ZONTIVITY 2mg film-coated tablets medication leaflet

Zontivity 2 mg film-coated tablets

Each film-coated tablet contains 2.08 mg of vorapaxar (as vorapaxar sulfate).

Each film-coated tablet contains 66.12 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

The film-coated tablets are yellow, oval-shaped, size 8.48 mm x 4.76 mm, with “351” on one side andthe MSD logo on the other side.

Zontivity is indicated for the reduction of atherothrombotic events in adult patients with

- a history of myocardial infarction (MI), co-administered with acetylsalicylic acid (ASA) and,where appropriate, clopidogrel; or

- symptomatic peripheral arterial disease (PAD), co-administered with acetylsalicylic acid (ASA)or, where appropriate, clopidogrel.

MI

The recommended dose of Zontivity is 2.08 mg to be taken once daily. Zontivity should be initiated atleast 2 weeks after a MI and preferably within the first 12 months from the acute event (seesection 5.1). 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. Continuedtherapy after this time must be based on a re-evaluation of the benefits and risks for the individual offurther therapy.

PAD

The recommended dose of Zontivity is 2.08 mg to be taken once daily. For patients being started on

Zontivity due to symptomatic PAD, therapy may be initiated at any time.

If a dose is missed:

A patient who misses a dose of Zontivity should skip the missed dose if it is within 12 hours of thenext scheduled dose and take the next dose at the regular scheduled time.

Coadministration with other antiplatelet medicinal products

MI

Patients taking Zontivity should also take acetylsalicylic acid with or without clopidogrel according totheir indications or standard of care. There is limited clinical experience with prasugrel and noexperience with ticagrelor in the Phase 3 studies. Therefore, vorapaxar should not be used withprasugrel or ticagrelor. Vorapaxar should not be initiated in patients taking prasugrel or ticagrelor andin case of need for additional therapy with these agents, vorapaxar should be stopped.

PAD

Patients taking Zontivity should also take acetylsalicylic acid or clopidogrel according to theirindications or standard of care.

No dose adjustment is necessary in the elderly (see sections 4.4 and 5.2).

No dose adjustment is required in patients with renal impairment (see section 5.2). However, reducedrenal function is a risk factor for bleeding and should be considered before initiating Zontivity. Thereis limited therapeutic experience in patients with severe renal impairment or end stage renal disease.

Therefore, Zontivity should be used with caution in such patients.

Reduced hepatic function is a risk factor for bleeding and should be considered before initiating

Zontivity. No dose adjustment is required in patients with mild hepatic impairment. Zontivity shouldbe used with caution in patients with moderate hepatic impairment. Because of the limited therapeuticexperience and the increased inherent risk of bleeding in patients with severe hepatic impairment,

Zontivity is contraindicated in such patients (see sections pct. 4.3, pct. 4.4, and 5.2).

The safety and efficacy of Zontivity in children aged less than 18 years have not yet been established.

No data are available.

Oral use. The tablet may be taken with or without food.

- Patients with a history of stroke or transient ischaemic attack (TIA) (see section 5.1).

- Patients with a history of intracranial haemorrhage (ICH).

- Patients with any active pathological bleeding (see sections 4.4 and 4.8).

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (seesection 4.4).

- Severe hepatic impairment.

General risk of bleeding

Zontivity increases the risk of bleeding, including ICH and sometimes fatal bleeding. Whenadministered in addition to standard care, generally acetylsalicylic acid and a thienopyridine,compared with standard care alone, Zontivity increased the risk of GUSTO (Global utilization ofstreptokinase and tpa for occluded arteries) moderate or severe bleeding (see section 4.8).

Zontivity increases the risk of bleeding in proportion to the patient’s underlying bleeding risk. Theunderlying risk of bleeding (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinalbleeding, or active peptic ulcer disease) should be considered before initiating Zontivity. General riskfactors for bleeding include older age (however, no dose adjustment is necessary in the elderly (seesection 5.2)), low body weight, and reduced renal or hepatic function. In these subgroups, Zontivityshould only be prescribed after careful assessment of individual potential risks and benefits and theneed for co-medication that may further increase the risk of bleeding. A history of bleeding disordersand use of certain concomitant medicinal products (e.g., anticoagulant and fibrinolytic therapy, andchronic nonsteroidal anti-inflammatory drugs (NSAIDS), selective serotonin reuptake inhibitors,serotonin norepinephrine reuptake inhibitors) may also increase the risk of bleeding in patients taking

Zontivity.

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

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

Bleeding should be suspected in any patient who is hypotensive and has recently undergone coronaryangiography, 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.

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, including those with history of stroke, a higher rate of ICH was observed in patientsweighing <60 kg compared to patients weighing ≥60 kg. Zontivity should be used with caution inpatients with a body weight <60 kg.

Patients should be advised to inform physicians and dentists that they are taking Zontivity before anysurgery is scheduled and before any new medicinal product is taken.

In the TRA 2ºP-TIMI 50 trial, although CABG-related TIMI major bleeding was observed in patientstaking vorapaxar (see section 4.8), patients who continued therapy with vorapaxar while undergoing

CABG did not show an increased risk of major bleeding compared to placebo. There is lessinformation about other types of surgery but the overall evidence does not suggest an excessive risk ofmajor bleeding. Patients undergoing urgent CABG, PCI, non CABG surgery, or other invasiveprocedures while on Zontivity may remain on Zontivity. However, if a patient is to undergo electivesurgery, if clinically feasible, Zontivity should be discontinued at least 30 days prior to surgery.

Withholding Zontivity for a brief period will not be useful in preventing or managing an acutebleeding event because of its long half-life (see section 5.2). There is no known treatment to reversethe antiplatelet effect of Zontivity. Based on results of pre-clinical studies that investigated bleedingwhile on vorapaxar on the background of acetylsalicylic acid and clopidogrel, it may be possible torestore hemostasis by administering exogenous platelets. (See section 5.3.)

Seve re hepatic impairment increases the risk of bleeding; therefore, the use of Zontivity in thesepatients is contraindicated (see sections 4.2 and 5.2).

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 endstage renal disease. Therefore, Zontivity should be used with caution in such patients.

Discontinuation of Zontivity

Interruption of Zontivity treatment should be avoided. If Zontivity must be temporarily discontinued,restart it as soon as possible. Patients who experience a stroke, TIA, or ICH while on Zontivity shouldhave therapy discontinued permanently (see sections 4.8 and 5.1). Patients experiencing acutecoronary syndrome (ACS) while on Zontivity can remain on Zontivity.

Zontivity contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapplactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Effects of other medicinal products on vorapaxar

Vorapaxar is eliminated primarily by metabolism, with significant contribution by CYP3A. Vorapaxaris also a substrate of CYP2J2; therefore, there is a potential for potent inhibitors of CYP2J2 to result inincreases in vorapaxar exposure.

Strong CYP3A inhibitors

Co-administration of ketoconazole (400 mg once-daily) with vorapaxar significantly increased thevorapaxar mean Cmax and AUC by 93% and 96%, respectively. Concomitant use of Zontivity withstrong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin,nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin andconivaptan) should be avoided.

Phase 3 data suggest that co-administration of a weak or moderate CYP3A inhibitor with vorapaxardoes not increase bleeding risk or alter the efficacy of vorapaxar. No dose adjustment for vorapaxar isrequired in patients taking weak to moderate inhibitors of CYP3A.

Strong CYP3A inducers

Co-administration of rifampin (600 mg once-daily) with vorapaxar substantially decreased thevorapaxar mean Cmax and AUC by 39% and 55%, respectively. Concomitant use of Zontivity withstrong (potent) inducers of CYP3A (e.g., rifampin, carbamazepine and phenytoin) should be avoided.

Medicinal products that increase gastric pH

No clinically relevant differences in vorapaxar pharmacokinetics were observed following dailyco-administration of an aluminium hydroxide/magnesium carbonate antacid or pantoprazole (a protonpump inhibitor).

Effects of vorapaxar on other medicinal products

Vorapaxar is a weak inhibitor of the intestinal P-glycoprotein (P-gp) transporter. Co-administration ofvorapaxar (40 mg) and digoxin (0.5 mg single-dose) increased digoxin Cmax and AUC by 54% and 5%,respectively. No dosage adjustment of digoxin or Zontivity is recommended. Patients receivingdigoxin should be monitored as clinically indicated.

CYP2C8 substrates

Co-administration with vorapaxar did not alter the single-dose pharmacokinetics of rosiglitazone(8 mg), a CYP2C8 substrate not marketed in the EU.

Anti coagulants

When Zontivity was co-administered with warfarin, there were no alterations in the pharmacokineticsor pharmacodynamics of warfarin. Clinical experience involving co-administration of oralanticoagulants with vorapaxar is limited, and there is no experience with oral Factor Xa or Factor IIainhibitors in the vorapaxar Phase 3 program. The coadministration of Zontivity with anticoagulantse.g., warfarin and new oral anticoagulants (NOACs), should be avoided. (See section 4.4.)

In patients treated with Zontivity the concomitant use of heparin (including LMWH) might beassociated with an increased risk of bleeding and caution is advised. (See section 4.4.)

When Zontivity was co-administered with prasugrel, no clinically significant pharmacokineticinteraction was demonstrated. There is limited experience with prasugrel and no experience withticagrelor in the vorapaxar Phase 3 studies. Vorapaxar should not be used with prasugrel or ticagrelor(see section 4.2).

There are no reliable data on the use of vorapaxar in pregnant women. No relevant effects wereobserved in animals (see section 5.3). Zontivity should be used during pregnancy only if the potentialbenefit to the mother justifies the potential risk to the foetus.

It is not known whether vorapaxar is excreted in human breast milk. Studies in rats have shownvorapaxar and/or its metabolites are excreted in milk. Due to the unknown potential for adversereactions in breast-feeding infants from Zontivity, discontinue breast-feeding or discontinue Zontivity;taking into account the importance of the medicinal product to the mother.

There are no data on fertility in humans administered Zontivity. No effects on fertility were observedin animal studies (see section 5.3).

Zontivity has no or negligible influence on the ability to drive and use machines.

The most common adverse reaction reported during treatment is bleeding. Among the commonbleeding events, epistaxis is the most frequent.

Adverse reactions were evaluated in 19,632 patients treated with Zontivity [13,186 patients, including2,187 patients treated for more than 3 years, in the TRA 2°P TIMI 50 (Thrombin Receptor Antagonistin Secondary Prevention of Atherothrombotic Ischemic Events) study and 6,446 patients in the

TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)study]. The adverse reactions of bleeding in Table 1 are summarized for the TRA 2°P TIMI 50 study.

Non-bleeding adverse reactions in Table 1 are summarized for both the TRA 2°P TIMI 50 and

TRACER studies. (See Table 1.)

Tabulated list of Adverse Reactions

Adverse reactions are classified according to frequency and System Organ Class. Frequencies aredefined as:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100);rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from theavailable data).

Table 1: Tabulated List of Adverse Reactions

System Organ Class Common Uncommon

Blood and lymphatic system disorders Anaemia

Eye disorders Conjunctival haemorrhage,diplopia

Vascular disorders Haematoma Haemorrhage

Respiratory, thoracic and mediastinal Epistaxisdisorders

Gastrointestinal disorders Gastritis, Gastrointestinalhaemorrhage, Gingivalbleeding, Melaena, Rectalhaemorrhage

Skin and subcutaneous tissue Increased tendency to bruise Ecchymosis, Skindisorders haemorrhage

Renal and urinary disorders Haematuria

Injury, poisoning, and procedural Contusion Wound haemorrhagecomplications

The adverse reactions in the vorapaxar-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.

Bleeding category definitions:

GUSTO severe: fatal, intracranial, or bleeding with hemodynamic compromise requiring intervention;

GUSTO moderate: bleeding requiring transfusion of whole blood or packed red blood cells withouthemodynamic compromise.

TIMI Major: Clinically apparent with >50 g/L decrease in haemoglobin or intracranial haemorrhage.

TIMI Minor: Clinically apparent with 30-50 g/L decrease in haemoglobin.

The results for the bleeding endpoints in the post-MI or PAD patients with no history of stroke or TIAare shown in Table 2.

Tabl e 2: Non-CABG-Related Bleeds in Post-MI or PAD Patients with No History of Stroke or

TIA

Placebo Zontivity(n= 10,049) (n=10,059)

Endpoints Patients with Patients†,‡events with events Hazard Ratio‡(%) K-M %* (%) K-M (95% CI) p-value%*

GUSTO Bleeding Categories

Severe 105(1.0%) 1.3% 115 (1.1%) 1.3% 1.09 (0.84-1.43) 0.503

Moderate 138 (1.4%) 1.6% 229 (2.3%) 2.6% 1.67 (1.35-2.07) <0.001

TIMI Bleeding Categories

Major 183 (1.8%) 2.1% 219 (2.2%) 2.5% 1.20 (0.99-1.46) 0.069

Minor 80 (0.8%) 0.9% 150 (1.5%) 1.7% 1.88 (1.44-2.47) <0.001

ICH 39 (0.4%) 0.5% 49 (0.5%) 0.6% 1.25 (0.82-1.91) 0.294

Fatal Bleeding 20 (0.2%) 0.3% 19 (0.2%) 0.3% 0.95 (0.51-1.78) 0.872

* K-M estimate at 1,080 days† Hazard ratio is Zontivity group versus placebo group‡ Hazard ratio and p-value were calculated based on Cox PH model with covariates treatment and stratificationfactors (qualifying atherosclerotic disease and planned thienopyridine use)

The effect of Zontivity on GUSTO severe or moderate bleeding relative to placebo was shown to beconsistent across the subgroups examined.

In TRA 2°P - TIMI 50, 367 post-MI or PAD patients with no history of stroke or TIA underwent

CABG surgery. The percentages of patients who underwent CABG surgery and had CABG-relatedbleeds are shown in Table 3. Rates were similar for Zontivity and placebo.

Table 3: CABG-Related Bleeds

Post-MI or PAD Patients with No History of Stroke or TIA

Placebo Zontivity(n=196) (n=171)

Endpoints Patients with events (%) Patients with events (%)

TIMI Bleeding Category

Major 10 (5.1%) 11 (6.4%)

Overall Population

Placebo Zontivity(n=230) (n=189)

TIMI Bleeding Category

Major 13 (5.7%) 12 (6.3%)

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

Medicinal product discontinuation

For p ost-MI or PAD patients with no history of stroke or TIA, the rate of study drug discontinuationbecause of adverse reactions was 6.8% for Zontivity and 6.9% for placebo. Bleeding was the mostcommon adverse reaction leading to study drug discontinuation for both treatments (3.0% for

Zontivity and 1.8% for placebo).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Platelet inhibition with vorapaxar is gradual and reversible. Treatment of presumed overdose shouldaddress signs and symptoms.

As vorapaxar is highly protein-bound, haemodialysis is unlikely to be effective in the treatment of anoverdose.

In humans, vorapaxar has been administered in single doses up to 120 mg and daily doses of 5 mg forup to 4 weeks without observation of dose-associated adverse events or identification of a specificrisk.

Platelet transfusion may be considered as supportive therapy should bleeding occur (see section 5.3).

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excluding heparin,

ATC code: B01AC26.

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

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

At a dose of 2.5 mg of vorapaxar sulfate (equivalent to 2.08 mg vorapaxar) daily, vorapaxarconsistently achieves ≥80% inhibition of TRAP-induced platelet aggregation within one week ofinitiation of treatment. The duration of platelet inhibition is dose and concentration dependent.

Inhibition of TRAP-induced platelet aggregation at a level of ≥80% may last for 2 to 4 weeks afterdiscontinuation of daily doses of vorapaxar sulfate 2.5 mg. The duration of these pharmacodynamiceffects is consistent with the drug’s elimination half-life.

Consistent with its selective molecular target (PAR-1), vorapaxar has no effect on ADP-inducedplatelet aggregation in healthy subjects and patient populations.

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 multipledose (28 days) administration of vorapaxar. No meaningful changes in P-selectin, sCD40L andhs-C RP concentrations were observed in patients treated with vorapaxar in the Phase 2/3 clinical trials.

Evaluation of Zontivity on QTc interval

The effect of vorapaxar on the QTc interval was evaluated in a thorough QT study and in otherstudies. Vorapaxar had no effect on the QTc interval at single doses up to 120 mg.

Zontivity has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI,stroke, and urgent coronary revascularization (UCR).

The clinical evidence for the effect of Zontivity in patients with a history of myocardial infarction,defined as a spontaneous MI ≥2 weeks but 12 months prior, is derived from TRA 2°P - TIMI 50(Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events). TRA2°P - TIMI 50 was a multicenter, randomized, double-blind, placebo-controlled study conducted inpatients who had evidence or a history of atherosclerosis involving the coronary, cerebral, orperipheral vascular systems. Patients were randomized to receive daily treatment with 2.5 mgvorapaxar sulfate (n=13,225) or placebo (n=13,224) in addition to other standard therapy. The study’sprimary endpoint was the composite of cardiovascular death, MI, stroke, and UCR. The composite ofcardiovascular death, MI, and stroke were assessed as secondary endpoint. The median duration oftreatment with vorapaxar was 823 days (interquartile range: 645-1016 days).

The findings for the primary efficacy composite endpoint show a 3-year Kaplan-Meier (K-M) eventrate of 11.2% in the Zontivity group compared with that of 12.4% in the placebo group (Hazard Ratio[HR]: 0.88; 95% Confidence Interval [CI], 0.82 to 0.95; p=0.001) and demonstrated superiority of

Zontivity over placebo in preventing CV death, MI, stroke, or UCR.

The findings for the key secondary efficacy endpoint, a 3-year K-M event rate of 9.3% in the Zontivitygroup compared with that of 10.5% in placebo group (HR: 0.87; 95% CI, 0.80 to 0.94; p <0.001).

Although the TRA 2°P - TIMI 50 trial was not designed to evaluate the relative benefit of Zontivity inindividual patient subgroups, the benefit was most apparent in patients who were enrolled on the basisof a recent MI as indicated by a history of spontaneous MI ≥2 weeks but 12 months prior (post-MI or

PAD patient population) with no history of stroke or TIA. Of these patients, 10,080 received Zontivity(8,458 post-MI and 1,622 PAD) and 10,090 received placebo (8,439 post-MI and 1,651 PAD) inaddition to standard of care, including antiplatelet therapy with acetylsalicylic acid and thienopyridine.

Of the patients with MI without a history of stroke or TIA, 21% were receiving acetylsalicylic acidwithout thienopyridine, 1% was receiving a thienopyridine without acetylsalicylic acid, and 77% werereceiving both acetylsalicylic acid and a thienopyridine when they enrolled in the trial. Of the patientswith PAD without a history of stroke or TIA, 61% were receiving acetylsalicylic acid withoutthienopyridine, 8% were receiving a thienopyridine without acetylsalicylic acid, and 27% werereceiving both acetylsalicylic acid and a thienopyridine when they enrolled. In post-MI and PADpatients, the median duration of treatment with Zontivity in these patients was 2.5 years (up to4 years). This background therapy was to be continued during the trial at the treating physician'sdiscretion, per standard of care.

The post-MI patient population with no history of stroke or TIA was 88% Caucasian, 20% female, and29% ≥65 years of age, with a median age of 58 years, and included patients with diabetes (21%) andpatients with hypertension (62%). The median Body Mass Index was 28.

The PAD patient population with no history of stroke or TIA was 90% Caucasian, 29% female, and57% ≥65 years of age, with a median age of 66 years, and included patients with diabetes (35%) andpatients with hypertension (82%). The median Body Mass Index was 27.

In the cohort of post-MI or PAD patients with no history of stroke or TIA, the findings for the primaryand key secondary composite endpoints are consistent with the overall population (see Figure 1 and

Table 4).

Amo ng patients with a qualifying MI, Zontivity was initiated at least 2 weeks after the MI and withinthe first 12 months from the acute event. Within that period the effect was similar regardless of thetime from qualifying MI to the start of therapy with Zontivity.

The treatment effect of vorapaxar on the primary and key secondary endpoints was shown to bedurable and persistent over the length of the TRA 2°P - TIMI 50 study.

Figure 1: Time to First Occurrence of CV death, MI, Stroke or UCR in Post-MI or PAD

Patients with No History of Stroke or TIA

ZONTIVITY (Z) ( 896 /10080)11.8% (P)

Placebo (P) (1073 /10090)10.1% (Z)2 HR 95% CI p-value(Z) vs (P) 0.83 (0.76, 0.90) <.0010 180 360 540 720 900 1080

Days from Randomization

No. at Risk:

ZONTIVITY (Z) 9745 9502 9261 7670 5394 2464

Placebo (P) 9659 9351 9087 7556 5364 2467

Incidence (%)

Table 4: Primary and Key Secondary Efficacy Endpoints in Post-MI or PAD Patients with No

Hist ory of Stroke or TIA

Placebo Zontivity(n=10,090) (n=10,080)

Endpoints Patients Patients‡,§with events* with Hazard Ratio(%) K-M %† events* K-M %† (95% CI) p-value§(%)

Primary Efficacy 1,073 11.8% 896 (8.9%) 10.1% 0.83 (0.76-0.90) <0.001

Endpoint (10.6%)(CVdeath/MI/stroke/UCR)

CV Death 154 (1.5%) 129 (1.3%)

MI 531 (5.3%) 450 (4.5%)

Stroke 123 (1.2%) 91 (0.9%)

UCR 265 (2.6%) 226 (2.2%)

Key Secondary 851 (8.4%) 9.5% 688 (6.8%) 7.9% 0.80 (0.73-0.89) <0.001

Efficacy Endpoint(CV death/MI /stroke) §

CV Death 160 (1.6%) 132 (1.3%)

MI 562 (5.6%) 464 (4.6%)

Stroke 129 (1.3%) 92 (0.9%)

* Each patient was counted only once (first component event) in the component summary that contributed to theprimary efficacy endpoint† K-M estimate at 1,080 days‡ Hazard ratio is Zontivity group versus placebo group§ Cox proportional hazard model with covariates treatment and stratification factors (qualifying atheroscleroticdisease and planned thienopyridine use)

In the cohort of post-MI or PAD patients with no history of stroke or TIA, the net clinical outcomeanalysis based on multiple occurrences of endpoints (CV Death/MI/Stroke/GUSTO Severe) isconstant over time at each of the censoring times examined (12, 18, 24, 30, and 36 months) atcumulative 6-month intervals. (See Table 5.)

Table 5: Multiple Occurrences of Net Clinical Outcome (CV Death/MI/Stroke/GUSTO Severe*)in Post-MI or PAD Patients with No History of Stroke or TIA

Hazard

Placebo Zontivity Ratio†,‡n=10,049 n=10,059 (95% CI) p-value‡

Randomization to 12 months

Total Events 474 401 0.83 (0.73 - 0.0080.95)

Patients with only one Event 337 269

Hazard

Placebo Zontivity Ratio†,‡n=10,049 n=10,059 (95% CI) p-value‡

Patients with two Events 49 47

Patients with ≥3 Events 11 12

Randomization to 18 months

Total Events 703 564 0.79 (0.71 - <0.0010.89)

Patients with only one Event 463 361

Patients with two Events 82 67

Patients with ≥3 Events 21 21

Randomization to 24 months

Total Events 903 741 0.81 (0.73 - <0.0010.89)

Patients with only one Event 554 456

Patients with two Events 114 80

Patients with ≥3 Events 34 38

Randomization to 30 months

Total Events 1,070 893 0.82 (0.75 - <0.0010.90)

Patients with only one Event 658 524

Patients with two Events 121 102

Patients with ≥3 Events 46 48

Randomization to 36 months

Total Events 1,166 987 0.83 (0.76 - <0.0010.91)

Patients with only one Event 700 569

Patients with two Events 138 112

Patients with ≥3 Events 52 55

* Includes all CV Death, MI, Stroke and GUSTO severe events up to each timepoint as indicated in the table.† Hazard Ratio is vorapaxar group versus placebo group.‡ Hazard Ratio and p-value were calculated based on Andersen-Gill model with covariates treatment andstratification factor (planned thienopyridine use).

In post-MI or PAD patients with no history of stroke or TIA, an analysis of multiple occurrences ofadjudicated endpoints indicates that Zontivity was associated with a reduction in the incidence ofrecurrent events.

Among post-MI or PAD patients without a history of stroke or TIA, Zontivity appeared to reduce therate of definite stent thrombosis (HR 0.71 (0.51-0.99 for adjudicated “definite”) vs. placebo in subjectsreceiving any stent before or during the study.

Patients with a history of PAD but without a history of stroke or TIA randomized to vorapaxar hadfewer peripheral revascularization procedures (15.4% v 19.3%, 3-year KM rates; HR 0.82 [0.71-0.94,95% CI]; P=0.005) and fewer hospitalizations for acute limb ischemia (2.0% v 3.3%; HR 0.59 [0.40 -0.86]; P=0.007) than patients randomized to placebo.

The treatment effect of Zontivity was consistent with the overall results across many subgroups,inclu ding sex; age; renal insufficiency; medical history of diabetes mellitus; tobacco use; concomitanttherapies at baseline including thienopyridine, acetylsalicylic acid, and statins.

In TRA 2°P - TIMI 50, among patients who entered the trial, those with a history of ischaemic strokehad a higher 3 year K-M event rate for ICH on Zontivity plus standard care (2.7%) than on standardcare alone (0.9%). In post-MI or PAD patients with no history of stroke or TIA, the 3 year K-M eventrates for ICH were 0.6% and 0.5% for Zontivity plus standard care and standard care alone,respectively.

In the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary

Syndrome) trial, comprising patients with a NSTEACS (non-ST segment elevation acute coronarysyndrome) who were largely antiplatelet naive, vorapaxar, with a loading dose of 40 mg and thenmaintained at 2.5 mg/day in addition to standard of care, initiated within 24 hours of NSTEACS, didnot achieve its primary efficacy endpoint (cardiovascular death, MI, stroke, urgent coronaryrevascularization, and recurrent ischemia with rehospitalisation) and there was an increased risk of

GUSTO moderate or severe bleeding.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Zontivity in one or more subsets of the paediatric population in prevention of arterialthromboembolism (see section 4.2 for information on paediatric use).

After oral administration of a single vorapaxar sulfate 2.5 mg dose, vorapaxar is rapidly absorbed andpeak concentrations occur at a median tmax of 1 hour (range: 1 to 2) under fasted conditions. The meanabsolute bioavailability of vorapaxar from the 2.5 mg dose of vorapaxar sulfate is 100%.

Ingestion of vorapaxar with a high-fat meal resulted in no meaningful change in AUC with a small(21%) decrease in Cmax and delayed tmax (45 minutes). Zontivity may be taken with or without food.

Co-administration of an aluminium hydroxide/magnesium carbonate antacid or proton pump inhibitor(pantoprazole) did not affect vorapaxar AUC with only small decreases in Cmax. Therefore, Zontivitymay be administered without regard to co-administration of agents that increase gastric pH (antacid orproton pump inhibitor).

The mean volume of distribution of vorapaxar is approximately 424 litres. Vorapaxar and the majorcirculating 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 redblood cells.

Vorapaxar is eliminated by metabolism, with CYP3A4 and CYP2J2 responsible for formation of M20,its major active circulating metabolite, and M19, the predominant metabolite identified in excreta. Thesystemic exposure of M20 is ~20% of the exposure to vorapaxar.

The primary route of elimination is through the faeces, with approximately 91.5% of radiolabeled dosepredicted to be recovered in the faeces compared to 8.5% in the urine. Vorapaxar is eliminatedprimarily in the form of metabolites, with no vorapaxar detected in urine. The apparent terminalhalf-life for vorapaxar is 187 hours (range 115-317 hours) and is similar for the active metabolite.

Vorapaxar exposure increases in an approximately dose-proportional manner following single doses of1 to 40 mg and multiple doses of 0.5 to 2.5 mg of vorapaxar sulfate. The systemic pharmacokinetics ofvorapaxar are linear with accumulation (6-fold) predictable from single- to multiple-dose data.

Stead y-state is achieved by 21 days following once-daily dosing.

The effects of renal (end-stage renal disease undergoing haemodialysis) and hepatic impairment on thepharmacokinetics of vorapaxar were evaluated in specific pharmacokinetic studies and aresummarized below:

Renal Impairment

Pharmacokinetics of vorapaxar are similar between patients with end-stage renal disease (ESRD)undergoing haemodialysis and healthy subjects. Based on population pharmacokinetic analysis usingdata from healthy subjects and patients with atherosclerotic disease, vorapaxar mean AUC is estimatedto be higher in patients with mild (17%) and moderate (34%) renal impairment compared to those withnormal renal function; these differences are not considered to be clinically relevant. No doseadjustment is necessary for patients with renal impairment, including subjects with ESRD. There islimited therapeutic experience in patients with severe renal impairment or end stage renal disease.

Therefore, Zontivity should be used with caution in such patients.

Hepatic Impairment

Pharmacokinetics of vorapaxar are similar between patients with mild (Child Pugh, 5 to 6 points) tomoderate (Child Pugh, 7 to 9 points) hepatic impairment and healthy patients. Reduced hepaticfunction is a risk factor for bleeding and should be considered before initiating Zontivity. No doseadjustment is required for patients with mild hepatic impairment. Zontivity should be used withcaution in patients with moderate hepatic impairment. Zontivity is contraindicated in patients withsevere hepatic impairment (Child Pugh, 10 to 15 points) (see sections 4.3 and 4.4).

Age, gender, weight and race were included as factors assessed in the population pharmacokineticmodel to evaluate vorapaxar pharmacokinetics in healthy subjects and patients:

Pharmacokinetics of vorapaxar are similar between elderly, including those ≥75 years of age, andyounger patients. No dose adjustment is necessary (see section 4.4).

The mean estimated vorapaxar Cmax and AUC were 30% and 32% higher, respectively, in femalescompared to males. These differences are not considered to be clinically relevant and no doseadjustment is necessary.

Weight

The mean estimated vorapaxar Cmax and AUC were 35% and 33% higher, respectively, in patients witha body weight of <60 kg compared to those weighing 60-100 kg. By comparison, vorapaxar exposure(AUC and Cmax) is estimated to be 19-21% lower in patients with a body weight of >100 kg comparedto those weighing 60-100 kg. In general, a body weight <60 kg is a risk factor for bleeding. Zontivityshould be used with caution in patients with a body weight <60 kg.

The mean estimated vorapaxar Cmax and AUC were 24% and 22% higher in Asian patients comparedto that of Caucasians. Vorapaxar exposure (AUC and Cmax) in patients of African descent is estimatedto be 17-19% lower compared to that of Caucasians. These differences are not considered to beclinically relevant and no dose adjustment is necessary.

Drug Interactions

Effects of vorapaxar on other medicinal products

In vitro metabolism studies demonstrate that vorapaxar is unlikely to cause clinically significantinhibition of human CYP1A2, CYP2B6, CYP3A, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Noclinically meaningful inhibition of CYP2B6, CYP3A, CYP2C19, or CYP2D6 by M20 is expected. Inaddition, no clinically meaningful inhibition of OATP1B1, OATP1B3, BCRP, OAT1, OAT3, and

OCT2 by vorapaxar or M20 is anticipated. Based upon in vitro data, chronic administration ofvora paxar is unlikely to induce the metabolism of drugs metabolized by major CYP isoforms.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity, carcinogenic potential, and fertility.

In repeat dose oral toxicity studies in rodents and monkeys, the principal treatment-related findingswere urinary bladder and ureter hyperplasia in mice, hepatic vascular thrombi, lymphoid necrosis andretinal vacuolation in rats and phospholipidosis in all species. Phospholipidosis occurs at acceptablehuman to animal safety margins and was reversible. The clinical significance of this finding iscurrently unknown.

No defects were observed in embryo-foetal developmental studies in rats and rabbits at exposuressufficiently in excess of human exposure at the recommended human dose (RHD). Pre and postnatalstudies in rats only showed some inconsistent developmental effects at exposures sufficiently in excessof human exposure at the RHD of 2.08 mg vorapaxar. The overall no effect level for the pre- andpostnatal development effects was 5 mg/kg/day (6.8-times [female animals] the human steady-stateexposure at 2.5 mg/day).

Vorapaxar had no effects on fertility of male and female rats at exposures sufficiently in excess ofhuman exposure at the RHD.

Vorapaxar was not mutagenic or genotoxic in a battery of in vitro and in vivo studies.

Vorapaxar did not increase bleeding time in non-human primates when administered alone at 1 mg/kg.

Bleeding time was prolonged slightly with administration of acetylsalicylic acid alone or incombination with vorapaxar. Acetylsalicylic acid, vorapaxar, and clopidogrel in combination producedsignificant prolongation of bleeding time. Transfusion of human platelet rich plasma normalisedbleeding times with partial recovery of ex vivo platelet aggregation induced with arachidonic acid, butnot induced with ADP or TRAP. Platelet poor plasma had no effect on bleeding times or plateletaggregation. (See section 4.4.)

No vorapaxar-related tumours were observed in 2-year rat and mouse studies at oral doses up to30 mg/kg/day in rats and 15 mg/kg/day in mice (8.9 and 30 times the recommended therapeuticexposures in humans based on plasma exposure to vorapaxar for rats and mice, respectively).

Lactose monohydrate

Cellulose, microcrystalline (E460)

Croscarmellose sodium (E468)

Povidone (E1201)

Magnesium stearate (E572)

Lactose monohydrate

Hypromellose (E464)

Titanium dioxide (E171)

Triacetin (E1518)

Iron oxide yellow (E172)

Not applicable.

2 years

Store in the original package in order to protect from moisture.

This medicinal product does not require any special temperature storage conditions.

Packs of 7, 28, 30 and 100 film-coated tablets in aluminium/aluminium blister cards.

Packs of 10 and 50 film-coated tablets in aluminium/aluminium unit-dose blister cards.

Not all pack sizes may be marketed.

Any unused medicinal product or material should be disposed of in accordance with localrequirements.

Merck Sharp & Dohme Ltd

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

EU/1/14/976/001

EU/1/14/976/002

EU/1/14/976/003

EU/1/14/976/004

EU/1/14/976/005

EU/1/14/976/006

Date of first authorisation:19 January 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.