ZONTIVITY Film-coated tablet Ref.[9380] Active ingredients: Vorapaxar

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 vorapaxartreated 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 2ºP-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.

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 C_max 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 C_max 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 C_max 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 with ticagrelor in the vorapaxar Phase 3 studies. Vorapaxar should not be used with prasugrel or ticagrelor (see section 4.2).

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).

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

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:

Blood and lymphatic system disorders

Uncommon: Anaemia

Eye disorders

Uncommon: Conjunctival haemorrhage, diplopia

Vascular disorders

Common: Haematoma Haemorrhage

Respiratory, thoracic and mediastinal disorders

Uncommon: Epistaxis

Gastrointestinal disorders

Uncommon: Gastritis, Gastrointestinal haemorrhage, Gingival bleeding, Melaena, Rectal haemorrhage

Skin and subcutaneous tissue disorders

Common: Increased tendency to bruise

Uncommon: Ecchymosis, Skin haemorrhage

Renal and urinary disorders

Common: Haematuria

Injury, poisoning, and procedural complications

Common: Contusion

Uncommon: 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 TIA are shown below.

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 Medicinal 2.

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

* 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 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:

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 Appendix V.

Not applicable.