Zontivity

Overdose

There is no known treatment to reverse the antiplatelet effect of ZONTIVITY, and neither dialysis nor platelet transfusion can be expected to be beneficial if bleeding occurs after overdose. Inhibition of platelet aggregation can be expected for weeks after discontinuation of normal dosing. There is no standard test available to assess the risk of bleeding in an overdose situation.

Contraindications

ZONTIVITY is contraindicated in patients with a history of stroke, TIA, or ICH because of an increased risk of ICH in this population.

Discontinue ZONTIVITY in patients who experience a stroke, TIA, or ICH.

ZONTIVITY is contraindicated in patients with active pathological bleeding such as ICH or peptic ulcer.

Undesirable effects

The following serious adverse reaction is also discussed elsewhere in the labeling:

• Bleeding.

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.

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

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.

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.

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

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.

Therapeutic indications

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).

Pharmacodynamic properties

At the recommended dose, ZONTIVITY achieves ≥ 80% inhibition of TRAP-induced platelet aggregation within one week of initiation of treatment. The duration of platelet inhibition is dose- and concentration-dependent. Inhibition of TRAP-induced platelet aggregation at a level of 50% can be expected at 4 weeks after discontinuation of daily doses of ZONTIVITY 2.08 mg, consistent with the terminal elimination half-life of vorapaxar.

In healthy volunteer studies, no changes in platelet P-selectin and soluble CD40 ligand (sCD40L) expression or coagulation test parameters (TT, PT, aPTT, ACT, ECT) occurred after single- or multiple-dose (28 days) administration of vorapaxar. No meaningful changes in P-selectin, sCD40L, or hs-CRP concentrations were observed in patients treated with vorapaxar in the phase 2/3 clinical trials.

The effect of vorapaxar on the QTc interval was evaluated in a thorough QT study and in other studies. Vorapaxar had no effect on the QTc interval at single doses up to 48 times the recommended dose.

Pharmacokinetic properties

Vorapaxar exposure increases in an approximately dose-proportional manner following single doses up to 16 times the recommended dose. Vorapaxar pharmacokinetics are similar in healthy subjects and patients.

After oral administration of a single ZONTIVITY 2.08 mg dose under fasted conditions, peak concentrations (Cmax) occur at 1 hour post-dose (range: 1 to 2 h). The mean absolute bioavailability as determined from a microdosing study is approximately 100%.

Ingestion of vorapaxar with a high-fat meal resulted in no meaningful change in AUC with a small (21%) decrease in Cmax and delayed time to peak concentration (45 minutes). ZONTIVITY may be taken with or without food.

The mean volume of distribution of vorapaxar is approximately 424 liters (95% CI: 351-512). Vorapaxar and the major circulating active metabolite, M20, are extensively bound ( ≥ 99%) to human plasma proteins. Vorapaxar is highly bound to human serum albumin and does not preferentially distribute into red blood cells.

Vorapaxar is eliminated by metabolism via CYP3A4 and CYP2J2. The major active circulating metabolite is M20 (monohydroxy metabolite) and the predominant metabolite identified in excreta is M19 (amine metabolite). The systemic exposure of M20 is ~20% of the exposure to vorapaxar.

The primary route of elimination is through the feces. In a 6-week study, 84% of the administered radiolabeled dose was recovered as total radioactivity with 58% collected in feces and 25% in urine. Vorapaxar is eliminated primarily in the form of metabolites, with no unchanged vorapaxar detected in urine.

Vorapaxar exhibits multi-exponential disposition with an effective half-life of 3-4 days and an apparent terminal elimination half-life of 8 days. Steady-state is achieved by 21 days following once-daily dosing with an accumulation of 5- to 6-fold. The apparent terminal elimination half-life for vorapaxar is approximately 8 days (range 5-13 days) and is similar for the active metabolite. The terminal elimination half-life is important to determine the time to offset the pharmacodynamic effect.

The effects of intrinsic factors on the pharmacokinetics of vorapaxar are presented in Figure 2.

In general, effects on the exposure of vorapaxar based on age, race, gender, weight, and moderate renal insufficiency were modest (20-40%; see Figure 2). No dose adjustments are necessary based upon these factors. Because of the inherent bleeding risks in patients with severe hepatic impairment, ZONTIVITY is not recommended in such patients.

Figure 2: Effect of Intrinsic Factors on the Pharmacokinetics of Vorapaxar

† See WARNINGS AND PRECAUTIONS and Use In Specific Populations

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

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.

Qualitative and quantitative composition

ZONTIVITY tablets, 2.08 mg vorapaxar, are yellow, oval-shaped, film-coated tablets with “351” on one side and the Merck logo on the other side.

ZONTIVITY tablets, 2.08 mg vorapaxar, are yellow, oval-shaped, film-coated tablets with “351” on one side and the Merck logo on the other side. They are supplied as follows:

NDC 0006-0351-31 bottles of 30 tablets
NDC 0006-0351-54 bottles of 90 tablets
NDC 0006-0351-48 unit dose packages of 100 tablets (one carton containing 10 10-count blister cards)

Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). Store tablets in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.

Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). Store in the original package until use.

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. Manufactured by: MSD International GmbH (Singapore Branch), Singapore 638414, Singapore. Revised: 04/2015

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding, including ICH and fatal bleeding.

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. 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.

Strong CYP3A inhibitors increase and inducers decrease ZONTIVITY exposure. Avoid concomitant use of ZONTIVITY with strong CYP3A inhibitors or inducers.

Advise the patient to read the FDA-approved Patient Labeling (Medication Guide).

• 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.

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.

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.

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.

No dose adjustment is required in patients with renal 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.

Dosage (Posology) and method of administration

Take one tablet of ZONTIVITY 2.08 mg orally once daily, with or without food.

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. There is limited clinical experience with other antiplatelet drugs.

Interaction with other medicinal products and other forms of interaction

An interaction study with vorapaxar and warfarin in healthy subjects did not demonstrate a clinically significant pharmacokinetic or pharmacodynamic interaction.

Vorapaxar did not affect prasugrel pharmacokinetics and prasugrel did not affect vorapaxar pharmacokinetics following multiple-dose administration at steady-state. The pharmacokinetic interaction between vorapaxar and clopidogrel has not been evaluated. However, the use of vorapaxar on a background of clopidogrel is supported by the clinical data from TRA 2°P and TRA•CER.

The effects of other drugs on the pharmacokinetics of vorapaxar are presented in Figure 3 as change relative to vorapaxar administered alone (test/reference). Phase 3 data suggest that coadministration of a weak or moderate CYP3A inhibitor with vorapaxar does not increase bleeding risk or alter the efficacy of vorapaxar. No dose adjustment for ZONTIVITY is required in patients taking weak to moderate inhibitors of CYP3A.

Figure 3: Effects of Other Drugs on the Pharmacokinetics of Vorapaxar

† See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS
‡ See DOSAGE AND ADMINISTRATION

In vitro metabolism studies demonstrate that vorapaxar or M20 is unlikely to cause clinically significant inhibition or induction of major CYP isoforms or inhibition of OATP1B1, OATP1B3, BCRP, OAT1, OAT3, and OCT2 transporters.

Specific in vivo effects on the pharmacokinetics of digoxin, warfarin, rosiglitazone and prasugrel are presented in Figure 4 as a change relative to the interacting drug administered alone (test/reference). Vorapaxar is a weak inhibitor of the intestinal P-glycoprotein (P-gp) transporter. No dosage adjustment of digoxin or ZONTIVITY is required.

Figure 4: Effects of Vorapaxar on the Pharmacokinetics of Other Drugs

† See WARNINGS AND PRECAUTIONS
‡ See DOSAGE AND ADMINISTRATION