Vorapaxar

Reduced hepatic function is a risk factor for bleeding and should be considered before initiating vorapaxar. No dose adjustment is required in patients with mild hepatic impairment. Vorapaxar 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, vorapaxar is contraindicated in such patients.

No dose adjustment is required in patients with renal impairment. However, reduced renal function is a risk factor for bleeding and should be considered before initiating vorapaxar. There is limited therapeutic experience in patients with severe renal impairment or end stage renal disease. Therefore, vorapaxar should be used with caution in such patients.

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.

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 vorapaxar with strong (potent) inducers of CYP3A (e.g., rifampin, carbamazepine and phenytoin) should be avoided.

When vorapaxar 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 vorapaxar with anticoagulants e.g., warfarin and new oral anticoagulants (NOACs), should be avoided.

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

When vorapaxar 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.

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 vorapaxar is recommended. Patients receiving digoxin should be monitored as clinically indicated.

Patients should be advised to inform physicians and dentists that they are taking vorapaxar 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, 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 vorapaxar may remain on vorapaxar. However, if a patient is to undergo elective surgery, if clinically feasible, vorapaxar should be discontinued at least 30 days prior to surgery.

Withholding vorapaxar for a brief period will not be useful in preventing or managing an acute bleeding event because of its long half-life. There is no known treatment to reverse the antiplatelet effect of vorapaxar. 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.

There are no reliable data on the use of vorapaxar in pregnant women. No relevant effects were observed in animals. Vorapaxar should be used during pregnancy only if the potential benefit 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 shown vorapaxar and/or its metabolites are excreted in milk. Due to the unknown potential for adverse reactions in breast-feeding infants from vorapaxar, discontinue breast-feeding or discontinue vorapaxar; taking into account the importance of the medicinal product to the mother.

Fertility

There are no data on fertility in humans administered vorapaxar. No effects on fertility were observed in animal studies.

Vorapaxar 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 vorapaxar [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 the following list are summarized for the TRA 2°P TIMI 50 study. Non-bleeding adverse reactions are summarized for both the TRA 2°P TIMI 50 and TRACER studies.

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).

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 1.

Table 1. 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 vorapaxar 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 vorapaxar 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 2. Rates were similar for vorapaxar and placebo.

Table 2. 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 vorapaxar and 6.9% for placebo. Bleeding was the most common adverse reaction leading to study drug discontinuation for both treatments (3.0% for vorapaxar and 1.8% for placebo).