Zontivity - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Zontivity 2 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient(s) with known effect:

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

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

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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.

4.2 Posology and method of administration

PosQiQgy

MI

The recommended dose of Zontivity is 2.08 mg to be taken once daily. Zontivity should be initiated at least 2 weeks after a MI and preferably within the first 12 months from the acute event (see section 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. Continued therapy after this time must be based on a re-evaluation of the benefits and risks for the individual of further 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 the next 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 accordi their indications or standard of care. 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.

PAD

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

Elderly

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

Renal impairment

No dose adjustment is required in patients with renal impairment (see section 5.2). However, 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.

Hepatic impairment

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 should be used with caution in patients with moderate hepatic impairment. Because of the limited therapeutic experience and the increased inherent risk of bleeding in patients with severe hepatic impairment, Zontivity is contraindicated in such patients (see sections 4.3, 4.4, and 5.2).

Paediatric population

The safety and efficacy of Zontivity in children aged less than 18 years have not yet been established. No data are available.

Method of administration

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

4.3 Contraindications

• • 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 (see

• section 4.4).

• •     Severe hepatic impairment.

4.4 Special warnings and precautions for use

General risk of bleeding

Zontivity increases the risk of bleeding, including ICH and sometimes fatal bleeding. When administered in addition to standard care, generally acetylsalicylic acid and a thienopyridine, compared with standard care alone, Zontivity increased the risk of GUSTO (Global utilization of streptokinase 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. The underlying risk of bleeding (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal bleeding, or active peptic ulcer disease) should be considered before initiating Zontivity. General risk factors for bleeding include older age (however, no dose adjustment is necessary in the elderly (see section 5.2)), low body weight, and reduced renal or hepatic function. In these subgroups, 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 concomitant medicinal products (e.g., anticoagulant and fibrinolytic therapy, and 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.

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.

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.

Bleeding should be suspected 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.

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 patients weighing <60 kg compared to patients weighing >60 kg. Zontivity should be used with caution in patients with a body weight <60 kg.

Surgery

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

In the TRA 2°P-TIMI 50 trial, although CABG-related TIMI major bleeding was observed in patients taking 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 less information about other types of surgery but the overall evidence does not suggest an excessive risk of major bleeding. Patients undergoing urgent CABG, PCI, non CABG surgery, or other invasive procedures while on Zontivity may remain on Zontivity. However, if a patient is to undergo elective surgery, 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 acute bleeding event because of its long half-life (see section 5.2). 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 the background of acetylsalicylic acid and clopidogrel, it may be possible to restore hemostasis by administering exogenous platelets. (See section 5.3.)

Severe hepatic impairment

Severe hepatic impairment increases the risk of bleeding; therefore, the use of Zontivity in these patients is contraindicated (see sections 4.2 and 5.2).

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.

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 should have therapy discontinued permanently (see sections 4.8 and 5.1). Patients experiencing acute coronary syndrome (ACS) while on Zontivity can remain on Zontivity.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on vorapaxar

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

Strong CYP3A inhibitors

Co-administration of ketoconazole (400 mg once-daily) with vorapaxar significantly increased the vorapaxar mean Cmax and AUC by 93% and 96%, respectively. 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) should be avoided.

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

Strong CYP3A inducers

Co-administration of rifampin (600 mg once-daily) with vorapaxar substantially decreased the vorapaxar mean Cmax and AUC by 39% and 55%, respectively. Concomitant use of Zontivity with strong (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 daily co-administration of an aluminium hydroxide/magnesium carbonate antacid or pantoprazole (a proton pump inhibitor).

Effects of vorapaxar on other medicinal products

Digoxin

Vorapaxar is a weak inhibitor of the intestinal P-glycoprotein (P-gp) transporter. Co-administration of vorapaxar (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 receiving digoxin 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.

Anticoagulants

When Zontivity was co-administered with warfarin, there were no alterations in the pharmacokinetics or pharmacodynamics of warfarin. Clinical experience involving co-administration of oral anticoagulants with vorapaxar is limited, and there is no experience with oral Factor Xa or Factor IIa inhibitors in the vorapaxar Phase 3 program. The coadministration of Zontivity with anticoagulants e.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 be associated with an increased risk of bleeding and caution is advised. (See section 4.4.)

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

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

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

Adverse reactions were evaluated in 19,632 patients treated with Zontivity [13,186 patients, including 2,187 patients treated for more than 3 years, in the TRA 2°P TIMI 50 (Thrombin Receptor Antagonist in 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 are defined 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 the available 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 disorders	Epistaxis
Gastrointestinal disorders		Gastritis, Gastrointestinal haemorrhage, Gingival bleeding, Melaena, Rectal haemorrhage
Skin and subcutaneous tissue disorders	Increased tendency to bruise	Ecchymosis, Skin haemorrhage
Renal and urinary disorders	Haematuria
Injury, poisoning, and procedural complications	Contusion	Wound haemorrhage

Description of selected adverse reactions

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

Bleeding

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 without hemodynamic 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 TIA are shown in Table 2.

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

	Placebo (n= 10,049)		Zontivity (n=10,059)
Endpoints	Patients with events (%)	K-M %*	Patients with events (%)	K-M -. %	Hazard Ratio (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

t Hazard ratio is Zontivity group versus placebo group

J Hazard ratio and p-value were calculated based on Cox PH model with covariates treatment and stratification

factors (qualifying atherosclerotic disease and planned thienopyridine use)

The effect of Zontivity on GUSTO severe or moderate bleeding relative to placebo was shown to be consistent 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-related bleeds 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
2^"	Placebo (n=196)	Zontivity (n=171)
Endpoints	Patients with events (%)	Patients with events (%)
TIMI Bleeding Category
Major	10(5.1%)	11 (6.4%)
Overall Population
	Placebo (n=230)	Zontivity (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 addressing the source of bleeding while providing supportive care.

Medicinal product discontinuation

For post-MI or PAD patients with no history of stroke or TIA, the rate of study drug discontinuation because of adverse reactions was 6.8% for Zontivity and 6.9% for placebo. Bleeding was the most common adverse reaction leading to study drug discontinuation for both treatments (3.0% for Zontivity and 1.8% for placebo).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system

listed in

4.9 Overdose

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

a              ' h' h! t h a h d' 1 ' ' in t h ff f ' th t t t f

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

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

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

\OX

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excluding heparin, ATC code: B01AC26.

Mechanism of action

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

Pharmacodynamic eff ects^

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.

At a dose of 2.5 mg of vorapaxar sulfate (equivalent to 2.08 mg vorapaxar) daily, vorapaxar consistently 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 >80% may last for 2to 4 weeks after discontinuation of daily doses of vorapaxar sulfate 2.5 mg. The duration of these pharmacodynamic effects is consistent with the drug’s elimination half-life.

Consistent with its selective molecular target (PAR-1), vorapaxar has no effect on ADP-induced platelet 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 multiple dose (28 days) administration of vorapaxar. No meaningful changes in P-selectin, sCD40L and hs-CRP 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 other studies. Vorapaxar had no effect on the QTc interval at single doses up to 120 mg.

Clinical efficacy and safety

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 <12months prior, is derived from TRA 2°P – TIMI 5n (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events). TRA 2°P – TIMI 50 was a multicenter, randomized, double-blind, placebo-controlled study conducted in patients who had evidence or a history of atherosclerosis involving the coronary, cerebral, or peripheral vascular systems. Patients were randomized to receive daily treatment with 2.5 mg vorapaxar sulfate (n=13,225) or placebo (n=13,224) in addition to other standard therapy. The study’s primary endpoint was the composite of cardiovascular death, MI, stroke, and UCR. The composite of cardiovascular death, MI, and stroke were assessed as secondary endpoint. The median duration of treatment 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) event rate 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 Zontivity group 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 in individual patient subgroups, the benefit was most apparent in patients who were enrolled on the basis of 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) in addition 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 acid without thienopyridine, 1% was receiving a thienopyridine without acetylsalicylic acid, and 77% were receiving both acetylsalicylic acid and a thienopyridine when they enrolled in the trial. Of the patients with PAD without a history of stroke or TIA, 61% were receiving acetylsalicylic acid without thienopyridine, 8% were receiving a thienopyridine without acetylsalicylic acid, and 27% were receiving both acetylsalicylic acid and a thienopyridine when they enrolled. In post-MI and PAD patients, the median duration of treatment with Zontivity in these patients was 2.5 years (up to 4 years). 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 with no history of stroke or TIA was 88% Caucasian, 20% female, and 29% >65 years of age, with a median age of 58 years, and included patients with diabetes (21%) and patients 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, and 57% >65 years of age, with a median age of66 years, and included patients with diabetes (35%) and patients 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 primary and key secondary composite endpoints are consistent with the overall population (see Figure 1 and Table 4).

Among patients with a qualifying MI, Zontivity was initiated at least 2 weeks after the MI and within the first 12 months from the acute event. Within that period the effect was similar regardless of the time 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 be durable 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

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

	Placebo (n=10,090)		Zontivity (n=10,080)		Hazard Ratio§ (95% CI)	P-value§
Endpoints	Patients with events* (%)	K-M ‚%‘	Patients with events* (%)	K-M "%'
Primary Efficacy Endpoint (CV death/MI/stro­ke/UCR)	1,073 (10.6%)	11.8%	896 (8.9%)	10.1%	0.83 (0.76–0.90)	<0.001
CV Death MI Stroke UCR	154 (1.5%) 531 (5.3%) 123 (1.2%) 265 (2.6%)		129 (1.3%) 450 (4.5%) 91 (0.9%) 226 (2.2%)			>
Key Secondary Efficacy Endpoint (CV death / MI / stroke) §	851 (8.4%)	9.5%	688 (6.8%)	7.9%	0.80 (0.73–0.89)	<0.001
CV Death MI Stroke	160 (1.6%) 562 (5.6%) 129 (1.3%)	<	132 (1.3%) 464 (4.6%) 92 (0.9%)

* Each patient was counted only once (first component event) in the component summary that contributed to the primary 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 atherosclerotic disease and planned thienopyridine use)

In the cohort of post-MI or PAD patients with no history of stroke or TIA, the net clinical outcome analysis based on multiple occurrences of endpoints (CV Death/MI/Stro­ke/GUSTO Severe) is constant over time at each of the censoring times examined (12, 18, 24, 30, and 36 months) at cumulative 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

	Placebo n=10,049	Zontivity n=10,059	Hazard Ratio'.' (95% CI)	p-value'
Randomization to 12 months
Total Events	474	401	0.83 (0.73 –0.95)	0.008
Patients with only one Event	337	269

	Placebo n=10.049	Zontivity n=10.059	Hazard Ratio'.' (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 –0.89)	<0.001
Patients with only one Event	463	361
Patients with two Events	82	67		x
Patients with >3 Events	21	21
Randomization to 24 months
Total Events	903	741	0.81 (0.73 -^ 0.89) Q	X <0.001
Patients with only one Event	554	456
Patients with two Events	114	80
Patients with >3 Events	34	38	S’
Randomization to 30 months
Total Events	1,070	893	0.82 (0.75 –0.90)	<0.001
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 –0.91)	<0.001
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 and stratification factor (planned thienopyridine u­se).

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

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

Patients with a history of PAD but without a history of stroke or TIA randomized to vorapaxar had fewer 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, including sex; age; renal insufficiency; medical history of diabetes mellitus; tobacco use; concomitant therapies 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 stroke had a higher 3 year K-M event rate for ICH on Zontivity plus standard care (2.7%) than on standard care alone (0.9%). In post-MI or PAD patients with no history of stroke or TIA, the 3 year K-M event rates 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 coronary syndrome) who were largely antiplatelet naive, vorapaxar, with a loading dose of 40 mg and then maintained at 2.5 mg/day in addition to standard of care, initiated within 24 hours of NSTEACS, did not achieve its primary efficacy endpoint (cardiovascular death, MI, stroke, urgent coronary revascularization, and recurrent ischemia with rehospitalisation) and there was ad risk of GUSTO moderate or severe bleeding.

Paediatric population

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 arterial thromboembolism (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

After oral administration of a single vorapaxar sulfate 2.5 mg dose, vorapaxar is rapidly absorbed and peak concentrations occur at a median tmax of 1 hour (range: 1 to 2) under fasted conditions. The mean absolute 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, Zontivity may be administered without regard to co-administration of agents that increase gastric pH (antacid or proton pump inhibitor).

Distribution

The mean volume of distribution of vorapaxar is approximately 424 litres. 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.

rmation

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. The  systemic exposure of M20 is ~20% of the exposure to vorapaxar.

Elimination

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

Linearity/non-linearity

Vorapaxar exposure increases in an approximately dose-proportional manner following single doses of 1 to 40 mg and multiple doses of 0.5 to 2.5 mg of vorapaxar sulfate. 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.

Specific populations

The effects of renal (end-stage renal disease undergoing haemodialysis) and hepatic impairment on the pharmacokinetics of vorapaxar were evaluated in specific pharmacokinetic studies and are summarized 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 using data from healthy subjects and patients with atherosclerotic disease, vorapaxar mean AUC is estimated to be higher in patients with mild (17%) and moderate (34%) renal impairment compared to those with normal renal function; these differences are not considered to be clinically relevant. No dose adjustment is necessary for patients with renal impairment, including subjects with ESRD. 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.

Hepatic Impairment

Pharmacokinetics of vorapaxar are similar between patients with mild (Child Pugh, 5 to 6 points) to moderate (Child Pugh, 7 to 9 points) hepatic impairment and healthy patients. Reduced hepatic function is a risk factor for bleeding and should be considered before initiating Zontivity. No dose adjustment is required for patients with mild hepatic impairment. Zontivity should be used with caution in patients with moderate hepatic impairment. Zontivity is contraindicated in patients with severe 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 pharmacokinetic model to evaluate vorapaxar pharmacokinetics in healthy subjects and patients:

Elderly

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

Gender

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

Weight

The mean estimated vorapaxar Cmax and AUC were 35% and 33% higher, respectively, in patients with a 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 compared to those weighing 60–100 kg. In general, a body weight <60 kg is a risk factor for bleeding. Zontivity should 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 compared to that of Caucasians. Vorapaxar exposure (AUC and Cmax) in patients of African descent is estimated to be 17–19% lower compared to that of Caucasians. These differences are not considered to be clinically 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 significant inhibition of human CYP1A2, CYP2B6, CYP3A, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. No clinically meaningful inhibition of CYP2B6, CYP3A, CYP2C19, or CYP2D6 by M20 is expected. In addition, 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 of vorapaxar is unlikely to induce the metabolism of drugs metabolized by major CYP isoforms.

5.3 Preclinical safety data

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

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

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

Vorapaxar had no effects on fertility of male and female rats at exposures sufficiently in excess of human 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 in combination with vorapaxar. Acetylsalicylic acid, vorapaxar, and clopidogrel in combination produced significant prolongation of bleeding time. Transfusion of human platelet rich plasma normalised 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 section 4.4.)

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

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Lactose monohydrate

Cellulose, microcrystalline (E460)

Croscarmellose sodium (E468)

Povidone (E1201)

Magnesium stearate (E572)

Film coating

Lactose monohydrate Hypromellose (E464) Titanium dioxide (E171) Triacetin (E1518)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

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

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

6.5 Nature and contents of container

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 card Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/14/976/004

EU/1/14/976/005

EU/1/14/976/006