Data from FDA - Curated by EPG Health - Last updated 29 September 2017

Indication(s)

1 INDICATIONS AND USAGE ZONTIVITY is a protease-activated receptor-1 (PAR-1) antagonist indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). ZONTIVITY has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization. (1.1) 1.1 Patients with History of Myocardial Infarction (MI) or with Peripheral Arterial Disease (PAD) ZONTIVITY ® is indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). ZONTIVITY has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR).

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Advisory information

contraindications
4 CONTRAINDICATIONS History of stroke, TIA, or ICH. (4.1) Active pathologic bleeding. (4.2) 4.1 History of Stroke, Transient Ischemic Attack (TIA), or Intracranial Hemorrhage (ICH) ZONTIVITY is contraindicated in patients with a history of stroke, TIA, or ICH because of an increased risk of ICH in this population [see Adverse Reactions (6)]. Discontinue ZONTIVITY in patients who experience a stroke, TIA, or ICH [see Adverse Reactions (6.1) and Clinical Studies (14)]. 4.2 Active Pathologic Bleeding ZONTIVITY is contraindicated in patients with active pathological bleeding such as ICH or peptic ulcer [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
Adverse reactions
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)]. Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aralez Pharmaceuticals at 1-866-207-6592 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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. 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 Placebo (n=10,049) ZONTIVITY (n=10,059) Endpoints Patients with events (%) K-M %K-M estimate at 1,080 days. Patients with events (%) K-M % Hazard RatioClinically 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 ≥9%). , Hazard ratio is ZONTIVITY group vs. placebo group. (95% CI) GUSTO Bleeding Categories Severe 82 (0.8%) 1.0% 100 (1.0%) 1.3% 1.24 (0.92 - 1.66) Moderate or Severe 199 (2.0%) 2.4% 303 (3.0%) 3.7% 1.55 (1.30 - 1.86) Any GUSTO Bleeding (Severe/Moderate/Mild) 1769 (17.6%) 19.8% 2518 (25.0%) 27.7% 1.52 (1.43 - 1.61) Fatal Bleeding 14 (0.1%) 0.2% 16 (0.2%) 0.2% 1.15 (0.56 - 2.36) Intracranial Hemorrhage (ICH) 31 (0.3%) 0.4% 45 (0.4%) 0.6% 1.46 (0.92-2.31) Clinically Significant Bleeding 950 (9.5%) 10.9% 1349 (13.4%) 15.5% 1.47 (1.35 - 1.60) Gastrointestinal Bleeding 297 (3.0%) 3.5% 400 (4.0%) 4.7% 1.37 (1.18-1.59) 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. Figure 1 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 (4)]. 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 ZONTIVITY N=19,632 Placebo N=19,607 n (%) n (%) Anemia 982 (5.0) 783 (4.0) Depression 477 (2.4) 405 (2.1) 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION One tablet of ZONTIVITY orally once daily. (2.1) Use with aspirin and/or clopidogrel according to their indications or standard of care. There is limited clinical experience with other antiplatelet drugs and none with ZONTIVITY as the only antiplatelet agent. (2.2) 2.1 General Dosing Information Take one tablet of ZONTIVITY 2.08 mg orally once daily, with or without food. 2.2 Coadministration with Other Antiplatelet Drugs There is no experience with use of ZONTIVITY alone as the only administered antiplatelet agent. ZONTIVITY has been studied only as an addition to aspirin and/or clopidogrel. Use ZONTIVITY with aspirin and/or clopidogrel according to their indications or standard of care [see Clinical Studies (14)]. There is limited clinical experience with other antiplatelet drugs.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of ZONTIVITY use in pregnant women. Risk Summary Based on data in rats and rabbits, ZONTIVITY is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background. No embryo/fetal toxicities, malformations or maternal toxicities were observed in rats exposed during gestation to 56 times the human systemic exposure at the recommended human dose (RHD). No embryo/fetal toxicities, malformations or maternal toxicities were observed in rabbits exposed during gestation to 26 times the human systemic exposure at the RHD. The No Adverse Effect Level (NOAEL) for decreased perinatal survival and body weight in off-spring exposed in utero and during lactation was 31 times the human systemic exposure at the RHD. Both male and female pups displayed transient effects on sensory function and neurobehavioral development at weaning at 67 times the human exposure at the RHD, whereas female pups displayed decreased memory at 31 times the human exposure at the RHD. However, animal studies are not always predictive of a human response. ZONTIVITY should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Animal Data In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of vorapaxar at 0, 5, 25, and 75 mg/kg from implantation to closure of the fetal hard palate (6th to 17th day of gestation). Maternal systemic exposures were approximately 0, 7, 56, and 285 times greater than exposures in women treated at the RHD based on AUC. No embryo/fetal toxicities, malformations, or maternal toxicities were observed in rats receiving exposures up to 56 times the human systemic exposure at the RHD. In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of vorapaxar at 0, 2, 10, or 20 mg/kg from implantation to closure of the fetal hard palate (7th to 19th day of gestation). The NOAEL for maternal and fetal toxicity was equal to or above the highest dose tested. However, an overall increase in the number of litters with any malformation was observed at the highest dose, where systemic exposures were 89-fold higher than the human exposure at RHD. The effects of vorapaxar on prenatal and postnatal development were assessed in pregnant rats dosed at 0, 5, 25, or 50 mg/kg/day from implantation through the end of lactation. Rat pups had decreased survival and body weight gain from birth to postnatal day 4 and decreased body weight gain for the overall pre-weaning period at exposures 67 times the human exposure at the RHD. Both male and female pups displayed effects on sensory function (acoustic startle) and neurobehavioral (locomotor assay) development on post-natal day (PND) 20 and 21, but not later (PND 60, 61) in development, whereas decreased memory was observed in female pups on PND 27 at 31 times the human exposure at the RHD. In utero and lactational exposure did not affect fertility or reproductive behavior of offspring at exposures up to 67 times the RHD. 8.3 Nursing Mothers It is unknown whether vorapaxar or its metabolites are excreted in human milk, but it is actively secreted in milk of rats. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZONTIVITY, discontinue nursing or discontinue ZONTIVITY. 8.4 Pediatric Use The safety and effectiveness of ZONTIVITY in pediatric patients have not been established. 8.5 Geriatric Use In TRA 2°P, in post-MI or PAD patients without a history of stroke or TIA, 33% of patients were ≥65 years of age and 9% were ≥75 years of age. The relative risk of bleeding (ZONTIVITY compared with placebo) was similar across age groups. No overall differences in safety or effectiveness were observed between these patients and younger patients. ZONTIVITY increases the risk of bleeding in proportion to a patient's underlying risk. Because older patients are generally at a higher risk of bleeding, consider patient age before initiating ZONTIVITY [see Adverse Reactions (6.1)]. 8.6 Renal Impairment No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment is required in patients with mild and moderate hepatic impairment. Based on the increased inherent risk of bleeding in patients with severe hepatic impairment, ZONTIVITY is not recommended in such patients [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 Nursing Mothers It is unknown whether vorapaxar or its metabolites are excreted in human milk, but it is actively secreted in milk of rats. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZONTIVITY, discontinue nursing or discontinue ZONTIVITY.

Interactions

7 DRUG INTERACTIONS 7.1 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 (5.2) and Clinical Pharmacology (12.3)]. Strong CYP3A Inducers Avoid concomitant use of ZONTIVITY with strong inducers of CYP3A (e.g., rifampin, carbamazepine, St. John's Wort and phenytoin) [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

More information

Category Value
Authorisation number NDA204886
Agency product number IN66038E6C
Orphan designation No
Product NDC 70347-208
Date Last Revised 31-07-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1537045
Storage and handling Storage of bottles Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). [See USP Controlled Room Temperature.] Store tablets in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.
Marketing authorisation holder Aralez Pharmaceuticals Us Inc.
Warnings WARNING: BLEEDING RISK Do not use ZONTIVITY in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH); or active pathological bleeding [see CONTRAINDICATIONS (4.1, 4.2)]. Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding, including ICH and fatal bleeding [see Warnings and Precautions (5.1)]. WARNING: BLEEDING RISK See full prescribing information for complete boxed warning. Do not use ZONTIVITY in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH); or active pathological bleeding. (4.1, 4.2) Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding, including ICH and fatal bleeding. (5.1)