ucers decrease ZONTIVITY exposure. Avoid concomitant use of ZONTIVITY with strong CYP3A inhibitors or inducers [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
6 ADVERSE REACTIONS
The following serious adverse reaction is also discussed elsewhere in the labeling:
•Bleeding [see Boxed Warning and Warnings and Precautions (5.1)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
ZONTIVITY was eva luated for safety in 13,186 patients, including 2,187 patients treated for more than 3 years, in the Phase 3 study TRA 2°P TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events). The overall study population, patients who had evidence or a history of atherosclerosis involving the coronary (post-MI), cerebral (ischemic stroke), or peripheral vascular (documented history of PAD) systems, was treated once a day with ZONTIVITY (n=13,186) or placebo (n=13,166). Patients randomized to ZONTIVITY received treatment for a median of 2.3 years.
The adverse events in the ZONTIVITY-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 [see Contraindications (4)].
Bleeding
GUSTO severe bleeding was defined as fatal, intracranial, or bleeding with hemodynamic compromise requiring intervention; GUSTO moderate bleeding was defined as bleeding requiring transfusion of whole blood or packed red blood cells without hemodynamic compromise. (GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.)
The results for the bleeding endpoints in the post-MI or PAD patients without a history of stroke or TIA are shown in Table 1. ZONTIVITY increased GUSTO moderate or severe bleeding by 55%.
Table 1: Non-CABG-Related Bleeds in Post-MI or PAD Patients without a History of Stroke or TIA (First Dose to Last Dose + 30 Days) in the TRA 2°P Study
*Clinically significant bleeding includes any bleeding requiring medicalattention including ICH, or clinically significant overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥3 g/dL (or, when Hgb is not available, an absolute drop in hematocrit (Hct) of ≥15% or a fall in Hct of 9 to <15%).
†Hazard ratio is ZONTIVITY group vs. placebo group.
‡K-M estimate at 1,080 days.
The effects of ZONTIVITY on bleeding were examined in a number of subsets based on demographic and other baseline characteristics. Many of these are shown in Figure 1. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.
Figure 1: Subgroup Analyses (GUSTO Moderate or Severe Bleeding) in Post-MI or PAD Patients without a History of Stroke or TIA in the TRA 2°P Study (First Dose to Last Dose + 30 Days)
In TRA 2°P, 367 post-MI or PAD patients without a history of stroke or TIA underwent CABG surgery. Study investigators were encouraged not to discontinue treatment with study drug (i.e., ZONTIVITY or placebo) prior to surgery. Approximately 12.3% of patients discontinued ZONTIVITY more than 30 days prior to CABG. The relative risk for GUSTO moderate or severe bleeding was approximately 1.2 on ZONTIVITY vs. placebo.
Bleed |
