaluate the relative benefits and risks of ZONTIVITY in individual patient subgroups, patients with a history of stroke or TIA showed an increased risk of ICH.

Of the patients who comprised the post-MI and PAD strata and had no baseline history of stroke or TIA,10,080 were randomized to treatment with ZONTIVITY and 10,090 to placebo. These patients were 89% Caucasian, 22% female, and 33% ≥65 years of age, with a median age of 60 years. The population included patients with diabetes (24%) and patients with hypertension (65%).

Of the patients who qualified for the trial with MI without a history of stroke or TIA, 98% were receiving aspirin, 78% were receiving a thienopyridine, and 77% were receiving both aspirin and a thienopyridine when they enrolled in the trial. Of the patients who qualified for the trial with PAD without a history of stroke or TIA, 88% were receiving aspirin, 35% were receiving a thienopyridine, and 27% were receiving both aspirin and a thienopyridine when they enrolled. In post-MI or PAD patients without a history of stroke or TIA the 3-year K-M event rate for the primary efficacy endpoint (composite of time to first CV death, MI, stroke, or UCR) was 10.1% in the ZONTIVITY group compared to 11.8% in the placebo group (HR 0.83; 95% CI, 0.76 to 0.90; p<0.001) (see Figure 5 and Table 3 ).

The results for the key secondary efficacy endpoint (composite of time to first CV death, MI, or stroke) show a 3-year K-M event rate of 7.9% in the ZONTIVITY group compared to 9.5% in the placebo group (HR 0.80; 95% CI, 0.73 to 0.89; p<0.001) (see Table 3 ). The effect of chronic dosing with ZONTIVITY on the primary and key secondary endpoints was maintained for the duration of the trial (median follow up 2.5 years, up to 4 years). Figure 5: Time to First Occurrence of the Composite Endpoint of CV Death, MI, Stroke or UCR in Post-MI or PAD Patients without a History of Stroke or TIA in TRA 2°P Table 3: TRA 2°P: Time to First Event in Post-MI or PAD Patients without a History of Stroke or TIA Placebo (n=10,090) ZONTIVITY (n=10,080) Endpoints Patients with events Each patient was counted only once (first component event) in the component summary that contributed to the primary efficacy endpoint.

(%) K-M % K-M estimate at 1,080 days. Patients with events (%) K-M % Hazard Ratio Hazard ratio is ZONTIVITY group versus placebo group. , Cox proportional hazard model with covariates treatment and stratification factors (qualifying atherosclerotic disease and planned thienopyridine use). (95% CI) p-value Primary Composite Efficacy Endpoint (CV death/MI/stroke/UCR) , 1073 (10.6%) 11.8% 896 (8.9%) 10.1% 0.83… [Excerpted — this section continues on DailyMed.]

🧪 Nonclinical Toxicology ~1 min read ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in rats and mice dosed orally with vorapaxar for two years. Male and female rats dosed at 0, 3, 10 or 30 mg/kg/day showed no carcinogenic potential at systemic exposures (AUC) in males and females that were 9- and 29-fold, respectively, the human systemic exposure at the RHD. In male and female mice dosed at 0, 1, 5, and 15 mg/kg/day, vorapaxar showed no carcinogenic potential at systemic exposures (AUC) that were up to 30-fold the human systemic exposure.

Mutagenesis Vorapaxar was not mutagenic in the Ames bacterial reverse mutation assay and not clastogenic in an in vitro human peripheral blood lymphocyte assay or an in vivo mouse micronucleus assay after intraperitoneal administration. Impairment of Fertility Fertility studies in rats showed that vorapaxar had no effect on either male or female fertility at doses up to 50 mg/kg/day, a dose resulting in systemic exposures (AUC) in male and female rats that are 40 and 67 times, respectively, the human systemic exposure at the RHD.

13.2Animal Pharmacology Vorapaxar did not increase bleeding time in non-human primates when administered alone. Bleeding time was prolonged slightly with administration of aspirin or aspirin plus vorapaxar. The combination of aspirin, vorapaxar, and clopidogrel produced significant prolongation of bleeding time.

Transfusion of human platelet rich plasma normalized bleeding times with partial recovery of ex vivo platelet aggregation induced with arachidonic acid, but not induced with ADP or TRAP. Platelet poor plasma had no effect on bleeding times or platelet aggregation [see Warnings and Precautions (5.1) ].

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 175 words ▾

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies were conducted in rats and mice dosed orally with vorapaxar for two years. Male and female rats dosed at 0, 3, 10 or 30 mg/kg/day showed no carcinogenic potential at systemic exposures (AUC) in males and females that were 9- and 29-fold, respectively, the human systemic exposure at the RHD. In male and female mice dosed at 0, 1, 5, and 15 mg/kg/day, vorapaxar showed no carcinogenic potential at systemic exposures (AUC) that were up to 30-fold the human systemic exposure.

Mutagenesis Vorapaxar was not mutagenic in the Ames bacterial reverse mutation assay and not clastogenic in an in vitro human peripheral blood lymphocyte assay or an in vivo mouse micronucleus assay after intraperitoneal administration. Impairment of Fertility Fertility studies in rats showed that vorapaxar had no effect on either male or female fertility at doses up to 50 mg/kg/day, a dose resulting in systemic exposures (AUC) in male and female rats that are 40 and 67 times, respectively, the human systemic exposure at the RHD.

📄 Package Label / Principal Display Panel 50 words ▾

PRINCIPAL DISPLAY PANEL - 30 Tablet Bottle Label NDC 66992-208-30 Zontivity ® (vorapaxar) tablets 2.08 mg* Dispense the accompanying Medication Guide to each patient. *Each tablet contains 2.08 mg vorapaxar, equivalent to 2.5 mg vorapaxar sulfate. Rx only 30 Tablets WraSer Pharmaceuticals PRINCIPAL DISPLAY PANEL - 30 Tablet Bottle Label

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

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Orange Book / therapeutic-equivalence data ✓ Available
HCPCS J-code billing crosswalk — Not published for this NDC Most self-administered / retail products have no J-code — that is normal.
Medicaid utilization (CMS SDUD) — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold.
“Not published” reflects what the public FDA / CMS / NLM sources provide for this exact package code — it is a property of the data feeds, not a judgment about the product.

Questions about this listing

Why is there no price listed?
The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
What does the discontinued status mean for this NDC?
The labeler reported a marketing end date (or the listing was delisted), so this specific package is no longer actively marketed. Remaining stock may still be dispensed for a time, and the NDC stays valid for historical records and claims — but data feeds (pricing, labeling) typically stop updating for it. Other package sizes or other manufacturers' versions of the same medication may still be marketed — see the equivalents section where available.
Is the NDC printed on the package the same as the 11-digit billing NDC?
Yes, they identify this exact package in different formats. The form printed on the packaging and shown on DailyMed is the one the FDA registered. Insurance claims use a fixed 11-digit 5-4-2 format, so the short segment is padded with a leading zero and the dashes are dropped. The Identity section at the top of this page lists each form of this code.
Does this product come in other package sizes?
Yes — the FDA directory lists 1 other package presentation of this same product, including 90 tablets (66992-0208-90). Each has its own NDC and its own page — see the package list near the top of this page.
Who lists this product with the FDA?
WraSer Pharmaceuticals, LLC is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
Do I need a prescription for this product?
This NDC is listed with FDA as a prescription product, so it is dispensed under a prescriber's order. Your pharmacist can tell you whether any over-the-counter forms of the same medication exist.
This page identifies an FDA-listed package (the NDC) and reports public regulatory and pricing data about the listing. It is reference information, not a medical recommendation — talk to your pharmacist or prescriber about your own medication.
Where does this data come from?
Listing facts (marketing category, packager status, marketing dates) from the FDA openFDA NDC Directory; label availability from DailyMed; pricing coverage from CMS NADAC; equivalence scope from the FDA Orange Book.
← 66990-1025-01 · Toshiki 66993-0002-10 · Prasco →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.