Zontivity Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

ZONTIVITY™ (vorapaxar sulfate), co-administered with acetylsalicylic acid (ASA) with or without clopidogrel, according to their standard of care, is indicated for the reduction of atherothrombotic events in adult high-risk patients with a history of myocardial infarction (MI).

Geriatrics (≥65 years of age):

Older patients are generally at a higher risk of bleeding; consider patient age before initiating ZONTIVITY™. The relative risk of bleeding (vorapaxar compared with placebo) was similar across age groups. The risk of stroke and bleeding increases with age, but the risk-benefit profile of vorapaxar remains favorable in geriatric patients (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics (≥65 years of age) and ADVERSE REACTIONS).

Pediatrics (<18 years of age):

Safety and effectiveness of ZONTIVITY™ have not been established in children <18 years of age. Therefore ZONTIVITY™ is not indicated in this patient population.

CONTRAINDICATIONS

ZONTIVITY™ (vorapaxar sulfate) is contraindicated in

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• Patients with a history of stroke or transient ischemic attack (TIA) or who experience a stroke or TIA while on ZONTIVITY™ (see WARNINGS AND PRECAUTIONS, Neurologic).
• Patients with a history of intracranial hemorrhage (ICH) or who experience an ICH while on ZONTIVITY™ (see WARNINGS AND PRECAUTIONS, Bleeding).

• Patients with active pathological bleeding such as ICH or peptic ulcer (see WARNINGS AND

  PRECAUTIONS, Bleeding and ADVERSE REACTIONS).

• Patients with severe hepatic impairment (see WARNINGS AND PRECAUTIONS,

  Hepatic).

WARNINGS AND PRECAUTIONS

General

Discontinuation of ZONTIVITY™

Avoid interruption of ZONTIVITY™ treatment. If ZONTIVITY™ must be temporarily discontinued, restart it as soon as possible.

Lactose

ZONTIVITY™ contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Bleeding

Antiplatelet agents, including ZONTIVITY™, increase the risk of bleeding, including ICH and sometimes fatal bleeding. When administered in addition to standard care, generally aspirin and clopidogrel, ZONTIVITY™, compared with standard care alone, increased the risk of GUSTO moderate or severe bleeding (GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) (see ADVERSE REACTIONS).

Patients who experience an ICH while on ZONTIVITY^TM

Treatment with ZONTIVITY^TM should be discontinued (see CONTRAINDICATIONS, ADVERSE REACTIONS AND CLINICAL TRIALS).

Underlying bleeding risk and concomitant therapies

ZONTIVITY™ increases the risk of bleeding in patients with underlying bleeding risk. Consider the underlying risk of bleeding before initiating ZONTIVITY™. General risk factors for bleeding include:

• older age (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics

  (≥65 years of age)),

• low body weight (see WARNINGS AND PRECAUTIONS, Special Populations,

  Patients with low body weight (<60 kg)),

• reduced renal function (see WARNINGS AND PRECAUTIONS, Renal, Severe Renal

  Impairment) or

• reduced hepatic function (see CONTRAINDICATIONS and WARNINGS AND

  PRECAUTIONS, Hepatic, Severe Hepatic Impairment).

In these patients, ZONTIVITY™ should only be prescribed after careful assessment of individual potential risks and benefits and the need for co-medication that may further increase the risk of bleeding.

A history of bleeding disorders and use of certain medications (e.g., anticoagulant or fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs [NSAIDS], selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors) may also increase the risk of bleeding in patients taking ZONTIVITY™. Avoid concomitant chronic use of warfarin or other anticoagulants.

Severe Renal Impairment

Reduced renal function is a risk factor for bleeding and should be considered before initiating ZONTIVITY™. There is limited therapeutic experience in patients with severe renal impairment or end-stage renal disease. Therefore, ZONTIVITY™ should be used with caution in such patients.

Warfarin and other anticoagulants

There is limited experience with the concomitant use of vorapaxar with warfarin or other oral anticoagulants. The combination of vorapaxar with warfarin or other oral anticoagulants may increase the risk of bleeding and should be avoided.

Heparin

In patients treated with vorapaxar the concomitant use of heparin (including low molecular weight heparin (LMWH)) might be associated with an increased risk of bleeding and caution is advised.

Co-administration with other Antiplatelet Drugs

There is limited clinical experience with prasugrel and no experience with ticagrelor in the Phase 3 studies. Therefore, vorapaxar should not be used with prasugrel or ticagrelor and in case of need for additional therapy with these agents, vorapaxar should be stopped.

Surgery

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, even if the patient does not have any signs of bleeding.

Managing an acute bleeding event

Withholding ZONTIVITY™ for a brief period will not be useful in managing an acute bleeding event because of its long half-life (see WARNINGS AND PRECAUTIONS, Peri-Operative Considerations and ACTION AND CLINICAL PHARMACOLOGY). There is no known treatment to reverse the antiplatelet effect of ZONTIVITY™. Based on results of pre-clinical studies that investigated bleeding while on vorapaxar on a background of ASA and clopidogrel, it may be possible to restore hemostasis by administering exogenous platelets (see DETAILED PHARMACOLOGY).

Drug Interactions

Strong CYP3A Inhibitors

Avoid concomitant use of ZONTIVITY™ with strong CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, and ritonavir (see DRUG INTERACTIONS and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Strong CYP3A inducers

Avoid concomitant use of ZONTIVITY™ with strong CYP3A inducers, such as rifampicin, carbamazepine, and phenytoin (see DRUG INTERACTIONS and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Hepatic

Severe Hepatic Impairment

Patients with severe hepatic impairment have an increased inherent risk of bleeding and therefore the use of ZONTIVITY™ in these patients is contraindicated.

Neurologic

Patients with a history of stroke or transient ischemic attack (TIA)

ZONTIVITY™ is contraindicated in patients with a history of stroke or TIA because of an increased risk of ICH in this population (see CONTRAINDICATIONS). In the pivotal TRA 2°P

• TIMI 50 trial, among patients who entered the trial, those patients with a history of ischemic stroke had a higher 3 year Kaplan-Meier (K-M) event rate for ICH on ZONTIVITY™ plus standard care (2.7%) than on standard care alone (0.9%) (see CLINICAL TRIALS). In post-MI patients without a history of stroke or TIA, the 3 year K-M event rates for ICH were 0.54% and 0.45% for ZONTIVITY™ plus standard care and standard care alone, respectively (see CLINICAL TRIALS).

Patients who experience a stroke or TIA while on ZONTIVITY™

Treatment with ZONTIVITY™ should be discontinued (see CONTRAINDICATIONS, ADVERSE REACTIONS and CLINICAL TRIALS).

Peri-Operative Considerations

In the pivotal TRA 2°P - TIMI study, physicians were encouraged to continue study drug (i.e., ZONTIVITY™ or placebo) during the time surgery was performed. Patients undergoing CABG, PCI, non-CABG surgery, or other invasive procedures while on ZONTIVITY™ can continue the treatment with ZONTIVITY™ (see ADVERSE REACTIONS). If an antiplatelet effect is not desired, ZONTIVITY™ should be discontinued ≥30 days before the surgery.

Special Populations

Pregnant Women:

There is no experience on the use of ZONTIVITY™ during pregnancy. ZONTIVITY™ should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Women:

It is not known whether vorapaxar is excreted in human breast milk. Studies in rats have shown that after oral administration of ¹⁴C-vorapaxar, vorapaxar and/or its metabolites are excreted in milk. Because many drugs are excreted in human milk and due to the unknown potential for adverse reactions in nursing infants from ZONTIVITY™, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatrics (<18 years of age):

Safety and effectiveness of ZONTIVITY™ have not been established in children <18 years of age. Therefore ZONTIVITY™ is not indicated in this patient population.

Geriatrics (≥65 years of age):

Older patients are generally at a higher risk of bleeding; consider patient age before initiating ZONTIVITY™. In TRA 2°P - TIMI 50, 28.9% of post-MI patients without a history of stroke or TIA were ≥65 years of age and 7.3% were ≥75 years of age. The relative risk of bleeding (vorapaxar compared with placebo) was similar across age groups. The risk of stroke and bleeding increases with age, but the risk-benefit profile of vorapaxar remains favorable in geriatric patients. (see ADVERSE REACTIONS).

Patients with low body weight (<60 kg)

In general, a body weight <60 kg is a risk factor for bleeding. In TRA 2°P - TIMI 50, in vorapaxar-treated patients, higher rates of bleeding events (ICH, Clinically significant, Gusto severe or moderate) were observed in patients weighing <60 kg compared to patients weighing ≥60 kg. ZONTIVITY™ should be used with caution in patients with a body weight <60 kg.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In post-MI patients with no history of stroke or TIA, epistaxis was the most frequently reported bleeding event and was reported twice as much in the ZONTIVITY™ group compared to the placebo group (7.2% vs. 3.6%). Other bleeding events more frequently reported in the ZONTIVITY™ group than in the placebo group included hematuria (2.5% vs. 2.0%), hematoma (2.3% vs. 1.5%), rectal hemorrhage (1.4% vs. 1.0%), gingival bleeding (1.2% vs. 0.5%), melena (0.8% vs. 0.5%) and gastrointestinal hemorrhage (0.5% vs. 0.2%). Anemia was reported more frequently in patients treated with ZONTIVITY™ (2.5%) compared to placebo (1.9%).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

ZONTIVITY™ was evaluated for safety in the Phase 3 study TRA 2°P - TIMI 50 where patients with evidence or a history of atherosclerosis involving the coronary (post-MI), cerebral (ischemic stroke), or peripheral vasculature (documented history of PAD), were 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 with 2,187 patients treated for >3 years.

Adverse events (AEs) observed in post-MI patients without a history of stroke or TIA who received ZONTIVITY™ (n=8,444) or placebo (n=8,412) are shown below.

Bleeding

In post-MI patients with no history of stroke or TIA, the most common adverse reaction reported during treatment with ZONTIVITY™ was bleeding, including GUSTO Moderate or Severe, TIMI Minor or Major and clinically significant bleeding (Table 1). The most frequent origin for GUSTO Severe or Moderate bleeding was gastrointestinal.

Table 1 - TRA 2°P - TIMI 50 Bleeding Endpoints in Post-MI Patients without a History of Stroke or TIA

The effects of ZONTIVITY™ on GUSTO Moderate or Severe bleeding were examined in a number of subgroups 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. Of note, patients with a body weight <60 kg had a higher rate of GUSTO Moderate or Severe bleeding compared to patients with a body weight ≥60 kg (see WARNINGS AND PRECAUTIONS, Special Populations, Patients with low body weight (<60 kg)).

Figure 1 - Subgroup Analyses (GUSTO Moderate or Severe Bleeding) From Randomization to Last Visit in Post-MI Patients without a History of Stroke or TIA in the TRA 2°P Study

*the majority of patients were on Clopidogrel

SCH53048 (S) = ZONTIVITY™

During the TRA 2°P - TIMI 50 study, 288 post-MI 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. The rates of CABG-related TIMI Major were numerically similar between patients treated with ZONTIVITY™ (n=7, 5.3%) and placebo (n=7, 4.5%).

Bleeding events were treated in the same manner as for other antiplatelet agents including addressing the source of bleeding while providing supportive care.

0.125 0.25 0.5 1 2 4 8

Placebo (P) Better SCH53048 (S) Better

Hazard Ratio (95% CI)

Sex

Male

Female

Age

<65 yrs

>= 65 yrs

<75 yrs

>= 75 yrs

Race

White

Non-white

Asian

African-American

Body Weight

< 60 kg

>= 60 kg

Renal Insufficiency

eGFR <60 ml/min/1.73 m*m

eGFR >= 60 ml/min/1.73 m*m

History of Diabetes Mellitus

Yes

No

History of Heart Failure

Yes

No

Thienopyridine Use at Baseline

Yes

No

Aspirin Use at Baseline

Yes

No

<=100mg

>100mg to <300mg

>=300mg

Subgroup

13474

3382

11985

4871

15620

1236

14856

1991

661

348

857

15977

1968

14695

3613

13242

1410

15445

13202

3654

16574

282

12865

1477

2231

169

62

120

111

192

39

208

23

7

3

19

212

59

170

61

170

35

196

192

39

227

4

171

13

43

120

36

79

77

132

24

135

21

4

8

11

145

33

121

42

114

22

134

136

20

153

3

107

8

38

No. of Events

Total (3 yr KM rate)

Patients S P

1.42

1.69

1.54

1.39

1.46

1.57

1.53

1.16

2.09

0.37

1.78

1.46

1.54

1.43

1.47

1.49

1.60

1.46

1.42

1.86

1.49

1.25

1.59

1.78

1.12

(1.12, (1.12,

(1.16, (1.04, (1.17, (0.94,

(1.23, (0.64, (0.61, (0.10,

(0.85, (1.18,

(1.01, (1.13,

(0.99, (1.17,

(0.94, (1.17,

(1.14, (1.09,

(1.21, (0.28, (1.25, (0.74, (0.73,

1.79) 2.55)

2.05) 1.85) 1.82) 2.61)

1.90) 2.10) 7.16) 1.38)

3.74) 1.80)

2.36) 1.81)

2.18) 1.89)

2.73) 1.82)

1.77) 3.20)

1.82) 5.61) 2.02) 4.30) 1.74) HR (95% CI)

(2.8)

(4.5)

(2.3)

(5.2)

(2.8)

(7.0)

(3.2)

(2.9)

(2.2)

(2.1)

(5.2)

(3.0)

(6.2)

(2.7)

(4.1)

(2.9)

(6.1)

(2.9)

(3.3)

(2.7)

(3.1)

(4.0)

(2.9)

(2.7)

(4.5)

(2.1)

(2.6)

(1.5)

(4.0)

(2.0)

(4.9)

(2.1)

(2.7)

(1.7)

(5.4)

(3.0)

(2.1)

(4.8)

(1.8)

(2.7)

(2.0)

(3.5)

(2.1)

(2.4)

(1.3)

(2.2)

(2.3)

(1.9)

(1.7)

(4.2)

*

In post-MI patients with no history of stroke or TIA, there were more patients treated with ZONTIVITY™ who reported any treatment-related bleeding adverse event compared to those treated with placebo (18.4% vs. 12.1%). Epistaxis was the most frequently reported bleeding event and was reported twice as much in the ZONTIVITY™ group compared to the placebo group (5.6% vs. 2.6%). Other bleeding events more frequently reported in the ZONTIVITY™ group than in the placebo group included contusion (2.5% vs. 1.9%), increased tendency to bruise (2.6% vs. 1.6%), hematuria (1.5% vs. 1.1%), hematoma (1.6% vs. 1.0%), rectal hemorrhage (0.9% vs. 0.7%), gingival bleeding (0.9% vs. 0.5%), and gastrointestinal hemorrhage (0.3% vs. 0.1%).

Other Adverse Reactions

Anemia was reported more frequently in patients treated with ZONTIVITY™ (2.5%) compared to placebo (1.9%). There was no evidence of an association between ZONTIVITY™ treatment and non-bleeding causes of anemia, such as bone marrow suppression.

An increased rate of diplopia, irrespective of investigator attribution of causality, was observed with ZONTIVITY™ treatment (0.1%) vs placebo (0.02%) in post MI patients without a history of stroke or TIA. Most cases were classified as mild. While some cases resolved during continued treatment, information on resolution of symptoms was not available for some cases.

Drug Discontinuation

For post-MI patients without a history of stroke or TIA, the rate of study drug discontinuation because of adverse reactions was 6.0% for ZONTIVITY™ and 6.2% for placebo. Bleeding was the most common adverse reaction leading to study drug discontinuation for both treatments (2.9% for ZONTIVITY™ and 1.7% for placebo). Anemia was the most frequently reported event in the ZONTIVITY™ group (0.3%) that led to study drug discontinuation compared to placebo (0.1%).

DRUG INTERACTIONS

Drug-Drug Interactions

Overview

CYP P450 System

Inhibition of CYP enzymes: In vitro metabolism studies have demonstrated that vorapaxar is unlikely to cause clinically significant inhibition of human CYP1A2, CYP2B6, CYP3A, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. No clinically meaningful inhibition of CYP2B6, CYP3A, CYP2C19, or CYP2D6 is expected by M20, the major active circulating metabolite of vorapaxar.

Induction of CYP enzymes: Based upon in vitro data, chronic administration of vorapaxar is unlikely to induce the metabolism of drugs metabolized by major CYP isoforms.

Weak or Moderate CYP3A Inhibitors

Phase 3 data suggest that co-administration of a weak or moderate CYP3A inhibitor with ZONTIVITY^TM does not increase bleeding risk or alter the efficacy of vorapaxar.

Transporters

P-glycoprotein (P-gp) Transporter

Vorapaxar is a weak inhibitor of the intestinal P-glycoprotein (P-gp) transporter following consecutive, multiple-dose administration. Therefore, ZONTIVITY^TM can enhance the absorption or absorption rate of drugs that are P-gp substrates, such as digoxin.

Other Transporters

No clinically meaningful inhibition of OATP1B1, OATP1B3, BCRP, OAT1, OAT3, and OCT2 is anticipated by vorapaxar or M20.

Drug-Drug Interactions

Table 2 – Clinical Drug-Drug Interactions

Drug-Food Interactions

ZONTIVITY™ can be taken with or without food. Grapefruit juice is an inhibitor of CYP3A4, which may result in increased plasma concentrations of ZONTIVITY™; therefore, avoid concomitant use.

Drug-Herb Interactions

Interactions with herbal products have not been established. St. John’s Wort (Hypericum perforatum) is an inducer of CYP3A, which may result in reduced concentrations of ZONTIVITY™; therefore, avoid concomitant use.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Take one tablet of ZONTIVITY™ orally once daily, with or without food. ZONTIVITY™ should be co-administered with acetylsalicylic acid (ASA) with or without clopidogrel according to their indications or standard of care. ZONTIVITY™ should be initiated at least 2 weeks after a MI and within the first 12 months from the acute event (see CLINICAL TRIALS). A delayed onset of action (at least 7 days) should be expected when starting therapy with ZONTIVITY™.

There are limited data on the efficacy and safety of ZONTIVITY™ beyond 24 months. Continued therapy after this time must be based on a re-evaluation of the benefits and risks for the individual of further therapy.

Co-administration with Prasugrel and Ticagrelor:

There is limited clinical experience with prasugrel and no experience with ticagrelor in the Phase 3 studies. Therefore, vorapaxar should not be used with prasugrel or ticagrelor. Vorapaxar should not be initiated in patients taking prasugrel or ticagrelor and in case of need for additional therapy with these agents, vorapaxar should be stopped.

Missed Dose

If patients forget a dose, they should take it as soon as they remember. However, if it is nearly time for the next dose, they should skip the missed dose. They should not take two doses at the same time.

OVERDOSAGE

In humans, vorapaxar sulfate has been administered in single doses up to ~50 times the recommended daily dose, and twice the recommended daily dose for up to 4 weeks, without observation of dose-associated adverse events or identification of a specific risk. Treatment of presumed overdose should address signs and symptoms.

As vorapaxar is highly protein-bound, hemodialysis is unlikely to be effective in the treatment of an overdose.

Platelet transfusion may be considered as supportive therapy should bleeding occur (see DETAILED PHARMACOLOGY).

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Therapeutic Class

Vorapaxar is a selective and reversible inhibitor of the PAR-1 receptors on platelets.

Mechanism of Action

Vorapaxar inhibits thrombin-induced platelet aggregation in in vitro studies. In addition, vorapaxar inhibits thrombin receptor agonist peptide (TRAP)-induced platelet aggregation without affecting coagulation parameters. Vorapaxar does not inhibit platelet aggregation induced by other agonists such as adenosine diphosphate (ADP), collagen or a thromboxane mimetic.

Pharmacodynamics

At the recommended dose, ZONTIVITY™ achieves ≥80% inhibition of TRAP-induced platelet aggregation within 1 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™, consistent with the long terminal elimination half-life of vorapaxar (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

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.

Cardiac Electrophysiology

In a randomized, double-blind, placebo- and positive-controlled, parallel group ECG assessment study in healthy subjects (n=40/treatment arm), a single dose of ZONTIVITY™ 120 mg (48x therapeutic dose) had no effect on the QTcF interval, the QRS duration, the PR interval or heart rate.

Pharmacokinetics

Vorapaxar exposure increases in an approximately dose-proportional manner following single doses ≤ 16x the recommended dose. Vorapaxar pharmacokinetics are similar in healthy subjects and patients.

The primary pharmacokinetic parameters for vorapaxar are presented in the table below.

Table 3 – Summary of ZONTIVITY™ Pharmacokinetic Parameters following Multiple Oral Doses in

Healthy Subjects [Geometric Mean (95% Confidence Interval)]

The systemic pharmacokinetics of vorapaxar are linear with accumulation (6-fold) predictable from single- to multiple-dose data. Steady-state is achieved by 21 days following once-daily dosing. The apparent terminal half-life for vorapaxar and the active metabolite M20 are similar.

Absorption:

A single oral 2.5 mg dose of ZONTIVITY™ is rapidly absorbed and peak concentrations occur at a median T_max of 1 hour (range: 1-2 hours) under fasted conditions. The mean absolute bioavailability is 100% (90% CI: 98-116%).

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 T_max (by 45 minutes).

Distribution:

Vorapaxar and its 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, with CYP3A4 and CYP2J2 responsible for formation of M20 and M19, the predominant metabolite identified in excreta. The systemic exposure of M20 is ~20% of the exposure to vorapaxar.

Excretion:

The primary route of elimination is through the feces, with approximately 91.5% of radiolabeled dose predicted to be recovered in the feces compared to 8.5% in the urine. Vorapaxar is eliminated primarily in the form of metabolites, with no vorapaxar detected in urine.

Special Populations and Conditions

The effects of intrinsic factors on the pharmacokinetics (PK) of vorapaxar were evaluated in specific PK studies [end-stage renal disease (ESRD) undergoing hemodialysis and hepatic insufficiency] and in a population PK modeling analysis (gender, age, weight, race and mild or moderate renal insufficiency).

In general, older age (≥65 years and ≥75 years), Asian race, low body weight(<60 kg), female gender and mild or moderate renal insufficiency had modest (20-40%) effects on vorapaxar AUC and Cmax. The PK parameters of vorapaxar were similar between patients with mild to moderate hepatic insufficiency or ESRD patients and healthy subjects.

STORAGE AND STABILITY

Store at room temperature (15°C - 30°C) in the original package.

SPECIAL HANDLING INSTRUCTIONS

Store in a safe place out of the reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

ZONTIVITY™ film-coated 2.5 mg tablets are yellow, oval-shaped, debossed, with the Merck logo on one side and "351" on the other side. Available in blisters of 30 tablets.

Composition

ZONTIVITY™ is a film-coated tablet, containing 2.5 mg vorapaxar sulfate, which is equivalent to 2.08 mg vorapaxar.

During manufacture and storage of the drug product vorapaxar sulfate undergoes partial conversion to vorapaxar free base within controlled limits.

Non-medicinal ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone.

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

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: vorapaxar sulfate

Chemical name:

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.

Molecular formula and molecular mass: C₂₉H₃₃FN₂O₄·H₂SO₄; 590.7

Structural formula:

Physicochemical properties:

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.

CLINICAL TRIALS

Study demographics and trial design

Table 4 - Summary of patient demographics for the Overall Population and post-MI patients without a history of stroke or TIA in the TRA 2°P - TIMI 50 trial

The clinical evidence for the effectiveness of ZONTIVITY™ (vorapaxar sulfate) in post-MI patients without a history of stroke or TIA is derived from the TRA 2°P - TIMI 50 trial. TRA 2°P - TIMI 50 was a multicenter, randomized, double-blind, placebo-controlled study conducted initially, in patients who had evidence or a history of atherosclerosis involving the coronary (spontaneous MI), cerebral (ischemic stroke), or peripheral vasculature (documented peripheral arterial disease [PAD]). The MI and the ischemic stroke had to have occurred ≥2 weeks and ≤12 months before initiation of therapy. Following safety concerns (increased risk of ICH) associated with the use of ZONTIVITY™ in patients with a history of stroke, such patients were discontinued from the trial. The study’s primary endpoint was the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR), while the secondary endpoint was a composite of cardiovascular death, MI, and stroke. The following section focuses on the label population, the post-MI patients without a history of stroke or TIA.

Of the post-MI patients without a history of stroke or TIA, 8,458 were randomized to treatment with ZONTIVITY™ and 8,439 to placebo, both in addition to ASA and/or clopidogrel. The median duration of ZONTIVITY™ follow up in these patients was 2.5 years (up to 4 years). At enrollment, 98.3% of patients were receiving ASA and 77.6% were receiving clopidogrel. This background therapy was to be continued during the trial at the treating physician's discretion, per standard of care.

The post-MI patient population without a history of stroke or TIA was 88% Caucasian, 20% female, and 29% ≥65 years of age, with a median age of 58 years. There were 21% of patients who had diabetes and 62% who had hypertension.

Study results

Both primary and key secondary efficacy results demonstrated risk reduction (p=0.001) by ZONTIVITY™ in the overall population.

In post-MI patients without a history of stroke or TIA, the findings for the primary efficacy composite endpoint show a 3-year Kaplan-Meier event rate of 9.8% in the ZONTIVITY™ group compared with a rate of 11.4% in the placebo group. These results were statistically significant (Hazard Ratio [HR]: 0.82; 95% Confidence Interval [CI], 0.74-0.90; p<0.001) and demonstrated superiority of ZONTIVITY™ over placebo in preventing CV death, MI, stroke, or UCR. (See Figure 2 and Table 5)

The findings for the key secondary efficacy endpoint showed a 3-year Kaplan-Meier event rate of 7.4% in the ZONTIVITY™ group compared with a rate of 9.0% in the placebo group. These results were statistically significant (HR: 0.78; 95% CI, 0.70-0.88; p <0.001) (see Table 5). The effect was similar regardless of the time from qualifying MI to the start of the therapy with ZONTIVITY™.

The effect of chronic dosing with ZONTIVITY™ on the primary and key secondary endpoints was maintained for the duration of the study.

Figure 2 - Time to First Occurrence of CV death, MI, Stroke or UCR from Randomization to Last Visit in Post-MI Patients without a History of Stroke or TIA

Table 5 - Primary and Key Secondary Efficacy Endpoints in Post-MI Patients without a History of Stroke or TIA

Recurrence of events: In post-MI patients without a history of stroke or TIA, an analysis of multiple occurrences of adjudicated endpoints indicated that ZONTIVITY™ was associated with a reduction in the incidence of recurrent events (see Table 6).

Table 6 - Analysis of Multiple Occurrences of Adjudicated Primary and Secondary Composite Endpoint

Component Events From Randomization to Last Visit in Post-MI Patients without a History of Stroke or TIA

CABG: Analyses beginning at the time of CABG through last visit suggest continued effectiveness of ZONTIVITY™ in reducing primary endpoint events (HR 0.55, 95% CI 0.25-1.20). This benefit was seen as early as 30 days post operatively (HR 0.74, 95% CI 0.24-2.26).

Stent thrombosis:

Among post-MI patients without a history of stroke or TIA, ZONTIVITY™ reduced the rate of definite, definite or probable, and definite or probable or possible stent thrombosis vs. placebo in subjects receiving any stent before or during the study. The results were similar for drug-eluting and bare metal stents.

A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Many of these are shown in Figure 3 (primary endpoints) and Figure 4 (secondary endpoints). Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.

The treatment effect of ZONTIVITY™ was consistent with the overall results across many subgroups, including sex; age; renal insufficiency; medical history of diabetes mellitus; tobacco use; concomitant therapies at baseline including clopidogrel, aspirin, and statins.

Figure 3 - Subgroup Analysis for Primary Efficacy Endpoint in Subjects with No History of Stroke or TIA

Whose Qualifying Condition Was CAD: ITT Population Event Accrual Period: Randomization to Last Visit

*the majority of patients were on Clopidogrel SCH53048 (S) = ZONTIVITY™

Sex

Male

Female

Age

<65 yrs

>= 65 yrs

<75 yrs

>= 75 yrs

Race

White

Non-white

Body Weight

< 60 kg

>= 60 kg

Thienopyridine Use at Baseline

Yes

No

Aspirin Use at Baseline

Yes

No

<=100mg

>100mg to <300mg

>=300mg

Renal Insufficiency

eGFR <60 ml/min/1.73 m*m

eGFR >= 60 ml/min/1.73 m*m History of Diabetes Mellitus

Yes

No

Taking a Statin at Baseline

Yes

No

History of Tobacco Use

Never Used

History of Use

Current User

Subgroup

0.25 0.5 1 2 4

Placebo (P) Better SCH53048 (S) Better

13498

3399

12012

4885

15657

1240

14896

1992

861

16012

13235

3662

16613

284

12895

1481

2236

1975

14721

3623

13273

16117

780

4882

8687

3328

548

171

440

279

633

86

619

100

41

677

576

143

707

12

511

51

145

161

553

220

499

664

55

209

354

156

668

199

572

295

775

92

750

117

38

829

700

167

848

19

623

84

141

160

700

295

572

818

49

234

435

198

No. of Events

Total (3 yr KM rate)

Patients S P

0.81

0.82

0.77

0.89

0.81

0.88

0.81

0.89

1.07

0.80

0.82

0.82

0.82

0.56

0.81

0.64

1.00

0.84

0.79

0.73

0.86

0.81

0.94

0.86

0.81

0.79

(0.73,

(0.67,

(0.68,

(0.76,

(0.73,

(0.65,

(0.73,

(0.68,

(0.69,

(0.73,

(0.73,

(0.65,

(0.74,

(0.27,

(0.72,

(0.45,

(0.79,

(0.68,

(0.71,

(0.61,

(0.76,

(0.73,

(0.64,

(0.71,

(0.70,

(0.64,

0.91) 1.01)

0.87) 1.05) 0.90) 1.18)

0.90) 1.16)

1.66) 0.89)

0.91) 1.02)

0.91) 1.16) 0.91) 0.90) 1.26)

1.05) 0.89)

0.87) 0.97)

0.89) 1.38)

1.04) 0.93) 0.97) HR (95% CI)

(9.4)

(11.6)

(8.7)

(12.6)

(9.4)

(15.2)

(9.5)

(12.2)

(11.5)

(9.7)

(10.0)

(9.1)

(9.8)

(10.4)

(9.1)

(9.4)

14.4)

(17.0)

(8.7)

(14.5)

(8.6)

(9.6)

(14.7)

(9.8)

(9.2)

(11.6)

(11.0)

(13.1)

(10.5)

(13.8)

(11.0)

(16.8)

(11.2)

(13.0)

(10.0)

(11.5)

(11.8)

(10.2)

(11.4)

(14.1)

(10.8)

(12.2)

(14.1)

(18.5)

(10.6)

(18.0)

(9.6)

(11.2)

(16.2)

(11.0)

(11.0)

(13.2)

Hazard Ratio (95% CI)

*

Figure 4 - Subgroup Analyses (Secondary Endpoint) of the TRA 2°P - TIMI 50 From Randomization to Last Visit Post-MI Patients without a History of Stroke or TIA

*the majority of patients were on Clopidogrel

SCH53048 (S) = ZONTIVITY™

DETAILED 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 Sex

Male

Female

Age

<65 yrs

>= 65 yrs

<75 yrs

>= 75 yrs

Race

White

Non-white

Body Weight

< 60 kg

>= 60 kg

Thienopyridine Use at Baseline

Yes

No

Aspirin Use at Baseline

Yes

No

<=100mg

>100mg to <300mg

>=300mg

Renal Insufficiency

eGFR <60 ml/min/1.73 m*m

eGFR >= 60 ml/min/1.73 m*m

History of Diabetes Mellitus

Yes

No

Taking a Statin at Baseline

Yes

No

History of Tobacco Use

Never Used

History of Use

Current User

Subgroup

0.25 0.5 1 2 4

Placebo (P) Better SCH53048 (S) Better

Hazard Ratio

(95% CI)

13498

3399

12012

4885

15657

1240

14896

1992

861

16012

13235

3662

16613

284

12895

1481

2236

1975

14721

3623

13273

16117

780

4882

8687

3328

408

124

305

227

456

76

456

76

31

500

415

117

523

9

383

41

99

137

391

171

361

488

44

156

257

119

526

145

426

245

592

79

577

94

29

642

525

146

656

15

475

74

107

128

538

231

440

632

39

180

330

161

No. of Events

Total (3 yr KM rate)

Patients S P

0.77

0.83

0.72

0.88

0.76

0.91

0.78

0.84

1.06

0.77

0.79

0.76

0.79

0.56

0.80

0.58

0.90

0.91

0.73

0.73

0.81

0.77

0.95

0.84

0.77

0.74

(0.68,

(0.65,

(0.62,

(0.73,

(0.68,

(0.66,

(0.69,

(0.62,

(0.64,

(0.68,

(0.69,

(0.60,

(0.70,

(0.25,

(0.70,

(0.39,

(0.68,

(0.71,

(0.64,

(0.60,

(0.71,

(0.68,

(0.62,

(0.68,

(0.66,

(0.59,

0.88) 1.05)

0.83) 1.05) 0.86) 1.24)

0.88) 1.14)

1.76) 0.86)

0.90) 0.97)

0.88) 1.29) 0.91) 0.84) 1.18)

1.16) 0.83)

0.89) 0.93)

0.87) 1.47)

1.04) 0.91) 0.94) HR (95% CI)

(7.1)

(8.6)

(6.2)

(10.3)

(6.9)

(13.7)

(7.1)

(9.7)

(8.9)

(7.3)

(7.3)

(7.6)

(7.4)

(8.5)

(6.9)

(8.0)

(10.0)

(14.4)

(6.3)

(11.4)

(6.3)

(7.1)

(12.5)

(7.5)

(6.8)

(9.0)

(8.9)

(9.7)

(8.0)

(11.6)

(8.6)

(14.9)

(8.8)

(10.5)

(7.9)

(9.1)

(9.0)

(9.1)

(9.0)

(11.8)

(8.4)

(11.0)

(11.0)

(15.0)

(8.3)

(14.3)

(7.6)

(8.8)

(13.4)

(8.8)

(8.5)

(10.8)

*

ADP or TRAP. Platelet-poor plasma had no effect on bleeding times or platelet aggregation (see WARNINGS AND PRECAUTIONS, Bleeding).

TOXICOLOGY

Carcinogenesis

No vorapaxar-related tumors were observed in 2-year rat and mouse studies with vorapaxar at oral doses ≤30 mg/kg/day in rats and ≤15 mg/kg/day in mice (8.9x and 30 x the recommended therapeutic exposures in humans based on plasma exposure to vorapaxar for rats and mice, respectively).

Mutagenesis

Vorapaxar was not genotoxic in two in vitro tests (Ames bacterial gene mutation test, clastogenicity assay in human peripheral blood lymphocytes) and in one in vivo test (micronucleus test by intraperitoneal route in mice).

Reproduction

Vorapaxar had no effect on fertility of male or female rats at oral doses ≤50 mg/kg/day (at least 40x and 71x, respectively, the steady-state human plasma exposure at the recommended therapeutic dose).

Development

Reproductive and developmental toxicology studies in rabbits and rats at doses ≤20 and ≤75 mg/kg (89x and 285x, respectively, the steady-state human plasma exposure at the recommended therapeutic dose) revealed a slight decrease in offspring body weight, in rats only at the highest tested dose. There was no evidence of malformations in either species; however, animal studies are not always predictive of a human response.

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