"By Megan Brooks
Medscape Medical News
The US Food and Drug Administration (FDA) will require makers of prescription testosterone products to clarify the approved uses of these medications on the product label and add information"...
The following serious adverse reaction is also discussed elsewhere in the labeling:
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 evaluated 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.
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
|Patients with events
|K-M %*||Patients with events
|GUSTO Bleeding Categories|
(0.92 - 1.66)
|Moderate or Severe||199
(1.30 - 1.86)
| Any GUSTO Bleeding
(Severe/ Moderate/ Mild)
(1.43 - 1.61)
(0.56 - 2.36)
|Clinically Significant Bleeding†||950
(1.35 - 1.60)
|* K-M estimate at 1,080 days.
† Clinically significant bleeding includes any bleeding requiring medical attention 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.
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.
Bleeding events that occurred on ZONTIVITY were treated in the same manner as for other antiplatelet agents.
Use in Patients with History of Stroke, TIA, or ICH
In the TRA 2°P study, patients with a history of ischemic stroke had a higher rate for ICH on ZONTIVITY than on placebo. ZONTIVITY is contraindicated in patients with a history of stroke, TIA, or ICH [see CONTRAINDICATIONS].
Other Adverse Reactions
Adverse reactions other than bleeding were evaluated in 19,632 patients treated with ZONTIVITY [13,186 patients in the TRA 2°P study and 6,446 patients in the TRA•CER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study]. Adverse events other than bleeding that occurred at a rate that was at least 2% in the ZONTIVITY group and also 10% greater than the rate in the placebo group are shown in Table 2.
Table 2: TRA 2°P / TRA•CER - Percentage of Patients
Reporting Non-hemorrhagic Adverse Reactions at a Rate at Least 2% in the
ZONTIVITY Group and at Least 10% Greater than Placebo
|Rashes, Eruptions, and Exanthemas||439(2.2)||395(2.0)|
The following adverse reactions occurred at a rate less than 2% in the ZONTIVITY group but at least 40% greater than placebo. In descending order of rate in the ZONTIVITY group: iron deficiency, retinopathy or retinal disorder, and diplopia/oculomotor disturbances.
An increased rate of diplopia and related oculomotor disturbances was observed with ZONTIVITY treatment (30 subjects, 0.2%) vs. placebo (10 subjects, 0.06%). While some cases resolved during continued treatment, information on resolution of symptoms was not available for some cases.
Read the Zontivity (vorapaxar tablets) Side Effects Center for a complete guide to possible side effects
Effects Of Other Drugs On ZONTIVITY
Vorapaxar is eliminated primarily by metabolism, with contributions from CYP3A4 and CYP2J2.
Strong CYP3A Inhibitors
Avoid 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) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Strong CYP3A Inducers
Last reviewed on RxList: 5/28/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Zontivity Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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