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General Risk Of Bleeding
Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding, including ICH and fatal bleeding [see ADVERSE REACTIONS].
ZONTIVITY increases the risk of bleeding in proportion to the patient's underlying bleeding risk. Consider the underlying risk of bleeding before initiating ZONTIVITY. General risk factors for bleeding include older age, low body weight, reduced renal or hepatic function, history of bleeding disorders, and use of certain concomitant medications (e.g., anticoagulants, fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs [NSAIDS], selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors) increases the risk of bleeding [see Use in Specific Populations and CLINICAL PHARMACOLOGY]. Avoid concomitant use of warfarin or other anticoagulants.
Suspect bleeding 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.
Withholding ZONTIVITY for a brief period will not be useful in managing an acute bleeding event because of its long half-life. There is no known treatment to reverse the antiplatelet effect of ZONTIVITY. Significant inhibition of platelet aggregation remains 4 weeks after discontinuation [see OVERDOSAGE and CLINICAL PHARMACOLOGY].
Strong CYP3A Inhibitors Or Inducers
Strong CYP3A inhibitors increase and inducers decrease ZONTIVITY exposure. Avoid concomitant use of ZONTIVITY with strong CYP3A inhibitors or inducers [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Patient Counseling Information
Advise the patient to read the FDA-approved Patient Labeling (Medication Guide).
Benefits and Risks
- Summarize the benefits and potential side effects of ZONTIVITY.
- Tell patients to take ZONTIVITY exactly as prescribed.
- Inform patients not to discontinue ZONTIVITY without discussing it with the prescribing physician.
- Tell patients to read the Medication Guide.
Inform patients that they:
- May bleed and bruise more easily.
- Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.
Instruct patients to:
- Inform physicians and dentists that they are taking ZONTIVITY before any surgery or dental procedure.
- Tell the doctor performing any surgery or dental procedure to talk to the prescribing physician before stopping ZONTIVITY.
Tell patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so that the physician knows about other treatments that may affect bleeding risk.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies were conducted in rats and mice dosed orally with vorapaxar for two years. Male and female rats dosed at 0, 3, 10 or 30 mg/kg/day showed no carcinogenic potential at systemic exposures (AUC) in males and females that were 9- and 29-fold, respectively, the human systemic exposure at the RHD. In male and female mice dosed at 0, 1, 5, and 15 mg/kg/day, vorapaxar showed no carcinogenic potential at systemic exposures (AUC) that were up to 30-fold the human systemic exposure.
Vorapaxar was not mutagenic in the Ames bacterial reverse mutation assay and not clastogenic in an in vitro human peripheral blood lymphocyte assay or an in vivo mouse micronucleus assay after intraperitoneal administration.
Impairment of Fertility
Fertility studies in rats showed that vorapaxar had no effect on either male or female fertility at doses up to 50 mg/kg/day, a dose resulting in systemic exposures (AUC) in male and female rats that are 40 and 67 times, respectively, the human systemic exposure at the RHD.
Use In Specific Populations
Pregnancy Category B
There are no adequate and well-controlled studies of ZONTIVITY use in pregnant women.
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 offspring 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.
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.
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.
The safety and effectiveness of ZONTIVITY in pediatric patients have not been established.
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].
No dose adjustment is required in patients with renal impairment [see CLINICAL PHARMACOLOGY].
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 and CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/6/2015
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